The present invention relates to Kvl .5 potassium channel inhibitors
FIELD The present invention relates, inter alia, to compounds effective as Kvl .5 potassium channel inhibitors. The present invention further relates to inter alia, compositions comprising said Kvl.5 potassium channel inhibitors, and to methods for treating cardiac arrhythmia.
Article I. BACKGROUND OF THE INVENTION
Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia in the clinical setting. It affects nearly 3 million people in the United States and its prevalence increases with the aging of the population. AF is most often treated with class HI antiarrhythmic agents, acting at both the atrial and ventricular levels. Commonly used or prescribed antiarrhythmic drugs inhibit various potassium channels, and prolong ventricular repolarization. This prolongation can in turn precipitate the occurrence of life-threatening-ventricular arrhythmias, mainly Torsades de Pointes (TdP).
Atrial-selective antiarrhythmic agents offer the possibility of increased therapeutic efficacy and safety by minimizing cardiac proarrhythmia inherent in traditional antianhythmic therapies.
There is therefore a long felt need for atrial-selective antiarrhythmic agents which do not affect ventricular rhythm. In addition, there is a long felt need for atrial-selective antiarrhythmic agents which are compatible with other cardiac devices, protocols, therapies, and medications. The present invention addresses this and other needs.
OF THE INVENTION
The l-N-arnino-2-imidazolidinones of the present invention are a new class of compounds. Compounds of this class have been found to inhibit Kvl. 5 potassium channels function. The compounds of the present invention have formula I:

Formula Remove

or a pharmaceutically acceptable salt thereof,
wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R2 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl, or -C(0)R23 wherein R23 is optionally substituted C1-C6
linear or branched alkyl or optionally substituted C3-C6, cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) optionally substituted C1C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally
substituted aryl, or optionally substituted heteroaryl; iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from
a) hydrogen;
b) optionally substituted C1 -C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
wherein R7 is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, optionally
substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6
linear or branched alkoxy, -OH, or -CO2R10, wherein R10 is optionally
substituted C1-C6 linear or branched alkyl; or R8 and R9 can be taken
together with the atom to which they are bound to form an optionally
substituted ring having from 3 to 7 ring atoms and optionally containing
one or more additional heteroatom ring atoms independently selected
from N, 0,or S; or
f) R5 and R6 can be taken together with the atom to which they are bound to
form an optionally substituted ring having from 3 to 7 ring atoms and
optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; v) -C(NR11)R12; wherein R11 is
a) hydrogen;
b) optionally substituted C1-C6, linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R12 is

a) optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
R is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR14R15;
R14 and R15 are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl; vi) -SO2R16;
wherein R16 is optionally substituted aryl, optionally substituted C1-C6, linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl; or
17.
vii) -C(0)R";
wherein R is optionally substituted aryl or optionally substituted heteroaryl;
viii) -C(0)OR!8;
wherein R18 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl;
L, L1, and L are each independently:
-[C(R,9)2]n-
each R19 is, at each occurrence, independently selected from hydrogen, methyl, or ethyl;
n is 1 to 4; and
x, y, and z are each independently 0 or 1.
Compounds of the present invention include those in which:
R is optionally substituted phenyl;
R! is optionally substituted phenyl;
R2 is hydrogen, C1-C6 linear or branched alkyl, Cj-C6 cycloalkyl, or -C(0)R23 wherein
R23 is C1-C6, linear or branched alkyl or C3C6 cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally
substitued aryl, or optionally substituted heteroaryl; iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from
a) hydrogen;
b) C1-C6 linear or branched alkyl;
c) C3-C7 cycloalkyl;
d) -OR7;
wherein R7 is hydrogen or C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, -OH, or -CO2R10 wherein R10 is C1-C6 linear or branched alkyl; or R8 and R9 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; or f) R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; v) -C(NR11)R12;
wherein Rn is
a) hydrogen;
b) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl:
c) -OH; or
d) -CN; and R12 is

a) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
b) -OR13;
wherein R13 is hydrogen, C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, or phenyl; or
c) -NR,4R15;
R14andR15 are each independently hydrogen, phenyl, C1-C6 linear or branched alkyl, or C3-C6 cycloalkyl; vi) -SO2R16;
wherein R16 is phenyl, C1-C6 linear or branched alkyl or C3-C6 cycloalkyl; vii) -C(O)R!7;
wherein R17 is aryl or C1-C5 heteroaryl; viii) -C(O)OR18;
wherein R18 is C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, or phenyl; L, L , and L are each independently:
4C(R19)2]n-each R19 is, at each occurrence, independently selected from hydrogen, methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof.
Compounds of the present invention include those in which: R is optionally substituted phenyl; R1 is optionally substituted phenyl;
R2 is hydrogen, C1-C4 linear or branched alkyl, or C3-C4 cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl; iii) -C(O)R4;
wherein R4 is C1-C6 linear or branched alkyl or C3-C6 cycloalkyl; iv) -C(O)NR5R6;
wherein R and R are each independently seleC1ed from
a) hydrogen;
b) C1 -C6 linear or branched alkyl;
c) C3-C7 cyclic alkyl;
d) -OR7;
wherein R is hydrogen or C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, C1-C6 linear or
branched alkyl, C1-C6 linear or branched alkoxy, -OH, -CO2R10 wherein
R10 is C1-C6 linear or branched alkyl; or R8 and R9 can be taken together
to form a ring having from 3 to 7 ring atoms; or
f) R5 and R6 can be taken together to form a ring having from 3 to 7 ring
atoms; v) -C(NRn)R12; wherein R!' is
a) hydrogen;
b) C1-C6 linear or branched alkyl;
c) -OH; or
d) -CN; and R12 is

a) C1-C6 linear or branched alkyl;
b) -OR13;
R1 is hydrogen, C1-C6 linear or branched alkyl, or phenyl; or
c) -NR14R15;
R14 and R15 are each independently hydrogen, or C1-C6 linear or branched alkyl; vi) -SO2R16;
wherein R16 is phenyl; or C1-C6 linear or branched alkyl; vii) -C(O)R17;
wherein R17 is C1-C5 heteroaryl; viii) -C(O)OR18;
wherein R18 is C1-C6 linear or branched alkyl; L, L1, and L2 are each independently:
[C(R19)2ln-
each R19 is, at each occurrence, independently chosen from hydrogen, methyl, or ethyl;
n is 1 to 4; and
x, y, and z are each independently 0 or I; or a pharmaceuticaly acceptable salt form
thereof.
The present invention further relates to compositions comprising: an effeC1ive amount of one or more compounds according to the present invention and an exC1pient.
The present invention also relates to a method for treating or preventing cardiac arrhythmias, including, for example, atrial fibrillation and atrial flutter, said method comprising administering to a subjeC1 an effeC1ive amount of a compound or composition according to the present invention.
The present invention yet further relates to a method for treating or preventing cardiac arrhythmias, including, for example, atrial fibrillation and atrial flutter, wherein said method comprises administering to a subject a composition comprising an effeC1ive amount of one or more compounds according to the present invention and an exC1pient.
The present invention also relates to a method for treating or preventing disease or conditions assoC1ated with cardiac arrhythmias, including, for example, thromboembolism, stroke, and heart failure. Said methods comprise administering to a subjeC1 an effeC1ive amount of a compound or composition according to the present invention.
The present invention yet further relates to a method for treating or preventing disease or conditions assoC1ated with cardiac arrhythmias, including, for example, thromboembolism, stroke, and heart failure, wherein said method comprises administering to a subjeC1 a composition comprising an effeC1ive amount of one or more compounds according to the present invention and an exC1pient.
The present invention further relates to a process for preparing the Kvl .5 potassium channel inhibitors of the present invention.
These and other objeC1s, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless
otherwise speC1fied. All temperatures are in egrees Celsius (° C) unless otherwise speC1fied. All documents C1ted are in relevant part, incorporated herein by reference; the
C1tation of any document is not to be constnxed as an admission that it is prior art with respeC1 to the present invention.
Article IV. DETAILED DESCRIPTION OF THE INVENTION
The Kvl .5 potassium channel inhibitors of the present invention are capable of treating and preventing arrhythmia in the atrial portion of the human heart or in the heart of certain animals. It has been discovered that funC1ional Kvl .5 potassium channels are found in human atrial tissue but not in human ventricular myocytes. Without wishing to be limited by theory, it is believed the inhibition of the Kv 1.5 voltage-gated Shaker-like potassium (K+) ion channel can ameliorate, abate, or otherwise cause to be controlled, atrial fibrillation and flutter without prolonging ventricular repolarization.
Throughout the description, where compositions are described as having, including, or comprising speC1fic components, or where processes are described as having, including, or comprising speC1fic process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the reC1ted components, and that the processes of the present teachings also consist essentially of, or consist of, the reC1ted processing steps.
In the application, where an element or component is said to be included in and/or seleC1ed from a list of reC1ted elements or components, it should be understood that the element or component can be any one of the reC1ted elements or components and can be seleC1ed from a group consisting of two or more of the reC1ted elements or components.
The use of the singular herein includes the plural (and vice versa) unless speC1fically stated otherwise. In addition, where the use of the term "about" is before a C6uantitative value, the present teachings also include the speC1fic C6uantitative value itself, unless speC1fically stated otherwise.
It should be understood that the order of steps or order for performing certain aC1ions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or aC1ions can be conduC1ed simultaneously.
As used herein, unless otherwise noted, "'alky!" whether used alone or as part of a substituent group refers to straight and branched carbon chams having i to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or I to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C1.C6,) shall refer independently to the
number of"carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl containing substituent. Non-limiting examples of alkyl groups include methyl ethyl, n-propyl, iso-propyi, n-butyi, sec-butyl, iso-butyl, (en-butyl, and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, i -chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like In substituent groups with multiple alkyl groups such as (C1,6alky])2amino, the alkyl groups may be the same or different.
As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1 -propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chloro\inyl), 4-hydroxybuten-1 -yl, 7-hydroxy-7-methyloC1-4-en-2-yl, 7-hydroxy-7-methyIoC1-3,5-dien-2-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-l-yl. Alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3-ynyl, and the like.
As used herein, "cycloalkyl," whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g.. cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical struC1ure. Cycloalkyl nngs can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cyclooC1anyl, decahnyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethyicyC1ohex-l-yl, oC1ahydropentalenyl, oC1ahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3f/-mden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1/Mluorenyl. The term "cycloalkyl" also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1 ]hexanyl, bicyclo[2.2.1 ]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2,2,2joC1anyl, and bicyclo[3.3,3]undecanyl.
"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the speC1fied number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -C6, -CF2CF3). Haloalkyl groups can optionally be substituted wtth one or more substituents 111 addition to halogen. Examples of haloalkyl groups include, but are not limited to, iluoromethyl, dichloroethyl, trifluoromethyl, trichioromethyl, pentafluoroethyl, and pentachloroethyl groups.
The term "aryl," wherein used alone or as part of another group, is defined herein as an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replaC1ng one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1 -yl, and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]oC1a-l,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
[0001] The terms "heterocyclic" and/or "heterocycle," whether used alone or as part of another group, are defined herein as one or more rings (e.g.. 2 or 3 rings) having from 3 to 20 atoms wherein at least one atom in at least one nng is a heteroatom seleC1ed from mtrogen (N), oxygen (O), or sulfur (S) and wherein further the nng that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or more fused rings, the
non-heteroatom bearing ring may be aryl (e.g.. indolinyl, tetrahvdrooqumolinyl, chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently seleC1ed from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted.
Non-limiting examples of heterocyclic units having a singie ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolmyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofliranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-ony] (valerolaC1am), 2,3,4,5-tetrahydro-lH-azepinyl, 2,3-dihydro-lH-indole, and 1,2,3,4-tetrahydro-C6uinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6.7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroC6uinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cyclooC1a[b]pyrrolyl.
The term '"heteroaryl," whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom seleC1ed from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused nngs, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-1H-cyelopentapynmidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently seleC1ed from nitrogen (N), oxygen (O), or sulfur (S) One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [l,2,3Jtnazolyl, [ 1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl nngs containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazoiyl, benzthiazolyl, benztriazolyl, C1nnolinyl, naphthyridinyl, phenanthndinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 1H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-of]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-l -ti-
indolyl,quinazpliny1, 5-methyl quinoxalinyI, quinazoiiny), quinolmyl. 8-hydroxy-quinolinyl, and iso quinolinyl.
One non-limiting example of a heteroaryl group as described above is C1-C6 heteroaryl, which has I to 5 carbon ring atoms and ai least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently seleC1ed from nitrogen (N). oxygen (O), or sulfur (Si. Examples of C1-C6 heteroaryl include, but are not limited to, triazinyl, lhiazol-2-yi, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolm-5-yL furan-2-yl. furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yi, pyridin-3-yl, and pyridin-4-yl.
Unless otherwise noted, when two substituents are taken together to form a ring having a speC1fied number of ring atoms (e.g., R6 and R" taken together with the N to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently seleC1ed from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.
The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspeC1ed to suffer.
As used herein, "therapeutically effeC1ive" refers to a substance or an amount that eliC1ts a desirable biological aC1ivity or effeC1.
Except when noted, the terms "subjeC1" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subjeC1" or "patient" as used herein means any mammalian patient or subjeC1 to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subjeC1 patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk faC1ors assoC1ated with a targeted or suspeC1ed disease or condition or to determine the status of an existing disease or condition in a subjeC1. These screening methods include, for example, conventional work-ups to determine risk faC1ors that may be assoC1ated with the targeted or suspeC1ed disease or condition. These and other routine
methods allow the cliniC1an to seleC1 patients in need of therapy using the methods and compounds of the present invention.
For the purposes of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4-tetrahydroC6umoline having the formula:
[I ^ !
1!
is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro-1H-cyclopentapyrimidine having the formula:
is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For
example, l,2,3,4-tetrahydro-[l,8]naphfhyridine having the formula:
!i .N. „N. rT -V
is, for the purposes of the present invention, considered a heteroaryl unit.
The term "substituted" is used throughout the speC1fication. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., ! to 10) substituents as defined herein below. The substituents are capable of replaC1ng one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that reC6uires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term '•substituted" is used throughout the present speC1fication to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of die hydrogen atoms may be replaced. For example, difluoromethyl is a substituted d alkyl;
trifluoromethyl is a substituted C, alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)oC1anyl is a substituted C6 alkyl; 3-guamdinopropyl is a substituted C3 alkyl; and 2-carboxypyridinyl is a substituted heteroaryl.
The variable groups defined herein, e.g., alkyl, alkenyl, cycloalkyl, heterocycle, aryl, and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted with one or more substituents. Optionally substituted groups will be so indicated.
The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (F, C1, Br, 1), - CN, NC2 oxo (=O), -OR25 SR25, -N(R25)2, -NR25C(O)R25, S02R25. S02OR2\ S02N(R23)2. C(O)R2\ C(O)OR25, -C(O)N(R25)2, C1.6 alkyl, C,_6 haloalkyi, C16 alkoxy, C2.., alkenyl, C2s alkynyl, C3-14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl. alkenyl, alkynyl, haloalkyi, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e.g., 1-6 or 1-4) groups seleC1ed trom halogen, -CN, -NO2, oxo, and R25; wherein R25, at each occurrence, independently is hydrogen, OR26, -SR26, -C(O)R26, -€(O)OR26, -C(O)N(R2")2, S02R2', -S(O)2OR26, N(R26)2, NR26C(O)R26, C1-6 alkyl, C1-6 haloalkyi, C2.« alkenyl, C2.8 alkynyl, cycloalkyl (e.g., CV6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R28' units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R26 at each occurrence, independently is hydrogen, C1_6 alkyi, C1.6, haloalkyi, C2-8 alkenyl group, C2-8 alkynyl group, cycloalkyl (e.g., C3-6 cycloalkyl), aryl,, heterocycle, or heteroaryl, or two R 6 units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably have 3 to 7 ring atoms.
In some embodiments, the substituents are seleC1ed from
1) -OR25; for example, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3;
ii) -C(O)R25; for example, -COCH3, COCH2CH3, -OOCH2CH2CH3;
iii) -C(O)OR25; for example, -CO2CH3, -C02CH2CH3, -C02CH2CH2CH3;
IV) -C(O)N(R25)2; for example, -CONH2, -CONHCH3, --CON(CH3)2;
v) -N(R25)2; for example, NH2, -NHCH3, -N(CH3)2, NH(CH2CH3);
vi) -NR25COR25; for example, -NHCOCH3, -NHCOCH2CH3, -NHCOC6Hs;
vii) halogen; -F, --C1, -Br, and -I;
viii) C1-C4 linear or branched haloalkyl; for example, CH2F, --CF3, -CC13;
ix) -SO2R25; for example, -SO2CH3, -SO2CH2CH3, SO2C6H5;
x) -S02N(R25)2; for example, S02NH2; S02NHCH3; S02NHC6H5;
xi) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
xii) cyano; and
xiii) nitro
wherein each R25 is independently hydrogen, optionally substituted C1-C6 linear or branched alkyl (e.g., optionally substituted C1-C4 linear or branched alkyl) or optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted C3-C4 cycloalkyl); or two R25 units can be taken together to form a ring comprising 3 to 7 ring atoms. In certain aspeC1s, each R25 is independently hydrogen, C1-C6 linear or branched alkyl optionally substituted with halogen or C3-C 6cycloalkyl or C3-C6 cycloalkyl
At various places in the present speC1fication, substituents of compounds are disclosed in groups or in ranges. It is speC1fically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1_6 alkyl" is speC1fically intended to individually disclose C1, C2,
C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6,
C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6, alkyl.
For the purposes of the present invention the terms "compound," "analog," and "composition of matter" stand eC6ually well for the Kv 1.5 potassium channel inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms "compound," "analog," and "composition of matter" are used interchangeably throughout the present speC1fication.
Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass C1s and trans isomers of compounds containing
alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liC6uid chromatography.
Pharmaceutically acceptable salts of compounds of the present teachings, which can have an aC1dic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of aC1dic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). SpeC1fic non-limiting examples of inorganic bases include NaHCCO3, Na2CCO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic aC1ds. For example, salts can be formed from the following aC1ds: acetic, propionic, laC1ic, benzenesulfonic, benzoic, camphorsulfonic, C1tric, tartaric, sucC1nic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, laC1ic, maleic, malic, malonic, mandelic, methanesulfonic, muC1c, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, sucC1nic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable aC1ds.
When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R20)2, each R20 may be the same or different than the orner). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Kvl.5 Potassium Channel Inhibitors
The Kvl.5 potassium channel inhibitors of the present invention are 5-spirocyclic-4-imidazolidinones, and include all enantiomeric and diasteriomeric forms and salts of compounds which are members of the genus named and referred to herein as 1-(R -substituted)-2,3,8-(substituted)-4-oxo-l,3,8-triaza-spiro[4.5]decanes having the formula (I):

Formula Remove

wherein the core scaffold is numbered in die following manner;
Formula Remve

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the
formula: Remove

has the chemical name l-methyl-2-(4-trifluoromethylphenyl)-3-[2-(4-methoxyphenyl)-
ethyl]-4-oxo-l,3>8-triaza-spiro[4.5]decane-8-carboxylic aC1d /erf-butyl ester.
For the purposes of the present invention, a compound depiC1ed by the racemic
formula, for example:

Formula Reomve

or mixtures thereof, or in the case where a second chiral center is present, all diastereomers. However, the term 5-spirocyclic-4-imidazolidinones is used in general to refer to the genus, which encompasses the compounds of the present invention, throughout the speC1fication.
The particular embodiments and illustrations herein relating to particular aspeC1s of the present invention may be combined in the compounds of the present invention.
In the present invention, R is optionally substituted phenyl. The phenyl group can be substituted with any of the substituents provided herein. Examples of suitable substituents include, but are not limited to halogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched haloalkyl, optionally substituted C3-C6 cycloalkyl, -OR20, -CN, -N(R20)2, -C02R20, ^C(O)N(R20)2, -NR20C(-0)R20, -NO2, and -SO2R20; each R20 is independently hydrogen, optionally substituted C1-C6 (e.g., C1-C4) linear or branched alkyl, optionally substituted C1-C6 linear or branched haloalkyl, optionally substituted C3-C6 cycloalkyl (e.g., C3-C4 cycloalkyl), optionally substituted aryl, optionally substituted heterocycle, or optionally substituted heteroaryl; or two R units can be taken together to form a ring comprising from 3 to 7 nng atoms. When two R units are taken together to form a ring, the ring may comprise additional heteroatoms seleC1ed independently from oxygen, nitrogen, or sulfur, and the ring optionally may be substituted. Non-limiting examples of rings formed when two R20 units are taken together include: piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl. In certain aspeC1s, the substituents on the optionally substituted linear or branched alkyl group is a C3-C6 cycloalkyl. The phenyl group can be substituted at any position on the ring, e.g., meta, para, and/or ortho positions.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, or 3,4,5-trichlorophenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 3,5-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, or 3,4,5-triethylphenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropyl-phenyl, 2-(cyclopropylmethyl)phenyl, 3-(cyclopropylmethyl)phenyl, 4-(cyclopropyl-methyl)phenyl, 2-«o-butylphenyl, 3-iso-butylphenyl, 4-wo-butylphenyl, 2-tert-butylphenyl, 3-ferf-butylphenyl, 4-tert-butylphenyl, 2-cyclobutylphenyl, 3-cyclobutyl-phenyl, 4-cyclobutylphenyl, 2-(cyclobutylmethyl)phenyl, 3-(cyclobutylmethyl)phenyl, or 4-(cyclobutyl-methyl)phenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxy-phenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-
dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyi, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, or 2,4,6-trihydroxy-phenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-fluoromethoxyphenyl, 2-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3-fluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-fluoromethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-bis(fluoromethoxy)phenyl, 2,4-bis(difluoromethoxy)phenyl, 2,4-bis(trifluoromeihoxy)phenyl, 3,5-bis(fluoromethoxy)-phenyl, 3,5-bis(difluoromethoxy)pb.enyl, or 3,5-bis(trifluoromethoxy)phenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,3-dicyano-phenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophmyl, 3,4-dicyanophenyl, 2,3,4-tricyanophenyl, 2,3,5-tricyanophenyl, 2,3,6-tricyanophenyl, 2,4,5-tricyanophenyl, 3,4,5-tricyanophenyl, or 2,4,6-tricyanophenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-dinitrophenyl, 2,4-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl, 2,3,4-trinitrophenyl, 2,3,5-trinitrophenyl, 2,3,6-trmitrophenyl, 2,4,5-trinitrophenyl, 3,4,5-trinitrophenyl, or 2,4,6-trinitropheny.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2,6-dimethyl-4-fluorophenyl, 2,6-dimethyl-3-fiuorophenyl, 2,6-dimethyl-4-chlorophenyl, 2,6-di-tert-butyl-4-hydrC6xyphenyl, 2,6-difluoro-4-chlorophenyl, 2,6-difluoro-3-chlorophenyl, 2-hydroxy-4-methyiphenyl, 2-hydroxy-5-methylphenyl, 2,6-dihydroxy-4-terf-butylphenyl, or 2,6-difluoro-4-cyanophenyl.
Exemplaiy embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 3-dimemylaminophenyl, 4-dimethylaminophenyl, 3-diethylaminophenyl, 4-diethylammopheayl, 3-methylsulfanylphenyl, 4-methylsulfanyl-phenyl, 3-
ethylsulfanylphenyl, 4-ethylsulfanylphenyl, 3-propylsulfanylphenyl, or 4-propylsulfanylphenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R is 2-aminophenyl, 2-(Af-methylamino)phenyl, 2-(AyV-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(iVr/V-diethylamino)phenyl, 3-aminophenyl, 3-(JV-methylamino)phenyl, 3-(Ar^V-dimethylamino)phenyl, 3-(/V-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4-aminophenyl, 4-(7V-methylamino)phenyl, 4-(NJ\/-dimethylamino)phenyl, 4-(7V-ethylamino)phenyl, or 4-(AyV-diethylamino)phenyl.
R1 is optionally substituted phenyl. The phenyl group can be substituted with any of the substituents provided herein. Examples of suitable substituents include, but are not limited to: halogen, optionally substituted C1-C6 (e.g., C1-C4) linear or branched alkyl, optionally substituted C1-C6 linear or branched haloalkyl optionally substituted C3-C6 (e.g., C3-C4) cycloalkyl, -OR21, -CN, -N(R2I)2, -CO2R2i,
C(O)N(R21)2, -NR21C(O)R21, -S02R21, and -N02; each R21 is independently hydrogen, optionally substituted C1-C6 linear or branched alkyl (e.g., C1-C4 linear or branched alkyl), optionally substituted C1-C6 linear or branched haloalkyl, optionally substituted C3-C6 cycloalkyl (e.g., C3-C4 cycloalkyl), optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle; or two R2' units can be taken together to form a ring comprising from 3-7 ring atoms. When two R21 units are taken together to form a ring, the ring may comprise additional heteroatoms chosen from oxygen, nitrogen, or sulfur, and the ring optionally may be substituted. Non-limiting examples of rings formed when two R21 units are taken together include: piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl. In certain aspeC1s, the substituent on the optionally substituted linear or branched alkyl group is a C3-C6 cycloalkyl. The phenyl group can be substituted at any position on the ring, e.g., meta, para, and/or ortho positions.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R' is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifiuorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, or 3,4,5-trichlorophenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R1 is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 3,5-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 3,4,5-triethylphenyl 2-isopropylphenyl, 3-isopropylphenyl, or 4-isopropylphenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R1 is 2-cyclopropylphenyl, 3-cyclopropylpfaenyl, 4-cyclopropyl-phenyl, 2-(cyclopropylmethyl)phenyl, 3-(cyclopropylmethyl)phenyl, 4-(cyclopropyl-methyl)phenyl, 2-wo-butylphenyl, 3-iso-butylphenyl, 4-iso-butylphenyl, 2-terf-butylphenyl, 3-terf-butylphenyl, 4-tert-butylphenyl, 2-cyclobutylphenyl, 3-cyclobutyl-phenyl, 4-cyclobutylphenyl, 2-(cyclobutylmethyl)phenyl, 3-(cyclobutylmethyl)phenyl, or 4-(cyclobutylmethyl)phenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein R1 is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxypheiyl, 23,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-trifluoromethyl-phenyl, 3-tri-fluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoromethoxyphenyl, 2-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3-fluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-fluoromethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-bis(fluoromethoxy)phenyl, 2,4-bis(difluoromethoxy^)henyl, 2,4-bis(trifJuoromethoxy)phenyl, 3,5-bis(fluoromethoxy)-phenyl, 3,5-bis(difluoromethoxy)phenyl, or 3,5-bis(trifluoromethoxy)phenyl.
Exemplary embodiments of the present invention include a compound of Formula (I) wherein R1 is 2-aminophenyi, 2-(Af-methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-{N-ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(yV-ethylammo)phenyl, 3-(NJV-diethylamino)phenyl, 4-aminophenyl, 4-(Ar-methylamino)phenyl, 4-(iV,/v-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, or 4-(N,N-diethylamino)phenyl.
In the present invention, R2 is hydrogen, optionally substituted C1C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or -C(O)R23 wherein R23 is optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl.
Compounds of the present invention include those wherein R2 is hydrogen, optionally substituted C1-C4 linear or branched alkyl, optionally substituted C3-C4 cycloalkyl, or -C(O)R23 wherein R23 is optionally substituted O -C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutieaHy acceptable salt form thereof wherein R2 is optionally substituted C|-C4 linear or branched alkyl, optionally substituted C3-C4 cycloalkyl or --C(O)R23 wherein R23 is optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl.
Compounds of the present invention include those wherein R2 is not hydrogen. Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutieally acceptable salt form thereof wherein R2 is C3-C4 cycloalkyl or C1-C4 linear or branched alkyl optionally substituted with C3-C6 cycloalkyl.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmacesutically acceptable salt form thereof wherein R2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, or cyclopropylmethyl.
Compounds of the present invention include those wherein R3 is seleC1ed from:
i) hydrogen;
ii) optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl; iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; iv) -C(O)NR5R6;
wherein R5 and R6 are each independently seleC1ed from
a) hydrogen;
b) optionally substituted C6 -C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
wherein R7 is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, optionally
substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6
linear or branched alkoxy, -OH, or -CO2R10, wherein R10 is optionally
substituted C1-C6 linear or branched alkyl; or R8 and R9 can be taken
together with the atom to which they are bound to form an optionally
substituted ring having from 3 to 7 ring atoms and optionally containing
one or more additional heteroatom ring atoms independently seleC1ed
from N, 0,or S; or
f) R5 and R6 can be taken together with the atom to which they are bound to
form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently seleC1ed from N, 0,or S; v) -C(NRn)R12; wherein R1' is
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R12 is
a) optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
R13 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NRl4R15;
R14andR15 are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl; vi) -S02R16;
wherein R16 is optionally substituted aryl, optionally substituted C1-C6 linear or
branched alkyl, or optionally substituted C3-C6 cycloalkyl; vii) -C(O)R17;
wherein R17 is optionally substituted aryl or optionally substituted heteroaryl; viii) -C(O)OR18;
wherein R is optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl, or optionally substituted aryl.
Exemplary embodiments of the present invention include a compound of Formula
[I) or a pharmaceutically acceptable salt form thereof wherein R3 is seleC1ed from:
i) hydrogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl; lii) -C(O)R4;
wherein R4 is C1-C6 linear or branched alkyl or C3-C6 cycloalkyl; iv) -C(O)NR5R6;
wherein R5 and R6 are each independently seleC1ed from
a) hydrogen;
b) C1-C6 linear or branched alkyl;
c) C3-C7 cyclic alkyl;
d) -OR7;
wherein R7 is hydrogen or C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R andR are each independently hydrogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, -OH, -CO2R10 wherein
R10 is C1-C6 linear or branched alkyl or R8 and R9 can be taken together to
form a ring having from 3 to 7 ring atoms; or
f) R5 and R6 can be taken together to form a ring having from 3 to 7 ring
atoms; v) -C(NRn)R12; wherein R1! is
a) hydrogen;
b) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R!2 is

