NZ713143B2 - Opioid receptor ligands and methods of using and making same - Google Patents
Opioid receptor ligands and methods of using and making same Download PDFInfo
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- NZ713143B2 NZ713143B2 NZ713143A NZ71314312A NZ713143B2 NZ 713143 B2 NZ713143 B2 NZ 713143B2 NZ 713143 A NZ713143 A NZ 713143A NZ 71314312 A NZ71314312 A NZ 71314312A NZ 713143 B2 NZ713143 B2 NZ 713143B2
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Abstract
Disclosed herein are compounds of formula I, wherein the variables are defined in the specification. These compounds can act as opioid receptor ligands, which compounds can be used in the treatment of, for example, pain and pain related disorders. In one embodiment the compound is [(4-chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine. ethyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine.
Description
Opioid Receptor Ligands and Methods of Using and Making Same
FIELD
This application relates to a family of compounds acting as opioid receptor ligands. Such
compounds may provide therapeutic benefit in the treatment of pain.
BACKGROUND
Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids,
including most clinical analgesics. Three molecularly and pharmacologically distinct
opioid receptor types have been described: δ, κ and μ. Furthermore, each type is believed
to have sub-types. All three of these opioid receptor types appear to share the same
functional mechanisms at a cellular level. For example, activation of the opioid receptors
causes inhibition of adenylate cyclase, and recruits β-arrestin.
When therapeutic doses of morphine are given to patients with pain, the patients report
that the pain is less intense, less discomforting, or entirely gone. In addition to
experiencing relief of distress, some patients experience euphoria. However, when
morphine in a selected pain-relieving dose is given to a pain-free individual, the
experience is not always pleasant; nausea is common, and vomiting may also occur.
Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical
activity, reduced visual acuity, and lethargy may ensue.
There is a continuing need for new OR modulators to be used as analgesics. There is a
further need for OR agonists as analgesics having reduced side effects. There is a further
need for OR agonists as analgesics having reduced side effects for the treatment of pain,
immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric
conditions, urological and reproductive conditions, medicaments for drug and alcohol
abuse, agents for treating gastritis and diarrhea, cardiovascular agents and/or agents for
the treatment of respiratory diseases and cough.
SUMMARY
This application describes opioid receptor (OR) ligands. It also describes methods of
modulating opioid receptor activity using the compositions described herein. Certain
compositions described herein act as opioid receptor agonists. Other compositions
described herein act as opioid receptor antagonists.
This application describes compounds having the structure of Formula I:
In the structure above, variables A , A , A , A , A , B , B , B , B , B , and D can be
1 2 3 4 5 1 2 3 4 5 1
selected from the respective groups of chemical moieties later described. OR ligand
derivatives and mimetics are also provided. Also provided are processes for preparing
these compounds.
This application also describes pharmaceutical compositions comprising one or more
compounds as described in this application a pharmaceutically acceptable carrier.
Naturally, the compounds described herein can be employed in any form, such as a solid
or solution (e.g., aqueous solution) as is described further below. The compounds
described herein, for example, can be obtained and employed in a lyophilized form alone
or with suitable additives.
Also provided are methods for treating pain and pain-related disorders. Such a method
would comprise administering a therapeutically effective amount of one or more
compounds described herein to a subjector subject in need thereof.
[01012A] SPECIFIC ASPECTS OF THE PRESENT DISCLOSURE
[0012B] Specific aspects of the present disclsoure are described below:
- a compound having the formula
or a pharmaceutically acceptable salt thereof.
- a compound, having the formula
or a pharmaceutically acceptable salt thereof.
- pharmaceutical compositions comprising the above compounds and a pharmaceutically
acceptable carrier.
-Pharmaceutical compositions of the above further comprising at least one additional analgesic
or non-opioid analgesic.
-Pharmaceutical composition of the above further comprising at least one anti-constipation agent.
-The pharmaceutical compositions may comprise an enantiomeric excess of at least 90%, at least
95%, at least 98% or at least 99% of
-A compound having a formula of
or a pharmaceutically acceptable salt thereof,
wherein:
R and R are independently H or CH ;
21 22 3
D is an optionally substituted aryl;
B is H or optionally substituted alkyl; and
B is an optionally substituted thiophenyl.
or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable
salt thereof, and pharmaceutically acceptable carrier.
-Use of the compounds, or a pharmaceutically acceptable salt thereof, and composiitons
described above, for the manufacture of a medicament for treating pain.
-Use of a compound having a formula of
or a pharmaceutically acceptable salt thereof,
in the preparation of a medicament suitable for parenteral administration for the treatment of
pain.
DETAILED DESCRIPTION
This application describes a family of compounds, OR ligands, with a unique profile.
The compounds described herein act as agonists or antagonists of opioid receptor (OR)-
mediated signal transduction. The ligands of these receptors can be used to treat
pathologies associated with ORs including pain and pain related disorders.
Compounds also comprise Formula I:
wherein: A is null, CH , CHR , CR R , CH, CR , O, S, SO, SO , NH or NR ; A is null,
1 2 1 1 2 1 2 1 2
CH , CHR , CR R , CH, CR , O, S, SO, SO , NH or NR ; A is null, CH , CHR , CR R ,
2 5 5 6 5 2 5 3 2 7 7 8
O, S, SO, SO , NH, NR , CH or CR ; A is null, CH , cycle of the formula C(CH ) ,
2 7 7 4 2 2 n
where n = 2-5, CHR , CR R , O, S, SO, SO , NH, NR , CH or CR ; and A is null, CH ,
9 9 10 2 9 9 5 2
CHR , CR R , CH CH , CHR CH , CH CHR , CHR CHR , O, S, SO, SO , NH,
11 11 12 2 2 11 2 2 11 11 12 2
NR , CH or CR .
11 11
No more than 2 out of 5 A (specifically A , A , A , A , A ) can be null at the same time.
a 1 2 3 4 5
The number of heteroatoms from A to A cannot exceed 2 at the same time, and O-O, S-
O; S-S; S-N fragments in the ring structure are excluded from this composition.
The ring containing A , A , A , A , A and the carbon connected to D can be fused with
1 2 3 4 5 1
another ring, such as benzene, pyridine, pyrimidine, furan, thiophene or pyridazine, but
not limited to these ezamples, where the resulting bicycle is chemically stable and
synthetically accessible. It is also understood that the above-mentioned fused rings could
be multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl,
hydroxyl, alkyloxy, formyl, acetyl, amino, alkylamino, dialkylamino, mercaptanyl,
alkylmercaptanyl, and other small substitution groups. The bonds between A and A , A
1 2 2
and A , A and A , A and A can independently be a single bond or a double bond. The
3 3 4 4 5
bonds between A and A , A and A , A and A , A and A cannot be a double bond at
1 2 2 3 3 4 4 5
the same time.
A and A can be connected by a carbon bridge. Examples of such a bridge include –
CH -, and -CH CH -.
2 2 2
B is CH , CHR , CR R , O, S, SO, SO , NH, NR , CR or CO. B is CH , CHR ,
1 2 13 13 14 2 13 13 2 2 15
CR R , CR or CO. B is H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl,
16 15 3
alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or alkylsulfonyl.
B is null, C -C alkyl, CH , CH CH , CHR , CR R or CO. In some embodiments,
4 1 6 2 2 2 19 19 20
when B is an alkyl one or more of the hydrogens can be replaced with a deuterium. B is
alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle or
arylalkyl.
Aryl, carbocycle (non-aromatic)/heterocycle (non-aromatic with 1-3 heteroatoms,
including O, N, S) are either unsubstituted, or substituted with small substitution groups.
Small substitution groups can be cyano, halogen, alkyl, branched alkyl, halogenated
alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,
alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl,
arylalkyl, carbocycle or carbocycle-alkyl. In some embodiments, the small substitution
groups are selected from F, Cl, Br, CH , CH CH , CH F, CHF , CF , n-Pr, n-Bu, i-Bu,
3 2 3 2 2 3
sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF , NH , NHMe, NMe ,
3 2 2
methoxycarbonyl, methanesuflonyl, Ph, benzyl, MeSO , formyl, and acetyl.
Carbocycle may contain double bonds, but they should not be aromatic.
D is an aryl group or a carbocycle.
An aryl group is either a monocyclic aromatic group or a bicyclic aromatic group, which
may contain heteroatoms in the aromatic group (e.g. heteroaryl). The following
structures are some examples of representive aryl groups, but the aryl groups are not
limited to those examples:
Carbocycle is either a monocyclic or a bicyclic non-aromatic ring system. The following
structures are some examples of representative carbocycle, but the carbocycle is not
limited to those examples:
wherein X , and X in the carbocycle examples are independently O, S, N, NH or NR .
1 2 18
The aryl groups can be independently mono or multiply substituted with cyano, halogen,
alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino,
dialkylamino, mercaptanyl, alkylmercaptanyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, and/or other small
substitution groups. In some embodiments, the small substitution groups are selected
from F, Cl, Br, CH , CH CH , CH F, CHF , CF , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu,
3 2 3 2 2 3
CN, OH, OMe, OEt, O-iPr, OCF , NH , NHMe, NMe , methoxycarbonyl,
3 2 2
methanesulfonyl, Ph, benzyl, formyl, and acetyl.
D is an aryl, or a carbocycle.
R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , and R are
1 2 5 6 7 8 9 10 11 12 13 14 15 16 18 19 20
independently: cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated
alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl,
alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated
alkylcarbonyl, arylcarbonyl or alkoxycarbonyl. In some embodiments, R , R , R , R , R ,
1 2 5 6 7
R , R , R , R , R , R , R , R , R , R , R , and R are independently F, Cl, Br,
8 9 10 11 12 13 14 15 16 18 19 20
CH , CH CH , CH F, CHF , CF , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe,
3 2 3 2 2 3
OEt, O-i-Pr, methoxycarbonyl, phenyl, benzyl, formyl or acetyl, whenever the resulting
structure is stable.
R and R , R and R , R and R , R and R , R and R , R and R , R and R , R
1 2 5 6 7 8 9 10 11 12 13 14 15 16 19
and R , or R and R can form a monocycle.
15 19
Me is methyl; Et is ethyl; i-Pr is i-propyl; t-Bu is t-butyl; Ph is phenyl.
In some embodiments, the following compounds can be excluded from the genus of
compounds:
1) 2-[({2-[2-Ethylmethyl(4-methylphenyl)oxanyl]ethyl}amino)methyl]phenol
2) 2-[({2-[2-Ethyl(4-fluorophenyl)methyloxanyl]ethyl}amino)methyl]phenol
3) {2-[2,2-Dimethyl(4-methylphenyl)oxan-4yl]ethyl}[(4-methoxyphenyl)methyl]amine
4) {2-[(4S*, 4R*)-2,2-dimethyl(4-methylphenyl)oxanyl]ethyl}[(1R)
phenylethyl]amine
) {2-[(4S*, 4R*)-2,2-dimethyl(4-methylphenyl)oxanyl]ethyl}[(1S)
phenylethyl]amine
6) Benzyl({2-[2,2-dimethyl(4-methylphenyl)oxanyl]ethyl})amine
7) 2-[({2-[2-Ethyl(4-fluorophenyl)methyloxanyl]ethyl}amino)methyl]phenol
8) Benzyl[2-(2,2-dimethylphenyloxanyl)ethyl]amine
9) {2-[2-Ethyl(4-fluorophenyl)methyloxanyl]ethyl}[(4-
methoxyphenyl)methyl]amine
) [(3,4-Dimethoxyphenyl)methyl]({2-[4-(4-fluorophenyl)-2,2-dimethyloxan
yl]ethyl})amine
11) {2-[4-(4-Methoxyphenyl)-2,2-dimethyloxanyl]ethyl}(1-phenylethyl)amine
12) [(4-Chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxanyl]ethyl})amine
13) Benzyl({2-[2-ethyl(2-methoxyphenyl)methyloxanyl]ethyl})amine
14) [(3,4-dimethoxyphenyl)methyl]({2-[2-ethyl(2-methoxyphenyl)methyloxan
yl]ethyl})amine
) 4-[({2-[4-(2-Methoxyphenyl)-2,2-dimethyloxanyl]ethyl}amino)methyl]-N,N-
dimethylaniline
16) Benzyl({2-[4-(4-fluorophenyl)-2,2-dimethyloxanyl]ethyl})amine
17) {2-[2,2-dimethyl(4-methylphenyl)oxanyl]ethyl}(1-phenylethyl)amine
18) [2-(2,2-Dimethylphenyloxanyl)ethyl][(4-methoxyphenyl)methyl]amine
19) {2-[4-(4-Fluorophenyl)-2,2-dimethyloxanyl]ethyl}[(4-methoxyphenyl)methyl]amine
) [(3,4-Dimethoxyphenyl)methyl][2-(2,2-dimethylphenyloxanyl)ethyl]amine
This application also describes compounds having the structure of Formula II-1 and II-2:
II-1
II-2
wherein A is CH , CHR , CR R ; A is CH , CHR , CR R or a cycle of the formula C(CH ) ,
2 2 5 5 6 4 2 9 9 10 2 n
where n = 2-5.
Further R R , R , and R are independently CH , CH CH , CH F, CHF , CF , n-Pr, n-
6 9 10 3 2 3 2 2 3
Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. Further, R and R , or R and R can form a
6 9 10
monocyclic carbocycle.
A and A can be connected by a carbon bridge. This bridge can be –CH - or -CH CH -.
2 4 2 2 2
Further B is selected from the following: H, alkyl, branched alkyl, aryl, arylalkyl,
alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl.
In some embodiments, B is C -C alkyl. In some embodiments, B is H.
3 1 5 3
Further B is null, C -C alkyl, CH , CH CH CHR , CR R or CO. Further, R and
4 1 6 2 2 2, 19 19 20 19
R can form a monocycle of the formula (CH ) , where n = 2-4. B is alkyl, branched
2 n 5
alkyl, carbocycle, carbocycle-substituted alkyl, aryl or arylalkyl.
Further D is an aryl. Examples of the aryl groups are shown above.
Each aryl group can be independently mono or multiply substituted with F, Cl, Br, CH ,
CH CH , CH F, CHF , CF , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-
2 3 2 2 3
iPr, OCF , NH , NHMe, NMe , methoxycarbonyl, Ph, benzyl, formyl, or acetyl. That is,
3 2 2
each aryl group may be multiply substituted with the same substituent (i.e., 2 chloro
groups) or just be multiply substituted, albeit with different groups (e.g. an aryl group
with 1 chloro and 1 methyl group would be considered multiply substituted).
This application also describes compounds having the structure of Formula III:
wherein A is CH , CHR or CR R ; A is CH , CHR , CR R or a cycle of the formula
2 2 5 5 6 4 2 9 9 10
C(CH ) , where n = 2-5.
Further R , R , R , and R are independently CH , CH CH , CH F, CHF , CF , n-Pr, n-
6 9 10 3 2 3 2 2 3
Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. R and R , or R and R can form a monocyclic
6 9 10
carbocycle.
A and A can be connected by a carbon bridge. The bridge can be –CH - or -CH CH -.
2 4 2 2 2
Further B is selected from H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl,
branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or alkylsulfonyl.
Further B is null, C -C alkyl, CH , CH CH , CHR , CR R or CO. Further, R and
4 1 6 2 2 2 19 19 20 19
R can form a monocycle of the formula (CH ) , where n = 2-4. B is alkyl, branched
2 n 5
alkyl, carbocycle, carbocycle-substituted alkyl, aryl or arylalkyl.
Further D is an aryl. Examples of the aryl groups are shown above.
The aryl groups can be mono or multiply substituted with F, Cl, Br, CH , CH CH , CH F,
3 2 3 2
CHF , CF , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF , NH ,
2 3 3 2
NHMe, NMe , methoxycarbonyl, Ph, benzyl, formyl, or acetyl.
This application also describes compounds having the structure of Formula IV-1, IV-2,
or IV-3, V, or VI:
IV-1
IV-2
IV-3
wherein R and R are, independently, H or CH ; A is CH , CR R or a cycle of the
21 22 3 4 2 9 10
formula C(CH ) , where n = 2-5.
Further R and R are independently CH or CH CH .
9 10 3 2 3
Further B is H, C -C alkyl or branched alkyl.
3 1 6
Further B is null, C -C alkyl, CH , CH CH ,or -CHCH .
4 1 6 2 2 2 3
B is -(CH ) CH , where n = 2-3, -C(CH ) , cyclohexyl, cyclopentyl, aryl or arylalkyl.
2 n 3 3 3
The aryl group can be selected from the list below:
Each aryl groups can be mono or multiply substituted with F, I, Cl, Br, CH , CN, OH,
OMe, OEt, OCF , CF , or methanesulfonyl.
Further, in some embodiments, D is a phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl which
can be independently mono or multiply substituted with F, Cl, Br, OCF , CF , or CH .
3 3 3
This application also describes compounds having the structure of Formula V-1, V-2, V-
3, VI-1, VI-2, or VI-3:
V-1,
V-2,
V-3,
VI-1,
VI-2, or
VI-3
wherein D is an aryl; B is an aryl or carbocycle.
In some embodiments, each aryl group is independnetly selected from the list below:
, or .
In some embodiments, each aryl group is idependently mono or multiply substituted. In
some embodiments, each aryl group can be independently mono or multiply substituted
with I, F, Cl, Br, CH , CN, OH, OMe, OEt, OCF , CF , or methane sulfonyl. Further, in
3 3 3
some embodiments, the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.