a) C1-C6 linear or branched alkyl;
b) -OR13;
R13 is hydrogen, C1-C6 linear or branched alkyl, or phenyl; or
c) -NR14R15;
R14 and R15 are each independently hydrogen, or C1-C6, linear or branched alkyl; vi) -SC6jR16;
wherein Ri6 is phenyl; or C\-C(, linear or branched alkyl; vii) -C(O)R17;
wherein R is C1-C5 heteroaryl; viii) -C(O)OR18;
wherein R18 is C1-C6 linear or branched alkyl;
In some embodiments, R3 is hydrogen.
In other embodiments, R3 is optionally substituted C|-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl. Examples of R3 include, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, cyclopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dknethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimetiiylbutyl, 3,3-dimethylbutyl, and cyclohexyl.
In some embodiments, R3 is -C(O)R4, wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted
heterocyC1e. Nonlimiting examples of R include methyl, ethyl, n-propyl, ISO-propyl,
cyclopropyl, n-butyl, sec-butyl, i.vo-butyl, tert-butyl, cyclobuiyl, n-pentyl, 2-methylbutyl,
3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, cyclopentyl, n-hexyl, I-
methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-
dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-
dimethylbutyl, or cyclohexyl. Non-limiting examples of RJ include C(O)CH3.
C(O)cyclopropyl, and -C(O)CH2cyclopropyl.
In other embodiments, R is C(O)NR?R'0, wherein each R and R° are each independently seleC1ed from:
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl,
d) -OR7;
wherein R' is hydrogen or optionally substituted CVC6, linear or branched alkyl;
e) NRHR9,
wherein R and R are each independently hydrogen, optionally
substituted C6-C6 linear or branched alkyl, optionally substituted Cs-C1,
linear or branched alkoxy, -OH, or CO,-.R!', wherein R10 is optionally
substituted C1-C6, linear or branched alkyl; or R8 and R9 can be taken
together with the atom to which they are bound to form an optionally
substituted ring having from 3 to 7 ring atoms and optionally containing
one or more additional heteroatom ring atoms independently seleC1ed
from N, 0,or S; or
f) R3 and R6 can be taken together with the atom to which they are bound to
form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently seleC1ed from N, 0,or S. In exemplary embodiments of the present invention, R" is C(O)NR5R6 wherein each R5 and R are each independently seleC1ed from
a) hydrogen;
b) C\-C(, linear or branched alkyl;
c) C3-C7 cyclic alkyl;
d) OR.
R is hydrogen or C1C6, linear or branched alkyl:
e) NRSR''';
R8 and R4 are each independently hydrogen, C1C6 linear or branched alkyl, C|-C«, linear or branched alkoxy. -OH or C02R \ wherein R' is C1-C6 linear or branched alkyl; or R8 and R9 can be taken together to from a ring having from 3 to 7 ring atoms; or f) R5 and Rft can be taken together to form an optionally substituted ring
having from 3 to 7 ring atoms. Exemplary compounds of the invention include those wherein R5 and R6 are each independently seleC1ed from hydrogen, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C7 cycloalklyi. Nonlimitmg examples include methyl, ethyl, n-propyl, wo-propyl, cyclopropyl, n-butyl, sec-butyl, /so-butyl, ter/-butyl. cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Nonlimiting examples of R' include -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, -C(O)N(CH2CH3)2, €(O)N(CH3)2, and -C(O)NH[CH(CH3)2].
In some embodiments, R3 is C(O)NR5R6 and R5 is OR7 or NR8R9; thereby forming R" units having the formula C(O)NR6OR or -C(O)NRt>NRiiR9, wherein, in exemplary embodiments, R6 is hydrogen, methyl, ethyl, n-propyl, /sopropyl, n-butyl, sec-butyl, /so-butyl, or tert-butyl; R is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, wo-butyl, or tert-b\xtyl; R8 and R9 are each independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, /.vo-butyl, left-butyl, methoxy, ethoxy, n-propoxy, zso-propoxy, n-butoxy , sec-butoxy, /so-butoxy, or tert-butoxy; or Rs is -CO2R!0, R9 is hydrogen and RK) is optionally substituted C1-C6 linear or branched alkyl, non-limiting examples of which include methyl, ethyl, n-propyl, /.vo-propyl, n-butyl , sec-butyl, iso-butyl, and tert-butyl. Nonlimiting examples of R are C(O)NHOH, -€(O)NHOCH3, -C(O)NHNH2, C(O)NHOCH2CH3, -C(O)NCH3OCHj, C(O)NHNHC(O)OCH3, or - C(O)NHNHC(O)OC(CH3)3
In some embodiments, RJ is --C'(O)NR5R° and R5 and Ru are taken together with the nitrogen to which they are attached to form an optionally substituted ring having from 3 to 7 ring atoms. Nonlimiting examples of rings formed from R and R' include aziridinyl, azetidinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyi. morpholinyl, and piperidin-1-yl.
In some embodiments, R7 is C(NR' ')RL wherein R:' is hydrogen, optionally substituted C1-C6 linear or branched alkyl or optionally substituted tyc<, cycloalkyl; hydroxyl (OH); or cyano (--CN); and R * is optionally substituted (VG, linear or branched alkyl or optionally substituted CrC„ cycloalkyl; OR . wherein R1 is hydrogen, optionally substituted aryl, optionally substituted C1C6, linear or branched alkyl or optionally substituted C3-C1, cycloalkyl; or NR|4R\ wherein R1" and Rb are each independently hydrogen, optionally substituted aiyl, optionally substituted C|-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl. Nonhmiting examples of R3 include -C(NCN)NH2, C(NCN)NHCH3, and -C(NCN)NHC6H5.
Non-limiting examples of the alkyl groups of R11, R1", and R1', include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyi, sec-butyl, iso-butyl, and tert-
14 IS
butyl. Non-limiting examples of R and R groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, ter t-butyl, and phenyl.
In some embodiments, R3 is SO2R16 wherein R16 is optionally substituted aryl (e.g., optionally substituted phenyl), optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl. Non-hmiting examples of R16 groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and phenyl. Nonlimiting examples of R3 include SO2CH3, SO2C6H5, SO2CH2CH3, and SO2CH(CH3)2.
In some embodiments, R3 is -C(O)R' wherein R! is optionally substituted aryl or optionally substituted heteroaryl. Non-limiting examples include imidazol-I -yl, \H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yi, thiophen-2-yI, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridm-2-yl, pyridin-3-yI, and pyridin-4-yl, triazinyl, thiazol-2-yl, and thiazol-4-yl
In some embodiments, RJ is C(O)ORl8 wherein R18 is optionally substituted C\-Ck linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl. Non-limiting examples of R18 groups include methyl, ethyl, n-propyl, /so-propyl, cyclopropyl, n-butyl, sec-butyl, Mobutyl, and tert-buiyl. Nonhmiting examples of R3 include -C(O)OCH3, C(O)C6CH2CH3, ■C(O)OCH(CH3)2, and C(O)OC(CH3)3.
Exemplary embodiments of the present invention include a compound of Formula I or a pharmaceutically acceptable salt form thereof wherein R6 is hydrogen. C(O)R4; -C(O)NR5R6, -C(O)NR5OR7; -C(O)NR5NRV, -C(NR; !)R l SC)2Ri6
-C(O)ORlx, or-C(O)R17; R4 is -CH3, -CH2CH3, -CH:.CH;CH.,, -CH(CH,);, cyclopropyl. cyclobutyl, cyclopentyl, or cyclohexyl: R is hydrogen. -C6h. -C H>( 'H;,, or -CH(CH3)2; R6 is hydrogen, -CH3, or -CH2CH3; or R? and Rr are taken together to form aziridin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-(methyl)piperazin-l-yl, morpholin-4-yl; R is hydrogen.
CH3, 0 r-CH2CH3; R8 is hydrogen; R" is hydrogen,-C(O)OCH3, or -C(O)OC(CH3),; Rn is OH, or CM; R12 -NH2, -CH3, or -NRuRiS; R 4 is hydrogen, CH3. or phenyl; R1' is hydrogen, CH3, or phenyl; R!6 is CH3, -CH2CH3, -CH(CH3)2, or -C0H5; RiK is -CH3, -CH2CH3, -CH(CH3)2, -C6H5,or -C(CH3)3; and Rr is imidazolin-1-yl, isoxazolin-5-yl, furan-2-yl, thiophen-2-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl.
Exemplary embodiments of the present invention include a compound of Formula I or a pharmaceutically acceptable salt form thereof wherein R is hydrogen, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2. -C(O)NHCH3, -C(O)N(CH,)2. -C(O)NH[CH(CH3)2], -C(O)NHCH2CH3, -C(O)N(CH2CH3), -C1O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)OC(CH3)3, -C(O)NHOH, -C(O)NHOCH3, -C(O)N(CH3)OCH3, -C(O)NHNH2,-C(O)NHOCH2CH3, -C(O)NCH3CX.'H3,
C(O)NHNHC(O)OCH3,-<:(O)NHNHC(O)OC(CH3)3,-C(NCN)NH2,-C(NCN)NHCH3, -C(NCN)NHC6H5, -C(O)azmdin-l-yl, -C(O)azetidm-l-yl, -C(O)pyrrolidin-l-yl, -C(O)piperidin-l-yl, -C(O)piperazin-1-yl, -C(C6)morpholin-4-yl, -C (O)imidazolin-l-yl, -C(O)isoxazolin-5-yl, -SO2CH3, -SO2CH2CH3> -SO2CH(CH3)2, or SO2C6Hs.
In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents. provided herein.
L, Ll, and L" are linking units each independently having the formula:
[C(Rl\ each R19 unit present in a linking unit is independently chosen from hydrogen, methyl, or ethyl; n is 1 to 4; x, y, and z are each independently 0 or I. When x is eC6ual to 0, linking group L is absent, and when x is eC6ual to 1, linking group L ss present. Likewise, when y is eC6ual to 0, linking group L is absent, and when y is eC6ual to 1, linking group L1 is present. In addition, when z is eC6ual to 0, linking group L is absent, and when z is eC6ual to 1, linking group L- is present.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein x is 1 and I is --CH2CH2 (ethylene). Compounds according 10 these embodiments have the formula
(II) or a pharmaceutically acceptable salt form thereof:

Formula Remove
L , L'\ y, and 7 are the same as defined herein
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein x is 1 and L is -CH2- (methylene). Compounds according to these embodiments have the formula (111) or a pharmaceutically acceptable salt form thereof:

Formula Remove
L", y, and z are the same as defined herein.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein y is 0 and the
compounds have the formula (IV) or a pharmaceutically acceptable salt form thereof:

Formula Remove
, R!, R2, R3, L, L2, x, and z are the same as defined herein.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein y is 1 and L1 is "CH2 (methylene). Compounds according to these embodiments have the formula (V) or a pharmaceutically acceptable salt form thereof:

Formula Remove
L", x, and z are the same as defined herein.
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein z is 0 and the compounds have the formula (VI) or a pharmaceutical^ acceptable salt form thereof:

Formula Remove

L ', x, and y are the same as defined herein
Exemplary embodiments of the present invention include a compound of Formula (I) or a pharmaceutically acceptable salt form thereof wherein z is I and L- is CH2- (methylene). Compounds according the these embodiments have the formula (VII)
or a pharmaceutically acceptable salt form thereof
o
(VII)
As it relates to the Kvl.5 potassium channel inhibitors of the present invention the linking units L, L , and L" may be present or absent in any combination. For example, in some compounds according to the invention, x is 1, y is 0 and z is 0; in other embodiments, x is 1, y is 0 and z is 1; in still other embodiments, x is 1, y is I and z is 0.
The skilled praC1itioner will understand that combinations of the embodiments provided herein are encompassed within the scope of the present invention.
Compounds of the present invention include 4-oxo-l,3,8-tnaza-spiro[4.5]decanes having the formula (VIII) or a pharmaceutically acceptable salt form thereof:
Compounds of the present invention include compounds having the formula (IX) or a pharmaceutically acceptable salt form thereof:
wherein non-limiting examples of R and R are defined herein below in "fable i.
Table Remove
Compounds of the present invention include compounds having the formula (X or a pharmaceutically acceptable salt form thereof:
CH3 (X) wherem non-limiting examples of R, R!, and R4 are defined herein below in Table II.
TABLE II Remove
Compounds of the present invention include compounds having the formula (XI) or a pharmaceutically acceptable salt form thereof:
Formula Remove

(XI) wherein non-limiting examples of R, R1, R5, and Rb are defined herein below in Table HI.
TABLE III

Table Remove

Compoimds of the present invention include compounds having the formulas (XII) or (XID) or a pharmaceutically acceptable salt form thereof:
TABLE REMOVE

Compoimds of the present invention include compounds having the formula
(XIV) or a pharaiaceutically acceptable salt form thereof:

FORMULA REMOVE

(XIV) wherein non-limiting examples of R, R1, R", and R12 are defined herein below in Table VI.
TABLE REMOVE
Compounds of the present invention include compounds having the formula (XV) or a pharmaceutically acceptable salt form herein below in Table VII.

TABLE REMOVE

4 -methoxyphenyl 4-methoxyphenyl 4-methoxyphenyl
4-methoxyphenyl

4-tnfluoromethylphenyl \ C.H',
4-cyclopropylphenyl Cr,H;
4-diethylammophenyl > -OJrU
4-difluoromethoxyphenyl i C^HA

Compounds of the present invention include compounds having the formula (XVI) or a pharmaceutically acceptable salt form thereof:

riii (XV i) wherein nonlimiting examples of R, R', and R1 are defined herein below in Fable Vlll,
\Compounds of the present invention include compounds having the formula (XVII) or a pharmaceuticallv acceptable salt fonn thereof:

thiophen-2-yl thiophen-2-yl thiophen-2-y] thiophen-2-yl thiophen-2-yl

4-methoxyphenyl

4-difluoromethoxyphenyl j C(O)imidazolin-l-yl

Compounds of the present invention include 4-oxo-l ,3,8-triaza-spiro[4.5]-decanes having the formula (XX) or a pharmaceuticaily acceptable salt
form thereof:

C1l, (XX) wherein non-limiting examples of R, R1 and R are defined herein below in Table XII.
TABLE XII

TABLE REMOVE

phenyl j 4-trifluoromethylphenyi
phenyl 4-cyclopropylphenyl
phenyl I 4-diethylaminophenyl
4-difluoromethoxyphenyl 4-ferf-butylpheny!
phenyl phenyl
phenyl { 4-trifluoromethylphenyl
phenyl 4-cyC1opropylpheny!
phenyl
phenyl
phenyl
4-diethylarmnophenyt
4-difluoromethoxyphenyl ! 4-ter/-butylphenyl j
4-trifluoromethylpheny! 4-cyclopropylphenyl
4-diethylam inophen yl 4-difluoromethoxyphenyl j 4-rer/-butylphenyl
4-trifluoromethylphenyl
phenyl 4-cyclopropylphenyl
phenyl j 4-diethylaminophenyl
phenyl ] 4-difluoromethoxyphenyl
-i
phenyl phenyl
4-ferf-butylphenyl 4-trifluoromethylphenyl
phenyl i 4-cyclopropylphenyl
phenyl j 4-diethylaminophenyl
[_
phenyl ] 4-difluoromethoxyphenyl
phenyl
4-*er?-butylphenyl
phenyl 4-trifluoromethylphenyl
phenyl phenyl
4-cyclopropylphenyl
i
! 4-diethylaminophenyl
phenyl phenyl
4-difluoromethoxyphenyl i 4-fer/-butylphenyi
H
-H
-H
-H "
C(6)CH,
C:(O)CH V
^C(O)CH^
C(d)CHU
C(OJCH.-

-I-

■C(C))cyclopropyl C{0)cyclopropyi C(O)cyclopropyl C(O)cyclopropy 1
-C(())cyclopropyl
-:<^NH7
C(O)NH:
C{OJNH;"
C(O)NH: C(O)NHCHr C((5)NHCHV
^C(O)NHCH?"
^(CONCCH^r
--£(6$ipylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester, 3, (858 mg, 1.7 mmol in 4 mL of DMF) and CSCO3 (648 mg, 2.0 mmol) in a 2.0 - 5.0 mL Emry's process vial eC6uipped with a stir bar is added Mel (479 mg, 3.4 mmol) via pipette. The reaC1ion mixture is then capped, stirred 30 seconds and heated in a Biotage Initiator 60 microwave for 25 minutes at 90 °C. The reaC1ion is then cooled to room temperature and diluted with EtOAc (100 mL) and washed with water (2 x 50 mL). The remaining aC6ueous layer is then extraC1ed with EtOAc (2 x 30 mL). The combined organic extraC1s are then dried over anhydrous Na2SC>4 and evaporated to dryness. The crude residue is then purified over silica to afford 512 mg (58% yield) of the desired produC1. 'H-NMR (300 MHz, CDC13) o 7.23 (d, 2H, J=8.1Hz), 7.10 (d, 2H, J=8.0Hz), 7.05 (d, 2H, J=8.4Hz), 6.84 (d, 2H, J=8.4Hz), 4.52 (s, 1H), 4.10 (m, 1H), 3.90 (m, 2H), 3.80 (s, 3H), 3.20 (m, 1H), 3.05 (m, 1H), 2.76 (m, 2H), 2.50 (m, 1H), 2.03 (s, 3H), 1.93 (m, 1H), 1.58 (m, 3H), 1.40 (s, 9H), 1.15 (m, 1H), 1.01 (m, 2H), 0.7(m, 2H); ,3C-NMR (75 MHz, CDC13) 8 175.0; 158.7, 155.0, 146.1, 134.5, 130.4, 130.2, 128.9, 126.1, 114.1, 79.8, 79.7, 60.4, 55.6, 41.0, 40.6, 40.4, 32.9, 32.3, 30.4,28.8, 15.6, 10.0; MS MH+ = 520.1; elemental analysis: theory C31H41N3O4 C 71.65, H 7.95, N 8.09; found C 71.98, H 7.57, N 7.83.
Preparation of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: To a solution of the 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-buty\ ester, 4, (10.26 g, 19.7 mmol) in CH9C12 (100 mL) is added trifluoroacetic aC1d (25 mL). After stirring at room temperature for 3 hours, die aC6ueous NaHCC>3 (saturated, 200 mL) is added slowly and resulting mixture is stirred for 30 minutes at room temperature. The resulting two layers are separated and the aC6ueous layer is extraC1ed with CH2C12 (100 mL). The organic layers are combined and washed widi aC6ueous NaHC03 and dried over NaS04. The solvent is removed in vacuo to afford 9.2 g (87% yield) of the desired produC1 as a white solid. ' H-NMR (300 MHz, CDC13) 8 7.23 (d, 2H, J=8.0Hz), 7.11 (d, 2H, J=8.5Hz), 7.07 (d, 2H, J=8.6Hz), 6.84 (d, 2H, J=8.6Hz), 4.54 (s, 1H), 4.07 (m, 1H), 3.89 (m, 2H), 3.79 (s, 3H), 3.17 (m, 3H), 2.79 (m, 2H), 2.53 (m, 1H), 2.08 (s, 3H), 1.93 (m, 4H), 1.22 (m, 1H), 1.04 (m, 2H), 0.77 (m, 2H); l3C-NMR (75 MHz,CDCl3)5 175.0; 158.7, 146.2, 134.3, 130.4, 130.3, 128.8, 126.2, 114.1,79.8,59.5, 55.6, 42.0,41.5, 40.4, 32.9, 31.8, 30.3, 25.7, 15.6, 10.0, 9.9; MS MH+ = 420.5; elemental analysis: theory C27H34N403 + 0.9 H20 C 61.20, H 6.22, N 9.91; found C 60.98, H 6.62, N 10.00.
The following are further non-limiting examples of compounds of formula (IX).
Compound 2: 2-(4-fert-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: ' H-NMR (300 MHz, CDC13) 6 7.47 (d, 2H, J=8.7Hz), 7.29 (d, 2H, J=8.7Hz), 7.07 (d, 2H, J=8.9Hz), 6.85 (d, 2H, J=8.7Hz), 4.66 (s, 1H), 3.80 (s, 3H), 3.74 (m, 3H), 3.11 (m, 1H), 2.80 (s, 3H), 2.78 (m, 2H), 2.52 (m, 1H), 2.13 (s, 3H), 1.93 (m, 2H), 1.85 (m, 1H), 1.36 (s, 9H), 1.31 (m, 2H); I3C-NMR (75 MHz, CDC13)8 175.0; 158.7, 155.4, 155.0, 134.5, 130.3, 129.9, 128.6, 126.2, 114.2, 79.9, 58.9, 55.6, 41.6, 41.2,40.3, 35.1, 32.7, 31.7, 30.2, 29.4, 24.0; MS MH+ = 436.1; elemental analysis: theory C27H37N3O2 + 2.3 C63COOH C 54.39, H 5.68, N 6.02; found C 54.27, H 5.67, N 5.94.
Compound 3: 2-(4-Difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-l,3,8-triaza-spiro[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 8 7.35 (d, 2H, J=8.4Hz), 7.18 (d, 2H, J=8.5Hz), 7.07 (d, 2H, J=8.4Hz), 6.85 (d, 2H, J=8.6Hz), 6.57, 6.33 (s, s, 1H), 4.56 (s, 1H), 3.90 (m, 2H), 3.80 (s, 3H), 3.16 (m, 3H), 2.81 (m, 1H), 2.69 (m, 1H), 2.53 (m, 1H), 2.08 (s, 3H), 1.91 (m, 4H), 1.24 (m, 1H); !3C-NMR (75 MHz,
CDC13)5 175.0; 158.7, 152.4, 134.6, 130.4. 130.2, 120.0, 119.5, 116.0, 114.2, 112.6, 79.3, 59.6, 55.6,42.0, 41.6, 40.5, 33.0, 32.0, 30.3, 26.0; MS MH+ = 446.4; elemental analysis: theory C24H29F2N3O3 + 0.5 C63COOH C 59.75, H 5.92, N 8.36; found C 59.41, H 5.92, N 8.19.
EXAMPLE 2
Example 2 provides methods for preparing representative compounds of formula (X). The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.
Compound 4: 8-Cyclopropylcarbonyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one.
Preparation of 8-cyclopropylcarbonyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one, 5, (238 mg contained 0.5 mmol TFA salt, 0.5 mmol) in CH2C12 (15 mL) is added triethylamine (200 mg, 2 mmol) and cyclopropanecarbonyl chloride (208 mg, 2 mmol). The solution is stirred for 5 hours at room temperature. Methylene chloride (100 mL) is added and the resulting mixture is washed with NaHCC>3 (saturated aC6ueous), H2O, dried over Na2SC>4 and purified over silica to afford 92.7 mg (35% yield) of the desired produC1. 'H-NMR (300 MHz, CDC13) 6 7.24 (d, 2H, J=8.6Hz), 7.12 (d, 2H, J=8.6Hz), 7.07 (d, 2H, J=8.6Hz), 6.85 (d, 2H, J=8.6Hz), 4.65 (m, IH), 4.59 (s, IH), 4.24 (m, 2H), 3.91 (m, IH), 3.80 (s, 3H), 3.20 (m, IH), 2.78 (m, 2H), 2.69 (m, IH), 2.06 (s, 3H), 1.97 (m, 2H), 1.81 (m, 3H), 1.22 (m, IH), 1.06 (m, 4H), 0.82 (m, 4H); 13C-NMR (75 MHz, CDC13) 8 176.0; 173.0, 158.7, 146.4, 133.7, 130.4, 130.2, 128.9, 126.2, 114.2, 79.8,60.6,55.7,40.6,32.9,30.4, 15.6, 11.4, 10.1, 10.0, 7.8; MS MH+- 488.3; HRMS: theory C30H37N3O3 488.2913; found 488.2922.
The following are further non-limiting examples of compounds of formula X of the present invention
Compound 5: 8-Acetyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: !H NMR (CDC13) 5 7.21 (d, 2H, J= 8.0 Hz), 7.09(d,2H,7=8.1 Hz), 6.84-6.80 (m, 2H), 4.61-4.41 (m, 2H), 4.26-4.07 (m, IH), 3.97-3.45 (m, 6H), 3.07-2.87 (ra, IH), 2.84-2.60 (m, 2H), 2.58-2.41 (m, IH), 2.11 (s, 3H), 2.03 (s, 3H), 1.98-1.78 (m, 2H), 1.75-1.48 (m, 2H), 1.32-1.11 (m, IH), 1.08-0.96 (m, 2H), 0.81-0.67 (m, 2H); ESI-MS (m/z): (M+Hf) 462.
Compound 6: 8-Cyclopropylcarbonyl-2-(4-difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 5 7.33 (d, 2H, J=8.4Hz), 7.16 (d, 2H, J=8.4Hz), 7.04 (d, 2H, J=8.4Hz), 6.83(d, 2H, J=8.4Hz), 6.57 (t, IH, J=81.6Hz), 4.57 (s, IH), 4.45 (m, IH), 4.20 (m, 0.5H), 4.13 (m, IH), 3.88 (m, IH), 3.80 (s, 3H), 3.63 (m, IH), 3.03 (m, 0.5H), 2.79 (m, IH), 2.70 (m, IH), 2.55 (m, IH), 2.03 (s, 3H), 1.72 (m, 4H), 1.29 (m, IH), 0.99 (m, 2H), 0.78 (m, 2H); MH+ = 514.2; elemental analysis: theory C28H33F2N3O4 C 65.48, H 6.48, N 8.18; found C 65.83, H 6.46, N 8.09.
EXAMPLE 3
Example 3 provides methods for preparing representative compounds of formula (XI). The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.
Compound 7: 2-(4-Cyelopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide.
Preparation of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide: To a solution of the 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one, 5, (3.0 g, 7.1 mmol) in CH2C12 (100 mL) is added trimethylsilyl isocyanide (2.4 g, 21.4 mmol), TEA (0.84 mL, 7.3 mmol). After stirring at room temperature for 18 hours, the aC6ueous NaHCCh (saturate, 50 mL) is added and resulting mixture is stirred for 30 minutes at the room temperature. Two layers are separated and aC6ueous layer is extraC1ed with CH2C12 (2 x 100 mL). The organic layers are combined and washed with
aC6ueous NaHCC>3 and dried over NaSO^. The solvent is removed in vacuo to a crude residue which is purified over silica to afford 2.48 g (85% yield) of the desired produC1. 1 H-NMR (300 MHz, CDC13) 8 7.20 (d, 2H, J=8.2Hz), 7.10 (d, 2H, J=8.2Hz), 7.03 (d, 2H, J=8.6Hz), 6.84 (d, 2H, J=8.7Hz), 4.60 (b, 2H), 4.54 (s, IH), 3.99 (m, IH), 3.89 (m, 3H), 3.80 (s, 3H), 3.23 (m, IH), 2.76 (m, 2H), 2.51 (m, IH), 2.04 (s, 3H), 1.93 (m, IH), 1.76 (m, 3H), 1.21 (m, IH), 1.03 (m, 2H), 0.74 (m, 2H); 13C-NMR (75 MHz, CDC13) 5 175.0; 158.7, 158.4, 146.1, 134.4, 130.5, 130.2, 128.9, 126.2, 114.1, 79.8,60.3,55.7, 41.5, 40.5, 40.4, 32.9, 32.6, 30.4, 26.3, 15.6, 10.0, 9.9; MS MH+ = 463.3; elemental analysis: theory C27H34N4O3 C 70.10, H 7.41, N 12.11; found C 70.07, H 7.47, N 12.09.
For exemplary compounds of formula (XI) wherein one of R5 or R6 are C1-C4 linear or branched alkyl, the procedure exemplified in Example 4 can be followed. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein.
EXAMPLE 4
Compound 8: 2-(4-Cyclopropylphenyl)-3 -[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l>3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d methyl amide
Preparation of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)euiyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d methyl amide: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triaza-spiro[4.5]decan-4-one, 5, (238 mg contained 0.5 mmol TFA salt, 0.5 mmol) in CH2C12 (10 mL) is added triethytamine (152 mg, 2 mmol) and meuiyl isocyanate (114 mg, 2 mmol). The solution is stirred for 5 hours at room temperature. Methylene chloride (100 mL) is added and the resulting mixture is washed with NaHCCh (saturated aC6ueous), H2O, dried over Na2SC>4 and the solvent removed under reduced pressure to a crude residue which is purified over sihca to afford 145 mg (61 % yield) of the desired produC1. 'H-NMR (300 MHz, CDC13) 5 7.22 (d, 2H, J=8.4Hz), 7.10 (d, 2H, J=8.1Hz), 7.03 (d, 2H, J=8.4Hz), 6.84 (d, 2H, J=8.8Hz), 4.53 (s, IH), 4.45 (m, IH), 3.94-3.87 (m, 3H), 3.82 (s, 3H), 3.79 (m, IH), 3.19 (m, IH), 2.84 (d, 3H, J=4.8Hz), 2.72 (m, 2H), 2.50 (m, IH),
2.02 (s, 3H), 1.95 (m, IH), 1.67 (m, 3H), 1.22 (m, IH). 1.03 (m, 2H), 0.76 (m, 2H); 1JC-NMR (75 MHz, CDC13) 5 176.0; 158.7, 158.6. 146.1, 134.4, 130.5, 130.2, 128.9, 126.1, 114.1, 79.8, 60.4, 55.7, 41.1, 40.5, 40.2, 32.9, 32.5, 30.4, 28.1, 26.3, 15.6, 10.0, 9.9; MS MH+ = 477.3; elemental analysis: theory CzgHj^Oj + 0.5 H20 C 69.25, H 7.68, N 11.54; found C 69.14, H 7.56, N 11.63.
For exemplary compounds of formula (XI) wherein both of R-s or Rb are C1-C4 linear, branched or cyclic alkyl or R5 or R6 are taken together to form a C3-C7 cyclic aikyl ring can be made by the procedure provided in Example 5. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein.
EXAMPLE 5
Compound 9: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyi]-l-memyl-8-(piperidine-l-carbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one.
Preparation of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-(piperidine-l-carbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triazaspiro[4.53decan-4-one trifluoroacetate, 5, (0.13 g, 0.25 mmol) in CH2C12 (5.0 mL) is added triethylamine (0.09 mL, 0.65 mmol) and 1-piperidinecarbonyl chloride (0.04 mL, 0.32 mmol). The reaC1ion mixture is stirred at room temperature for 20 hours. The crude material is purified over silica to afford 0.1 g of the desired produC1. "H NMR (CDC13) 8 7.20 (d, 2H, J= 8.0 Hz), 7.07 (d, 2H, J= 8.1 Hz), 7.03 (d, 2H,J = 8.6 Hz), 6.81 (d, 2H,/= 8.5 Hz), 4.51 (s, IH), 3.90-3.83 (m, 2H), 3.78 (s, 3H), 3.62-3.57 (m, 2H), 3.21-3.16 (m, 5H), 2.74-2.65 (m, 2H), 2.56-2.42 (m, IH), 2.02 (s, 3H), 1.73-1.57 (m, 9H), 1.14-1.10 (m, IH), 1.02-0.97 (m, 2H), 0.75-0.69 (m, 2H); ESI-MS (m/z): (M+H+) 531.
The following are further non-limiting examples of compounds of formula (XI).
Compound 10: 2-{4-(Diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l ,3,8-triaza-spiro[4.5 ]decane-8-carboxylic aC1d amide: ' H-NMR (300 MHz, CDC13) 5 7.16 (d, 2H, J=8.4Hz), 7.08 (d, 2H, J=8.5Hz), 6.83 (d, 2H, J=8.4Hz),
6.68 (d, 2H, J=8.6Hz), 4.58 (s, 2H), 4.49 (s, IH), 4.01 (m, IH), 3.90-3.62 (m, 3H), 3.80 (s, 3H), 3.40 (C6, 4H, J=6.9Hz, J=13.9Hz), 3.35 (m, IH), 2.77 (m, 2H), 2.50 (m, IH), 2.05 (s, 3H), 1.88-1.65 (m, 3H), 1.20 (t, 6H, J=7.0Hz); l3C-NMR (75 MHz, CDC13) 8 175.0; 158.6, 158.4, 149.1, 130.8, 130.2, 130.0, 123.0, 114.1, 111.6,79.9,77.6,60.2,55.7,44.7,
41.6, 40.5, 33.0, 32.6, 30.4, 26.1, 12.9; MS MH* = 494.3; elemental analysis: theory
C2gH39N503 + 1.0 H20 C 65.73, H 8.08, N 13.69; found C 65.50, H 7.82, N 13.67.
Compound 11: 2-(4-Trifluoromethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide: ' H-NMR (300 MHz, CDC13) 5 7.69 (d, 2H, J=7.8Hz), 7.47 (d, 2H, J=7.9Hz), 7.07 (d, 2H, J=8.5Hz), 6.86 (d, 2H, J=8.4Hz), 4.61 (s, IH), 4.52 (s, 2H), 3.99-3.87 (m, 3H), 3.81 (s, 3H), 3.73 (m, IH), 3.28 (m, IH), 2.78 (m, IH), 2.65-2.52 (m, 2H), 2.04 (s, 3H), 1.80-1.65 (m, 3H), 1.22 (m, IH); 13C-NMR (75 MHz, CDC13) 8 175.0; 158.8, 158.3, 141.8, 130.2, 129.4, 126.0, 114.2, 79.5, 77.6, 60.3, 55.7, 41.5, 40.6, 40.3, 33.0, 32.6, 30.4, 26.5; MS MH+ = 491.1; elemental analysis: theory C25H29F3N403 C 61.21, H 5.96, N 11.42; found C 61.42, H 6.09, Nil.48.
Compound 12: 2-(4-ter/-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide: 'H-NMR (300 MHz, CDC13) 8 7.44 (d, 2H, J=8.3Hz), 7.28 (d, 2H, J=8.3Hz), 7.06 (d, 2H, J=8.4Hz), 6.84 (d, 2H, J=8.4Hz), 4.57 (s, IH), 4.45 (s, 2H), 4.07 (m, IH), 3.87 (m, 3H), 3.80 (s, 3H), 3.24 (m, IH), 2.76 (m, 2H), 2.53 (m, IH), 2.06 (s, 3H), 1.80 (m, 2H), 1.65 (m, IH), 1.36 (s, 9H), 1.23 (m, IH); 13C-NMR (75 MHz, CDC13) 8 175.0; 158.7. 158.3, 153.1, 134.3, 130.5, 130.2, 128.6, 125.9, 114.1, 79.8, 60.3, 55.7, 41.6, 40.5, 40.4, 35.1, 32.9, 32.6,
31.7, 30.4, 26.3; MS Mlf = 479.1; elemental analysis: theory C28H38N403 + 0.7 H20 C
68.46, H 8.08, N 11.41; found C 68.22, H 7.79, N 11.30.
Compound 13: 2-(4-Difluorometlioxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l -methyl-4-oxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide: ' H-NMR (300 MHz, CDC13) 8 7.39 (d, 2H, J=8.4Hz), 7.18 (d, 2H, J=8.6Hz), 7.06 (d, 2H, J=8.6Hz), 6.85 (d, 2H, J=8.4Hz), 6.57, 6.33 (s, s, IH), 4.56 (m, 3H), 3.99 (m, IH), 3.91 (m, 2H), 3.80 (s, 3H), 3.24 (m, 3H), 2.81 (m, IH), 2.70 (m, IH), 2.53 (m, IH), 2.04 (s, 3H), 1.91 (m, 4H), 1.23 (m, IH); 13C-NMR (75 MHz, CDC13) 8 175.0; 158.8, 158.3, 152.4, 134.7, 130.5, 130.3, 130.2, 120.0, 119.5, 116.0, 114.2, 112.5, 79.4, 60.3, 55.7, 41.5, 40.6, 33.0, 32.6, 30.4,26.4; MS Mlf = 489.0; elemental analysis: theory C25H30F2N4O4 + 0.5 H20 C 60.35, H 6.28, N 11.26; found C 60.63, H 6.08, N 11.20.
Compound 14: 2-(4-Cydopropylphenyl)-3-[2-(4-trilluoromethoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide: 'H-NMR (300 MHz, CDC13) 8 7.20 (d, 2H, J=7.3Hz), 7.10 (m, 6H), 4.79 (br, 2H), 4.56 (s, IH), 3.88 (m, 4H), 3.22 (m, IH), 2.78 (m, 2H), 2.56 (m, IH), 2.04 (s, 3H), 1.93 (m, IH), 1.73 (m, 3H), 1.19 (m, IH), 1.01 (m, 2H), 0.74 (m, 2H); MH+ = 517.2; elemental analysis: theory C27H3,F3N403 + 0.72mol H20 C 61.24, H 6.17, N 10.58; found C 61.25, H 5.88, N 10.32.
Compound 15: 2-(4-/erf-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d ethyl amide: 'H-NMR (300 MHz, CDC13) 8 7.45 (d, 2H, J=8.3Hz), 7.29 (d, 2H, J=8.3Hz), 7.06 (d, 2H, J=8.4Hz), 6.85 (d, 2H, J=8.7Hz), 4.62 (s, IH), 3.97-3.84 (m, 3H), 3.81 (s, 3H), 3.72 (m, IH), 3.32 (C6, 2H, J=7.4Hz, J=14.5Hz), 3.24 (m, IH), 2.78 (m, 2H), 2.54 (m, IH), 2.08 (s, 3H), 1.73 (m, 3H), 1.36 (s, 9H), 1.25 (m, IH), 1.18 (t, 3H, J=7.2Hz); 13C-NMR (75 MHz, CDC13) 8 175.0; 158.7, 158.2, 153.4, 133.4, 130.4, 130.2, 128.7, 126.0, 114.2,79.8,60.7,55.7, 41.1, 40.7, 40.2, 36.3, 35.1, 32.9, 32.2, 31.7, 30.5, 26.3, 15.8; MS MH+ = 507.2; HRMS: theory C30H42N4O3 507.3335; found 507.3319.
Compound 16: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d isopropylamide: 'H-NMR (300 MHz, CDC13) 8 7.28 (d, 2H, J=8.9Hz), 7.11 (d, 2H, J=8.2Hz), 7.06 (d, 2H, J=8.2Hz), 6.82 (d, 2H, J=8.6Hz), 4.56 (s, IH), 4.02 (m, IH), 3.98 (m, 4H), 3.81 (s, 3H), 3.69 (m, IH), 3.51 (m, IH), 3.15 (m, IH), 2.74 (m, 2H), 2.49 (m, IH), 2.05 (s, 3H), 1.95 (m, IH), 1.71 (m, 2H), 1.24 (m, IH), 1.95 (s, s, 6H), 1.04 (m, 2H), 0.73 (m, 2H); 13C-NMR (75 MHz, CDC13) 8 176.0; 158.7, 157.5, 146.3, 133.9, 130.5, 130.2, 128.9, 126.2, 114.2, 79.8, 60.5, 55.7, 43.1, 41.1, 40.6, 40.2, 32.9, 30.4, 26.2, 23.8, 15.6, 10.1, 10.0; MS MH+ = 505.3; elemental analysis: theory C30H40N4O3 + 0.4 C63COOH C 67.23, H 7.40, N 10.18; found C 67.57, H 7.42, N 10.23.
Compound 17: 2-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l ,3,8-triaza-spiro[4;5]decane-8-carboxylic aC1d isopropylamide: 'H-NMR (300 MHz, CDC13) 8 7.21 (d, 2H, J=7.0Hz), 6.99 (d, 2H, J=7.0Hz), 6.87 (d, 2H, 8.6 Hz), 6.77 (d, 2H, J=8.5Hz), 4.49 (s, IH), 4.45 (br, IH), 3.91 (m, 4H), 3.80 (s, 3H), 3.75 (s, 3H), 3.14 (m, IH), 2.72 (m, 2H), 2.47 (m, IH), 1.99 (s, 3H), 1.66 (m, 3H), 1.21 (m ,1H), 1.13 (s, 3H), 1.11 (s, 3H); MH+ = 495.3; elemental analysis: theory C6g^N^ + 4.64mol H20 C 58.16, H 8.24, N 9.67; found C 58.16, H 8.11, N 9.46.
Compound 18: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d dimethylamide: 'H NMR (CDCh) 5 7.20 (d, 2H, J = 8.1 Hz), 7.07 (d, 2H, J = 8.1 Hz), 7.03 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H,J = 8.6 Hz), 4.51 (s, IH), 4.00-3.81 (m, 2H), 3.78 (s, 3H), 3.63-3.58 (m, 2H), 3.22-3.11 (m, IH), 2.80 (s, 6H), 2.77-2.63 (m, 2H), 2.56-2.42 (m, IH), 2.02 (s, 3H), 1.93-1.88 (m, IH), 1.74-1.67 (m, 3H), 1.15-1.11 (m, IH), 1.01-0.97 (m, 2H), 0.74-0.69 (m,2H); ESI-MS (m/z): (M+H+)491.
Compound 19: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d diethylamide: *H NMR (CDC13) 8 7.20 (d, 2H, J = 8.0 Hz), 7.07 (d, 2H, J = 8.2 Hz), 7.04 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.5 Hz), 4.52 (s, IH), 3.90-3.83 (rn, 2H), 3.78 (s, 3H), 3.60-3.55 (m, 2H), 3.22-3.13 (m, 5H), 2.74-2.63 (m, 2H), 2.51-2.47 (m, IH), 2.03 (s, 3H), 1.93-1.89 (m, IH), 1.73-1.68 (m, 3H), 1.14-1.09 (m, 7H), 1.03-0.97 (m, 2H), 0.74-0.69 (m, 2H); ESI-MS (m/z): (M+H+)519.
Compound 20: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l -methyl-4-oxo-13,8-triaza-spiro[4.5]decane-8-carboxylic aC1d cyclopentylamide: !H-NMR (300 MHz, CDC13) 5 7.23 (d, 2H, J=8.0Hz), 7.11 (d, 2H, J=8.4Hz), 7.06 (d, 2H, J=8.6Hz), 6.82 (d, 2H, J=8.6Hz), 4.53 (s, IH), 4.39 (m, IH), 4.13 (m, IH), 3.96 (m, IH), 3.91 (m,2H), 3.81 (s, 3H), 3.69 (m, IH), 3.18 (m, IH), 3.17 (m, 2H), 2.74 (m, IH), 2.66 (m, 3H), 2.65 (m, 3H), 1.76-1.42 (m, 6H), 1.40 (m, 3H), 1.22 (m, IH), 1.01 (m, 2H), 0.73 (m,2H); l3C-NMR(75 MHz, CDC13) 5 176.0; 158.7, 157.8, 146.3, 134.4, 130.5, 130.2, 128.9, 126.1, 114.1, 79.9, 60.4, 55.7, 52.9, 52.5, 41.1, 40.5, 40.1, 34.0, 32.9, 32.4, 30.4, 26.2, 24.0, 23.9,15.6, 10.0, 9.9; MS MH+ = 531.3; elemental analysis: theory C32H42N4O3 + 0.5 H20 C 71.21, H 8.03, N 10.38; found C 71.13, H 8.21, N 10.68.
For exemplary compounds of formula (XI) wherein R5 and R6 are taken together to form a ring having 4 atoms the following procedure can be used. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein.
Compound 21: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-(azetidin-l-ylcarbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one. To a solution of 2-
(4-cyelopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triazaspiro[4.5]decan-4-one trifluoroacetate, 5, (0.12 g, 0.22 mmol) in CH2C12 (5.0 mL) at 0 °C1s added diisopropylethyl amine (0.10 mL, 0.57 mmol) and trichloromethyl chloroformate (25 uL, 0.21 mmol). The reaC1ion mixture is stirred at 0 °C for 45 minutes then at room temperature for 45 minutes followed by re-cooling the reaC1ion to 0 °C after which azetidine (0.25 g, 4.38 mmol) is added. The reaC1ion mixture stirred with warming to room temperature for 68 hours. The crude material is purified over silica to afford 0.08 g of the desired produC1. lH NMR (CDC13) 5 7.20 (d, 2H, J= 8.1 Hz), 7.07 (d, 2H, J= 8.2 Hz), 7.03 (d, 2H, J= 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 4.51 (s, IH), 4.03-3.93 (m, 4H), 3.86-3.82 (m, 2H), 3.78 (s, 3H), 3.75-3.63 (m, 2H), 3.20-3.06 (m, IH), 2.80-2.59 (m, 2H), 2.55-2.42 (m, IH), 2.28-2.14 (m, 2H), 2.00 (s, 3H), 1.96-1.85 (m, IH), 1.79-1.51 (in, 3H), 1.18-1.07 (m, IH), 1.02-0.98 (m, 2H), 0.75-0.71 (m, 2H); ESI-MS (m/z): (M+H+) 503.
Compound 22: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,3,8-triaza-spiro[4.5]decan-4-one: *H NMR (CDC13) 8 7.21 (d, 2H, J= 8.1 Hz), 7.09 (d, 2H, J = 8.1 Hz), 7.05 (d, 2H, J= 8.7 Hz), 6.82 (d, 2H, /= 8.7 Hz), 4.53 (s, IH), 4.08-3.82 (m, 2H), 3.80 (s, 3H), 3.65-3.60 (m, 2H), 3.30-3.16 (m, 6H), 2.78-2.62 (m, 2H), 2.56-2.43 (m, IH), 2.34 (s, 3H), 2.03 (s, 3H), 1.96-1.90 (m, IH), 1.75-1.62 (m, 3H), 1.23-1.21 (m, 2H), 1.16-1.12 (m, 2H), 1.05-0.98 (m, 2H), 0.76-0.71 (m,2H); ESI-MS (m/z): (M+H+) 546.
Compound 23: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-8-(pyrrolidin-l-ylcarbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one: 'H NMR (CDC13) 6 7.20 (d, 2H, J = 8.1 Hz), 7.08 (d, 2H, J = 8.1 Hz), 7.04 (d, 2H, J = 8.7 Hz), 6.81 (d, 2H, J= 8.7 Hz), 4.52 (s, IH), 4.12-3.82 (m, 2H), 3.78 (s, 3H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 5H), 3.22-3.14 (m, IH), 2.78-2.62 (m, 2H), 2.55-2.48 (m, IH), 2.03 (s, 3H), 1.94-1.67 (m, 7H), 1.17-1.12 (m, IH), 1.03-0.97 (m, 2H), 0.75-0.70 (m, 2H); ESI-MS (m/z): (M+H+)517.
Compound 24: 2-{4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethylj-l-methyl-8-(marplK)lm-4-ylcarbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one: !H NMR (CDClj) 5 7.19 (d, 2H, J= 8.0 Hz), 7.07 (d, 2H, J= 8.1 Hz), 7.03 (d, 2H, J= 8.6 Hz), 6.80 (d, 2H, J= 8.5 Hz), 4.51 (s, IH), 4.00-3.80 (m, 2H), 3.77 (s, 3H), 3.72-3.55 (m, 5H), 3.23-3.09 (m, 4H), 2.73-2.65 (m, 2H), 2.55-2.42 (m, IH), 2.01 (s, 3H), 1.92-1.89 (m,
1H), 1.72-1.64 (m, 3H), 1.20-1.09 (m, 3H), 1.02-0.96 (m, 2H), 0.74-0.70 (m, 2H); ESI-MS(m/z): (M+H+)533.
EXAMPLE 6
Example 6 outlines the preparation of exemplary compounds according to the present invention wherein R3 is -C(O)NRJ(OR7). The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein
Compound 25: 2-(4-cyclopropylphenyl)-7V-methoxy-3-[2-(4-methoxvpheiiyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide
Preparation of 2-(4-cyclopropylphenyl)-Ar-methoxy-3-[2-(4-methoxyphenyl)ethyl]-l-memyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide: To the solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triazaspiro[4.5]-decan-4-one, 5, (100 mg, 0.19 mmol) and Et3N (66 uL, 0.47 mmol) in CH2C12 (2 mi,) at 0 °C1s added triphosgene (31 mg, 0.1 mmol). The resulting solution is stirred at 0 °C for 15 minutes then at room temperature for 1 hour. The mixture is re-cooled to 0 °C and added dropwise to a cold mixture of O-methyl hydroxylamine hydrochloride (207 mg, 2.5 mmol) and Et3N (500 uL, 3.6 mmol) in CH2C12 (2 mL). The resulting mixture is stirred at room temperature for 3.5 days followed by stirring at 40 °C overnight. The mixture is diluted with ethyl acetate and washed with water, saturated NH4C1, and brine. The organic layer is dried over Na2SC>4 and the solvent is removed under reduced pressure. The crude material is purified over silica (gradient heicanes/2-propanol 100:0 to 80:20) to afford 41 mg of the desired produC1 as a white amorphous powder. ]H NMR (300 MHz, CDC13) 5 7.51 (s, 1H), 7.18 (d, 2H, J= 8.1 Hz), 7.06 (d, 2H, J= 8.1 Hz), 7.02 (d, 2H, J= 8.7 Hz), 6.80 (d, 2H, J = 8.4 Hz), 4.50 (s, 1H), 3.84 (m, 4H), 3.77 (s, 3H), 3.70 (s, 3H), 3.17 (m, 1H), 2.69 (m, 2H), 2.49 (m, 1H), 2.00 (s, 3H), 1.90 (m, 1H), 1.69 (m, 3H), 1.17 (m, 1H), 0.99 (m, 2H), 0.71 (m, 2H); 13C NMR (75 MHz, CDC13) § 174.9, 159.1, 158.5, 146.0, 134.0, 130.3, 130.0, 128.6, 125.9, 113.9, 79.6, 64.2, 60.1, 55.4,40.6,40.3, 39.9, 32.7, 32.3, 30.1, 26.1, 15.4, 9.8, 9.7; (MH+) 493.
Compound 26: 2-(4-Cyclopropylphenyl)-/V-hydroxy-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide: 'H NMR (300 MHz, CDC13) 8 7.34 (bs, 1H), 7.19 (d, 2H, J= 8.1 Hz), 7.07 (d, 2H, J= 8.1 Hz), 7.03 (d, 2H, J= 8.4 Hz), 6.81 (d, 2H, J= 8.7 Hz), 4.52 (s, IH), 3.83 (overlapping m and s, 8H), 3.21 (m, IH), 2.70 (m, 2H), 2.50 (m, IH), 2.00 (s, 3H), 1.91 (m, IH), 1.71 (m, 3H), 1.18 (m, IH), 1.00 (m, 2H), 0.72 (m, 2H); 13C NMR (75 MHz, CDC13) 8 174.8,
161.2, 158.5, 146.0, 133.9, 130.3, 130.0, 128.7, 126.0, 113.9, 79.6, 60.0, 55.5, 40.3, 39.8,
32.7, 32.1, 30.1, 26.0, 15.4, 9.8, 9.7; (MH+) 478.
Compound 27: 2-(4-cyclopropylphenyl)-N-ethoxy-3-(4-methoxyphenethyl)-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide: !H NMR (300 MHz, CDC13) 8 7.37 (bs, IH), 7.19(d, 2H,J = 7.8 Hz), 7.07 (d, 2H, J= 8.4 Hz), 7.02 (d, 2H, J = 8.7 Hz), 6.80 (d, 2H, J= 8.7 Hz), 4.51 (s, IH), 3.87 (overlapping m and s, 9H), 3.18 (m, IH), 2.69 (m, 2H), 2.49 (m, IH), 2.00 (s, 3H), 1.91 (m, IH), 1.68 (m, 3H), 1.23 (m, 4H), 1.00 (m, 2H), 0.71 (m, 2H); I3C NMR (75 MHz, CDC13) 8 174.9, 159.4, 158.5, 146.0, 134.0,
130.3, 130.0, 128.7, 125.9, 113.9, 79.6, 71.8, 60.1, 55.4, 40.7, 40.3, 40.0, 32.7, 32.3,
30.1, 26.1, 15.4, 13.7, 9.8, 9.7; (MH+) 507.
Compound 28: 2-(4-Cyclopropylphenyl)-A^-methoxy-3-[2-(4-methoxyphenyl)ethyl]-Ar,l-dimelhyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide: 'H NMR (300 MHz, CDC13) 8 7.20 (d, 2H, J= 8.4 Hz), 7.07 (d, 2H, 7= 8.1 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J= 8.7 Hz), 4.52 (s, IH), 3.96-3.79 (overlapping m, 4H), 3.78 (s, 3H), 3.58 (s, 3H), 3.23 (m, IH), 2.95 (s, 3H), 2.70 (m, 2H), 2.49 (m, IH), 2.02 (s, 3H), 1.96-1.59 (overlapping m, 4H), 1.16 (m, IH), 1.00 (m, 2H), 0.72 (m, 2H); 13C NMR (75 MHz, CDC13) 8 175.1, 162.3, 158.5, 145.9, 134.2, 130.3, 130.0, 128.7, 126.0, 113.9, 79.6, 60.3, 58.9, 55.4,42.3, 41.5, 40.3, 37.0, 32.7, 30.2, 26.3, 15.4, 9.9, 9.8; (MH+) 507.
EXAMPLE 7
Example 7 herein below outline the preparation of exemplary compounds according to the present invention wherein R3 is -C(O)NR5NR8R9. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein
Compound 29: tert-Buty\ 2-({2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-8-yl} carbonyl)hydrazine carboxylate
Preparation of ter/-butyl 2-( {2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-8-yl}carbonyl)hydrazinecarboxylate: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyrj-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one, 5, (0.12 g, 0.23 mmol) in CH2C12 (5.0 mL) at 0 °C1s added diisopropylethyl amine (0.10 mL, 0.57 mmol) and trichloromethyl chloroformate (25 uL, 0.21 mmol). The reaC1ion mixture is stirred at 0 °C for 45 minutes and at room temperature for 2 hours followed by re-cooling to 0 °C and addition of tert-butylcarbazate (0.05 g, 0.35 mmol). The cooling bath is removed and the reaC1ion is stirred for 19 hours after which time the reaC1ion mixture is adsorbed onto silica and washed with solvent to afford 0.09 g of the desired produC1. 'H NMR (CDC13) 5 7.01 (d, 2H, J = 7.9 Hz), 6.89 (d, 2H, J= 7.9 Hz), 6.84 (d, 2H, J= 8.3 Hz), 6.62 (d, 2H, J = 8.3 Hz), 6.21 (bs, 2H), 4.34 (s, 1H), 3.78-3.59 (m, 4H), 3.09-2.93 (m, 3H), 2.58-2.45 (m, 2H), 2.38-2.24 (m, 1H), 1.84 (s, 3H), 1.75-1.71 (m, 1H), 1.63-1.49 (m, 3H), 1.28 (s, 9H), 1.09-0.97 (m, 2H), 0.85 (m, 2H), 0.56-0.51 (m, 2H); ESI-MS (m/z): (M+H+) 578.
EXAMPLE 8
Exemplary Compounds of formula (XIV) can be prepared by the procedures and examples outlined in example 8. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein.
Compound 30: 7Y-cyano-2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboximidamide
Preparation of 8-(phenyl-/Vr-cyano-l-carbimidate)-2-(4-methoxvphenyl)-3-[2-{4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: To the solution of 2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one (202 mg, 0.49 mmol) in 10 mL of /so-propanol is added diphenyl cyanocarbodiirnide (235mg, 0.99 mmol), and triethylamine (0.15mL) via syringe. The
reaC1ion is then stirred at 80 °C for 40 hours. The solvent is removed in vacuo and the resulting residue purified over silica to afford 203 mg (74% yield) of the desired produC1. 'H-NMR (300 MHz, CDC13) S 7.45 (m, 2H), 7.29 (m, 3H). 7.1 I (m, 4H), 6.95 (d, 2H, J=8.3Hz), 6.83 (d, 2H, J=4.79Hz), 4.56 (s, 1H), 4.16 (m, 2H), 3.86 (s, 3H), 3.79 (m, 1H), 3.64 (s, 3H), 3.46 (m, 1H), 2.75 (m, 2H), 2.55 (m, 1H), 2.08 (s, 3H), 1.85 (m, 3H), 1.29 (m, 2H); MH+ = 554.3; elemental analysis: theory C32H35N5O4 + 4.55mol H20 C 60.46, H 6.99, N 11.01; found C 60.46, H 6.68, N 10.89.
Preparation of 7V-cyano-2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboximidamide: To a solution of the ammonia (7M in MeOH, 2.5mL, 17.5 mmol) in a 2.0 - 5.0 mL Emry's process vial eC6uipped with a stir bar is added 8-(phenyl-N-cyano-l -carbimidate)-2-(4-methoxy-phenyl)-3-[2-(4-methoxy-phenyl)ethyl]-1 -methyl-1,3,8-triaza-spiro[4.5]decan-4-one (147 mg, 0.27 mmol). The reaC1ion mixture is then capped, stirred 30 seconds, and heated in a Biotage Initiator 60 microwave for 30 minutes at 180 °C. The crude residue is then purified over silica to afford 86mg (68% yield) of the desired produC1. 'H-NMR (300 MHz, CDC13) 8 7.28 (d, 2H, J=8.4Hz), 7.05 (d, 2H, J=8.2Hz), 6.94 (d, 2H, J=8.2Hz), 6.83(d, 2H, J=8.2Hz), 5.71 (s, 1H), 4.55 (br, 1H), 4.13 (m, 4H), 3.86 (s, 3H), 3.81 (s, 3H), 3.33 (m, 1H), 2.77 (m, 2H), 2.54 (m, 1H), 2.05 (s, 3H), 1.76 (m, 3H), 1.28 (m ,1H); MH+ = 477.2; elemental analysis: theory C26H32N603 + 0.43mol H20 C 64.48, H 6.84, N 17.35; found C 64.48, H 6.78, N 16.98.
The following are further non-limiting examples of compounds of formula XIV of the present invention.
Compound 31: 8-(Cyano-1 -carboxamidine)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-l-methyl-1,3,8-triaza-spiro[4.5]decan-4-one. An alternative name for this compound is (E)-N'-cyano-2-(4-cyclopropylphenyl)-3-(4-methoxyphenethyl)-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboximklamide
A solution of phenyl N-cyano-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]-decane-8-carboximidoate (0.14 g, 0.28 mmol) in 7.0 N NH3 in MeOH (3.5 mL) is irradiated in a Biotage Initiator microwave for 30 minutes at 150 °C. The reaC1ion mixture is adsorbed silica gel and
purified by normal phase chromatography to yield 0.04 g of the desired produC1. H NMR (300 MHz, CDC13) 8 7.20 (d, 2H, J = 8.0 Hz), 7.09 (d, 211, J = 8.0 Hz). 7.04 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4 Hz), 5.71 (s, 2H), 4.53 (s, 1H), 4.15-3.86 (m, 3H), 3.80 (s, 3H), 3.53-3.37 (m, 1H), 2.82-2.60 (m, 2H), 2.58-2.43 (m, 1H), 2.06 (s, 3H), 1.97-1.80 (m, 2H), 1.79-1.59 (m, 2H), 1.33-1.14 (m, 2H), 1.03-0.99 (m, 2H), 0.76-0.73 (m, 2H); ESI-MS (m/z): (M+H+) 487.
EXAMPLE 9
Exemplary compounds of formula (XV) can be prepared by the procedures and examples outlined herein below in Example 9. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein
Compound 32: 2-(4-cyclopropylphenyl)-8-methanesulfonyl-3-[2-(4-methoxy-phenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one
Preparation of 2-(4-cyclopropylphenyl)-8-methanesulfonyl-3-[2-(4-methoxy-phenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: To a solution of the 2-(4-cyclopropylphenyl)-3-[2-{4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro{4.5]-decan-4-one, 5, (210 mg, 0.5 mmol) in CH2C12 (10 mL) is added methanesulfonyl chloride (114 mg, 1.0 mmol), triethylamine (TEA) (200 mg, 7.3 mmol). After stirring at room temperature for 3 hours, the CH2C12 is evaporated and the residue dissolved in EtOAc (100 mL). The EtOAc layer is washed with aC6ueous NaHCCh, H2O and dried over NaSO,*. The solvent is removed in vacuo and the resulting crude material is purified by HPLC to afford 160 mg (64% yield) of the desired produC1. *H-NMR (300 MHz, CDC13) 5 7.23 (d, 2H, J=7.7Hz), 7.11 (d, 2H, J=7.7Hz), 7.05 (d, 2H, J=8.4Hz), 6.83 (d, 2H, J=8.0Hz), 4.56 (s, 1H), 3.80 (s, 3H), 3.76-3.68 (m, 4H), 3.09 (m, 1H), 2.83 (s, 3H), 2.72 (m, 2H), 2.56 (m, 1H), 2.06 (s, 3H), 1.91 (m, 4H), 1.24 (m, 1H), 1.04 (m, 2H), 0.75 (m,2H); 13C-NMR(75 MHz, CDC13) 5 175.0; 158.7, 146.3, 134.1, 130.4, 130.2, 128.8, 126.2, 114.1, 79.9, 59.5, 55.7, 43.0, 42.6, 40.6, 34.7, 32.9, 32.6, 30.3, 26.6, 15.6, 10.1, 10.0; MS MH* = 498.0; elemental analysis: theory C27H35N3O4S C 65.16, H 7.09, N 8.44; found C 65.20, H 6.77, N 8.37.
The following are further non-limiting examples of compounds of formula (XV)of the present invention.
Compound 33: 2-(4-?er/-Butylphenyl)-8-methanesulfonyl-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 5 7.45 (d, 2H, J=8.1 Hz), 7.29 (d, 2H, J=8.3Hz), 7.04 (d, 2H, J=8.4Hz), 6.83 (d, 2H, J=8.5Hz), 6.70 (bs, 1H), 4.67 (s, 1H), 4.05 (m, 1H), 3.92 (m, 1H), 3.80 (s, 3H), 3.44 (m, IH), 3.34 (m, 2H), 2.80 (m, 2H), 2.55 (m, 1H), 2.15 (s, 3H), 2.05 (m, 3H), 1.37 (s,9H), 1.28 (m, 1H); 13C-NMR (75 MHz, CDC13) S 175.0; 158.8, 153.5, 133.3, 130.3, 130.2, 128.6, 126.1, 114.2, 80.0, 60.0, 55.6, 42.9, 42.5, 40.9, 35.1, 34.8, 32.9, 32.4, 31.6, 30.4,26.8; MS MH+ = 514.1; elemental analysis: theory C28H39N3O2 + 0.5 C63COOH C 61.03, H 6.98, N 7.36; found C 61.15, H 7.01, N 7.36.
Compound 34: 2-(4-Trifluoromethylphenyl)-8-methanesulfonyl-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 5 7.70 (d, 2H, J=8.1Hz), 7.47 (d, 2H, J=8.1Hz), 7.06 (d, 2H, J=8.5Hz), 6.85 (d, 2H, J=8.8Hz), 4.63 (s, 1H), 3.89-3.82 (m, 2H), 3.81 (s, 3H), 3.79-3.66 (m, 2H), 3.11 (m, 1H), 2.84 (s, 3H), 2.79 (m, 1H), 2.66-2.54 (m, 2H), 2.07 (s, 3H), 1.94-1.85 (m, 3H), 1.31 (m, 1H); ,3C-NMR(75 MHz, CDC13) 6 175.0; 158.9, 141.6, 130.2, 129.4, 126.1, 122.3, 114.2, 79.6, 77.6, 59.6, 55.7, 42.9, 42.5, 40.7, 34.8, 33.0, 32.6, 30.3, 26.8; MS MH+ = 526.1; elemental analysis: theory C25H30F3N3O4S + 0.2 H20 C 56.74, H 5.79, N 7.94; found C 56.35, H 5.70, N 7.63.
EXAMPLE 10 Exemplary compounds of formula (XVI) can be prepared by the procedures and examples outlined herein below in Example 10. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein
Compound 35: Ethyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate
Preparation of ethyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-tnazaspiro[4.5]decan-
4-one, 5, (0.12 g, 0.22 mmol) in CH2Cl2 (5.0 mL) is added triethylamine (0.09 mL, 0.65 mmol) and ethyl chloroformate (0.03 mL, 0.31 mmol). The reaC1ion mixture is stirred at room temperature for 20 hours. The crude produC1 is purified over silica to afford 0.08 g of the desired produC1. 'H NMR (CDC13) 5 7.12 (d, 2H. J = 8.2 Hz), 7.00 (d, 2H, J= 8.1 Hz), 6.95 (d, 2H,7= 8.6 Hz), 6.73 (d, 2H, J = 8.6 Hz), 4.44 (s, IH), 4.09-3.74 (m, 6H), 3.71 (s, 3H), 3.09 (bs, IH), 2.67-2.56 (m, 2H), 2.48-2.35 (m, IH), 1.94 (s, 3H), 1.87-1.81 (m, IH), 1.76-1.41 (m, 3H), 1.19 (t, 3H, J = 7.1 Hz), 1.13-1.03 (m, IH), 0.94-0.91 (m, 2H), 0.67-0.62 (m, 2H); ESI-MS (m/z): (M+H+) 492.
The following are further non-limiting examples of compounds of formula (XVI) of the present invention.
Compound 36: Isopropyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate: 'H NMR (CDC13) S 7.20 (d, 2H, J = 8.1 Hz), 7.08 (d, 2H, J = 8.1 Hz), 7.03 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J= 8.6 Hz), 4.96-4.88 (m, IH), 4.51 (s, lH),4.13-3.82 (m, 3H), 3.78 (s, 3H), 3.15 (bs, IH), 2.79-2.63 (m, 2H), 2.56-2.42 (m, IH), 2.02 (s, 3H), 1.95-1.89 (m, IH), 1.81-1.47 (m, 3H), 1.25 (d, 6H,J = 6.3 Hz), 1.20-1.09 (m, IH), 1.02-0.98 (m, 2H), 0.75-0.71 (m, 2H); ESI-MS (m/z): (M+H+) 506.
Compound 37: terf-Butyl 2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate: 'H-NMR (300 MHz, CDC13) 5 7.24 (d, 2H, J=8.6Hz), 7.06 (d, 2H, J=8.2Hz), 6.94 (d, 2H, J=8.5Hz), 6.81 (d, 2H, J=8.2Hz), 4.52 (s, IH), 3.93 (m, 4H), 3.85 (s, 3H), 3.79 (s, 3H), 3.18 (m, IH), 2.78-2.67 (m, 2H), 2.51 (m, IH), 2.03 (s, 3H), 1.74 (m, 3H), 1.48 (s, 9H), 1.18 (m, IH); MS MH+ =510.2.
Compound 38: tert-Butyl 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate: H-NMR (300 MHz, CDClj) 8 7.45 (d, 2H, J=8.2Hz), 7.30 (d, 2H, J=8.2Hz), 7.07 (d, 2H, J=8.2Hz), 6.85 (d, 2H, J=8.2Hz), 4.57 (s, IH), 4.00 (m, 4H), 3.82 (s, 3H), 3.18 (m, IH), 2.83 (m, 2H), 2.56 (m, IH), 2.07 (s, 3H), 1.77 (m, 3H), 1.50 (s, 9H), 1.37 (s, 9H), 1.15 (m, IH); MS MH+ =536.0.
Compound 39: tert-Butyl 2-(4-diethylaminophenyl)-3-[2-(4-methoxypheoyI)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate: lH-
NMR (300 MHz, CDC13) 8 7.17 (d, 2H, J=8.7Hz), 7.09 (d, 2H, J=8.7Hz), 6.85 (d, 2H, J=8.7Hz), 6.66 (d, 2H, J=8.7Hz), 4.49 (s, IH), 4.00 (m, 4H), 3.84 (s, 3H), 3.41 (m, 4H), 3.18 (m, 1H),2.80 (m, 2H), 2.56 (m, IH), 2.06 (s, 3H), 1.75 (m, 3H), 1.49 (s, 9H), 1.21 (m, 6H), 1.15 (m, IH); MS MH+ =551.1.
Compound 40: tert-Butyl 2-(4-difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate: lH-NMR (300 MHz, CDC13) 5 7.37 (d, 2H, J=8.6Hz), 7.18 (d, 2H, J=8.4Hz), 7.07 (d, 2H, J=8.8Hz), 6.85 (d, 2H, J=8.2Hz), 6.58, 6.33 (s, s, IH), 4.57 (s, IH), 3.94 (m, 4H), 3.85 (s, 3H), 3.23 (m, IH), 2.79 (m, IH), 2.69 (m, IH), 2.55 (m, IH), 2.05 (s, 3H), 1.78 (m, IH), 1.50 (m, 2H), 1.42 (s, 9H), 1.18 (m, IH); MS MH+ =547.2.
Compound 41: Methyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxypfaenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate: "H-NMR (300 MHz, CDC13) 6 7.25 (d, 2H, J=7.7Hz), 7.22 (d, 2H, J=7.6Hz), 7.07 (d, 2H, J=7.1Hz), 6.85 (d, 2H, J=7.4Hz), 4.58 (s, IH), 4.06 (m, 1H0, 3.94 (m, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.73 (m, IH), 3.21 (m, IH), 2.79 (m, 2H), 2.57 (m, IH), 2.03 (s, 3H), 1.79 (m, IH), 1.61 (m, 3H), 1.21 (m, IH), 1.04 (m, 2H), 0.73 (m, 2H); MS MH+ =478.2.
EXAMPLE 11 Exemplary ccompounds of formula (XVII) can be prepared by the procedures and examples outlined herein below in Example 11. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein
Compound 42: 2-(4-Cyclopropylphenyl)-8-(isoxazol-5-yl-carbonyl)-3-[2-(4-methoxyphenyl)emyl]-1 -methyl-1,3,8-triazaspiro[4.5]decan-4-one
Prep»ationof2-(4-cyclopropylphenyl)-8-(isoxazol-5-ylcarbonyl)-3-[2-(4-methoxyphenyl)tethyl]-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triazaspiro{4.5]-decan-4-one triftuoroacetate (0.13 g, 0.25 mmol) in CH2C12 (5.0 mL) is added triethylamine (0.17 mL, 1.22 mmol) and isoxazole-5-carbonyl chloride (0.04 g, 0.29 mmol). The reaC1ion mixture is stirred at room temperature for 20 hours. The crude produC1 is purified over silica to afford 0.05 g of die desired produC1. !H NMR (CDC13) 5 8.17-8.15 (m, IH), 7.07-7.04 (m, 2H), 6.94-6.87 (m, 4H), 6.69-6.58 (m, 3H), 4.51-4.28
(m, 2H), 4.19-3.67 (m, 3H), 3.63, 3.61 (s, retainers, 3H), 3.49-3.35, 3.14-2.99 (m, IH), 2.69-2.45 (m, 2H), 2.43-2.26 (m, IH), 1.89 (s,3H), 1.83-1.45 (m, 5H), 1.13-1.08 (m, 2H), 0.89-0.82 (m, 2H), 0.60-0.55 (m, 2H); ESI-MS (m/z): (M+H+)514.
Exemplary compounds of formula XVIII of the present invention can be prepared by the same procedures as outlined herein by replaC1ng 4-methoxyphenethyl amine with 3-phenylpropyl amine. The following are non-limiting examples of compounds according of formula XVIII of the present invention. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.
Compound 43: 2-(4-Cyclopropylphenyl)-1 -methyl-3-(3-phenylpropyl)-1,3,8-triazaspiro[4.5]-decan-4-one: 'H-NMR (300 MHz, CDC13) 5 7.25 (m, 4H), 7.23 (m, IH), 7.09 (m, 4H), 4.77 (s, IH), 3.75 (m, IH), 3.50 (m, IH), 3.34 (br, IH), 3.23 (m, IH), 3.06 (m, 2H), 2.59 (m, IH), 2.48 (m, 2H), 2.17 (s, 3H), 1.92 (m, 1H), 1.84 (m, 2H), 1.64 (m, 4H), 1.00 (m, 2H), 0.73 (m, 2H); l3C-NMR (75 MHz, CDC13) 6 175.5, 145.9, 141.6, 134.7, 128.7, 128.6, 128.4, 126.1, 126.0, 79.7, 60.2, 42.7, 42.2, 39.6, 33.6, 33.3, 30.5, 29.2, 27.4, 15.5, 9.9; ESI/MS MH+ = 404.1; elemental analysis: theory C26H33N3O + 0.23 mol H20 C 76.59, H 8.27, N 10.30; found C 76.59, H 8.41, N 10.28.
Compound 44: 8-Acetyl-2-(4-cyclopropylphenyl)-3-(3-phenylpropyl)-l -methyl-l,3,8-triazaspiro-[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 5 7.23 (m, 5H), 7.08 (m, 4H), 4.78 (s, IH), 4.59 (m, IH), 4.23 (m, 0.5H), 3.69 (m, 2H), 3.48 (m, IH), 3.20 (m, 0.5H), 2.65 (m, IH), 2.45 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.95 (m, 2H), 1.66 (m, 5H), 1.00 (m, 2H), 0.80 (m, 2H); MH+ = 446.2; elemental analysis: theory C28H35N3O2 + 2.03 mol H20 C 69.75, H 8.17, N 8.71; found C 69.75, H 7.88, N 8.63.
Compound 45: 8-Cyclopropanecarbonyl-2-(4-cyclopropylphenyl)-3-(3-phenylpropyl)-l-methyl-l,3,8-triazaspiro-[4.5]decan-4-one: !H-NMR (300 MHz, CDC13) 5 7.25 (m, 4H), 7.19 (m, IH), 7.08 (m, 4H), 4.79 (s, IH), 4.58 (m, IH), 4.30 (m, 0.5H), 4.23 (m, IH), 3.74 (m, IH), 3.52 (m, IH), 3.26 (m, 0.5H), 2.65 (m, IH), 2.52 (m, 2H), 2.13 (s, 3H), 1.95 (m 2H), 1.80 (m, 4H), 1.59 (m, 2H), 1.01 (m, 4H), 0.76 (m, 4H); MH+ = 472.3; elemental analysis: theory C30H37N3O2 + 0.28mol H20 C 75.69, H 7.94, N 8.82; found C 75.60, H 7.67, N 8.56.
Compound 46: 8-Cyclopropanecarbonyl-2-(4-methoxyphenyl)-3-(3-phenylpropyl)-l-methyl-l,3,8-triazaspiro-[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 8 7.21 (m, 5H), 7.07 (d, 2H, J=7.3Hz), 6.91 (d, 2H. J=8.4Hz), 4.78 (s, IH), 4.55 (m, IH), 4.16 (m 1.5H), 3.85 (s, 3H), 3.78 (m, IH), 3.50 (m IH), 3.24 (m, 0.5H), 2.64 (m, IH), 2.51 (m, 2H), 2.12 (s, 3H), 1.89 (m IH), 1.82 (m, 3H), 1.66 (m, 3H), 1.01 (m, 2H), 0.77 (m, 2H); MH+ = 462.2; elemental analysis: theory C28H35N3O3 C 72.86, H 7.64, N 9.10; found C 72.54, H 7.51, N 9.23.
[0002] Compound 47: 2-(4-Cyclopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-[4.5]decane-8-carboxylic aC1d tert-butyl ester: 'H-NMR (300 MHz, CDC13) 8 7.23 (m, 5H), 7.07 (m, 4H, J=7.0Hz), 4.77 (s, 1H), 4.06 (br, 2H), 3.85 (br, IH), 3.51 (m, IH), 3.32 (br, IH), 2.61 (m, IH), 2.49 (m, 2H), 2.13 (s, 3H), 1.93 (m, IH), 1.79 (m, 4H), 1.63 (m, 2H), 1.50 (s, 9H), 1.00 (m, 2H), 0.74 (m, 2H); l3C-NMR (75 MHz, CDC13) 6 175.2, 155.3, 146.0, 141.5, 134.5, 128.7, 128.6, 128.4, 126.2, 126.1, 79.8, 79.6, 60.3, 39.6, 33.3, 32.9, 30.4, 29.2, 28.7, 26.5, 15.5, 9.9; ESI/MS MH+ = 504.2; elemental analysis: theory C31H41N3O3 + 0.95 mol H20 C 71.49, H 8.30, N 8.06; found C 71.49, H 8.36, N 8.24.
Compound 48: tert-butyl 2-(4-tert-butylphenyl)-4-oxo-3-(3-phenylpropyl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate: ' H-NMR (300 MHz, CDC13) 8 7.45 (d, 2H, J=8.2Hz), 7.26 (m, 4H), 7.17 (m, IH), 7.05 (d, 2H, J=7.3Hz), 5.35 (s, IH), 4.00 (br, 2H), 3.56 (m, IH), 3.22 (m, IH), 2.99 (m, IH), 2.76 (m, IH), 2.51 (m ,2H), 2.19 (m, IH), 1.90 (m, 2H), 1.81 (m, 2H), 1.70 (m, 2H), 1.52 (br, IH), 1.46 (s, 9H), 1.34 (s, 9H); 13C-NMR (75 MHz, CDC13) 8 176.9, 154.8, 153.1, 141.4, 135.6, 128.6, 128.4, 127.1, 126.4, 126.2, 79.8, 74.4, 60.5, 40.6, 35.0, 34.5, 33.2, 32.0, 31.6, 28.8, 28.7; ESI/MS MH+ = 506.5.
Compound 49: 2-(4-Cyclopropylphenyl)-1 -methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-[4.5]decane-8-carboxylic aC1d amide: 'H-NMR (300 MHz, CDC13) 5 7.25 (m, 4H), 7.23 (m, IH), 7.09 (m, 4H), 4.77 (s, IH), 3.75 (m, IH), 3.50 (m, IH), 3.34 (br, IH), 3.23 (m, IH), 3.06 (m, 2H), 2.59 (m, IH), 2.48 (m, 2H), 2.17 (s, 3H), 1.92 (m, IH), 1.84 (m, 2H), 1.64 (m, 4H), 1.00 (m, 2H), 0.73 (m, 2H); 13C-NMR (75 MHz, CDC13)8 174.8, 158.2, 145.6, 141.0, 134.0, 128.3, 128.2, 128.0, 125.8, 125.7, 79.4, 59.8, 41.0, 40.0, 39.2, 32.9, 32.4, 30.0, 28.8, 26.0, 15.1, 9.5; ESI/MS MH+ = 447.1; elemental analysis: theory C24H34N4O2 + 0.71 mol H20 C 70.59, H 7.77, N 12.19; found C 70.57, H 7.68, N 12.13.
Compound 50: 2-(4-tert-Butylphenyl)-1 -methyl-4-oxo-3-(3-phenyipropyl)-l,3,8-triazaspiro-[4.5]decane-8-carboxylic aC1d amide: 'H-NMR (300 MHz, CDC13) 5 7.38 (d, 2H, J=7.0Hz), 7.27 (d, 2H, J=7.0Hz), 7.21 (d, 2H, J=7.5Hz), 7.15 (m, 1H), 7.03 (d, 2H, J=7.5Hz), 5.05 (br, 2H), 4.79 (s, 1H), 3.99 (m, 2H), 3.84 (m, 1H), 3.43 (m, 2H), 2.67 (m, 1H), 2.47 (m, 2H), 2.13 (s, 3H), 1.82 (m, 3H), 1.61 (m, 3H), 1.34 (s, 9H); 13C-NMR (75 MHz, CDC13) 8 175.2, 158.7, 152.9, 141.4, 134.4, 128.6, 128.4, 126.2, 125.8, 79.8, 60.2, 41.4, 40.4, 39.7, 35.0, 33.3, 32.8, 31.6, 30.5, 29.2, 26.5; ESI/MS MH+ = 463.6; elemental analysis: theory C28H36N4O3 + 0.76 mol H20 C 70.60, H 8.36, N 11.76; found C 70.60, H 8.24, N 11.75.
Compound 51: 2-(4-Cyclopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-[4.5]deeane-8-carboxylic aC1d methylamide. An alternative name for this compound is 2-(4-cyclopropylphenyl)-A^,l-dimethyl-4-oxo-3-(3-phenylpK)pyl)-1,3,8-triazaspiro[4.53deeane-8-carboxamide. JH-NMR (300 MHz, CDC13) 6 7.25 (m, 5H), 7.04 (m, 4H), 4.95 (br, 1H), 4.76 (s, 1H), 4.02 (m, 2H), 3.91 (m, 2H), 3.79 (m, 2H), 3.42 (m, 2H), 2.81 (s, 3H), 2.59 (m, 1H), 2.49 (m, 2H), 2.10 (s, 3H), 1.94 (m, 1H), 1.80 (m, 3H), 1.26 (m, IB), 0.99 (m, 2H), 0.72 (m, 2H); MH+ = 461.3; elemental analysis: theory C28H36N4O2 + L17 mol H20 C 69.82, H 8.02, N 11.63; found C 69.82, H 7.69, N 11.65.
Compound 52: 2-(4-Cyclopropylphenyl)-1 -methyl -4-oxo-3 -(3 -phenylpropyl)-l,3,8-triazaspiro-[4.5]decane-8-carboxylic aC1d isopropyl amide: !H-NMR (300 MHz, CDC13) 8 7.24 (in, 4H), 7.17 (m, 1H), 7.04 (m, 4H), 4.77 (s, 1H), 4.42 (br, 1H), 3.96 (m, 3H), 3.74 (m, 1H), 3.43 (m, 2H), 2.59 (m, 1H), 2.46 (m, 2H), 2.11 (s, 3H), 1.81 (m, 4H), 1.63 (m, 3H), 1.17 (s, 3H), 1.16 (s, 3H), 0.95 (m, 2H), 0.72 (m, 2H); MH+ = 489.3; elemental analysis: theory C30H40N4O2 + 1.14 mol H20 C 70.76, H 8.36, N 1 LOO; found C 70.75, H 8.04, N 11.13.
Compound 53: 2-(4-Cyclopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3J8-triazaspiio-[4.5]decane-8-carboxylic aC1d dimethylamide: 'H-NMR (300 MHz, CDC13) 8 7.23 (m, 4H), 7.14 (m, 1H), 7.08 (m, 4H), 4.78 (s, 1H), 3.97 (m, 1H), 3.72 (m, 2H), 3.44 (m, 2H), 2.84 (s, 6H), 2.61 (m, 1H), 2.43 (m, 2H), 2.14 (s, 3H), 1.91 (m, 2H), 1.81 (m, 2H), 1.63 (m, 3H), 1.03 (m, 2H), 0.76 (m, 2H); MH+ = 475.3; elemental analysis: theory C29H38N4C62 + 1.70mol H20 C 68.93, H 8.26, N 11.09; found C 68.94, H 7.93, N 10.84.
Compound 54: 2-(4-Cyclopropylphenyl)-8-methanesulfonyl-1 -methyl-3-(3-phenylpropyl)-l,3,8-triazaspiro-[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 5 7.27
(m, 4H), 7.21 (m, 1H), 7.08 (m, 4H), 4.80 (s, 1H), 3.81 (m, 3H), 3.46 (m, 1H), 3.32 (m, 1H), 2.84 (s, 3H), 2.66 (m, 1H), 2.49 (m, 2H), 2.06 (s, 3H), 2.00 (m 4H), 1.74 (m, 1H), 1.62 (m, 2H), 1.03 (m, 2H), 0.74 (m, 2H); MH+ = 482.2; "elemental analysis: theory C27H35N303S + 1.21mol H20 C 64.41, H 7.49, N 8.35; found C 64.41, H 7.32, N 8.06.
Exemplary compounds of formula XIX (L- eC6ual to methylene, -CH2-) can be prepared according to the examples 12 and 13 or with modifications which are routine to the artisan.
EXAMPLE 12
Compound 55: 2- {2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]dec-8-yl} acetamide
Preparation of 2-{2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]dec-8-yl} acetamide: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triaza-spiro[4.5]decan-4-one, (238 mg contained 0.5 mmol TFA salt, 0.5 mmol) in acetonitrile (15 mL) is added tnethylamine (100 mg, 1 mmol) and 2-bromoacetamide (137 mg, 1 mmol). The resulting mixture is stirred for 3 hours at room temperature. EtOAc (100 mL) and H20 (50 mL) are added and the layers separated. The organic layer is washed with NaHCCh (saturated aC6ueous), H20, dried over Na2S04 and concentrated under reduced pressure to a residue which is purified over silica to afford 154 mg (65% yield) of the desired produC1. lH-NMR (300 MHz, CDC13) 6 7.22 (d, 2H, J=8.1 Hz), 7.15 (d, 1H, J=4.1 Hz), 7.10 (d, 2H, J=8.0Hz), 7.04 (d, 2H, J=8.5Hz), 6.82 (d, 2H, J=8.5Hz), 5.73 (d, 1H, J=4.6Hz), 4.51 (s, 1H), 3.84 (m, 1H), 3.78 (s, 3H), 3.32 (m, 1H), 3.09 (s, 2H), 2.77 (m, 5H), 2.51 (m, 1H), 2.08 (s, 3H), 1.94(m, 1H), 1.82 (m, 3H), 1.25 (m, 1H), 1.05 (m, 2H), 0.76 (m,2H); l3C-NMR (75 MHz, CDC13) 8 177.0; 175.0, 158.6, 146.1, 134.6, 130.7, 130.2, 128.9, 126.1, 114.1, 79.9, 61.7, 59.6, 55.7, 50.5, 50.0, 40.6, 33.1, 32.9, 30.6, 26.6, 15.6, 10.0, 9.9; MS Mff = 477.1; elemental analysis: theory C28H38N403 + 0.2 H20 C 70.03, H 7.64, N 11.67; found C 69.84, H 7.60, N 11.60.
EXAMPLE 13
Compound 56: 8-Cyclopropylmethyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenylethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one
[0003] Preparation of 8-cyclopropylmethyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxy-phenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one, 5, (476 mg contained 0.5 mmol TFA salt, 1.0 mmol) in C1CH2CH2C1 (10 mL) is added cyclopropancarbaldehyde (84 mg, 1.2 mmol), glaC1al acetic aC1d (0.1 mL) and sodium triacetoxyborohydride (233 mg, 1.1 mmol). The resulting mixture is stirred for 24 hours at room temperature. The reaC1ion mixture is diluted with CH2C12 and washed with NaHCC>3 (50 mL, saturated aC6ueous). The organic layer is removed and the aC6ueous layer extraC1ed by CH2C12 (50 mL). The combined organic layers are washed with NaHCCh, H20, dried over Na2SC«4 and purified via HPLC to afford 293 mg (62% yield) of the desired produC1. ' H-NMR (300 MHz, CDC13) 5 7.23 (d, 2H, J=8.2Hz), 7.12 (d, 2H, J=8.2Hz), 7.08 (d, 2H, J=8.6Hz), 6.84 (d, 2H, J=8.6Hz), 4.56 (m, 1H), 3.92 (m, 2H), 3.80 (s, 3H), 3.62 (m, 1H), 3.50 (m, 1H), 3.16 (m, 1H), 2.94 (m, 2H), 2.73 (m, 2H), 2.54 (m, 1H), 2.32 m, 2H), 2.07 (s, 3H), 1.97 (m, 2H), 1.22 (m, 2H), 1.07 (m, 2H), 0.82 (m, 4H), 0.42 (m, 2H); 13C-NMR (75 MHz, CDC13) 5 175.0; 162.5, 158.8, 146.5, 133.3, 130.3, 130.1, 128.8, 126.3, 114.7, 114.1, 79.9, 62.0, 58.4, 55.6,49.0,48.7,40.3,32.9,30.1,24.1, 15.6, 10.1, 10.0, 5.9, 5.0; MS MH+=488.3; elemental analysis: theory C36H39N3O2 + 1.2 C63COOH C 63.75, H 6.64, N 6.88; found C 63.87, H 6.75, N 6.76.
The following is a non-limiting example of a compound of formula XIX of the present invention.
Compound 57: 2- {2-(4-Difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]dec-8-yl} acetamide: 'H-NMR (300 MHz, CDC13) 8 7.84 (b, 2H), 7.33 (d, 2H, J=8.5Hz), 7.16 (d, 2H, J=8.8Hz), 7.03 (d, 2H, J=8.4Hz), 6.82 (d, 2H, J=8.5Hz), 6.57, 6.33 (s, s, 1H), 4.56 (s, 1H), 4.09 (m, 1H), 3.99 (s, 2H), 3.83 (m, 1H), 3.81 (s, 3H), 3.60 (m, 2H), 3.39 (m, 1H), 2.77 (m, 2H), 2.55 (m, 1H), 2.33 (m, 2H), 2.07 (s, 3H), 1.94 (m, 1H), 1.35 (m, 1H); 13C-NMR (75 MHz, CDC13) 5 175.0; 163.0, 161.9, 158.9, 152.6, 133.6, 130.4, 130.2, 130.0, 122.2, 120.0, 116.0, 114.2, 112.0, 79.5,
77.8, 58.0, 55.6, 50.8, 50.4, 40.7, 32.8, 29.9, 24.1; MS MH+ = 503.2; elemental analysis: theory C26H32F2N4O4 + 1.8 C63COOH C 50.23, H 4.81, N 7.92; found C 50.57, H 5.00, N 7.83.
Exemplary compounds of formula XX of the present invention can be prepared by the procedure outlined in Example 14 herein below. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein.
EXAMPLE 14
Compound 58: 2-(4-ter/-Butylbenzyl)-3-[2-(4-methoxyphenyl)ethyl]-l -methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylic aC1d amide.
Preparation of 2-(4-terf-butylbenzyl)-3-[2-(4-methyoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester: To the solution of crude ter/-butyl4-((4-methoxyphenethyl)carbamoyl)-4-aminopiperidine-l-carboxylate, 2, (1.88 g, 5.0 mmol in 10 mL of methanol) and K2CO3 (1.38 g, 10.0 mmol) in a 10-20 mL Emry's process vial eC6uipped with a stir bar is added 2-(4-/erf-butylphenyl)acetaldehyde (885 mg, 5.0 mmol) via pipette. The reaC1ion mixture is capped, stirred 30 seconds and heated in a Biotage Initiator 60 microwave for 25 minutes at 90 °C. The reaC1ion is cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (2 x 100 mL), dried over NajSC^ and concentrated under reduced pressure to a crude residue which is purified over silica to afford 920 mg (34% yield) of die desired produC1. 'H-NMR (300 MHz, CDC13) 5 7.37 (d, 2H, J=8.4), 7.11 (m, 4H), 6.86 (d, 2H, J=8.8Hz), 4.55 (s, 1H), 4.02 (m, 1H), 3.95 (m, 2H), 3.81 (s, 3H), 3.24 (m, 1H), 3.18 (m, 2H), 3.10-2.75 (m, 4H), 1.84 (m, 1H), 1.66 (m, 1H), 1.48 (m, 1H), 1.42 (s, 9H), 1.32 (s, 9H), 1.30 (m, 1H), 1.02 (m, 1H); 13C-NMR (75 MHz, CDC13) 8 177.0; 158.7, 155.0, 132.2, 130.5, 129.7, 128.3, 126.0, 124.8, 120.5, 114.3,79.9,71.3,59.7,55.6,42.1,40.0,39.8,34.8,34.2,32.9,31.7, 28.8; MS MJf = 536.4; elemental analysis: theory C32H4SN3O4 + 0.5 H20 C 70.66, H 8.51, N 7.71; found C 70.99, H 8.29, N 7.28.
Preparation of 2-(4-?err-butylbenzyl)-3-[2-(4-memyoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester: To the solution of the 2-(4-ter/-butylbenzyl)-3-[2-(4-methyoxyphenyl)ethyl]-4-oxo-1,3,8-triaza-