In some embodiments, D is an optionally mono or multiply substituted aryl. In some
embodiments, B is an optionally mono or multiply substituted aryl or carbocycle. In
some embodiments, D or B is independently selected from the group consisiting of:
, , ,
, , ,
wherein the cabocycle is cyclohexyl, cyclohexenyl or cyclopentyl.
In some embodiments, D is optionally mono or multiply substituted phenyl, 2-pyridil, 3-
pyridyl, or 4-pyridyl. In some embodimetns, D is optionally substituted with one or more of F,
Cl, Br, I, OCF , CH , and CF . In some embodiments, D is not substituted.
3 3 3 1
In some embodiments, B is optionally mono or multiply substituted
, , , ,
, , , ,
, , , , ,
, , , or .
In some embodiments, B is substituted with one or more of Cl, Br, F, I, OMe, CN, CH ,
methanesulfonyl, and CF . In some embodiments, B is substituted with two or more of
Cl, Br, F, I, OMe, CN, CH , CF , and methanesulfonyl, or a combination thereof. That is
B can have two or more substituents but not all of the plurality of substituents needs to
be the same.
In some embodiments, compounds having stuctures of Formula VII-1, VII-2., or VII-3
VII-1, VII-2,
or VII-3
are provided, wherein D is an optionally substituted heteroaryl or aryl, B is H or alkyl,
B is an optionally substituted aryl or heteroaryl, and R and R are each hydrogren or
26 27
an isotope thereof. In some embodiments, R and R are deuterium. In some
26 27
embodiments, R or R are independently alkyl. In some embodiments, B is C -C
26 27 3 1 5
alkyl.
In some embodiments, the compound has a structure of Formula VIII or an enantiomer
thereof
27 26
21 4
VIII, wherein D1 is an optionally
substituted heteroaryl or aryl, B3 is H or alkyl, B5 is an optionally substituted aryl or
heteroaryl, and R26 and R27 are each hydrogren or an isotope thereof. In some
embodiments, R26 and R27 are deuterium. In some embodiments, R26 or R27 are
independently alkyl. A4 is as described herein. In some embodiments, B3 is C1-C5
alkyl. In some embodiments, the enantiomer is the R or S enantiomer at the carbon that
is connected to D1.
In some embodiments, a compound has the structure of Formula IX or an enantiomer
thererof
In some embodiments, the enantiomer is the R or S enantiomer at the carbon that is
connected to D .
In some embodiments, a compound has the structure of Formula X or an enantiomer
thereof
In some embodiments, the enantiomer is the R or S enantiomer at the carbon that is
connected to D1.
In some embodiments of the structures described herein, D1 is an optionally substiuted
pyridyl group or phenyl group. In some embodiments, D1 is an optionally substiuted 2-
pyridyl, 3-pyridyl, or 4-pyridyl group or phenyl group. In some embodiments, D1 is
optionally substituted with one or more of, H, OH, alkyl alcohol, halo, alkyl, amide,
cyano, alkoxy, haloalkyl, or aklylsulfonyl. In some embodiments, D1 is optionally
subsituted with one or more of H, OH, Cl, Br, F, I, OMe, CN, CH , CF .
In some embodiments of the strucutres described herein, B is an optionally substituted
thiophene group. In some embodiments, B is substituted with an alkoxy group. In some
embodiments, B is substituted with a C -C alkoxy group. In some embodiments, B is
1 5 5
substituted with a methoxy group. In some embodiments, B is . In
some embodiments, B is , , ,
, , , ,
, , ,
, , , ,
, , , ,
, , or , wherein R , R and R
23 24, 30
are each independently null, H, OH, cycle, aryl, branched or unbranched alkyl alcohol,
halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl,
nitrite, alkylsulfanyl, and R is H or alkyl. In some embodiments, R and R together
23 24
form a aryl or cycle that is attached to one or more of the atoms of B . R R , and R
23 24 30
can also be further substituted. In some embodiments, R , R , and R are each
23 24 30
independently H, NH , OH, Cl, Br, F, I, OMe, CN, CH , phenyl, C -C carbocycle,
2 3 3 6
methanesulfonyl, CF , , , or
wherein R is H or an alkyl. In some embodiments, R is a C -C alkyl. In some
29 29 1 6
embodiments, one of R , R , and R is H. In some embodiments, at least one of R ,
23 24 30 23
R , and R is H. In some embodiments, two of R , R , and R are H.
24 30 23 24 30
The following compounds and others described herein have agonist activity for OR
mediated signal transduction:
[(4-chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxanyl]ethyl})amine
[(3,4-dimethoxyphenyl)methyl][2-(2,2-dimethylphenyloxanyl)ethyl]amine
2-[({2-[2-ethylmethyl(4-methylphenyl)oxanyl]ethyl}amino)methyl]phenol
[2-(2,2-dimethylphenyloxanyl)ethyl][(2-fluorophenyl)methyl]amine
4-[({2-[4-(2-methoxyphenyl)-2,2-dimethyloxanyl]ethyl}amino)methyl]-N,N-
dimethylaniline
2-[({2-[2-ethyl(4-fluorophenyl)methyloxanyl]ethyl}amino)methyl]phenol
[(3-methoxythiophenyl)methyl]({2-[(9R)(pyridinyl)oxaspiro[4.5]decan
yl]ethyl})amine.
In some embodiments, compounds, such as the ones described herein are provided. In
some embodiments, a compound selected from the compounds described in the Examples
is provided. The compounds can be used in any of the methods described herein,
including, but not limited to, treating pain.
Thus, the application provides methods of generating agonist activity in OR mediated
signal transduction through administration of one or more of the above recited
compounds to a subject or subject in need thereof.
Various atoms in the compositions described herein can be isotopes that occur at lower
frequency. Hydrogen can be replaced at any position in the compositions described
herein with deuterium. Optionally, hydrogen can also be replaced with tritium. Carbon
12 13
( C) can be replaced at any position in the compositions described herein with C or
14 14 15 16
C. Nitrogen ( N) can be replaced with N. Oxygen ( O) can be replaced at any
17 18 32
position in the compositions described herein with O or O. Sulfur ( S) can be
33 34 36
replaced at any position in the compositions described herein with S, S or S.
Chlorine ( Cl) can be replaced at any position in the compositions described herein with
37 79
Cl. Bromine ( Br) can be replaced at any position in the compositions described herein
with Br.
Selected compounds described herein are agonists and antagonists of Opioid Receptors
(ORs). The ability of the compounds to stimulate OR mediated signaling may be
measured using any assay known in the art to detect OR mediated signaling or OR
activity, or the absence of such signaling/activity. "OR activity" refers to the ability of an
OR to transduce a signal. Such activity can be measured, e.g., in a heterologous cell, by
coupling an OR (or a chimeric OR) to a downstream effector such as adenylate cyclase.
A "natural ligand-induced activity" as used herein, refers to activation of the OR by a
natural ligand of the OR. Activity can be assessed using any number of endpoints to
measure OR activity.
Generally, assays for testing compounds that modulate OR-mediated signal transduction
include the determination of any parameter that is indirectly or directly under the
influence of a OR, e.g., a functional, physical, or chemical effect.
Samples or assays comprising ORs that are treated with a potential activator, inhibitor, or
modulator are compared to control samples without the inhibitor, activator, or modulator
to examine the extent of inhibition. Control samples (untreated with inhibitors) are
assigned a relative OR activity value of 100%. Inhibition of an OR is achieved when the
OR activity value relative to the control is about 80%, 50%, or 25%. Activation of an OR
is achieved when the OR activity value relative to the control (untreated with activators)
is 110%, 150%, 200-500% (i.e., two to five fold higher relative to the control) or, 1000-
3000% or higher.
The effects of the compounds upon the function of an OR can be measured by examining
any of the parameters described above. Any suitable physiological change that affects
OR activity can be used to assess the influence of a compound on the ORs and natural
ligand-mediated OR activity. When the functional consequences are determined using
intact cells or animals, one can also measure a variety of effects such as changes in
intracellular second messengers such as cAMP.
Modulators of OR activity are tested using OR polypeptides as described above, either
recombinant or naturally occurring. The protein can be isolated, expressed in a cell,
expressed in a membrane derived from a cell, expressed in tissue or in an animal. For
example, neuronal cells, cells of the immune system, transformed cells, or membranes
can be used to test the GPCR polypeptides described above. Modulation is tested using
one of the in vitro or in vivo assays described herein. Signal transduction can also be
examined in vitro with soluble or solid state reactions, using a chimeric molecule such as
an extracellular domain of a receptor covalently linked to a heterologous signal
transduction domain, or a heterologous extracellular domain covalently linked to the
transmembrane and or cytoplasmic domain of a receptor. Furthermore, ligand-binding
domains of the protein of interest can be used in vitro in soluble or solid state reactions to
assay for ligand binding.