spiro[4.5]decane-8-carboxylic aC1d /er/-butyl ester (799.5 mg, 1.5 mmol in 10 mL of DMF) and CSCO3 (648 mg, 2.0 mmol) in a 10-20 mL Emry's process vial eC6uipped with a stir bar is added Mel (635 mg, 4.5 mmol) via pipet. The reaC1ion mixture is then capped, stirred 30 sec. and heated in a Biotage Initiator 60 microwave for 40 minutes at 90 °C. The reaC1ion is then cooled to room temperature and diluted with EtOAc (150 mL), washed with water (2 x 50 mL). The combined organic extraC1s are then dried over anhydrous NaaS04 and evaporated to dryness. The crude produC1 is purified over silica to afford 560 mg (68% yield) of the desired produC1. ' H-NMR (300 MHz, CDC13) 6 7.33 (d, 2H, J=8.5Hz), 7.18 (d, 2H, J=8.7Hz), 6.98 (d, 2H, J=8.8Hz), 6.77 (d, 2H, J=8.9Hz), 4.23 (s, IH), 3.97 (m, IH), 3.90 (m, 2H), 3.78 (s, 3H), 3.60 (m, IH), 3.20 (m, 2H), 2.94 (m, 2H), 2.65 (m, IH), 2.55 (m, IH), 2.27 (s, 3H), 1.63 (m, 2H), 1.47 (s, 9H), 1.36 (, m, IH), 1.33 (s, 9H), 1.04 (m, IH); ,3C-NMR (75 MHz, CDC13) 5 175.0; 158.7, 155.3, 150.0, 133.6, 130.4, 130.1, 129.7, 125.6, 114.1, 79.6, 76.9, 60.2, 55.6, 40.7, 40.2,40.0, 38.1, 34.8, 32.9, 32.7, 31.7, 31.4, 28.8, 27.5; MS MH+ = 550.2; elemental analysis: theory C33H47N3O4 C 72.10, H 8.62, N 7.64; found C 72.02, H 8.56, N 7.29.
Preparation of 2-(4-ter<-butylbenzyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-l,3,8-triazaspiro[4.5]decan4-one: To a solution of the 2-(4-ter/-butylbenzyl)-3-[2-(4-methyoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester (494 mg, 0.9 mmol) in CH2C12 (30 mL) is added TFA (7.5 mL). After stirring at room temperature for 3 h, the aC6ueous NaHCCh (saturated, 100 mL) is added slowly and resulting mixture is stirred for 30 minutes at the room temperature. Two layers are separated and aC6ueous layer is extraC1ed with CH2C12 (100 mL). The combined organic solvent is washed with aC6ueous NaHCC>3 and dried over NaSO.4. The solvent is removed in vacuo to give afford 435 mg (96% yield) of the desired produC1 as a white solid. 'H-NMR (300 MHz, CDC13) 5 7.34 (d, 2H, J=8.8Hz), 7.16 (d, 2H, J=8.5Hz), 7.02 (d, 2H, J=8.6Hz), 6.80 (d, 2H, J=8.6Hz), 4.24 (m, IH), 4.06 (m, IH), 3.79 (m, IH), 3.78 (s, 3H), 3.22 (m, IH), 3.13 (m, 3H), 3.06 (m, 2H), 2.73 (m, IH), 2.57 (m, IH), 2.32 (s, 3H), 1.92 (m, 2H), 1.84 (m, IH), 1.33 (s, 9H), 1.04 (m, IH); 13C-NMR (75 MHz,CDCl3)5 175.0; 158.7, 150.1, 133.2, 130.2, 130.1, 126.0, 114.1,77.8,58.8,55.6, 41.5, 41.1, 40.5, 37.7, 34.8, 32.7, 31.7, 31.0, 30.9, 25.9; MS MH+ = 450.2; HRMS: theory C28H39N3O2 450.3121; found 450.3114.
Preparation of 2-(4-ter/-butylbenzyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylic aC1d amide: To a solution of the 2-(4-tert-

butylbenzyl)-3-[2-(4-methoxyphenyl)ethylj-1 -methyl-1,3,8-triazaspiro[4.5]decan4-one (328 mg, 0.85 mmol) in CH2C12 (30 mL) is added trimethylsilyl isocyanate (460 mg, 3.4 mmol), TEA (252 mg, 2.5 mmol). After stirring at room temperature for 6 h, the aC6ueous NaHCC>3 (saturated, 50 mL) is added and resulting mixture is stirred for 30 minutes at the room temperature. After CH2C12 (100 mL) is added and two layers are separated. The organic layer is washed with FLO and dried over NaSC>4. The solvent is removed in vacuo to give crude produC1. The crude material obtained is purified over silica to afford 309 mg (74% yield) of the desired produC1. ' H-NMR (300 MHz, CDC13) 5 7.34 (d, 2H, J=8.4Hz), 7.18 (d, 2H, J=8.2Hz), 6.99 (d, 2H, J=8.6Hz), 6.80 (d, 2H, J=8.4Hz), 4.52 (m, 2H), 4.26 (m, 1H), 4.02 (m, 1H), 3.81 (m, 2H), 3.79 (s, 3H), 3.61 (m, 1H), 3.23 (m, 1H), 3.15 (m, 1H), 2.90 (m, 2H), 2.70 (m, 1H), 2.58 (m, 1H), 2.27 (s, 3H), 1.65 (m, 2H), 1.57 (m, 1H), 1.35 (s, 9H), 1.10 (m, 1H); 13C-NMR (75 MHz, CDC13) 5 175.0; 158.7, 158.3, 150.0, 133.5, 130.3, 130.1, 129.7, 125.6, 114.1, 77.8, 60.5, 55.6, 41.6, 40.7, 40.4, 38.0, 34.8, 32.8, 32.7, 31.7, 31.4, 27.4; MS MH+ = 493.3; elemental analysis: theory C29H40N4O3 C 70.70, H 8.18, N 11.37; found C 70.35, H 8.11, N 11.16.
EXAMPLE 15
Exemplary compounds of formula XXI of the present invention can be prepared by the procedure outlined in Example 15. The skilled praC1itioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds provided herein
Compound 59: 8-(2-Amino-2-methylpropionyl)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxypheiiyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one
Preparation of (2-{2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl} -1,1 -dimethyl-2-oxo-ethyl)-carbamic aC1d tert-butyl ester: To a solution of 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one, 5, (476 mg contained 0.5 mmol TFA salt, 1.0 mmol) in CHC13 (20 mL) is added triethylamine (202 mg, 2 mmol) and 1-hydroxybenzotriazole (HOBt) (137 mg, 1 mmol). The resulting mixture is stirred for 10 minutes at room temperature and 2-(tert-butoxycarbonylamino)-2-methyl-propanoic aC1d (203 mg, 1 mmol) is added. The reaC1ion mixture is stirred for 24 hours at room