Ligand binding to an OR, a domain, or chimeric protein can be tested in a number of
formats. Binding can be performed in solution, in a bilayer membrane, attached to a solid
phase, in a lipid monolayer, or in vesicles. Typically, in an assay described herein, the
binding of the natural ligand to its receptor is measured in the presence of a candidate
modulator. Alternatively, the binding of the candidate modulator may be measured in the
presence of the natural ligand. Often, competitive assays that measure the ability of a
compound to compete with binding of the natural ligand to the receptor are used. Binding
can be tested by measuring, e.g., changes in spectroscopic characteristics (e.g.,
fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or
changes in chromatographic or solubility properties.
Modulators may also be identified using assays involving β-arrestin recruitment. β-
arrestin serves as a regulatory protein that is distributed throughout the cytoplasm in
unactivated cells. Ligand binding to an appropriate OR is associated with redistribution
of β-arrestin from the cytoplasm to the cell surface, where it associates with the OR.
Thus, receptor activation and the effect of candidate modulators on ligand-induced
receptor activation, can be assessed by monitoring β-arrestin recruitment to the cell
surface. This is frequently performed by transfecting a labeled β-arrestin fusion protein
(e.g., β-arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution
using confocal microscopy (see, e.g., Groarke et al., J. Biol. Chem. 274(33):23263 69
(1999)).
Another technology that can be used to evaluate OR-protein interactions in living cells
involves bioluminescence resonance energy transfer (BRET). A detailed discussion
regarding BRET can be found in Kroeger et al., J. Biol. Chem., 276(16):12736 43 (2001).
Other assays can involve determining the activity of receptors which, when activated by
ligand binding, result in a change in the level of intracellular cyclic nucleotides, e.g.,
cAMP, by activating or inhibiting downstream effectors such as adenylate cyclase.
Changes in intracellular cAMP can be measured using immunoassays. The method
described in Offermanns & Simon, J. Biol. Chem. 270:15175 15180 (1995) may be used
to determine the level of cAMP. Also, the method described in Felley-Bosco et al., Am.
J. Resp. Cell and Mol. Biol. 11:159 164 (1994) may be used to determine the level of
cGMP. Further, an assay kit for measuring cAMP a is described in U.S. Pat. No.
4,115,538, herein incorporated by reference.
Transcription levels can be measured to assess the effects of a test compound on ligand-
induced signal transduction. A host cell containing the protein of interest is contacted
with a test compound in the presence of the natural ligand for a sufficient time to effect
any interactions, and then the level of gene expression is measured. The amount of time
to effect such interactions may be empirically determined, such as by running a time
course and measuring the level of transcription as a function of time. The amount of
transcription may be measured by using any method known to those of skill in the art to
be suitable. For example, mRNA expression of the protein of interest may be detected
using northern blots or their polypeptide products may be identified using immunoassays.
Alternatively, transcription based assays using reporter genes may be used as described in
U.S. Pat. No. 5,436,128, herein incorporated by reference. The reporter genes can be,
e.g., chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, β-
galactosidase and alkaline phosphatase. Furthermore, the protein of interest can be used
as an indirect reporter via attachment to a second reporter such as green fluorescent
protein (see, e.g., Mistili & Spector, Nature Biotechnology 15:961 964 (1997)).
The amount of transcription is then compared to the amount of transcription in either the
same cell in the absence of the test compound, or it may be compared with the amount of
transcription in a substantially identical cell that lacks the protein of interest. A
substantially identical cell may be derived from the same cells from which the
recombinant cell was prepared but which had not been modified by introduction of
heterologous DNA. Any difference in the amount of transcription indicates that the test
compound has in some manner altered the activity of the protein of interest.
Pharmaceutical Compositions/ Formulations
Pharmaceutical compositions can be formulated by standard techniques using one or
more physiologically acceptable carriers or excipients. The formulations may contain a
buffer and/or a preservative. The compounds and their physiologically acceptable salts
and solvates can be formulated for administration by any suitable route, including via
inhalation, topically, nasally, orally, parenterally (e.g., intravenously, intraperitoneally,
intravesically or intrathecally) or rectally in a vehicle comprising one or more
pharmaceutically acceptable carriers, the proportion of which is determined by the
solubility and chemical nature of the compound, chosen route of administration and
standard biological practice.
Pharmaceutical compositions can include effective amounts of one or more compound(s)
described herein together with, for example, pharmaceutically acceptable diluents,
preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers. Such
compositions may include diluents of various buffer content (e.g., TRIS or other amines,
carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially
in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic,
tribasic), etc. or TRIS-HCl or acetate), pH and ionic strength; additives such as detergents
and solubilizing agents (e.g., surfactants such as Pluronics, Tween 20, Tween 80
(Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol,
etc.), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g.,
Thimersol, benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugars such as
sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidones or dextran, etc.);
and/or incorporation of the material into particulate preparations of polymeric compounds
such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronic acid may
also be used. Such compositions can be employed to influence the physical state,
stability, rate of in vivo release, and rate of in vivo clearance of a compound described
herein. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing
Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference.
The compositions can, for example, be prepared in liquid form, or can be in dried
powder, such as lyophilized form. Particular methods of administering such compositions
are described infra.
Where a buffer is to be included in the formulations described herein, the buffer can be
selected from sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine,
lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium
phosphate, and tris(hydroxymethyl)-aminomethane, or mixtures thereof. The buffer can
also be glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, and
sodium phosphate or mixtures thereof.
Where a pharmaceutically acceptable preservative is to be included in a formulation of
one of the compounds described herein, the preservative can be selected from phenol, m-
cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl
p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or
mixtures thereof. The preservative can also be phenol or m-cresol.
The preservative is present in a concentration from about 0.1 mg/ml to about 50 mg/ml,
in a concentration from about 0.1 mg/ml to about 25 mg/ml, or in a concentration from
about 0.1 mg/ml to about 10 mg/ml.
The use of a preservative in pharmaceutical compositions is well-known to the skilled
person. For convenience reference is made to Remington: The Science and Practice of
Pharmacy, 19th edition, 1995.
The formulation may further comprise a chelating agent where the chelating agent may
be selected from salts of ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic
acid, and mixtures thereof.
The chelating agent can be present in a concentration from 0.1 mg/ml to 5 mg/ml, from
0.1 mg/ml to 2 mg/ml or from 2 mg/ml to 5 mg/ml.
The use of a chelating agent in pharmaceutical compositions is well-known to the skilled
person. For convenience reference is made to Remington: The Science and Practice of
Pharmacy, 19th edition, 1995.
The formulation of the compounds described herein may further comprise a stabilizer
selected from high molecular weight polymers and low molecular compounds where such
stabilizers include, but are not limited to, polyethylene glycol (e.g. PEG 3350),
polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts
(e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine,
aspartic acid, tryptophan, and threonine or any mixture thereof. The stabilizer can also be
L-histidine, imidazole or arginine.
The high molecular weight polymer can be present in a concentration from 0.1 mg/ml to
50 mg/m, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20
mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.
The low molecular weight compound can be present in a concentration from 0.1 mg/ml to
50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20
mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.
The use of a stabilizer in pharmaceutical compositions is well-known to the skilled
person. For convenience reference is made to Remington: The Science and Practice of
Pharmacy, 19th edition, 1995.
The formulation of the compounds described herein may further include a surfactant. IN
some embodiments, the surfactant may be selected from a detergent, ethoxylated castor
oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters,
poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g.
Tween-20, or Tween-80), monoglycerides or ethoxylated derivatives thereof,
diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives
thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins,
phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids
(sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate
sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium
lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts
thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium
deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl
ammoniopropanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants,
palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1-acyl-sn-glycero
phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl
ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g.
lauroyl and myristoyl derivatives of lysophosphatidylcholine,
dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is
cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the
postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and
lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio-
1-propanesulfonates, 3-cholamidopropyldimethylammoniopropanesulfonate,
dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin),
cationic surfactants (quarternary ammonium bases) (e.g. cetyl-trimethylammonium
bromide, cetylpyridinium chloride), non-ionic surfactants,
polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X-
100, Dodecyl β-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80,
Brij-35), fusidic acid derivatives--(e.g. sodium tauro-dihydrofusidate etc.), long-chain
fatty acids and salts thereof C6-C12 (e.g. oleic acid and caprylic acid), acylcarnitines and
derivatives, N -acylated derivatives of lysine, arginine or histidine, or side-chain
acylated derivatives of lysine or arginine, N -acylated derivatives of dipeptides
comprising any combination of lysine, arginine or histidine and a neutral or acidic amino
acid, N -acylated derivative of a tripeptide comprising any combination of a neutral
amino acid and two charged amino acids, or the surfactant may be selected from the
group of imidazoline derivatives, or mixtures thereof.
The use of a surfactant in pharmaceutical compositions is well-known to the skilled
person. For convenience reference is made to Remington: The Science and Practice of
Pharmacy, 19th edition, 1995.
Pharmaceutically acceptable sweeteners can be part of the formulation of the compounds
described herein. Pharmaceutically acceptable sweeteners include at least one intense
sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame
potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside
or sucralose (4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose), saccharin, sodium or
calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose,
sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel, and
honey.
Intense sweeteners are conveniently employed in low concentrations. For example, in the
case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based
on the total volume of the final formulation, or is about 0.06% in the low-dosage
formulations and about 0.08% in the high-dosage ones. The bulk sweetener can
effectively be used in larger quantities ranging from about 10% to about 35%, or from
about 10% to 15% (w/v).
The formulations of the compounds described herein may be prepared by conventional
techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in
Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such
conventional techniques of the pharmaceutical industry involve dissolving and mixing the
ingredients as appropriate to give the desired end product.
The phrase “pharmaceutically acceptable” or “therapeutically acceptable” refers to
molecular entities and compositions that are physiologically tolerable and preferably do
not typically produce an allergic or similar untoward reaction, such as gastric upset,
dizziness and the like, when administered to a human. As used herein, the term
“pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a
State government or listed in the U.S. Pharmacopeia or other generally recognized
pharmacopeia (e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R.
Gennaro edit. 1985)) for use in animals, and more particularly in humans.
Administration of the compounds described herein may be carried out using any method
known in the art. For example, administration may be transdermal, parenteral,
intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital,
ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal,
intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, or oral
administration. A pharmaceutical composition of the compounds described herein can be
for administration for injection, or for oral, pulmonary, nasal, transdermal, ocular
administration.
For oral administration, the pharmaceutical composition of the compounds described
herein can be formulated in unit dosage forms such as capsules or tablets. The tablets or
capsules may be prepared by conventional means with pharmaceutically acceptable
excipients, including binding agents, for example, pregelatinised maize starch,
polyvinylpyrrolidone, or hydroxypropyl methylcellulose; fillers, for example, lactose,
microcrystalline cellulose, or calcium hydrogen phosphate; lubricants, for example,
magnesium stearate, talc, or silica; disintegrants, for example, potato starch or sodium
starch glycolate; or wetting agents, for example, sodium lauryl sulphate. Tablets can be
coated by methods well known in the art. Liquid preparations for oral administration can
take the form of, for example, solutions, syrups, or suspensions, or they can be presented
as a dry product for constitution with water or other suitable vehicle before use. Such
liquid preparations can be prepared by conventional means with pharmaceutically
acceptable additives, for example, suspending agents, for example, sorbitol syrup,
cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example,
lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl
alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-
p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts,
flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for
oral administration can be suitably formulated to give controlled release of the active
compound.
For topical administration, the pharmaceutical composition of the compounds described
herein can be formulated in a pharmaceutically acceptable vehicle containing 0.1 to 10
percent, or 0.5 to 5 percent, of the active compound(s). Such formulations can be in the
form of a cream, lotion, sublingual tablet, aerosols and/or emulsions and can be included
in a transdermal or buccal patch of the matrix or reservoir type as are conventional in the
art for this purpose.
For parenteral administration, the compounds described herein are administered by either
intravenous, subcutaneous, or intramuscular injection, in compositions with
pharmaceutically acceptable vehicles or carriers. The compounds can be formulated for
parenteral administration by injection, for example, by bolus injection or continuous
infusion. Formulations for injection can be presented in unit dosage form, for example, in
ampoules or in multi-dose containers, with an added preservative. The compositions can
take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and
can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing
agents. Alternatively, the active ingredient can be in powder form for constitution with a
suitable vehicle, for example, sterile pyrogen-free water, before use.
For administration by injection, the compound(s) can be used in solution in a sterile
aqueous vehicle which may also contain other solutes such as buffers or preservatives as
well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make
the solution isotonic. The pharmaceutical compositions of the compounds described
herein may be formulated with a pharmaceutically acceptable carrier to provide sterile
solutions or suspensions for injectable administration. Injectables can be prepared in
conventional forms, either as liquid solutions or suspensions, solid forms suitable for
solution or suspensions in liquid prior to injection or as emulsions. Suitable excipients
are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium
glutamate, cysteine hydrochloride, or the like. In addition, if desired, the injectable
pharmaceutical compositions may contain minor amounts of nontoxic auxiliary
substances, such as wetting agents, pH buffering agents, and the like. If desired,
absorption enhancing preparations (e.g., liposomes) may be utilized. Suitable
pharmaceutical carriers are described in “Remington's pharmaceutical Sciences” by E. W.
Martin.
For administration by inhalation, the compounds may be conveniently delivered in the
form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use
of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a
pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or
insufflator can be formulated containing a powder mix of the compound and a suitable
powder base, for example, lactose or starch. For intranasal administration the compounds
described herein may be used, for example, as a liquid spray, as a powder or in the form
of drops.
The compounds can also be formulated in rectal compositions, for example, suppositories
or retention enemas, for example, containing conventional suppository bases, for
example, cocoa butter or other glycerides.
Furthermore, the compounds can be formulated as a depot preparation. Such long-acting
formulations can be administered by implantation (for example, subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be
formulated with suitable polymeric or hydrophobic materials (for example as an emulsion
in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for
example, as a sparingly soluble salt.
The compositions can, if desired, be presented in a pack or dispenser device that can
contain one or more unit dosage forms containing the active ingredient. The pack can, for
example, comprise metal or plastic foil, for example, a blister pack. The pack or
dispenser device can be accompanied by instructions for administration.
The compounds described herein also include derivatives referred to as prodrugs, which
can be prepared by modifying functional groups present in the compounds in such a way
that the modifications are cleaved, either in routine manipulation or in vivo, to the parent
compounds. Examples of prodrugs include compounds of the invention as described
herein that contain one or more molecular moieties appended to a hydroxyl, amino,
sulfhydryl, or carboxyl group of the compound, and that when administered to a patient,
cleaves in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group,
respectively. Examples of prodrugs include, but are not limited to, acetate, formate and
benzoate derivatives of alcohol and amine functional groups in the compounds of the
invention. Preparation and use of prodrugs is discussed in T. Higuchi et al., “Pro-drugs as
Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association
and Pergamon Press, 1987, both of which are incorporated herein by reference in their
entireties.
Dosages
The compounds described herein may be administered to a patient at therapeutically
effective doses to prevent, treat, or control one or more diseases and disorders mediated,
in whole or in part, by an OR-ligand interaction. Pharmaceutical compositions
comprising one or more of compounds described herein may be administered to a patient
in an amount sufficient to elicit an effective protective or therapeutic response in the
patient. An amount adequate to accomplish this is defined as "therapeutically effective
dose." The dose will be determined by the efficacy of the particular compound employed
and the condition of the subject, as well as the body weight or surface area of the area to
be treated. The size of the dose also will be determined by the existence, nature, and
extent of any adverse effects that accompany the administration of a particular compound
or vector in a particular subject.
Toxicity and therapeutic efficacy of such compounds can be determined by standard
pharmaceutical procedures in cell cultures or experimental animals, for example, by
determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose
therapeutically effective in 50% of the population). The dose ratio between toxic and
therapeutic effects is the therapeutic index and can be expressed as the ratio, LD50/ED50.
In some embodiments, compounds that exhibit large therapeutic indices are used. While
compounds that exhibit toxic side effects can be used, care should be taken to design a
delivery system that targets such compounds to the site of affected tissue to minimize
potential damage to normal cells and, thereby, reduce side effects.
The data obtained from cell culture assays and animal studies can be used to formulate a
dosage range for use in humans. In some embodiments, the dosage of such compounds
lies within a range of circulating concentrations that include the ED50 with little or no
toxicity. The dosage can vary within this range depending upon the dosage form
employed and the route of administration. For any compound described herein, the
therapeutically effective dose can be estimated initially from cell culture assays. A dose
can be formulated in animal models to achieve a circulating plasma concentration range
that includes the IC50 (the concentration of the test compound that achieves a half-
maximal inhibition of symptoms) as determined in cell culture. Such information can be
used to more accurately determine useful doses in humans. Levels in plasma can be
measured, for example, by high performance liquid chromatography (HPLC). In general,
the dose equivalent of a modulator is from about 1 ng/kg to 10 mg/kg for a typical
subject.