temperature. The reaC1ion is washed with water and the aC6ueous layer extraC1ed by CH2C12 (50 mL). The combined organic layers are washed with H2O, dried over Na2SC>4 and the solvent removed under reduced pressure and the resulting residue purified over silica to afford 460 mg (76% yield) of the desired produC1. ' H-NMR (300 MHz, CDC13) 5 7.22 (d, 2H, J=7.9Hz), 7.10 (d, 2H, J=7.9Hz), 7.06 (d, 2H, J=8.2Hz), 6.81 (d, 2H, J=8.3Hz), 5.02 (b, IH), 4.56 (s, IH), 4.47 (b, IH), 3.87 (m, IH), 3.80 (s, 3H), 3.20 (m, IH), 2.72 (m, 2H), 2.55 (m, IH), 2.00 (s, 3H), 1.93 (m, 2H), 1.78 (m, IH), 1.68 (m, 2H), 1.57 (m, IH), 1.53 (s, 3H), 1.47 (s, 3H), 1.44 (s, 9H), 1.22 (m,lH), 1.05 (m, 2H), 0.75 (m,2H); 13C-NMR(75 MHz, CDC13) 8 176.0; 163.0, 158.7, 154.4, 146.1, 134.4, 130.5, 130.2, 128.9, 126.1, 114.1, 79.9, 60.4, 57.0, 55.7, 40.5, 33.0, 30.4, 28.7, 26.6, 25.6, 15.6, 10.0, 9.9; MS MJrf = 605.2; elemental analysis: theory C35H48N4O5 + 0.5 H2C6 C 68.49, H 8.05, N 9.13; found C 68.51, H 8.04, N 8.95.
Preparation of 8-(2-amino-2-methylpropionyl)-2-(4-cyclopropylphenyl)-3-[2-(4-metiioxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one: To a solution of the (2- {2-(4-cyclopK)pylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl}-l,l-dimethyl-2-oxo-ethyl)-carbamic aC1d tert-butyl ester (320 mg, 0.5 mmol) in CH2C12 (10 mL) is added trifluoroacetic aC1d (2.5 mL). After stirring at room temperature for 2.5 hour, aC6ueous NaHC03 (saturated, 100 mL) is added slowly and resulting mixture is stirred for 30 minutes at the room temperature. The two layers which form are separated and the aC6ueous layer extraC1ed with CH2C12 (100 mL). The organic layers are combined and washed with aC6ueous NaHCC>3, H2O and dried over Na2SC>4. The solvent is removed in vacuo to afford 204 mg (82% yield) of the desired produC1 as a white solid. 'H-NMR (300 MHz, CDC13) 8 7.22 (d, 2H, J=7.9Hz), 7.09 (d, 2H, J=7.9Hz), 7.06 (d, 2H, J=8.2Hz), 6.83 (d, 2H, J=8.2Hz), 4.52 (m, 3H), 4.00 (m, IH), 3.89 (m, 2H), 3.79 (s, 3H), 3.20 (m, IH), 2.75 (m, 2H), 2.52 (m, IH), 2.02 (s, 3H), 1.94 (m, IH), 1.89-1.56 (m, 4H), 1.42 (s, 6H), 1.26 (m,lH), 1.02 (m, 2H), 0.73 (m, 2H); I3C-NMR (75 MHz, CDC13) 8 176.0; 175.0, 158.7, 146.1, 134.4, 130.5, 130.2, 128.9, 126.1, 114.1, 79.8, 60.4, 55.9, 55.6,42.5,41.3, 40.5, 33.2, 33.0, 30.4, 29.6, 26.8, 15.6, 10.0, 9.9; MS MH4" = 505.2; elemental analysis: theory C30H40N4O3 + 0.4 C63COOH C 67.23, H 7.40, N 10.18; found C 66.91, H 7.56, N 10.22.
Further compounds according to the present invention include:
Compound 60: 2-(4-ter/-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-buty\ ester. 'H-NMR (300 MHz, CDC13) 5 7.46 (d, 2H, J=8.4Hz), 7.21 (d. 2H, J=8.3Hz), 7.05 (d, 2H, J=8.8Hz), 6.86 (d, 2H, J=8.7 Hz), 5.04 (s, IH), 4.10 (m, IH), 3.92 (m, 2H), 3.81 (s, 3H), 3.17 (m, IH), 3.00 (m, IH), 2.89-2.81 (m, 2H), 2.63 (m, lH),2.17(m, IH), 1.58 (m,2H), 1.48 (s,9H), 1.45 (m, IH), 1.36 (s,9H), 1.28 (m, IH); 13C-NMR(75 MHz, CDCh) 6 177.0; 158.7, 155.0, 153.2, 135.5, 130.6, 130.2, 127.3, 126.5, 114.3, 79.9, 74.6, 60.5, 55.6, 41.9, 40.3, 35.1,
34.5, 34.4, 32.6, 31.8, 31.6, 28.8; MS MH+ = 522.5; elemental analysis: theory
C31H43N3O4 C 71.37, H 8.31, N 8.05; found C 70.99, H 7.91. N 7.78.
Compound 61: 2-(4-Diethylaminophenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d ter/-butyl ester. 'H-NMR (300 MHz, CDC13) 5 7.07 (m, 4H), 6.84 (d, 2H, J=8.4Hz), 6.69 (d, 2H, J=8.8Hz), 4.96 (s, IH), 4.01 (m, IH), 3.88 (m, 2H), 3.80 (s, 3H), 3.42 (C6, 4H, J=6.9Hz, J=14.1Hz), 3.18 (m, IH), 3.00 (m, IH), 2.91 (m, IH), 2.80 (m, IH), 2.65 (m, IH), 2.17 (m, IH), 1.65 (m, 2H), 1.48 (m, IH), 1.47 (s, 9H), 1.30 (m,lH), 1.22 (t, 6H, J=6H); l3C-NMR (75 MHz, CDC13) 5 176.0, 158.6,155.0, 149.0, 130.8,128.7, 124.1, 114.2, 112.0,79.9,74.7,60.4,55.6,51.2,44.7, 41.8, 40.5, 39.7, 34.5, 32.6, 31.8, 28.8, 12.9; MS MH+ = 537.0.
Compound 62: 2-(4-Difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-spijx>[4.5]decane-8-carboxylic aC1d tert-butyl ester. 'H-NMR (300 MHz, CDC13) 8 7.28 (d, 2H, J=8.6Hz), 7.25 (d, 2H, J=8.6Hz), 7.04 (d, 2H, J=8.6Hz), 6.85 (d, 2H, J=8.6Hz), 6.56, 6.32 (s, s, IH), 5.04 (s, IH), 4.01 (m, 2H), 3.97 (m, 2H), 3.80 (s, 3H), 3.20 (m, IH), 3.00 (m, IH), 2.82 (m, 2H), 2.63 (m, IH), 2.20 (m, IH), 1.68 (m, IH), 1.48 (m, IH), 1.47 (s, 9H), 1.32 (m, IH); 13C-NMR (75 MHz, CDC13) 5 176.0, 158.8, 154.9, 152.3, 130.4, 130.1, 129.3, 120.5, 119.4, 115.9, 114.4, 112.4, 80.0, 74.0, 60.5,
55.6, 42.0, 40.0, 39.8, 34.5, 32.6, 31.9, 28.8; MS MH+ = 532.0.
Compound 63: 2-(4-ter^Butylphenyl)-8-methanesulfonyl-3-[2-(4-methoxyphenyl)ethyl]-l,3,8-triaza-spiro[4.5]decan-4-one: 'H-NMR (300 MHz, CDC13) 8 7.49 (d, 2H, J=8.3Hz), 7.20 (d, 2H, J=8.7Hz), 7.07 (d, 2H, J=8.4Hz), 6.85 (d, 2H, J=8.2 Hz), 5.26 (s, IH), 5.13 (bs, IH), 4.04 (m, IH), 3.81 (s, 3H), 3.74 (m, IH), 3.49 (m, IH), 3.28 (m, 2H), 2.88 (m, 2H), 2.80 (s, 3H), 2.67 (m, IH), 2.31 (m, IH), 1.85 (m, 2H), 1.74 (m, IH), 1.37 (s,9H); 13C-NMR(75 MHz, CDC13) 5 174.0; 159.0, 154.7, 131.1, 130.1, 129.6, 127.6, 126.8, 114.4, 73.3, 60.3, 55.6, 41.9, 35.5, 35.2, 33.1, 32.3, 31.5; MS MH+ =
500.1; elemental analysis: theory C27H37N3O4S + 1.2 C63COOH C 55.48, H 6.05, N 6.60; found C 55.29, H 5.85, N 6.52.
Compound 64: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza*spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester. An alternative name for this compound is tert-butyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate. 'H-NMR (300 MHz, CDC13) 8 7.40 (m, 4H), 7.05 (d, 2H, J=8.8Hz), 6.76 (d, 2H, J=8.7Hz), 5.04 (s, IH), 4.10 (m, IH), 3.92 (m, 2H), 3.81 (s, 3H), 3.20 (m, IH), 3.05 (m, IH), 2.80 (m, 2H), 2.56 (m, IH), 2.12 (m, IH), 1.80 (m, IH), 1.58 (m, 3H), 1.40 (s, 9H), 1.25 (m, IH), 1.00 (m, 2H), 0.7(m, 2H); 13C-NMR (75 MHz, CDC13) 5 177.0; 158.7, 155.0, 146.3, 135.5, 130.6, 130.1, 127.5, 126.7, 114.3, 79.9, 74.7, 60.4, 55.6, 41.8, 39.7, 39.4, 34.5, 32.6, 31.9, 28.8, 15.6, 10.0; MS MH+ = 506.2; elemental analysis: theory C30H39N3O4 + 0.1 C63COOH C 70.15, H 7.62, N 8.13; found C 70.32, H 7.37, N 8.11
Compound 65: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester: An alternative name for this compound is tert-butyl 2-(4-cyclopropylphenyl)-3-[2-(4-metlu)xvphenyl^myl]-l-memyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate. 'H-NMR (300 MHz, CDC13) 5 7.23 (d, 2H, J=8.1Hz), 7.10 (d, 2H, J=8.0Hz), 7.05 (d, 2H, J=8.4Hz), 6.84 (d, 2H, J=8.4Hz), 4.52 (s, IH), 4.10 (m, IH), 3.90 (m, 2H), 3.80 (s, 3H), 3.20 (m, IH), 3.05 (m, IH), 2.76 (m, 2H), 2.50 (m, IH), 2.03 (s, 3H), 1.93 (m, IH), 1.58 (m, 3H), 1.40 (s, 9H), 1.15 (m, IH), 1.01 (m, 2H), 0.7(m, 2H); 13C-NMR (75 MHz, CDC13)5 175.0; 158.7, 155.0, 146.1, 134.5, 130.4, 130.2, 128.9, 126.1, 114.1,79.8,79.7, 60.4, 55.6,41.0,40.6, 40.4, 32.9, 32.3, 30.4, 28.8, 15.6, 10.0; MS MH+ = 520.1; elemental analysis: theory C31H41N3O4 C 71.65, H 7.95, N 8.09; found C 71.98, H 7.57, N7.83
Compound 66: 2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one. 'H-NMR (300 MHz, CDC13) 5 7.29 (d, 2H, J=8.1Hz), 7.06 (d, 2H, J-8.0Hz), 6.94 (d, 2H, J=8.4Hz), 6.82 (d, 2H, J=8.4Hz), 4.55 (s, IH), 3.85 (s, 2H), 3.80 (s, 3H), 3.09 (bs, 2H), 3.01 (m, 2H), 2.72 (m, 2H), 2.50 (m, IH), 2.09 (s, 3H), 1.81 (m, 4H); MS MH+ = 410
Compound 67: 8-(phenyl-Ar-cyano-l-carbimidate)-2-(4-methoxyphraiyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triaza-spiro[4.5]decan-4-one. An alternative name is phenyl N-cyano-3-(4-methoxyphenethyl)-2-(4-methoxyphenyl)-l-methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carbimidate. 'H-NMR (300 MHz, CDC13) 5 7.45 (m, 2H), 7.29 (m, 3H), 7.11 (m, 4H), 6.95 (d, 2H, J=8.3Hz), 6.83 (d, 2H, J=4.79Hz), 4.56 (s, 1H), 4.16 (m, 2H), 3.86 (s, 3H), 3.79 (m, 1H), 3.64 (s, 3H), 3.46 (m, 1H), 2.75 (m, 2H), 2.55 (m, 1H), 2.08 (s, 3H), 1.85 (m, 3H), 1.29 (m, 2H); MH+ = 554.3; elemental analysis: theory C32H35N5O4 + 4.55mol H20 C 60.46, H 6.99, N 11.01; found C 60.46, H 6.68, N 10.89
Compound 68: 2-(4-tert-ylbenzyl)-3-[2-(4-methyoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-buty\ ester. An alternative name for this compound is tert-butyl 2-(4-tert-butylbenzyl)-3-(4-methoxyphenethyl)-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate. 'H-NMR (300 MHz, CDC13) 5 7.33 (d, 2H, J=8.5Hz), 7.18 (d, 2H, J=8.7Hz), 6.98 (d, 2H, J=8.8Hz), 6.77 (d, 2H, J=8.9Hz), 4.23 (s, 1H), 3.97 (m, 1H), 3.90 (m, 2H), 3.78 (s, 3H), 3.60 (m, 1H), 3.20 (m, 2H), 2.94 (m, 2H), 2.65 (m, 1H), 2.55 (m, 1H), 2.27 (s, 3H), 1.63 (m, 2H), 1.47 (s, 9H), 1.36 (, m, 1H), 1.33 (s, 9H), 1.04 (m, 1H); 13C-NMR (75 MHz, CDC13) 5 175.0; 158.7, 155.3, 150.0, 133.6, 130.4, 130.1, 129.7, 125.6, 114.1, 79.6, 76.9, 60.2, 55.6,40.7,40.2, 40.0, 38.1, 34.8, 32.9, 32.7, 31.7, 31.4, 28.8, 27.5; MS MH+ = 550.2; elemental analysis: theory C33H47N3O4 C 72.10, H 8.62, N 7.64; found C 72.02, H 8.56, N 7.29
Compound 69 : 2-(4-ferf-butylbenzyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one. 'H-NMR (300 MHz, CDC13) 5 7.34 (d, 2H, J=8.8Hz), 7.16 (d, 2H, J=8.5Hz), 7.02 (d, 2H, J=8.6Hz), 6.80 (d, 2H, J=8.6Hz), 4.24 (m, 1H), 4.06 (m, 1H), 3.79 (m, 1H), 3.78 (s, 3H), 3.22 (m, 1H), 3.13 (m, 3H), 3.06 (m, 2H), 2.73 (m, 1H), 2.57 (m, 1H), 2.32 (s, 3H), 1.92 (m, 2H), 1.84 (m, 1H), 1.33 (s, 9H), 1.04 (m, 1H); 13C-NMR(75MHz,CDC13)5 175.0; 158.7, 150.1, 133.2, 130.2, 130.1, 126.0, 114.1, 77.8, 58.8, 55.6, 41.5, 41.1, 40.5, 37.7, 34.8, 32.7, 31.7, 31.0, 30.9, 25.9; MS MH+ = 450.2; HRMS: theory C28H39N3O2 450.3121; found 450.3114
Compound 70: (2- {2-(4-cyclopropylphenyl)-3 -[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]dec-8-yl}-l,l-dimethyl-2-oxo-ethyl)-carbamic aC1d tert-butyl ester: ' H-NMR (300 MHz, CDC13) 8 7.22 (d, 2H, J=7.9Hz), 7.10 (d, 2H, J=7.9Hz), 7.06 (d, 2H, J=8.2Hz), 6.81 (d, 2H, J=8.3Hz), 5.02 (b, 1H), 4.56 (s, 1H), 4.47 (b, 1H), 3.87 (m, 1H), 3.80 (s, 3H), 3.20 (m, 1H), 2.72 (m, 2H), 2.55 (m, 1H), 2.00 (s, 3H), 1.93 (m, 2H), 1.78 (m, 1H), 1.68 (m, 2H), 1.57 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.44 (s, 9H), 1.22 (m,lH), 1.05 (m, 2H), 0.75 (m, 2H); 13C-NMR (75 MHz, CDC13) 5
176.0; 163.0, 158.7, 154.4,146.1, 134.4, 130.5, 130.2, 128.9, 126.1, 114.1,79.9,60.4, 57.0, 55.7, 40.5, 33.0, 30.4, 28.7, 26.6, 25.6, 15.6, 10.0, 9.9; MS MH* = 605.2; elemental analysis: theory C35H48N4O5 + 0.5 H20 C 68.49, H 8.05, N 9.13; found C 68.51, H 8.04, N8.95
Compound 71: Phenyl N-cyano-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]-decane-8-carboximidoate
Compound 72: 2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide; HRMS: calcd for C25H32N4O4 + H+, 453.24963; found (ESI, [M+H]+ Obs'd), 453.2489; HPLC Retention: 2.7 mm.
Compound 73: ter/-butyl 2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate; HRMS: calcd for C28H37N3O5 + H+, 496.28060; found (ESI, [M+H]+ Obs'd), 496.2807; HPLC Retention: 3.1 min.
Compound 74: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide; HRMS: calcd for C26H32N4O3 + H+, 449.25472; found (ESI, [M+H]+ Obs'd), 449.2550; HPLC Retention: 2.8 min.
Compound 75: Methyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate; HRMS: calcd for C27H33N3O4 + H+, 464.25438; found (ESI, [M+H]+ Obs'd), 464.2550; HPLC Retention: 3.0 min.
Compound 76: 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C26H35N3O2 + H+, 422.28020; found (ESI, [M+H]+ Obs'd), 422.2810; HPLC Retention: 2.9 min.
Compound 77: terf-butyl 2-(4-cyclopropylphenyl)-l-methyl-4-oxo-3-{2-[4-(u4fluoromethoxy)phenyl]ethyl}-l,3,8-triazaspiro[4.5]decane-8-carboxylate; HRMS: calcd for C31H38F3N3O4 + H+, 574.28872; found (ESI, [M+H]+ Obs'd), 574.2887; HPLC Retention: 3.5 min.
Compound 78: 2-(4-cyclopropylphenyl)-1 -methyl-3 - {2-[4-(trifluoromethoxy)phenyl]ethyl}-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C26H30F3N3O2 + H+, 474.23629; found (ESI, [M+H]+ Obs'd), 474.2371; HPLC Retention: 3.2 min.
Compound 79: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-8-(methylsulfonyi)-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C26H33N3O4S + H+, 484.22645; found (ESI, [M+H]+ Obs'd), 484.2270; HPLC Retention: 3.0 min.
Compound 80: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carbohydrazide; HRMS: calcd for C27H35N5O3 + H+, 478.28127; found (ESI, [M+H]+ Obs'd), 478.2814; HPLC Retention 2.9 min.
Compound 81: 2-[4-(difluoromethoxy)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 methyl-8-pentanoyl-l,3,8-triazaspiro[4.5jdecan-4-one; HRMS: calcd for C29H37F2N3O4 H+, 530.28249; found (ESI, [M+H]+ Obs'd), 530.2828; HPLC Retention: 3.2 min.
Compound 82: 8-(cyclopentylcarbonyl)-2-[4-(difluoromethoxy)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C30H37F2N3O4 + H+, 542.28249; found (ESI, [M+H]+ Obs'd), 542.2829; HPLC Retention: 3.2 min.
Compound 83: 8-(cyclopropylcarbonyl)-2-(4-isobutylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-1,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C31H41N3O3 + H+, 504.32207; found (ESI, [M+H]+ Obs'd), 504.3226; HPLC Retention: 3.4 min.
Compound 84: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboximidamide; HRMS: calcd for C27H35N5O2 + H+, 462.28635; found (ESI, [M+H]+ Obs'd), 462.2867; HPLC Retention: 3.0 min.
Compound 85: tertbutyl 2-(4-isobutylphenyl)-3-[2-(4-methoxyphenyl)ethyl] l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate; HRMS: calcd for C32H45N3O4 + H+, 536.34828; found (ESI, [M+H]+ Obs'd), 536.3487; HPLC Retention: 3.7 min.
Compound 86: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-A'', 1 -dimethyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboximidamide; HRMS: calcd for C28H37N5O2 + H+, 476.30200; found (ESI, [M+H]+ Obs'd), 476.3027; HPLC Retention: 3.0 min.
Compound 87: tertbutyl 2-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-l,3,8 triazaspiro[4.5]decane-8-carboxylate; HRMS: calcd for C28H37N3O4 + H+, 480.28568; found (ESI, [M+H]+ Obs'd), 480.2863; HPLC Retention: 3.1 min.
Compound 88: 2-{4-te^butylphenyl)-8-(cyclopropylcarbonyl)-3-[2-(4-methoxyphenyl)ethyl]-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C30H39N3O3 + H+, 490.30642; found (ESI, [M+H]+ Obs'd), 490.3071; HPLC Retention^.1 min.
Compound 89: 2-{2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)C1hyl]-1 -methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-8-yl}-yVv/V-dimethylacetamide; HRMS: calcd for C30H40N4O3 + H+, 505.31732; found (ESI, [M+H]+ Obs'd), 505.3180; HPLC Retention:
3.0 min.
Compound 90: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-8-D-prolyl-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd forC3iH4oN403 + H+, 517.31732; found (ESI, [M+H]+ Obs'd), 517.3176; HPLC Retention: 3.0 min.
Compound 91: 2-(4-cyclopropylphenyl)-8-( 1H-imidazol-l -ylcarbonyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C30H35N5O3 + H+, 514.28127; found (ESI, [M+H]+ Obs'd), 514.2813; HPLC Retention:
3.1 min.
Compound 92: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-8-(methylsulfonyl)-l-(trifluoroacetyl)-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C28H32F3N3O5S + H+, 580.20875; found (ESI, [M+H]+ Obs'd), 580.2090; HPLC Retention: 3.2 min.
Compound 93: 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C25H31N3O2 + H+, 406.24890; found (ESI, [M+H]+ Obs'd), 406.2494; HPLC Retention: 2.6 min.
Compound 94: 2-(4-terttylphenyl)-8-(ethylsulfonyl)-3-[2-(4-methoxyphenyl)emyl]-l,3,8-triazaspiro[4.5]decan-4-one; HRMS: calcd for C28H39N3O4S + H+, 514.27340; found (ESI, [M+H]+ Obs'd), 514.2740; Retention: 3.2
Compound 95: 1 -methyl-2-(4-trifluoromethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d ter?-butyl ester
Compound 96: 2-(4-/er<-butylbenzyl)-3-[2-(4-methyoxyphenyl)ethyI]-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester. An alternative name for this compound is tert-butyl 2-(4-tert-butylbenzyl)-3-(4-methoxyphenethyl)-4*oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate. 'H-NMR (300 MHz, CDC13) 5 7.37 (d, 2H, J=8.4), 7.11 (m, 4H), 6.86 (d, 2H, J=8.8Hz), 4.55 (s, IH), 4.02 (m, IH), 3.95 (m, 2H), 3.81 (s, 3H), 3.24 (m, IH), 3.18 (m, 2H), 3.10-2.75 (m, 4H), 1.84 (m, IH), 1.66 (m, IH), 1.48 (m, IH), 1.42 (s, 9H), 1.32 (s, 9H), 1.30 (m, IH), 1.02 (m, IH); l3C-NMR (75 MHz, CDC13)5 177.0; 158.7, 155.0, 132.2, 130.5, 129.7, 128.3, 126.0, 124.8, 120.5, 114.3, 79.9, 71.3, 59.7, 55.6, 42.1, 40.0, 39.8, 34.8, 34.2, 32.9, 31.7, 28.8; MS MH+ = 536.4;
elemental analysis: theory C32H45N3O4 + 0.5 H20 C 70.66, H 8.51, N 7.71; found C 70.99, H 8.29, N 7.28
Compound 97: tert-butyl 2-(4-tert-burylbenzyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate. !H-NMR (300 MHz, CDC13) 5 7.33 (d, 2H, J=8.5Hz), 7.18 (d, 2H, J=8.7Hz), 6.98 (d, 2H, J=8.8Hz), 6.77 (d, 2H, J=8.9Hz), 4.23 (s, IH), 3.97 (m, IH), 3.90 (m, 2H), 3.78 (s, 3H), 3.60 (m, IH), 3.20 (m, 2H), 2.94 (m, 2H), 2.65 (m, IH), 2.55 (m, IH), 2.27 (s, 3H), 1.63 (m, 2H), 1.47 (s, 9H), 1.36 (, m, IH), 1.33 (s, 9H), 1.04 (m, IH); l3C-NMR (75 MHz, CDC13) 5 175.0; 158.7,
155.3, 150.0, 133.6, 130.4, 130.1, 129.7, 125.6, 114.1, 79.6, 76.9, 60.2, 55.6, 40.7, 40.2,
40.0, 38.1, 34.8, 32.9, 32.7, 31.7, 31.4, 28.8, 27.5; MS MH+ = 550.2; elemental analysis:
theory C33H47N3O4 C 72.10, H 8.62, N 7.64; found C 72.02, H 8.56, N 7.29
Compound 98: (S)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-rriaza-spiro[4.5]decane-8-carboxylic aC1d amide. lH-NMR (300 MHz, CDC13) 6 7.20 (d, 2H, J=8.2Hz), 7.10 (d, 2H, J=8.2Hz), 7.03 (d, 2H, J=8.6Hz), 6.84 (d, 2H, J=8.7Hz), 4.60 (b, 2H), 4.54 (s, IH), 3.99 (m, IH), 3.89 (m, 3H), 3.80 (s, 3H), 3.23 (m, 1H),2.76 (m, 2H), 2.51 (m, IH), 2.04 (s, 3H), 1.93 (m, IH), 1.76 (m, 3H), 1.21 (m, IH), 1.03 (m, 2H), 0.74 (m, 2H); i3C-NMR (75 MHz, CDC13) 5 175.0; 158.7,
158.4, 146.1, 134.4, 130.5, 130.2, 128.9, 126.2, 114.1,79.8,60.3,55.7,41.5,40.5,40.4,
32.9, 32.6, 30.4,26.3, 15.6, 10.0, 9.9; MS MH+ = 463.3; elemental analysis: theory
C27H34N4O3 C 70.10, H 7.41, N 12.11; found C 70.07, H 7.47, N 12.09.
Compound 99: (R)-2-(4-cyclopropylphenyl)-3 -[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide. 'H-NMR (300 MHz, CDC13) 8 7.20 (d, 2H, J=8.2Hz), 7.10 (d, 2H, J=8.2Hz), 7.03 (d, 2H, J=8.6Hz), 6.84 (d, 2H, J=8.7Hz), 4.60 (b, 2H), 4.54 (s, IH), 3.99 (m, IH), 3.89 (m, 3H), 3.80 (s, 3H), 3.23 (m, IH), 2.76 (m, 2H), 2.51 (m, IH), 2.04 (s, 3H), 1.93 (m, IH), 1.76 (m, 3H), 1.21 (m, IH), 1.03 (m, 2H), 0.74 (m, 2H); 13C-NMR (75 MHz, CDC13) 5 175.0; 158.7, 158.4, 146.1, 134.4, 130.5, 130.2, 128.9, 126.2, 114.1,79.8,60.3,55.7,41.5,40.5,40.4, 32.9, 32.6, 30.4, 26.3, 15.6, 10.0, 9.9; MS MH+ = 463.3; elemental analysis: theory C27H34N4O3 C 70.10, H 7.41, N 12.11; found C 70.07, H 7.47, N 12.09.
Compound 100: 2-(4-ter*-Butylphenyl)-1 -methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-[4.5]decane-8-carboxylic aC1d tert-butyl ester
Compound 101: 2-(4-Cyclopropylphenyl)-Ar-ethoxy-3-[2-(4-methoxyphenyl)etliyl]-A^,l-dimethyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide
HPLC conditions for compounds 72-94 were as follows: Column: BDS Hypersil C8; mobile phase A: 10 mM NH4OAC1n 95% water / 5% ACN (pipette 6.67 mL of 7.5 M NH4OAC solution into 4743 mL H20, then add 250 mL of ACN to the solution and mix.); mobile phase B: 10 mM NH4OAC1n 5% water / 95% ACN (pipette 6.67 mL of 7.5 M NH4OAC solution into 243 mL H20. Then add 4750 mL of ACN to the solution and mix.); flow Rate: 0.800 mL/min; column Temperature: 40 °C; injeC1ion Volume: 5 SL; UV: monitor 214 nm and 254 nm; gradient table (time (min)/% B): 0.0/0; 2.5/100; 4.0/100; 4.1/0; 5.5/0.
PROCESS The present invention further relates to a process for preparing the Kv 1.5 potassium channel inhibitors of the present invention.
Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commerC1ally available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and funC1ional group transformations and manipulations can be readily obtained from the relevant sC1entific literature or from standard textbooks in the field. It will be appreC1ated that where typical or preferred process conditions (i.e., reaC1ion temperatures, times, mole ratios of reaC1ants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaC1ion conditions can vary with the particular reaC1ants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.
The processes described herein can be monitored according to any suitable method known in the art. For example, produC1 formation can be monitored by speC1roscopic means, such as nuclear magnetic resonance speC1roscopy (e.g., H or 13C), infrared speC1roscopy, speC1rophotometry (e.g., UV-visible), mass speC1rometry, or by chromatography such as high pressure liC6uid chromatograpy (HPLC), gas
chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
Preparation of the compounds can involve proteC1ion and deproteC1ion of various chemical groups. The need for proteC1ion and deproteC1ion and the seleC1ion of appropriate proteC1ing groups can be readily determined by one skilled in the art. The chemistry of proteC1ing groups can be found, for example, in Greene et al., ProteC1ive Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
The reaC1ions or the processes described herein can be carried out in suitable solvents which can be readily seleC1ed by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreaC1ive with the reaC1ants, intermediates, and/or produC1s at the temperatures at which the reaC1ions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaC1ion can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaC1ion step, suitable solvents for a particular reaC1ion step can be seleC1ed.
The first aspeC1 of the process of the present invention relates to a process for preparing 5-spirocyclic-4-imidazolidinone Kvl.5 potassium channel inhibitors having the formula:
H
wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
L and L1 are linking units each independently a unit having the formula:
4C(R19)2]n-each R19 is independently chosen from hydrogen, methyl, or ethyl; n is 1 to 4; and x and y are each independently 0 or 1.
The 5-spirocyclic-4-imidazolidinone formed in this synthesis also can serve as an intermediate for preparing Kvl.5 potassium channel inhibitors of the present invention having formula (I).
The first aspeC1 of the process of the present invention comprises the steps of:

a)

reaC1ing an amine having the fomula:
R—(L)—NH2 with an intermediate having the formula:

or an intermediate having the formula:


FORMULA REMOVE
wherein Z and Z are nitrogen proteC1ing groups such that Z and Z are each removable by a means which does not affeC1 and/or remove the other proteC1ing group and Z1 is capable of forming one or two bonds with nitrogen; to form an amide having the formula:

or the formula:

FORMULA REMOVE
N—-Z1

b)
c)

removing the proteC1ing group Z to form a mono-proteC1ed spirocyclic precursor amine having the formula:
H2N \ / ;
reaC1ing the mono-proteC1ed spirocyclic precursor amine formed in step (b) with an aldehyde having the formula:
R!-(L')—CHO to form a proteC1ed 5-spirocyclic-4-imidazolidinone having the formula:


d) removing the nitrogen proteC1ing group Z2 to form the 5-spirocyclic-4-
imidazolidinone Kvl.5 potassium channel inhibitor having the formula:

FORMULA REMOVE

The first step in the process of the present invention, step (a), relates to reaC1ing an amine with a proteC1ed intermediate having the formula:

Z and Z should each be removable by a means which does not affeC1 and/or remove the other proteC1ing group, that is, Z1 and Z2 should be capable of seC6uential removal. The process for removing Z1 should not effeC1 Z2 and vice versa. Z1 is a proteC1ing group which may form either one or two bonds with the primary amino unit of the intermediate. Examples of single bond proteC1ing groups include benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), [(9H-fluoren-9-yl)methoxy]carbonyl (Fmoc), and the like. Examples of two bond proteC1ing groups includes phthalimido. Any suitable single bond proteC1ing group can serve as Z provided the means for removing Z does not also remove Z2 or vice versa. The chemistry of proteC1ing groups can be found, for example, in Greene et al., ProteC1ive Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991).
Step (a) can be conduC1ed in the presence of a solvent, non-limiting examples of which include danethylformamide (DMF), dichloromethane (CH2C12), 1,1-dicbloroethane (CHC12CH3), dimethylsulfoxide (DMSO), ethyl acetate (EtOAc), and the like.
A catalyst may be used to aC1ivate the mtermediate carboxylic aC1d towards reaC1ion with the amine. Non-limiting examples of suitable catalysts include benzotriazole-2-yl-(oxy-tris-pyrrolidino)-phosphoniumhexafluorophosphate (PyBOP), 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate

(HATU), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC1), dicyclodhexylcarbodiimide (DCC), and the like.
In addition to an optional catalyst, an organic or inorganic base can be utilized to assist in ensuring the reaC1ivity of the amine. Non-limiting examples of organic bases include: triethylamine (TEA), diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), pyridine, and s-lutidine. The time and temperature of the reaC1ion can be adjusted by the formulator to achieve optimal yields. These adjustments are within the scope of ordinary conditions which are familiar to the artisan of skill.
The second step of the process of the present invention relates to the seleC1ive removal of the proteC1ing group Z1. This is accomplished in a manner which leaves the Z proteC1ing group intaC1. This differential removal of Z can be accomplished by seleC1ing the proper proteC1ing group in the previous steps or purchasing commerC1ally available compounds for use in the present process. This step can be carried out under any conditions which do not change or modify the core struC1ure of the molecule and which leaves the proteC1ing group Z2 intaC1. A non-limiting example of a group which is removed in this step is 9-fluorenylmethyl carbamate "Fmoc" which can removed by leating the intermediate formed in Step (a) in DMF, glyme, diglyme, dioxane, or omer ligh boiling solvent with a catalytic amount of an organic or an inorganic base, non-limiting examples of which include piperidine, morpholine, ethanolamine, sodium ;arbonate, sodium bicarbonate, and the like. Therefore, a proteC1ing group such as Tmoc" which is removable with base is compatible with Z2 proteC1ing groups which can ?e removed by aC1d cleavage, for example, tert-butoxycarbonyl (Boc), or hydrogenolysis, for example, Carbobenzyloxy (Cbz).
The third step of the process of the present invention relates to the reaC1ion of an ildehyde having the formula:
R'-tL1)—CHO vith a compound formed in step (b) wherein the Z1 proteC1ing group has been removed o form a proteC1ed 5-spirocyclic-4-imidazolidinone having the formula:

FORMULA REMOVE

In one embodiment, microwave radiation is used to heat the reaC1ion in step (c). The reaC1ion, if conduC1ed in the presence of a solvent, will comprise suffiC1ent solvent to insure complete solution of the reaC1ants. Non-limiting examples of solvents suitable for use include: C1-C6 linear, branched, or cyclic alcohols, inter alia, methanol, ethanol, iso-propanol, and the like; esters, inter alia, methyl acetate, ethyl acetate, and the like; halogenated C1-C2 alkanes, inter alia, methylene chloride, chloroform, carbon tetrachloride, 1,2 dichloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, and the like; ethers, inter alia, tetrahydrofuran, diethylether, methyl tert-butyl ether, and the like.
In addition to the optional presence of a solvent, an organic or inorganic base can also be used to further the rate of reaC1ion. Non-limiting examples of inorganic bases includes NaHC03, Na2C03, K2CO3, and the like.
As it relates to the final compounds of the present invention, in the case wherein Z2 serves as a proteC1ing group, as well as a suitable R3 unit, the produC1 of step (c) will result in a Kvl.5 potassium channel inhibitor according to the present invention. For example, if Z2 is a -SO2CH3 unit, this will serve the purpose of proteC1ing the ring nitrogen from reaC1ion and this unit is a R3 as described herein above and claimed herein below.
The fourth step of the process of the present invention relates to removal of the Z proteC1ing group. This step produces compounds wherein R is hydrogen. Compounds wherein R3 is hydrogen are both Kvl .5 potassium channel inhibitors, as well as intermediates for analogs wherein R comprises a moiety defined herein above. The conditions under which the R3 group is introduced is dependent upon the struC1ure of the moiety being introduced and the reaC1ivity of the reagent which introduces said moiety.
In one embodiment step (d) is followed by step (e):
e) reaC1ing said inhibitor formed in step (d) having the formula:
H with a reagent chosen from, for example:

TABLE REMOVE
to form a Kvl.5 potassium channel inhibitor having the formula:
R'-(L'£ H
as described herein above.
In some embodiments, the 1-position ring nitrogen (R2 unit) is alkylated prior to removal of the Z2 proteC1ing group (step (d) above). This embodiment includes:
d)(ii) reaC1ing the proteC1ed 5-spirocyclic-4-imidazolidinone formed in step (c) above having the formula:
with an alkylating agent to form an N-alkyl-5-spirocyclic-4-
imidazolidinone having the formula:
FORMULA REMOVE

eXii) removing the nitrogen proteC1ing group Z2 from the N-alkyl-5-spirocyclic-4-imidazolidinone formed in step (d)(ii) to form the 5-spirocyclic-4-imidazolidinone Kvl .5 potassium channel inhibitor having the formula:
R2
Step (d)(ii) utilizes an alkylating agent to introduce R2when R" is C1-C-6 linear or branched alkyl (e.g., methyl, ethyl, propyl, or isopropyl). Any alkylating agent is suitable for use, for example, methyl iodide, ethyl iodide, and the like. The reaC1ion can be conduC1ed in the presence of a solvent, in one iteration the solvent is a polar aprotic solvent, inter alia, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), and the like. A non-nucleophilic organic or inorganic base may be used to aC1ivate the compound formed in step (d) toward displacement of the alkylating agent's leaving group. In one embodiment, CsCC3is used. The reaC1ion can be conduC1ed at any temperature which the artisan finds suitable and adaptable to the relative reaC1ivities of the reagents at hand. In one embodiment, the reaC1ion is conduC1ed in a microwave reaC1or, however, the formulator may vary the time and temperature which is necessary without undue experimentation.
The fifth step of the process of the present invention relates to removal of the Z2 proteC1ing group. This step produces compounds wherein R3 is hydrogen. Compounds wherein R3 is hydrogen are both Kvl .5 potassium channel inhibitors, well as intermediates for analogs wherein R3 comprises a moiety defined herein above. The conditions under which the R3 group is introduced is dependent upon the struC1ure of the moiety being introduced and the reaC1ivity of the reagent which introduces said moiety.
In one embodiment step (e)(ii) is followed by step (f)(ii):
f)(ii) reaC1ing said inhibitor formed in step (e)(ii) having the formula:
as described herein above.