The amount and frequency of administration of the compounds described herein and/or
the pharmaceutically acceptable salts thereof will be regulated according to the judgment
of the attending clinician considering such factors as age, condition and size of the patient
as well as severity of the symptoms being treated. An ordinarily skilled physician or
veterinarian can readily determine and prescribe the effective amount of the drug required
to prevent, counter or arrest the progress of the condition. In general it is contemplated
that an effective amount would be from 0.001 mg/kg to 10 mg/kg body weight, and in
particular from 0.01 mg/kg to 1 mg/kg body weight. It may be appropriate to administer
the required dose as two, three, four or more sub-doses at appropriate intervals
throughout the day. Said sub-doses may be formulated as unit dosage forms, for example,
containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per
unit dosage form.
In some embodiments, the pharmaceutical preparation is in a unit dosage form. In such
form, the preparation is subdivided into suitably sized unit doses containing appropriate
quantities of the active component, e.g., an effective amount to achieve the desired
purpose. The quantity of active compound in a unit dose of preparation may be varied or
adjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg to about 750 mg,
from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg, according
to the particular application. The actual dosage employed may be varied depending upon
the requirements of the patient and the severity of the condition being treated.
Determination of the proper dosage regimen for a particular situation is within the skill of
the art. For convenience, the total dosage may be divided and administered in portions
during the day as required.
In some embodiments, one or more compounds described herein are administered with
another compound. The administration may be sequentially or concurrently. The
combination may be in the same dosage form or administered as separate doses. In some
embodiments, the another compound is another analgesic or pain reliever. In some
embodiments, the another compound is a non-opioid analgesic. Examples of useful non-
opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents,
such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,
flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,
muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic
acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,
fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,
niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and
pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-
opioid analgesics include the following, non-limiting, chemical classes of analgesic,
antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including
aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal,
salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophenol derivatives including
acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin,
sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and
ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic
acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones
(phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more
detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti-
inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman &
Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and
Raymond W. Ruddon eds., 9.sup.th ed 1996); and Glen R. Hanson, Analgesic,
Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of
Pharmacy Vol II 1196-1221 (A. R. Gennaro ed. 19.sup.th ed. 1995), which are hereby
incorporated by reference in their entireties.
The compounds described herein can also be administered Cox-II inhibitors. Examples of
useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof,
are described in U.S. Pat. No. 6,136,839, which is hereby incorporated by reference in its
entirety. Examples of Cox-II inhibitors include, but are not limited to, rofecoxib and
celecoxib.
The compounds described herein can also be administered with antimigraine agents.
Examples of useful antimigraine agents include, but are not limited to, alpiropride,
bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine,
ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride,
lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone,
pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,
zolmitriptan, and mixtures thereof.
The compounds described herein can also be administered with anti-constipation agents.
Examples of anti-constipation agents include, but are not limited to, laxatives or stool
softners. Examples of anti-constipation agents include, but are not limited to, be
docusate, poloxamer 188, psyllium, methylcellulose, carboxymethyl cellulose,
polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesium hydroxide,
magnesium sulfate, dibasic sodium phosphate, monobasic sodium phosphate, sodium
biphosphate or any combination thereof.
Medical Use
The compositions described herein may be useful for treating pain or pain associated
disorders. The compositions described herein may be useful for treating immune
dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions,
urological and reproductive conditions, medicaments for drug and alcohol abuse, agents
for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of
respiratory diseases and cough.
In some embodiments, methods of treating pain are provided. In some embodiments, one
or more compound described herein are administered to a subject to treat the pain. In
some embodiments, the pain can be post-operative pain. In some embodiments, the pain
is caused by cancer. In some embodiments, the pain is neuropathic pain. In some
embodiments, the pain is caused by trauma, such as but not limited to, blunt force trauma.
In some embodiments, the pain is caused by inflammation.
In some embodiments, the one or more compounds described herein can be administered
by any suitable route, including, but not limited to, via inhalation, topically, nasally,
orally, parenterally (e.g., intravenously, intraperitoneally, intravesically or intrathecally)
or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the
proportion of which is determined by the solubility and chemical nature of the compound,
chosen route of administration and standard practice.
Definitions
Unless otherwise defined, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art. Although methods
and materials similar or equivalent to those described herein can be used in the practice
or testing of the compositions and compounds described herein, suitable methods and
materials are described below. All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference in their entirety. In the case of
conflict, the present specification, including definitions, will control. In addition, the
materials, methods, and examples are illustrative only not intended to be limiting. Other
features and advantages of the compositions and compounds described herein will be
apparent from the following detailed description and claims.
The general chemical terms used throughout have their usual meanings. For example, the
term alkyl refers to a branched or unbranched saturated hydrocarbon group. The term “n-
alkyl” refers to an unbranched alkyl group. The term "C -C alkyl” refers to an alkyl
group having from x to y carbon atoms, inclusively, in the branched or unbranched
hydrocarbon group. By way of illustration, but without limitation, the term "C -C alkyl”
refers to a straight chain or branched hydrocarbon moiety having from 1 to 4 carbon
atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-
butyl. The term "C -C n-alkyl” refers to straight chain hydrocarbon moieties having
from 1 to 4 carbon atoms including methyl, ethyl, n-propyl, and n-butyl. C -C x can be
from 1 to 10 and y is from 2 to 20. The term “C -C cycloalkyl” refers to cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. The term “C -C cycloalkyl” also includes
cycloheptyl. Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyl linker
chain, as for example, but without limitation, cyclopropylmethyl, cyclopropylethyl,
cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl,
cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl,
cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Each alkyl, cycloalkyl, and
cycloalkylalkyl group may be optionally substituted, such as, but not limited to, as
specified herein. In some embodiments, the alkyl is a C -C , C -C , C -C , C -C , or C -
1 3 1 4 1 6 4 6 1
C alkyl.
The terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer to an alkyl
group, phenyl group, benzyl group, or pyrimidinyl group, respectively, that is bonded
through an oxygen atom. Each of these groups may be optionally substituted.
The terms “alkylthio”, “phenylthio”, and “benzylthio” refer to an alkyl group, phenyl
group, or benzyl group, respectively, that is bonded through a sulfur atom. Each of these
groups may be optionally substituted.
The term “C -C acyl” refers to a formyl group or a C -C alkyl group bonded through a
1 4 1 3
carbonyl moiety. The term “C -C alkoxycarbonyl” refers to a C -C alkoxy group
1 4 1 4
bonded through a carbonyl moiety.
The term "halo" refers to fluoro, chloro, bromo, or iodo. In some embodiments, the halo
groups are fluoro, chloro, and bromo. In some embodiments, the halo groups are fluoro
and chloro.
As used herein, “carbocycle” or "carbocyclic ring" is intended to mean, unless otherwise
specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or
tricyclic ring, any of which can be saturated, unsaturated (including partially and fully
unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to,
cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,
cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,
[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and
tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of
carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon
atoms link two non-adjacent carbon atoms. In some embodiments, the bridges are one or
two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a
tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be
present on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are
also included.
The term "heterocycle" is taken to mean a saturated or unsaturated 5- or 6-membered ring
containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring
optionally being benzofused. Exemplary heterocycles include furanyl, thiophenyl
(thienyl), pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl,
pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-
acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused
heterocyclic rings include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl,
quinolinyl, benzofuranyl, benzothiophenyl, indolyl, and the like, all of which may be
optionally substituted, which also of course includes optionally substituted on the benzo
ring when the heterocycle is benzofused.
The term “cycle” group is taken to mean a carbocylic ring, a carbocycle or a
heterocarbocyle.
As used herein, the phrase a “cycle of the formula” refers to a ring that can be formed
with the variable referred to. For example, in the structure , wherein A can be a
cycle of the formula C(CH ) , where n = 2-5, it means that A is a carbon and forms a ring
with itself with 2-5 CH groups, which could also be represented structurally as
.The variable “A” is not limited to carbon and can be another atom, such
as, but not limited to, a heteroatom, but the context in which the variable is used will
indicate the type of atom “A” could be. This is just a non-limiting example.
Additionally, the ring that is formed with “A” can also be substituted. Exemplary
substituents are described herein.
In some embodiments, heterocycles include, but are not limited to, pyridinyl, indolyl,
furanyl, benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, all of which may be
optionally substituted.