ENANTIOMER SEPARATION
The present invention provides enantiomerically pure R and S enantiomers of the compounds provided herein. Methods of resolving enantiomers are known in the art. For example, a supercritical fluid chromatography (SFC) method can be used to resolve the enantiomers. For example, using a SFC method, compound 7 was resolved into (S)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide and (R)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylicaC1d amide. 317 mg of Compound 7 (approximately 52% purity) was chromatographed on a Kromasil CN 20 x 250 mm column using 20% MeOH (0.2% dimethylethylamine) 80% CO2 (317 mg in 8 ml, 8 injeC1ions) to provide a pure compound. The material was immediately chirally resolved on a Chiralcel OJ-H 20 x 250 mm column using 35% MeOH 65% CO2 to provide the two enantiomers (S)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide (lOOmg, retention time 2.95 min) and (R)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide (96 mg, retention time 5.88 min).
Compounds listed and described herein have been found in many instances to exhibit aC1ivities (IC50) in the assays described or referenced herein at concentrations below 1 micromolar (uM).
Compounds of the present invention are effeC1ive as Kvl.5 potassium channel inhibitors. Accordingly, compounds of the present invention can be used to prevent or treat conditions that can be affeC1ed by inhibition of Kvl .5 potassium channel. Compounds of the present invention can be used to treat or prevent cardiac arrhythmias,
including atrial fibrillation and flutter. In preferred embodiments, compounds of the present invention are capable of inhibiting Kvl.5 potassium channels while having little or no inhibitory effeC1 on other ion channels in heart, including for example, ion channels in the ventricles. Accordingly, in particularly preferred embodiments, compounds of the present invention will prevent or treat cardiac arrhythmia while avoiding some of the common complications typically assoC1ated with inhibition of ion channels in the heart, including, for example, a prolongation of the C6T interval and an increased propensity for life threatening ventricular arrhythmias.
Compounds of the present invention can be used to treat or prevent atrial arrhythmias, including atrial fibrillation and atrial flutter, as well as conditions assoC1ated with atrial arrhythmias, including, for example, thromboembolism, stroke, and heart failure.
Compounds of the present invention can be used to produce long-term, as well as short term maintenance periods free of arrhythmia in patients with persistent or chronic atrial arrhythmias.
Compounds of the present invention can also be used to prophylaC1icly treat post surgical atrial arrhthmias.
Methods of the present invention thus include methods of inhibiting Kvl.5 potassium channel; methods of inhibiting Kvl.5 potassium channels while having little or no inhibitory effeC1 on other ion channels in heart, including for example, ion channels in the ventricles; methods of treating or preventing cardiac arrhythmias, including atrial fibrillation and flutter; methods for treating or preventing conditions assoC1ated with atrial arrhythmias, including, for example, thromboembolism, stroke, and heart failure; methods for produC1ng long-term, as well as short term maintenance periods free of arrhythmia in patients with persistent or chronic atrial arrhythmias; and methods for prophylaC1icly treating post surgical atrial arrhthmias. The methods can comprise administering an effeC1ive amount of a compound or composition of the present invention to a subjeC1.
The present invention also relates to the use of the 5-spirocyclic-4-lmidazolidinones according to the present invention in the manufaC1ure of a medicament for the treatment or prevention of atrial arrhythmias and related disorders.
The present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. This aspeC1 includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, exC1pients, and the like, can seleC1 one salt form of the present analogs over another since the compounds themselves are the aC1ive speC1es which mitigate the disease processes described herein.
FORMULATIONS
The present invention also relates to compositions or formulations which comprise the Kvl.5 potassium channel inhibitors according to the present invention. In general, the compositions of the present invention comprise an effeC1ive amount of one or more 5-spirocyclic-4-imidazolidinones and salts thereof according to the present invention which are effeC1ive for providing atrial-seleC1ive antiarrhythmia; and one or more exC1pients.
For the purposes of the present invention the term "exC1pient" and "carrier' are used interchangeably throughout the description of the present invention and said terms are defined herein as, "ingredients which are used in the praC1ice of formulating a safe and effeC1ive pharmaceutical composition."
The formulator will understand that exC1pients are used primarily to serve in delivering a safe, stable, and funC1ional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effeC1ive absorption by the reC1pient of the aC1ive ingredient. An exC1pient may fill a role as simple and direC1 as being an inert filler, or an exC1pient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the feet the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, exC1pients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical SC1ences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA
(1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspeC1ive and does not adversely interaC1 with the aC1ive ingredient. Accordingly, pharmaceutical^ acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary aC1ive ingredients can also be incorporated into the pharmaceutical compositions.
Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical earners. Applicable solid carriers can include one or more substances which can also aC1 as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, m a manner similar to that used for known antiarrhythmic agents. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liC6uids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compaC1ed in the shape and size desired. The powders and tablets can contain up to 99 % of the compound.
Capsules can contain mixtures of one or more compound(s) disclosed herein with inert fillers) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artifiC1al sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfaC1ants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic aC1d, sodium lauryl sulfate, talc, sugars, laC1ose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calC1um, polyvinylpyrrolidone, alginic aC1d, acaC1a gum, xanthan gum, sodium C1trate, complex silicates, calC1um carbonate, glyC1ne, sucrose, sorbitol, dicalC1um phosphate, calC1um sulfate, laC1ose, kaolin, mannitoi, sodium chloride, low
melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calC1um stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
LiC6uid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liC6uid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liC6uid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liC6uid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fraC1ionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liC6uid carriers are used in sterile liC6uid form compositions for parenteral administration. The liC6uid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceuticaUy acceptable propellants.
LiC6uid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injeC1ion. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liC6uid or solid form.
Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate C6uantities of the compound. The unit dosage forms can be
packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liC6uids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in direC1ing the compound(s) to the reC1pient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injeC1ions), reC1ally, vaginally, and transdermally.
When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effeC1ive dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical faC1ors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount suffiC1ent to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a speC1fiC1ndividual typically must be subjeC1ively determined by the attending physiC1an. The variables involved include the speC1fic condition and its state as well as the size, age and response pattern of the patient.
In some cases it may be desirable to administer a compound direC1ly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, sC6ueeze-aC1uated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liC6uid composition, a solid composition, or an aerosol composition. The liC6uid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a sC6ueeze-aC1uated nebulized spray dispenser. The solvents can be, for example, isotonic saline or baC1eriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with laC1ose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a
device that breaks or punC1ures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfaC1ants, and co-solvents, and can be administered by. for example, a metered device. The propellants can be a chiorofluorocarbon (C6C), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.
Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutical! y acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfaC1ant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liC6uid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
The pharmaceutical forms suitable for injeC1ion can include sterile aC6ueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injeC1able solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufaC1ure and storage and can be preserved against the contaminating aC1ion of microorganisms such as baC1eria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liC6uid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (reC1al and vaginal).
Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive
devices. The creams and ointments can be viscous liC6uid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.
Compounds described herein can be administered reC1ally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.
Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.
To increase the effeC1iveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effeC1ive in the treatment of the target disease. For example, other aC1ive compounds (i.e., other aC1ive ingredients or agents) effeC1ive in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.
Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subjeC1. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings melding its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or assoC1ation with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effeC1ive compounds or therapies for the treatment or inhibition of the pathological condition or disorder.
Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more 5-spirocyclic-4-imidazolidinones according to the present invention and one or more exC1pients; from
about 0.01 mg to about 100 mg of one or more 5-spirocyclic-4-imidazoiidinones according to the present invention and one or more exC1pients; and from about 0.1 mg to about 10 mg of one or more 5-spirocyclic-4-imidazolidinones according to the present invention; and one or more exC1pients.
PROCEDURES The following procedures can be utilized in evaluating and seleC1ing compounds as the Kvl.5 potassium channel inhibitors.
FLIPR L-type CalC1um Channel Assay1'2 HL-1 cells expressing endogenous L-type calC1um channels are removed from culture flasks using trypsin, plated on fibroneC1in/gelatin-coated, clear-bottomed, black-walled 96-well microplates in Claycomb media (JRH BiosC1ences #51800) containing 10% fetal bovine serum, 4 mM L-glutamine, and 10 uM norepinephrine, and grown to confluency overnight. The next day, growth medium is aspirated from confluent cell monolayers and replaced with 100 uL per well Tyrode's solution (in mM: 130 NaCl, 4 KC1, 1.8 CaCl2, 1.0 MgCl2,20 HEPES, 10 glucose, pH 7.35) and 50 uL per well FLIPR CalC1um Assay kit, component A (#R-8033, Molecular Devices Corporation) and incubated for 60 min. in a 5% CO2 37° C1ncubator. 50 uL per well test compounds are added to the plates and further incubated for 15 min. in a 5% CO2 37° C1ncubator. All final solutions contain the anion exchange inhibitor, probeneC1d (2.5 mM). The 96-well plates are then placed in the center position of the FLIPR l(FluorometriC1maging Plate Reader, Molecular Devices Corporation). Cell monolayers in each well are simultaneousiy illuminated at 488 nm with an Argon ion laser, and fluorescence emission is monitored using a 510-570 nm bandpass filter and a cooled CCD camera. To depolarize the plasma membrane and aC1ivate L-type calC1um channels, 50uL per well of 20 mM KC1 (final concentration) are dispensed simultaneously to all 96 wells using the FLIPR's automatic 96-well pipettor. Fluorescence measurements are captured for 5 min. following KC1 addition. CalC1um influx, expressed as % control, is calculated for each concentration of test compound and concentration-response curves and IC50 values are generated using GrapbPad Prism 4.0.
Kvl.5 Patch Clamp EP
Kvl.5 currents are recorded by the whole cell mode of patch clamp eleC1rophysiology.' Kvl .5 is stably over expressed in either HEK or LTK- cells. MicroeleC1rodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1.5 to 3 megaohms). The external solution is standard Tyrodes solution. The internal (microeleC1rode) solution contained: 110 mM KC1, 5 mM K9ATP, 5 mM
K4BAPTA, 1 mM MgCl2 and 10 mM HEPES, adjusted to pH 7.2 with KOH.
Command potentials are applied for 1 second to +60mV from a holding potential of -70 mV using Axon software (pClamp 8.1) and hardware (Axopatch ID, 200B). Compounds are prepared as 10-20mM DMSO stocks and diluted to appropriate test concentrations. After stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 5 seconds until no further changes in current are evident at a given compound concentration. Inhibition was measured at the end of the 1 second pulses and expressed relative to controls. Initial Kvl .5 inhibition is estimated by single point determinations done at 1 uM. Concentration response curves are generated for appropriate compounds utilizing at least four concentrations and an n = 3. Curve fitting and IC50 estimating are done using Graphpad software (Ver. 4).
HERG Patch Clamp EP HERG currents are recorded by the whole cell mode of patch clamp eleC1rophysiology as described by Hamill et al.3 HERG is stably over expressed in HEK cells. MicroeleC1rodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1.5 to 3 megaohms). The external solution is standard Tyrodes solution. The internal (microeleC1rode) solution contained: 110 mM KC1, 5 mM K2ATP, 5 mM
K4BAPTA, 1 mM MgCl2and 10 mM HEPES, adjusted to pH 7.2 with KOH.
Command potentials are applied for 2 seconds to +20mV from a holding potential of -80 mV using Axon software (pClamp 8.1) and hardware (Axopatch ID, 200B). Tail currents are generated by returning to -40mV for 2 seconds. Compounds are prepared as 10-20mM DMSO stocks and diluted to appropriate test concentrations. After stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 20 seconds until no further changes in current are evident at a given compound concentration. Inhibition of HERG is measured at the peak of the tail currents and expressed relative to controls. Initial HERG aC1ivity is estimated by single point
determinations run at lOuM. Concentration response curves are generated for appropriate compounds utilizing at least four concentrations and an n = 3. Curve fitting and IC50 estimating are done using Graphpad software (Ver. 4). (Claycomb et al., Proc Natl Acad SC1 USA 1998 Marl 7; 95(6): 2979-84; Xia M et al, J. Mol. Cell Cardiol., 204 Jan; 3(1): 111-9; Hamill et al., Pflugers Archiv. 391:85, 1981).
Results for representative compounds according to the present invention are listed in Table XTV below.

TABLE REMOVE

Kvl.5 Patch Clamp EP as described herein 2FLIPR L-type CalC1um Channel Assay as described herein 3HERG Patch Clamp EP as described herein
The following are additional methods that can be used to determine the suitability of the compounds of the present invention for use as Kvl .5 potassium channel inhibitors.
In Vivo Test Vehicle: Compounds are dissolved to a final concentration of 20-50 mg/ml, first in dimethyl acetamide (DMAC) then adding the balance of propylene glycol 200 (PEG200) for a ratio of DMAC/PEG200 (1:4).
Guinea Pig:(400-600g) The animals are induced and maintained at a surgical plane of anesthesia with isoflurane at 1.5-2%. An inC1sion is made in the neck and the carotid and jugular are isolated. Transducer-tipped catheters are introduced into the aorta and the left ventricle. A line for compound infusion is placed in the jugular. After 30 minutes for stabilization of the preparation the first dose is infused over 15 minutes

followed by 10 minutes recovery before the pattern is repeated for the second and third doses. The animal is monitored continuously for heart rate, blood pressure, ECG, left ventricular pressure, the first derivative of LV pressure maximum and minimum, body temperature and exhaled Pco2.
Miniswine: The animals are induced with an IM injeC1ion of ketamine/xylazine followed briefly by 1-1.5% isoflurane if needed for introduC1ion of a line into the vena cava in the neck. Following intubation, anesthesia is maintained with IV pentobarbital alone with boluses given every 30 minutes during the study. Two eleC1rode-tipped catheters are introduced via the jugular, one into the right atrium and the other into the right ventricle. The carotid artery is isolated and a transducer-tipped catheter introduced into the left ventricle. An inC1sion in the groin is used to access the femoral artery and vein. The artery is cannulated to monitor arterial pressure at the lower aorta and the vein is cannulated with an eleC1rode-tipped catheter advanced into the right atrium. An inC1sion is made above the fourth intercostal space and the ribs separated for access to the heart. The pericardium is opened and the left atrium is loosely clamped to the chest wall. A sensing and two paC1ng eleC1rodes are placed on the atrium. The arterial pressure, ECG, LV pressure, atrial eleC1rogram, body temperature, and exhaled Pco2 are monitored continuously.
When the surgical preparation is stable, baseline effeC1ive refraC1ory periods (ERPs) are determined at paced rates of 150, 200, 240, and 300 beats per minute from the right and left atriums, and the right ventricle. Compound is then infused over 15 minutes and the ERP determinations are repeated starting at the 12th minute of the infusion. The animal is allowed to stabilize, then about 15 minutes after the first dose a second dose is given over 15 minutes followed by ERPs. A third dose may be given. After the final iose the ERPs are determined every 15 minutes until the values are back at baseline. Blood samples are colleC1ed at baseline, at the end of each dose, and 15 minutes after the Inal dose.
While particular embodiments of the present invention have been illustrated and lescribed, it would be obvious to those skilled in the art that various other changes and nodifications can be made without departing from the spirit and scope of the invention, t is therefore intended to cover in die appended claims all such changes and nodifications that are within the scope of this invention.

WE CLAIM:
1. A compound having formula (I):

wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R2 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted
C3-C6 cycloalkyl or-C(O)R23, wherein R23 is optionally substituted C1-C6 linear
or branched alkyl or optionally substituted C3-C6 cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) optionally substituted C1-C6 linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryk
iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from:
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
wherein R7 is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NRV;
wherein R and R are each independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched alkoxy, -OH, or -CO2R10 wherein R10 is optionally substituted C1-C6 linear or branched alkyl; or R8 and R9

can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, O,or S; or
f) R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S;
-C(NR11)R12;
wherein R11 is
a) hydrogen;
b) optionally substituted C3-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R12 is

a) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
b) -OR13 ;
wherein R13 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR14R15;
wherein R14 and R15 are each independently hydrogen, optionally substituted aryl, optionally substituted C3-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl; SO2R16;
wherein R16 is optionally substituted aryl, optionally substituted C1-C6
linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
-C(O)R17;
wherein R is optionally substituted aryl or optionally substituted
heteroaryl; or
-C(O)OR18;

wherein R18 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyi, or optionally substituted aryl;
L, L1, and L2 are linking units each independently a unit having the formula:
-[C(R19)2]„
whrein each R19 is, at each occurrence, independently chosen from hydrogen, methyl, or ethyl;
n is 1 to 4; and
x, y, and z are each independently 0 or 1;
or a phaxmaceutically acceptable salt form thereof.
The compound according to Claim 1 wherein R1 is para-substituted phenyl.
3. The compound according to Claim 1 or Claim 2 wherein R is para-substituted phenyl.
4. The compound according to Claim 1 or 2 wherein R is phenyl optionally substituted with from 1 to 5 substituents independently selected from halogen, optionally substituted C1-C6linear or branched alkyl, optionally substituted C1-C6 linear or branched hakoaflkyl, optionally substituted C3-C8 cycloalkyi, -OR20, -CN, N(R20)2, -C02R20, -C(O)N(R20)2, -NR20C(O)R20, -NO2, or -S02R20; each R20 is independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched haloalkyl, optionally substituted C3-C8 cycloalkyi, optionally substituted aryl, optionally substituted heterocycle, or optionally substituted heteroaryl; or two R units can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S.
5. The compound according to Claim 4 wherein the optionally substituted alkyl, cycloalkyi, aryl, heterocycle, and heteoraryl groups are optionally substituted with from 1 to 5 substituents independently selected from -OR22; -C(O)R22; -C(O)OR22; -C(O)N(R22)2;-N(R22)2; -NR22COR22; halogen; C1-C6 linear or branched haloalkyl; -SO2R22; -S02N(R22)2; C1-C6 linear or branched alkyl; C3-C6 cycloalkyi; cyano; or nitro

wherein two R units can be taken together to form a ring comprising 3-7 ring atoms or each R22 is independently hydrogen, C1-C6 linear or branched, alkyl, or C3C6cycloalkyl.
6. The compound according to Claim 1 or 2 wherein R is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyL, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, or 3,4,5-trichlorophenyl.
7. The compound according to Claim 1 or 2 wherein R is 2-methylphenyl, 3-methylphenyi, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylpfaenyl, 3,4,5-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyL, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylpbettyl, 3,5-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, or 3,4,5-triethylphenyl.
8. The compound according to Claim 1 or 2 wherein R is 2-cyclopropylphenyl, 3-cyclopropylpheayl, 4-cyclopropylphenyl, 2-(cyclopropylmethyl)phenyl, 3-(cyclopropylmethyl)phenyl, 4-(cyclopropyhnethyl)phenyl, 2-«o-butylphenyl, 3-iso-butylphenyl, 4-iso-butylphenyl, 2-rer/-butylphenyl, 3-terf-butylphenyl, 4-tert-butylphenyl, 2-cyclobutylphenyl, 3-cyclobutylphenyl, 4-cyclobutylphenyl, 2-(cyclobutylmethyl)phenyl, 3-(cyclobutylmethyl)phenyl, or 4-(cyclobutyl-methyl)phenyl
9. The compound according to Claim 1 or 2 wherein R is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyI, 4-
118

hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, or 2,4,6-trihydroxy-phenyl.
10. The compound according to Claim 1 or 2 wherein R is 2-fluoromethoxyphenyl, 2-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3-fluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-fluoromethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-bis(fluoromethoxy)phenyl, 2,4-bis(difluoromethoxy)phenyl, 2,4-bis(trifluoromethoxy)phenyl, 3,5-bis(fluoromethoxy)phenyl, 3,5-bis(difluoromethoxy)phenyl, or 3,5-bis(trifluoromethoxy)phenyl.
11. The compound according to Claim 1 or 2 wherein R is 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,3-dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 2,3,4-tricyanophenyl, 2,3,5-tricyanophenyl, 2,3,6-tricyanophenyl, 2,4,5-tricyanophenyl, 3,4,5-tricyanophenyl, 2,4,6-tricyanophenyl, 2,6-dimethyl-4-fluorophenyl, 2,6-dimethyl-3-fluorophenyl, 2,6-dimethyl-4-chlorophenyl, 2,6-di-terf-butyl-4-hydroxyphenyl, 2,6-difluoro-4-chlorophenyl, 2,6-difluoro-3-chlorophenyl, 2-hydroxy-4-methylphenyl, 2-hydroxy-5-methylphenyl, 2,6-dihydroxy-4-tert-butylphenyl, or 2,6-difluoro-4-cyanophenyl.
12. The compound according to Claim 1 or 2 wherein R is 2-aminophenyl, 2-(N-methylamino)phenyl, 2-(iVJV-dimethylamino)phenyl, 2-(Ar-ethylamino)phenyl, 2-(Arr/V-diethylamino)phenyl, 3-aminophenyl, 3-(A-methylamino)phenyl, 3-(NJV-dimethylamino)pb.enyl, 3-(A/-ethylamino)phenyl, 3-(iV,vV-diethylamino)phenyl, 4-aminophenyl, 4-(A'-methylamino)phenyl, 4-(Af^/V-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, or 4-(JV,A/-diethylamino)phenyl.
13. The compound according to any one of Claims 1 or 3 to 12 wherein R1 is phenyl optionally substituted with from 1 to 5 substituents independently selected from halogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C.rCg cycloalkyl, -OR21, -CN, -N(R21)2, -C02R21, -C(O)N(R21)2, NR2,C(O)R21, -NO2, and

-SO2R21; each R2i is independently hydrogen, optionally substituted C1-C6, linear or branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heterocycle, or optionally substituted heteroaryl; or two R21 units can be taken together to form a ring comprising from 3-7 ring atoms.
14. The compound according to Claim 13 wherein the optionally substituted alkyl, cycloalkyl, aryl, heterocyle and heteroaryl groups are optionally substituted with from 1 to 5 substituents independently selected from -OR"; -C(O)R22; C(O)OR22; -C(O)N(R22)2;-N(R22)2; - NR22COR22; halogen; C,-C4 linear or branched haloalkyl; -SO2R22; -S02N(R22)2; C1-Q linear or branched alkyl; C3-Cs cycloalkyl; cyano; or nitro wherein two R22 units can be taken together to form a ring comprising 3-7 ring atoms or each R22 is independently hydrogen, C1-C6 linear or branched alkyl, or C3-C8 cycloalkyl.
15. The compound according to any one of Claims 1 or 3 to 12 wherein R1 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifiuorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichloropfaenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichiorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, or 3,4,5-trichlorophenyl.
16. The compound according to any one of Claims 1 or 3 to 12 wherein R1 is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethyIphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimemylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 3,5-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 3,4,5-triethylphenyl 2-isopropylphenyl, 3-isopropylphenyl, or 4-isopropylphenyl.

17. The compound according to any one of Claims 1 or 3 to 12 wherein R1 is 2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropyl-phenyl, 2-(cyclopropylmethyl)phenyl, 3-(cyclopropylmethyl)phenyl, 4-(cyclopropyl-methyl)phenyl, 2-iso-butylphenyl, 3-iso-butylphenyl, 4-iso-butylphenyl, 2-tert=butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-cyclobutylphenyl, 3-cyclobutylphenyl, 4-cyclobutylphenyl, 2-(cyclobutylmethyl)phenyl, 3-(cyclobutylmethyl)phenyl, or 4-(cyclobutylmethyl)phenyl.
18. The compound according to any one of Claims 1 or 3 to 12 wherein R! is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-fluoromethoxyphenyl, 2-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3-fluoromethoxyphenyl, 3-difluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-fluoromethoxyphenyl, 4-difhioromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-bis(fluoromethoxy)phenyl, 2,4-bis(difluorometlioxy)phenyl, 2,4-bis(trifluoromethoxy)phenyl, 3,5-bis(fluoromethoxy)phenyl, 3,5-bis(difluoromethoxy)phenyl, or 3,5-bis(trifluoromemoxy)phenyl.
19. The compound according to any one of Claims 1 to 18 wherein R2 is--C(O)R23, wherein R23 is C1-C6 linear or branched alkyl or C3-C6 cycloalkyl.
20. The compound according to any one of Claims 1 to 18 wherein R2 is C1-C6 linear or branched alkyl or C3-C6 cycloalkyl.
21. The compound according to any one of Claims 1 to 18 wherein R2 is methyl.
22. The compound according to any one of Claims 1 to 18 wherein R2 is ethyl, n-propyl, isopropyl, or cyclopropyl.
23. The compound according to any one of Claims 1 to 22 wherein R3 is -C(O)NR5R6 and R5 and R6 are each independently selected from

a) hydrogen;
b) C1-C6 linear or branched alkyl;
c) C3-C7 cycloalkyl;
d) -OR7, wherein R7 is hydrogen or C1C6, linear or branched alkyl; or
e) -NR8R9, wherein R8 and R9 are each independently hydrogen, C1-C6, linear or branched alkyl, C1-C6 linear or branched alkoxy, -OH, or CO2R10, wherein R10 is C1-C6 linear or branched alkyl; or R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S.

24. The compound according to any one of Claims 1 to 22 wherein R3 and R6 are each independently selected from hydrogen, methyl, ethyl, n-propyl, wo-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
25. The compound according to any one of Claims 1 to 22 wherein R3 is -C(O)NHCH2CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH2CH3)2, -C(O)N(CH3)2, or -C(O)NH[CH(CH3)2].
26. The compound according to any one of Claims 1 to 22 wherein R3 is-C(O)NH2, or-C(O)NHCH3.
27. The compound according to any one of Claims i to 22 wherein R3 is -((O)NR60R7 or -C(O)NR6R8R9 wherein R6 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl; R7 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl, and R8 and R9 are each independently selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy or hydroxy!.
28. The compound according to any one of Claims 1 to 22 wherein R3 is

-C(O)NR5R6, and R5 and R6 are taken together to form an optionally substituted ring having from 3 to 7 ring atoms.
29. The compound according to Claim 28 wherein R5 and R6 are taken together to form a ring selected from aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, orpiperidin-1-yl.
30. The compound according to any one of Claims 1 to 22 wherein R' is -C(NR11)R12, wherein R11 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, hydroxyl, or cyano; and R12 is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, -OR13, or -NR14R15, wherein R13 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, or phenyl; and R14 and R!5 are each independently selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl.
31. The compound according to any one of Claims 1 to 22 wherein R3 is -SO2R16 and R is phenyl, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl.
32. The compound according to any one of Claims 1 to 22 wherein R3 is -C(O)R17, wherein R17 is C1-C5 heteroaryl.
33. The compound according to Claim 32 wherein R17 is selected from triazinyl, thiazol-2-yl, tbiazol-=yl, imidazol-1-yl, lH-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
34. The compound according to any one of Claims 1 to 22 wherein R3 is -C(O)OR18, wherein R18 is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl.

35. The compound according to any one of Claims 1 to 22 wherein R" is C(O)OCH3, -C(O)OCH2CH3, C(O)OCH(CH3)2, or C(O)OC(CH3)3.
36. The compound according to any one of Claims 1 to 22 wherein R3 is =-C(O)R4, wherein R4 is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, or fen-butyl.
37. The compound according to any one of Claims 1 to 36 wherein x is 1 and L is -CH2CH2-.
38. The compound according to any one of Claims 1 to 36 wherein x is 1 and L is CH2CH2CH2-.
39. The compound according to any one of Claims 1 to 36 wherein x is 1 and L is CH2-.
40. The compound according to any one of Claims 1 to 36 wherein x is 0.
41. The compound according to any one of Claims 1 to 36 wherein y is 1 and L1 is -CH2-.
42. The compound according to any one of Claims 1 to 36 wherein y is 0.
43. The compound according to any one of Claims 1 to 36 wherein z is 1 and L2 is -CH2-.
44. The compound according to any one of Claims 1 to 36 wherein z is 0.
45. The compound according to any one of Claims 1 to 36 wherein x is 1, y is 0 and 7 is O
46. The compound according to Claim 45 wherein L is -CH2CH2-.

47. The compound according to Claim 1 wherein:
R3 is hydrogen, -C(O)R4; -C(O)NR5R6, -C(O)NR5OR7; -C(O)NR5NR8R9, -C(NR11)R!2, -S02R16, -C(O)OR18, or -C(O)Ri7;
R4 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
R5 is hydrogen, -CH3, -CH2CH3, or -CH(CH3)2;
R6 is hydrogen, -CH3, or -CH2CH3; or
R5 and R6 are taken together to form aziridin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-(methyl)piperazin-1 -yl, morpholin-4-yl;
R7 is hydrogen, -CH3, o r-CH2CH3,
R8 is hydrogen;
R9 is hydrogen, -C(O)OCH3, or -C(O)OC(CH3)3;
R11isOH,or-CN;
R12 -NH2, -CH3, or -NR14R15;
R14 is hydrogen, CH3, or phenyl;
R15 is hydrogen, CH3, or phenyl;
R16 is -CH3, -CH2CH3, -CH(CH3)2, or -C6H5;
R18 is -CH3, -CH2CH3, -CH(CH3)2, -C6H5, or -C(CH3)3; and
R17 is imidazolin-1-yl, isoxazolin-5-yl, furan-2-yl, thiophen-2-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl.
48. The compound according to claim 47 wherein R2 is C1-C6 linear or branched alkyl, or C3-C6 cycloalkyl.
49. The compound according to claim 48 wherein R2 is methyl
,1
50. The compound according to claim 48 or 49 wherein R and R are independently selected from phenyl optionally substituted with from 1 to 5 substituents independently selected from halogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched haloalkyl, optionally substituted C3-Cs cycloalkyl, -OR20, -CN, -N(R20)2, -CO2R20, -C(O)N(R20)2, -NR20C(O)R20, -NO2, or -S02R20; each R20 is independently hydrogen, optionally substituted d-C6 linear or branched alkyl,

optionally substituted C1-C6 linear or branched haloalkyi, or optionally substituted C3-C8 cycloalkyl; or two R20 units can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, O.or S.
51. The compound according to any one of Claims 48 to 50 wherein R and R1 are each para-substituted.
52. The compound according to any one of Claims 48 to 51 wherein R and R1 are independently selected from 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-difluoromethoxyphenyl, phenyl, or 4-tert-butylphenyl.
53. The compound according to any one of claims 1 to 22 or 37 to 52 wherein R3 is hydrogen, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NH[CH(CH3)2], -C(O)NHCH2CH3, -C(O)N(CH2CH3), -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)OC(CH3)3, -C(O)NHOH, -C(O)NHOCH3, -C(O)N(CH3)OCH3, -C(O)NHNH2, ~C(O)NHOCH2CH3, <:(O)NCH3OCH3, -C(O)NHNHC(O)OCH3, -C(O)NHNHC(O)OC(CH3)3, -C(NCN)NH2, -C(NCN)NHCH3 -C(NCN)NHC6H5, -C(O)aziridin-1 -yl, -C(O)azetidin-1 -yl, -C(O)pyrrolidin-1 -yl, -C(O)piperidin-l-yl, -C(O)piperazin-l-yl, -C(O)rnorpholin-4-yl, -C(O)imidazolin-l-yl, -C(O)isoxazolin-5-yl, -S02CH3, -S02CH2CH3, -S02CH(CH3)2, or S02C6H5.
54. The compound according to Claim 1 having formula (X):
(X)
wherein R is optionally substituted phenyl, said substitution selected from
i) halogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
iii) -OR20;

iv) -CN;
v) -N(R20)2;
vi) ~C02R20;
vii) -C(O)N(R20)2;
viii) -NR20C(O)R20;
ix) -NO2; or
x) -S2R20;
wherein each R20 is independently hydrogen, optionally substituted C1-C6 linear
or branched alkyl, or optionally substituted C3-C6 cycloalkyl; or two R20 units can
be taken together to form a ring comprising from 3-7 ring atoms;
R1 is optionally substituted phenyl, said substitution selected from
i) halogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
iii) -OR21;
iv) -CN;
v) -N(R21)2;
vi) -CO2R21;
vii) -C(O)N(R2,)2;
viii) -NR2,C(O)R21;
ix) -NO2; or
x) -SOjR21;
wherein each R21 is independently hydrogen, optionally substituted C1-C6 linear
or branched alkyl, or optionally substituted C3-C6 cycloalkyl; or two R21 units can
be taken together to form a ring comprising from 3-7 ring atoms; and
R4 is optionally substituted C1-C6 linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl; or a pharmaceutically acceptable salt form thereof.
55. The compound according to Claim 1 having the formula (XI):
R' ~N ^ / N—R5
\ t
CH3 R6
(XI)
wherein R is optionally substituted phenyl, said substitution selected from

i) halogen;
ii) C1-C6 linear or branched alkyl or C3-C6, cycloalkyi;
iii) -OR20;
iv) -CN;
v) -N(R20)2;
vi) -C02R20;
vii) -C(O)N(R20)2;
viii) -NR20C(O)R20;
ix) -NO?; or
x) -S02R20;
wherein each R20 is independently hydrogen, optionally substituted C1-C6, linear
or branched alkyl, or optionally substituted C3-C6, cycloalkyi; or two R20 units can
be taken together to form a ring comprising from 3-7 ring atoms;
R! is optionally substituted phenyl, said substitution selected from
i) halogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyi;
iii) -OR2';
iv) -CN;
v) ~N(R2!)2;
vi) -C02R21;
vii) ~C(O)N(R21)2;
viii) -NR2!C(O)R21;
ix) -NO2; or
x) -SO2R21;
wherein each R21 is independently hydrogen, optionally substituted C1C6 linear
or branched alkyl, or optionally substituted C3-C6 cycloalkyi; or two R21 units can
be taken together to form a ring comprising from 3-7 ring atoms; and
R5 and R6 are each independently selected from
a) hydrogen;
b) C1 -C6 linear or branched alkyl;
c) C3-C7 cyclic alkyl;
d) -OR7;
wherein R7 is hydrogen or C1-C6 linear or branched alkyl;

e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, C1-C6 linear or
branched alkyl, C1C6, linear or branched alkoxy, -OH, or -CO2R10 wherin
R10 is C1-C6 linear or branched alkyl; or f) R5 and R6 can be taken together to from a ring having from 3 to 7 ring
atoms; or a pharmaceutically acceptable salt form thereof.

wherein R is optionally substituted phenyl, said substitution selected from

Formula Removed

i) halogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl;
iii) -OR20;
iv) -CN;
v) -N(R20)2;
vi) -CO2R20;
vii) -C(O)N(R20)2;
viii) -NR20C(O)R20;
ix) -NO2; or
x) -SO2R20;
each R20 is independently hydrogen, optionally substituted C1-C6 linear,
branched, alkyl or optionally substituted C3-C6 cycloalkyl; or two R20 units can be
taken together to form a ring comprising from 3-7 ring atoms;
R! is optionally substituted phenyl, said substitution selected from
i) halogen;
ii) C1-C6 linear or branched alkyl or C3-C6 cycloalkyl; iii) -OR21; iv) -CN; v) -N(R21)2;
Formula Removed

wherein each R12 is independently hydrogen, optionally substitued C1C6, 1 linear or branched alkyl or optionally substituted C1-C6, cyC1oalkyl; or two R12' units can be taken together to form a ring compnsmg from 3-7 nng atoms; and R5 and R6 are each independently selected from
a) hydrogen;
b) C1-C6 linear or branched alkyl;
c) C3-C7 cyclic alkyl;
d) --OR7;
wherein R'7is hydrogen or C1C6 linear or branched alkyl;
e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, C1C6, linear or
branched alkyl, C1C6 linear or branched alkoxy, OH, or CO2R10
wherein Ri0 is C1-C6 linear or branched alkyl; or
f) R3 and R can be taken together to from a ring having from 3 to 7 ring
atoms, or a pharmaceutically acceptable salt form thereof.
57. The compound according to Claim 1 having the formula (XXII):

Formula Removed
b) -OR13;
wherein R13 is hydrogen, C1-C6 linear or branched alkyl, or phenyl; or
c) -NR14R15; and
R14 and R15 are each independently hydrogen, C1-C6 linear or branched alkyl, or a pharmaceutically acceptable salt form thereof.
58. The compound according to Claim 1 having the formula (XVI):

Formula Removed

wherein R is optionally substituted phenyl, said substitution selected from
i) halogen;

Formula Removed

ix) -NO2; or
x) -SO2R20;
each R2 is independently hydrogen, optionally substituted C1-C6 linear or
branched alkyl or optionally substituted C3-C6 cycloalkyl; or two R20 units can be
taken together to form a ring comprising from 3-7 ring atoms;
R1 is optionally substituted phenyl, said substitution selected from

Formula Removed

viii) -NR21C(O)R2!;
ix) -NO?; or
x) -S02R2';
wherein each R21 is independently hydrogen, optionally substituted C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl; or two R units can be taken together to form a ring comprising from 3-7 ring atoms; and
R18 is C1-C6 linear or branched alkyl; or a pharmaceutically acceptable salt form
thereof.
59. The compound according to Claim 1 wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocycle and heteroaryl groups are optionally substituted with from 1 to 5 substituents independently selected from -OR22; -C(O)R22; C(O)OR22;-C(O)N(R22)2; N(R22)2; -NR22COR22; halogen; C1-C6 linear or branched haloalkyl; -S02R22; -S02N(R22)2; CrC6 linear or branched alkyl optionally substituted with C3-C6 cycloalkyl; C3-C6 cycloalkyl; cyano; or nitro wherein two R22 units can be taken together to form a ring comprising 3-7 ring atoms or each R is independently hydrogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched haloalkyl, or C3-C6 cycloalkyl.
60. The compound according to Claim 1 wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocycle and heteroaryl groups are optionally substituted from 1 to 3 substituents independently selected from C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, halogen, or C1-C6 haloalkyl.
61. A compound according to Claim 1 wherein the optionally substituted heterocyle and optionally substituted heteroaryl groups are independently selected from optionally substituted pyrrohdinyl, optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted imidazolyl, optionally substituted isoxazolinyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted triazinyl, or optionally substituted thiazolyl.
62. A compound according to Claim 1 wherein the optionally susbstituted
heterocycle of R4 is pyrrolidinyl; the optionally substituted ring having from 3 to 7 ring
atoms of R5 and R6 is aziridinyl, azetidinyl, pyrrolidinyl, piperazinyl, 4-
methylpiperazinyl, morpholinyl or piperidinyl; and the optionally substituted heteroaryl
of R17 is imidazolyl, isoxazolinyl, furanyl, thiophenyl, pyrimidinyl, pyridinyl, triazinyl, or
thiazolyl.
63. A compound of claim 1 that is:
2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-rriaza-
spiro[4.5]decan-4-one; 2-(4-tert-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triaza-
spiro[4.5]decan-4-one; 2-(4-Difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-l,3,8-
triaza-spiro[4.5]decan-4-one; 8-Cyclopropylcarbonyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-
methyl-l,3,8-triaza-spiro[4.5]decan-4-one; 8-Cyclopropylcarbonyl-2-(4-difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)-
ethyl]-l-methyl-l,3,8-triazaspiro[4.5]decan-4-one; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d amide; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d methyl amide; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-(piperidine-
l-carbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one; 2-[4-(Diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-
triaza-spirot4.5]decane-8-carboxylic aC1d amide; 2-(4-Trifluoromethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-
l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide; 2-(4-tert-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d amide; 2-(4-Difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-
l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide;

2-(4-Cyclopropylphenyl)-3-[2-(4-trifluoromethoxyphenyl)ethyl]-l-methyl-4-oxo-
l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide; 2-(4-^r/-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d ethyl amide; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)emyl]-l-methyl-4-oxo-1,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d isopropylamide; 2-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-triaza-
spiro[4.5]decane-8-carboxylic aC1d isopropylamide; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d dimethylamide; 2-(4-Cyelopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d diethylamide; 2-(4-Cyelopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-mediyl-4-oxo-l,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d cyclopentylamide; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-8-(azetidin-1 -
ylcarbonyl)-l,3,8-triaza-spiro[4.5]decan-4-one; 2-(4-Cyelopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-[(4-
methylpiperazin-1 -yl)carbonyl]-1,3,8-triaza-spiro[4.5]decan-4-one; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-8-(pyrrolidin-1 -
yl-carbonyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-(morpholin-
4-yl-carbonyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 2-(4-Cyclopropylphenyl)-7V-methoxy-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-
oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide; terf-Butyl 2-( {2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l -methyl-
4-oxo-l,3,8-triazaspiro[4.5]dec-8-yl}carbonyl)hydrazinecarboxylate; 2-(4-Cyclopropylphenyl)-jV-hydroxy-3 -[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-
oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide; 2-(4-Cyclopropylphenyl)-A/-ethoxy-3-[2-(4-methoxyphenyl)ethyl]-Ar,l-dimethyl-
4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide; 2-(4-Cyclopropylphenyl)-Ar-methoxy-3 -[2-(4-methoxyphenyl)ethyl]-A^, 1 -
dimethyl-4-oxo-l,3,8-triazaspiro[4.5]decane-8-carboxamide;

Phenyl N-cyano-3-(4-methoxyphenethyl)-2-(4-methoxyphenyl)-1 -methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carbimidate; (E)~N'-cyano-2~(4-cyclopropylphenyl)-3-(4-methoxyphenethyl)-l-methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboximidamide; 2-(4-Cyclopropylphenyl)-8-methanesulfonyl-3-[2-(4-methoxy-phenyl)ethyl]-l-
methyl-1,3,8-triaza-spiro[4.5]decan-4-one; 2-(4-ferf-Butylphenyl)-8-methanesulfonyl-3 -[2-(4-methoxyphenyl)ethyl]-1 -
methyl-l,3,8-triaza-spiro[4.5]decan-4-one; 2-(4-Trifluoromethylphenyl)-8-methanesulfonyl-3-[2-(4-methoxyphenyl)ethyl]-l-
methyl-1,3,8-triaza-spiro [4.5] decan-4-one; Ethyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-
l,3>8-triazaspiro[4.5]decane-8-carboxylate; Isoprppyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-
oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate; tert-Butyl 2-(4-methoxyphenyl)-3-t2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboxylate; tert-Butyl 2-(4- tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboxylate; tert-Butyl 2-(4-diethylaminophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-
oxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate; tert-Butyl 2-{4-difluoromethoxyphenyl)-3-f 2-(4-methoxyphenyl)ethyl]-1 -methyl-
4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate; Methyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-
1,3,8-triazaspiro[4.5]decane-8-carboxylate; 2-(4-CyC1opropylphenyl)-8-(isoxazol-5-yl-carbonyl)-3-[2-(4-
methoxyphenyl)ethyl]-1 -methyl-1,3,8-triazaspiro[4.5]decan-4-one; 2-(4-Cyclopropylphenyl)-l -methyl-3-(3-phenylpropyl)-1,3,8-triazaspiro[4.5]-
decan-4-one; 8-Acetyl-2-(4-cyclopropylphenyl)-3-(3 -phenylpropyl)-1 -methyl-1,3,8-toiazaspiro-
[4.5]decan-4-one; 8-Cyclopropanecarbonyl-2-(4-cyclopropylphenyl)-3 -(3 -phenylpropyl)-1 -methyl-
l,3,8-triazaspiro-[4.5]decan-4-one;
8-CyclopropaHecarbonyl-2-(4-methoxyphenyl)-3-(3-phenylpropyl)-l-methyl-
l,3,8-triazaspiro-[4.5]decan-4-one; 2-(4-Cyclopropylphenyl)-1 -methyl-4-oxo-3 -(3 -phenylpropyl)-1,3,8-triazaspiro-
[4.5]decane-8-carboxylic aC1d ter/-butyl ester; 2-(4-/e«-Butylphenyl)-1 -methyl-4~oxo-3 -(3-phenylpropyl)-1,3,8-triazaspiro-
[4.5]deeane-8-carboxylic aC1d tert-butyl ester; 2-(4-Cyclopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-
[4.5]decane-8-carboxylic aC1d amide; 2-(4-tert-Butylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-
[4.5]decane-8-earboxylic aC1d amide; 2-(4-Cyclopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,358-triazaspiro-
[4.5]decane-8-carboxylic aC1d methylamide; 2-(4-Cyclopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-
[4.5]decane-8-carboxylic aC1d isopropyl amide; 2-(4-Cyelopropylphenyl)-l-methyl-4-oxo-3-(3-phenylpropyl)-l,3,8-triazaspiro-
[4.5]decane-8-carboxylic aC1d dimethylamide;
2-(4-Cyclorophlpheny1)-8-methanesulfonyl-l-methyl-3-(3-phenylpropyl)-l,3,8-
triazaspiro-[4.5]decan-4-one; 2-{2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triaza-spiro[4.5]dec-8-yl} acetamide; 8-cyclopropylmethyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxy-phenyl)ethyl]-l-
methyl-1,3,8-triaza-spiro[4.5]decan-4-one; 2- {2-(4-Difluoromethoxyphenyl)-3 -[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-
1,3,8-triaza-spiro[4.5]dec-8-yl} acetamide; 2-(4-tert-Batylbenzyl)-3-[2-(4-methyoxyphenyl)ethyl]-1-methyl-4-oxo-1,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester; 2-(4-terf-Butylbenzyl)-3-[2-(4-methoxyphenyl)ethylJ-1 -methyl-1,3,8-
triazaspiro[4.5]decan-4-one; 2-(4-tert-Butyibenzyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-
triazaspiro[4.5]decane-8-carboxylic aC1d amide; (2- {2-(4cyclopropylphenyl)-3-[2-(4-memoxyphenyl)ethyl]-1 -methyl-4-oxo-
1,3,8-triaza-spiro[4.5]dec-8-yl} -1,1 -dimethyl-2-oxo-ethyl)-carbamic aC1d
tert-butyl ester;
8-(2-Aniino-2-methylpropionyl)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxy-
phenyl)ethyl]-l -methyl-1,3,8-triaza-spiro[4.5]decan-4-one; 8-Acetyl-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-1,3,8-
triaza-spiro[4.5]decan-4-one; N'-cyano-2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboximidamide; l-methyl-2-(4-trifluoromethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-4-oxo-
l,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; or a pharmaceutically acceptable salt form thereof.
64. A compound of claim 1 that is:
(E)-N'-cyano-2-(4-cyclopropylphenyl)-3 -(4-methoxyphenethyl)-1 -methyl-4-oxo-
l,3r8-triazaspiro[4.5]decane-8-carboximidamide; 2-(4-meAoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triazaspiro[4.5]decane-8-carboxamide; tert-butyl 2-(4-cyclopropylphenyl)- l-methyl-4-oxo-3-{2-[4-
(trifluoromethoxy)phenyl]ethyl}-l,3,8-triazaspiro[4.5]decane-8-
carboxylate; 2-(4-cyclopropylphenyl)-l-methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyl}-
l,3,8-triazaspiro[4.5]decan-4-one; tert-butyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-
oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate; 2-(4-cy€iopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triazaspiro[4.5]decane-8-carbohydrazide; 2-[4-(difluoroniethoxy)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-
pentanoyl-1,3,8-triazaspiro[4.5]decan-4-one; 8-(cyclopentylcarbonyl)-2-[4-(difluoromethoxy)phenyl]-3-[2-(4-
methoxyphenyl)ethyl]-1 -methyl-1,3,8-triazaspiro[4.5]decan-4-one; 8-(cyelopropylcarbonyl)-2-(4-isobutylphenyl)-3-[2-(4-methoxyphenyi)ethyl]-l-
methyl-l,3,8-triazaspiro[4.5]decan-4-one; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-4-oxo-l,3,8-
triazaspiro[4.5]decane-8-carboximidamide;
tert-butyl 2-(4-isobutylphenyl)-3-[2-(4-methoxyphenyl)ethylj-1 -methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboxylate; 2-(4-cyclopropylphenyl)-N, 1 -dimethyl-4-oxo-3-(3-phenylpropyl)-l ,3,8-
triazaspiro[4.5]decane-8-carboxamide; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-N',l-dimethyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboximidamide; 2- {2-{4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-
triazaspiro[4.5]dec-8 -y 1} -N, N -dimethylacetamide; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-methyl-8-D-prolyl-
l,3,8-triazaspiro[4.5]decan-4-one; 2-(4-cyclopropylphenyl)-8-( 1 H-imidazol-1 -ylcarbonyl)-3-[2-(4-
methoxyphenyl)ethyl]-1 -methyl-1,3,8-triazaspiro[4.5]decan-4-one; or 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-8-(methylsulfonyl)-l-
(trifluoroacetyl)-1,3,8-triazaspiro [4.5 ] decan-4-one; 2-(4-memoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3,8-triaza-
spiro[4,5]decan-4-one; phenyl N-cyano-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l-
methyl-4-oxo-l,3,8-triazaspiro[4.5]-decane-8-carboximidoate; tert-butyl 2-(4-tert-butylbenzyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-
l,3,8-triazaspiro[4.5]decane-8-carboxylate; (S)-2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-1,3,8-
triaza-spiro[4.5]decane-8-carboxylic aC1d amide; (R)-2-(4-cyclopropylphenyl)-3 -[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxo-
l,3,8-triaza-spiro[4.5]decane-8-carboxylic aC1d amide; 2-(4-cyclopropylphenyl)-N-ethoxy-3-(4-methoxyphenethyl)-1 -methyl-4-oxo-
1,3,8-triazaspiro[4.5]decane-8-carboxamide; or a pharraaceutically acceptable salt form thereof.
65. A pharmaceutical composition comprising one or more compounds according to any one of Claims 1 to 64 and one or more exC1pients.
66. A method for treating or preventing atrial antiarrhythmia comprising administering an effective amount of a compound according to formula (I):

Formula Removed

wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R2 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl or -C(O)R23, wherein R23 is optionally substituted
C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) optionally substituted C1-C6 linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from:
a) hydrogen;
b) optionally substituted C1=C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
wherein R7 is hydrogen or optionally substituted C1-C6, linear or branched alkyl;
e) -NR8R9;
wherein R8 and R9 are each independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched alkoxy, -OH, or -CO2R10, wherein R10 is optionally substituted C1-C6 linear or branched alkyl; or R8 and R9 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms
and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; or
f) R5and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S;
-C(NR11)R12;
wherein R11 is
a) hydrogen;
b) optionally substituted C1C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R12 is

a) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
wherein R13 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR14R15;
wherein R!4 and R15 are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl; -SO2R16;
I fit
wherein R is optionally substituted aryl, optionally substituted C1-C6
linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
-C(O)R17;
wherein R17 is optionally substituted aryl or optionally substituted
heteroaryl; or
-C(O)OR18;
wherein R18 is optionally substituted C1-C6 linear or branched alkyl,
optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl;
L, L1, and L2 are linking units each independently a unit having the formula:
-[C(R19,)2]„-whrein each R19 is, at each occurrence, independently chosen from hydrogen,
methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof; to a subject.
67. A method for preventing or treating thromboembolism, stroke, or cardiac failure comprising administering an effective amount of a compound according to formula (I):

Formula Removed

wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R2 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl or ~C(O)R , wherein R is optionally substituted
C1-C6 linear or branched alkyl or optionally substituted C3-C6, cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) optionally substituted C1-C6 linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from:
a) hydrogen;
b) optionally substituted C1 -C6 linear or branched alkyl;
c) optionally substituted C3C7 cycloalkyl;
d) OR7;
wherein R7 is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
O Q
wherein R and R9 are each independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched alkoxy, OH, or -CO2R10, wherein R10 is optionally substituted C1-C6 linear or branched alkyl; or R8 and R9 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, O.or S; or f) R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; v) -C(NR11)R12; wherein R1' is
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R12is

a) optionally substituted C1 -C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
wherein R13 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR14R15;
wherein R1 and R1' are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C.rCg cycloalkyl: vi) -S02R16;
wherein R16 is optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl; vii) -C(O)R17;
wherein R17 is optionally substituted aryl or optionally substituted heteroaryl; or viii) -C(O)OR18;
wherein R18 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C= cycloalkyl, or optionally substituted aryl; L, L , and L are linking units each independently a unit having the formula:
-[C(R19)2]n-whrein each R1 is, at each occurrence, independently chosen from hydrogen,
methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof; to a subject.
68. Use of a compound according to formula (1) in the manufacture of a medicament:

(I)
wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R2 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl or -C(O)R23, wherein R23 is optionally substituted
C1-C6 linear or branched alkyl or optionally substituted C3-C6 cycloalkyl;
RJ is selected from:
i) hydrogen;
ii) optionally substituted C1 -C6, linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R is optionally substituted C1-C6, linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from:
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
wherein R7 is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
9
wherein R and R are each independently hydrogen, optionally substituted C1C6 linear or branched alkyl, optionally substituted C1-C= linear or branched alkoxy, -OH, or -CO2R10, wherein Ri0 is optionally substituted C1-C6 linear or branched alkyl; or R8 and R can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; or
f) R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; v) -C(NRn)R12;
wherein R11 is
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and Ruis

a) optionally substituted C=-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
wherein R13 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR14R15;
wherein R14 and R15 are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl; vi) -SO2Ri6;
wherein R16 is optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl; vii) -C(O)R17;
wherein R17 is optionally substituted aryl or optionally substituted heteroaryl; or viii) -C(O)OR18;
wherein R18 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; L, L , and L are linking units each independently a unit having the formula:
[C(R19)2]n whrem each R19 is, at each occurrence, independently chosen from hydrogen,
methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof.
69. Use of a compound according to formula (I) in the manufacture of a medicament for treating or preventing atrial antiarrhythmia:

Formula Removed

wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R2 is hydrogen, optionally substituted CrC6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl or -C(O)R23, wherein R23 is optionally substituted
C1-C6 linear or branched alkyl or optionally substituted C3-C=cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) optionally substituted C1-C6 linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from:
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
wherein R is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
Q Q
wherem R and R are each independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched alkoxy, -OH, or - CO2R10, wherein R10 is optionally substituted C1-C6 linear or branched alkyl; or R8 and R9

can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; or
f) R5 and R6 can be taken together with die atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S;
-C(NR")R12;
wherein R11 is
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R,2is

a) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
wherein R13 is hydrogen, optionally substituted C1\-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NRI4R15;
wherein R14 and Ri5 are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl;
-SO2R16;
wherein R is optionally substituted aryl, optionally substituted C1-C6
linear or branched alkyl, or optionally substituted CT,-C6 cycloalkyl;
-C(O)R17;
wherein R is optionally substituted aryl or optionally substituted
heteroaryl; or
-C(O)OR18;
wherein R is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; L, L , and L are linking units each independently a unit having the formula:
4C(R,Q)2]n
whrein each R is, at each occurrence, independently chosen from hydrogen,
methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof.
70. Use of a compound according to formula (I) in the manufacture of a medicament for preventing or treating thromboembolism, stroke, or cardiac failure:

Formula Removed

wherein R is optionally substituted phenyl;
R1 is optionally substituted phenyl;
R is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally
substituted C3-C6 cycloalkyl or -C(O)R23, wherein R23 is optionally substituted
C1-C6linear or branched alkyl or optionally substituted C3C6 cycloalkyl;
R3 is selected from:
i) hydrogen;
ii) optionally substituted C1-C6 linear or branched alkyl, or optionally
substituted C3-C6 cycloalkyl;
iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from: a) hydrogen;
b) optionally substituted C1]-C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl:
d) -OR7;
wherein R7 is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R8 and Ry are each independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched alkoxy, -OH, or -CO2R10, wherein R!0 is optionally substituted C1-C6 linear or branched alkyl; or R and R9 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; or f) R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, O,or S;
v) -C(NR11)R!2
wherein R1' is
a) hydrogen;
b) optionally substituted C1 -C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
c) -OH; or
d) -CN; and R12is

a) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
b) -OR13;
wherein R13 is hydrogen, optionally substituted C1C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR14R15;
wherein R14 and Rb are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl;
vi) -S02R16;
wherein R16 is optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl;
vii) -C(O)R17;
.17 •
wherein R is optionally substituted aryl or optionally substituted
heteroaryl; or viii) -C(O)OR18;
wherein R18 is optionally substituted C1-C6 linear or branched alkyl,
optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; L, L1, and L2 are linking units each independently a unit having the formula:
4C(R'9)2]n
whrein each R is, at each occurrence, independently chosen from hydrogen,
methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof.
71. A compound having formula (I):ii) optionally substituted C|-C6 linear or branched alkyl, or optionally-substituted C3-C6 cycloalkyl; iii) -C(O)R4;
wherein R4 is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; iv) -C(O)NR5R6;
wherein R5 and R6 are each independently selected from:
a) hydrogen;
b) optionally substituted C1-C6 linear or branched alkyl;
c) optionally substituted C3-C7 cycloalkyl;
d) -OR7;
-7
wherein R is hydrogen or optionally substituted C1-C6 linear or branched alkyl;
e) -NR8R9;
wherein R and R9 are each independently hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C1-C6 linear or branched alkoxy, -OH, or -CO2R10, wherein R10 is optionally substituted C1C6 linear or branched alkyl; or R8 and R9 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; or f) R5 and R6 can be taken together with the atom to which they are bound to form an optionally substituted ring having from 3 to 7 ring atoms and optionally containing one or more additional heteroatom ring atoms independently selected from N, 0,or S; v) --C(NR")R12; wherein R!' is
a) hydrogen;
b) optionally substituted C1 -C6 linear or branched alkyl, or optionally substituted C3-C= cycloalkyl;
c) -OH; or
d) -CN; and Ri2is
a) optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C1-C6 cycloalkyl;
b) -OR13;
wherein R!3 is hydrogen, optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; or
c) -NR,4R15;
wherein R14 and R15 are each independently hydrogen, optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C8 cycloalkyl; vi) -SO2R16;
wherein R!6 is optionally substituted aryl, optionally substituted C1-C6 linear or branched alkyl, or optionally substituted C3-C6 cycloalkyl; vii) -C(O)R!7;
wherein R17 is optionally substituted aryl or optionally substituted heteroaryl; or viii) -C(O)OR18;
wherein R1S is optionally substituted C1-C6 linear or branched alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted aryl; L, L1, and L2 are linking units each independently a unit having the formula:
-[C(R!9)2]n-whrein each R19 is, at each occurrence, independently chosen from hydrogen,
methyl, or ethyl; n is 1 to 4; and
x, y, and z are each independently 0 or 1; or a pharmaceutically acceptable salt form thereof.
72. The compound of claim 71 wherein R3 is hydrogen, -C(O)CH3, -
C(O)cyclopropyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NH[CH(CH3)2],
-C(O)NHCH2CH3, -C(O)N(CH2CH3), -C(O)OCH3, -C(O)OCH2CH3, -
C(O)OCH(CH3)2, -C(O)OC(CH3)3, -C(O)NHOH, -C(O)NHOCH3, -
C(O)N(CH3)OCH3, -C(O)NHNH2, C(O)NHOCH2CH3, C(O)NCH3OCH3,
C(O)NHNHC(O)OCH3, €(O)NHNHC(O)OC(CH3)3, -
C(NCN)NH2, -C(NCN)NHCH3, -C(NCN)NHC6H5, -C(O)azindin-1 -yl, -
C(O)azetidin-1 -yl, -C(O)pyrrolidin-1 -yl, -C(O)piperidin-1 -yl,
C(O)piperazin-l-yl, -C(O)morpholin-4-yl, -C(O)imidazolin-l-yl, -C(O)isoxazolin-5-yl, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, or SO2C6H5.
73. The compound of claim 71 that is
2-(4-Diethylaminophenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-
spiro[4.5]decane-8-carboxylic aC1d tert-buty\ ester; 2-(4-tert-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-
spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester; 2-(4-Difluoromethoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-triaza-
spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester; tert-butyl 2-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-1,3,8-
triazaspiro[4.5]decane-8-carboxylate; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-1,3,8-
triazaspiro[4.5]decane-8-carboxamide; methyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-l,3,8-
triazaspiro[4.5]decane-8-carboxylate; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-l,3,8-triazaspiro[4.5]decan-
4-one; 2-(4-tert-butylphenyl)-8-(ethylsulfonyl)-3-[2-(4-methoxyphenyl)ethyl]-l,3,8-
triazaspiro[4.5]decan-4-one; tert-butyl 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-1,3,8-
triazaspiro[4.5]decane-8-carboxylate; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-8-(methylsulfoQyl)-l,3,8-
triazaspiro[4.5]decan-4-one; tert-butyl 2-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-1,3,8-
triazaspiro[4.5]decane-8-carboxylate; 2-(4-tert-butylphenyl)-8-(cyclopropylcarbonyl)-3-[2-(4-methoxyphenyl)ethyl]-
1,3,8-triazaspiro[4.5]decan-4-one; or
2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,3,8-
triazaspiro[4.5]decan-4-one; tert-butyl2-(4-tert-butylphenyl)-4-oxo-3-(3-phenylpropyl)-l,3,8-
triazaspiro[4.5]decane-8-carboxylate; 2-(4-tert-Butylbenzyl)-3-[2-(4-methyoxyphenyl)ethyl]-4-oxo-1,3,8-triaza-
spiro[4.5]decane-8-carboxylic aC1d tert-butyl ester; 2-(4-terr-Butylphenyl)-8-methanesulfonyl-3-[2-(4-methoxyphenyl)ethyl]-l,3,8-triaza-spiro[4.5]decan-4-one;
or a pharmaceutically acceptable salt form thereof.
74. Kvl .5 potassium channel inhibitors, process for preparation thereof, a
composition containing the same and application thereof substantially such as herein
described