As used herein, the term “aromatic heterocycle” or “heteroaryl” is intended to mean a
stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which
consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5
or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case
of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic
(e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). The second ring can also
be fused or bridged as defined above for heterocycles. The nitrogen atom can be
substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as
defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and
S(O) , wherein p = 1 or 2). In certain compounds, the total number of S and O atoms in
the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,
chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,
imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-
oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl,
piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,
pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-
quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio, means an alkyl,
cycloalkyl, cycloalkylalkyl, alkoxy, or alkythio group, respectively, substituted one or
more times independently with a substituent selected from the group consisting of halo,
hydroxy, and C -C alkoxy. By way of illustration, but without limitation, examples
include trifluoromethyl, pentafluoroethyl, 5-fluorobromopentyl, 3-hydroxypropyloxy,
4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropyloxy, 3-ethoxy
chlorocyclohexyl, and the like. In some embodiments, substitutions include substitution
1-5 times with halo, each independently selected, or substituted 1-3 times with halo and
1-2 times independently with a group selected from hydroxy and C -C alkoxy, or
substituted 1-3 times independently with a group selected from hydroxy and C -C
alkoxy, provided that no more than one hydroxy and/or alkoxy substituent may be
attached through the same carbon.
The terms “substituted phenyl” and “substituted heterocycle” are taken to mean that the
cyclic moiety in either case is substituted. They can be substituted independently with
one or more substituents. They can be substituted independently with 1, 2, 3, 4, 5, 1-3, 1-
4, or 1-5 substituents. The substitution can be, independently, halo, alkyl, such as, but not
limited to, C -C alkyl, alkoxy, such as but not limited to, C -C alkoxy, and alklylthio,
1 4 1 4
such as but not limited to, C -C alkylthio, wherein each alkyl, alkoxy and alkylthio
substituent can be further substituted independently with C -C alkoxy or with one to five
halo groups; or substituted with one substituent selected from the group consisting of
phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the
phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy moiety can be further
substituted with one to two substituents selected from the group consisting of halo, C -C
alkyl, and C -C alkoxy; or substituted with one substituent selected from the group
consisting of C -C acyl and C -C alkoxycarbonyl, and further substituted with zero to
1 4 1 4
one substituent selected from the group consisting of halo, C -C alkyl, C -C alkoxy, and
1 4 1 4
C -C alkylthio. When a substituent is halo, in some embodiments, the halo groups are
fluoro, chloro, and bromo. The halo can also be iodo.
DMF means N,N-dimethylformamide.
As used herein, the phrase "pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the scope of sound
medical judgment, suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
By "pharmaceutical formulation" it is further meant that the carrier, solvent, excipients
and salt must be compatible with the active ingredient of the formulation (e.g. a
compound described herein). It is understood by those of ordinary skill in this art that the
terms “pharmaceutical formulation” and “pharmaceutical composition” are generally
interchangeable, and they are so used for the purposes of this application.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed
compounds wherein the parent compound is modified by making acid or base salts
thereof. Examples of pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable
salts include the conventional non-toxic salts or the quaternary ammonium salts of the
parent compound formed, for example, from non-toxic inorganic or organic acids. For
example, such conventional non-toxic salts include, but are not limited to, those derived
from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane
sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic,
ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,
glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide,
hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic,
malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic,
phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,
succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. The present
disclosure includes pharmaceutically acceptale salts of any compound(s) described
herein.
Pharmaceutically acceptable salts can be synthesized from the parent compound that
contains a basic or acidic moiety by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or
in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol,
isopropanol, or acetonitrile, and the like. Lists of suitable salts are found in Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p.
1445 (1990).
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals
(e.g., solubility, bioavailability, manufacturing, etc.) the compounds described herein can
be delivered in prodrug form and can be administered in this form for the treatment of
disease. "Prodrugs" are intended to include any covalently bonded carriers that release an
active parent drug of described herein in vivo when such prodrug is administered to a
mammalian subject. Prodrugs are prepared by modifying functional groups present in the
compound in such a way that the modifications are cleaved, either in routine manipulation
or in vivo, to the parent compound. Prodrugs include compounds described herein
wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the
prodrug is administered to a mammalian subject, it cleaves to form a free hydroxyl, free
amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not
limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional
groups in the compounds described herein.
"Stable compound" and "stable structure" are meant to indicate a compound that is
sufficiently robust to survive isolation to a useful degree of purity from a reaction
mixture, and formulation into an efficacious therapeutic agent.
As used herein, “treating” or “treatment” includes any effect e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the condition, disease,
disorder, etc. “Treating” or “treatment” of a disease state means the treatment of a
disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing
disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving
the disease-state, i.e., causing regression of the disease state.
As used herein, “preventing” means causing the clinical symptoms of the disease state not
to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or
predisposed to the disease state, but does not yet experience or display symptoms of the
disease state.
As used herein, “mammal” refers to human and non-human patients.
As used herein, the term "therapeutically effective amount" refers to a compound, or a
combination of compounds, described herein present in or on a recipient in an amount
sufficient to elicit biological activity, e.g. pain relief. In some embodiments, the
combination of compounds is a synergistic combination. Synergy, as described, for
example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs
when the effect of the compounds when administered in combination is greater than the
additive effect of the compounds when administered alone as a single agent. In general, a
synergistic effect is most clearly demonstrated at sub-optimal concentrations of the
compounds. Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or
some other beneficial effect of the combination compared with the individual
components.
All percentages and ratios used herein, unless otherwise indicated, are by weight.
Throughout the description, where compositions are described as having, including, or
comprising specific components, or where processes are described as having, including,
or comprising specific process steps, it is contemplated that compositions described
herein also consist essentially of, or consist of, the recited components, and that the
processes described herein also consist essentially of, or consist of, the recited processing
steps. Further, it should be understood that the order of steps or order for performing
certain actions are immaterial so long as the process remains operable. Moreover, two or
more steps or actions can be conducted simultaneously.
All enantiomers, diastereomers, and mixtures thereof, are included within the scope of
compounds described herein. In some embodiments, a composition comprising the R
enantiomer is free or substantially free of the S enantiomer. In some embodiments, a
composition comprising the S enantiomer is free or substantially free of the R enantiomer.
In some embodiments, a composition comprises an enantiomeric excess of at least, or
about, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% of either the R or the S enantiomer.
As used throughout this disclosure, the singular forms “a,” “an,” and “the” include plural
reference unless the context clearly dictates otherwise. Thus, for example, a reference to
“a composition” includes a plurality of such compositions, as well as a single
composition, and a reference to “a therapeutic agent” is a reference to one or more
therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled
in the art, and so forth. Thus, for example, a reference to "a host cell" includes a plurality
of such host cells, and a reference to "an antibody" is a reference to one or more
antibodies and equivalents thereof known to those skilled in the art, and so forth.
The claimed compounds in this invention can be prepared from the procedures described
in the schemes below.
Schemes
The following representative schemes illustrate how compounds described herein can be
prepared. The specific solvents and reaction conditions referred to are also illustrative
and are not intended to be limited. Compounds not described are either commercially
available or are readily prepared by one skilled in the art using available starting
materials.
In some embodiments, the same scheme is applied to 1-7 and 1-8A.
In some embodiments, the same scheme is applied to 1-7 and 1-8A.
In some embodiments, 4-1 is selected from the group consisting of
Following a sequence outlined in Scheme 2 or 3, intermediate 4-4 can be converted to the
opioid receptor ligands.
Other schemes can also be used. For example, the following schemes can be used alone
or in combination with other schems to prepare the compounds described herein.
In some embodiments, a process for preparing a compound having the structure of IV-1
is provided. In some embodiments, the
process comprises contacting with under suitable conditions to
form a compound having the structure of IV-1.
In some embodiments, the process is performed at room temperature. In some
embodiments, the process is performed in the presence of a borohydrate salt. In some
embodiments, the process is performed in the presence of sodium borohydrate. Solvents
can also be used to facilitate the preparation. The process can be modified to yield
different alkyl groups, such as, but not limited to, the scheme shown in Scheme 10.
Examples
The following examples are illustrative, but not limiting, of the methods and
compositions described herein. Other suitable modifications and adaptations of the
variety of conditions and parameters normally encountered in therapy and that are
obvious to those skilled in the art are within the spirit and scope of the compounds and
methods described herein.
Example 1:
Intermediate 1: methyl 2-cyano(oxanylidene)acetate
A 50 ml round-bottom flask equipped with a Dean-Stark distillation setup and condenser
was charged with tetrahydro-4H-pyranone (4.61 ml, 50 mmol), methyl cyanoacetate
(5.3 ml, 60 mmol), ammonium acetate (1 g, 13 mmol), acetic acid (0.57 ml, 10 mmol)
and benzene (30 ml). The mixture was refluxed until no more water collected in the
Dean-Stark (2 hours), cooled, benzene (30 ml) added and the organic layer washed with
water (50 ml). The aqueous layer was extracted with CH Cl (3x50 ml). The combined
organic phase was washed with sat. NaHCO (100 ml), brine (100 ml) dried (MgSO ),
filtered and concentrated. Purified by normal phase SiO chromatography (10 to 60%
EtOAc/hexanes) to afford methyl 2-cyano(oxanylidene)acetate as a colorless oil
(6.30g, 70%, m/z: 181.1 [M + H] observed).
Intermediate 2: methyl 2-cyano[4-(4-fluorophenyl)oxanyl]acetate
A round bottom flask was equipped with a condenser, addition funnel and rubber septum
with nitrogen inlet was charged with a solution of p-fluorophenylmagnesium bromide
(2.0 M in diethyl ether, 1.99 ml, 3.97mmol) and CuI (63 mg, 0.331 mmol) in 10 ml dry
diethyl ether (10 ml). Methyl 2-cyano(oxanylidene)acetate (600 mg, 3.31 mmol) in
diethyl ether (10 ml) was added drop-wise over 30 min while cooling the reaction flask in
an ice bath. The mixture was then stirred for 3h. The reaction mixture was poured into a
50 g ice/1 N HCl (25 ml) mixture. The product was extracted with Et O (3x50 ml),
washed with brine (50 ml), dried (NA SO ) and concentrated. Purified by normal phase
SiO chromatography (7% to 60% EtOAc/hexanes) to give methyl 2-cyano[4-(4-
fluorophenyl)oxanyl]acetate as a white solid (730 mg, 80%, m/z: 277.1 [M + Na]
observed).
Intermediate 3: 2-[4-(4-fluorophenyl)oxanyl]acetonitrile
To a pre-dissolved solution of KOH (441 mg, 7.87 mmol) in ethylene glycol (20 ml) was
added methyl 2-cyano[4-(4-fluorophenyl)oxanyl]acetate (1.09 g, 3.93 mmol). The
mixture was heated to 120 C for 3 h, and then cooled. H O was added (50 ml), the
product extracted with Et O (3x50 ml), washed with H O (50 ml), dried over NA SO ,
2 2 2 4
filtered and concentrated. Purified by normal phase SiO chromatography (5 to 40%
EtOAc/hexanes) to give 2-[4-(4-fluorophenyl)oxanyl]acetonitrile as a colorless oil
(450 mg, 78%, m/z: 219.1 [M + H] observed).
Intermediate 4: 2-[4-(4-fluorophenyl)oxanyl]ethanamine
To a solution of 2-[4-(4-fluorophenyl)oxanyl]acetonitrile (450 mg, 2.05 mmol) in
anhydrous ether (15 ml) at 0 C was added dropwise LAH (1.0 M in Et O, 4.1 ml, 4.11
mmol). After 2 h the reaction was quenched with 1 ml H O, 0.1 ml 15% NaOH and then
1 ml H O. The reaction mixture was extracted with Et O (3x20 ml), dried over NA SO
2 2 2 4
and concentrated to give 2-[4-(4-fluorophenyl)oxanyl]ethanamine as an yellow oil,
which used without further purification (450 mg, 94%, m/z: 223.1 [M + H] observed).
Example 2: benzyl({2-[4-(4-fluorophenyl)oxanyl]ethyl})amine (Compound 8)
To a solution of 2-[4-(4-fluorophenyl)oxanyl]ethanamine (250 mg, 1.12 mmol) in
anhydrous CH Cl (5 ml) and NA SO (159 mg, 1.12 mmol) at rt was added
2 2 2 4
benzaldehyde (0.17 ml, 1.68 mmol). The reaction was stirred overnight. The reaction
mixture was filtered and concentrated. The residue was dissolved in 5 ml MeOH at 0 C
and NaBH added in one portion (51 mg, 1.34 mmol). The reaction was stirred at 0 C for
1 h. The solution was then quenched with H O (10 ml), extracted with CH Cl (3x20 ml),
2 2 2
washed with brine (10 ml) and dried over NA SO . Purified by normal phase SiO
2 4 2
chromatography (0 to 10% MeOH/CH Cl ) to give benzyl({2-[4-(4-fluorophenyl)oxan
yl]ethyl})amine as a colorless oil (200 mg, 60%, m/z: 314.2 [M + H] observed).
Intermediate 5: 2,2-dimethyl(4-methylphenyl)oxanol
n-BuLi (26.3 ml, 1.6 M in hexane, 42 mmol) was added dropwise to a solution of 4-
bromo-toluene (7.70 g, 45 mmol) in THF (100 ml) at -78 C under N . The resulting
mixture was stirred at -78 C for 30 min and a solution of tetrahydro-2,2-dimethyl-4H-
pyranone (3.84 g, 30 mmol) in THF (20 ml) was added. The resulting mixture was
stirred at -78 C for another 20 min and quenched by adding MeOH (10 ml). The reaction
was concentrated under vacuum and the resulting residue was diluted with EtOAc (500
ml) and washed with sat. NH Cl (250 ml), brine (250 ml), dried and concentrated to give
2,2-dimethyl(4-methylphenyl)oxanol as a white solid, which was used without
further purification (5.41 g, 82%).
H NMR (400 MHz, CDCl ) δ 7.36 – 7.26 (m, 2H), 7.11 (d, J = 8.0, 2H), 4.10 (td, J =
12.0, 2.2, 1H), 3.71 (ddd, J = 11.8, 5.0, 2.1, 1H), 2.28 (s, 3H), 2.11 (ddd, J = 13.7, 12.2,
.0, 1H), 1.72 (dt, J = 14.2, 8.3, 2H), 1.58 (dq, J = 13.8, 2.2, 1H), 1.44 (s, 3H), 1.38 (s,
1H), 1.14 (s, 3H).
Intermediate 6: 2,2-dimethyl(4-methylphenyl)(propenyl)oxane
Allyltrimethylsilane (4.34 ml, 27.2 mmol) was added to a solution of 2,2-dimethyl(4-
methylphenyl)oxanol (3.0 g, 13.6 mmol) in dry CH Cl (100 ml) at 0 C, followed by
BF -OEt (3.42 ml, 27.2 mmol). The resulting mix was stirred at 0 C for 1h. The
reaction was quenched with H O (10 ml) and diluted with CH Cl (10 ml), and washed
2 2 2
with sat. NaHCO (20 ml), brine (20 ml), dried and concentrated. Purified by normal
phase SiO chromatography (5 to 40% EtOAc/hexanes) to give 2,2-dimethyl(4-
methylphenyl)(propenyl)oxane as a colorless oil, which was used crude (2.49 g,
75%).
Intermediate 7: 2-[2,2-dimethyl(4-methylphenyl)oxanyl]acetaldehyde
O gas was passed through a solution of 2,2-dimethyl(4-methylphenyl)(propen-
1-yl)oxane (1.21 g, 5 mmol) in CH Cl (50 ml) at -78 C until the solution turned light
blue (about 5 min). After additional 5 minutes, the reaction mix was purged with oxygen
gas for 15 min before adding triphenylphosphine (2.62 g, 10 mmol). The reaction was
stirred at rt for 4h and concentrated. Purified by normal phase SiO chromatography (10
to 60% EtOAc/hexanes) to give 2-[2,2-dimethyl(4-methylphenyl)oxan
yl]acetaldehyde as a colorless oil (641 mg, 52%).
H NMR (400 MHz, CDCl ) δ 9.42 – 9.27 (m, 1H), 7.26 (dd, J = 9.9, 8.0, 2H), 7.20 (t, J
= 8.7, 2H), 3.94 – 3.75 (m, 2H), 2.69 (dd, J = 14.6, 2.5, 1H), 2.51 – 2.38 (m, 2H), 2.35 (s,
3H), 2.26 (dd, J = 13.9, 2.3, 1H), 1.84 (ddd, J = 14.3, 11.0, 4.6, 1H), 1.76 (d, J = 13.9,
1H), 1.23 (s, 3H), 0.73 (s, 3H).
Example 3: {2-[2,2-dimethyl(4-methylphenyl)oxanyl]ethyl}[(3-
methylphenyl)methyl]amine (Compound 32)
A mixture of 2-[2,2-dimethyl(4-methylphenyl)oxanyl]acetaldehyde (61.6 mg, 0.25
mmol), 3-methylbenzylamine (63 µl, 0.5 mmol) and acetic acid (50 µl, 8.6 mmol) in
CH Cl (3 ml) was stirred at rt for 1h before it adding sodium triacetoxyborohydride (106
mg, 0.50 mmol). The resulting mixture was stirred at rt for 18 h.The mix was
concentrated and disolved in MeOH and purified by HPLC to give {2-[2,2-dimethyl
(4-methylphenyl)oxanyl]ethyl}[(3-methylphenyl)methyl]amine as a white solid (35
mg, 40%, m/z: 352.3 [M + H] observed).
Intermediate 8: methyl 2-cyano[(9Z)oxaspiro[4.5]decanylidene]acetate
A 100 ml round-bottom flask equipped with a Dean-Stark distillation setup and
condenser was charged with 6-oxaspiro[4.5]decanone (6 g, 39 mmol, which was
prepared according to Hanschke, E. Chem. Ber. 1955, 88, 1053), methyl cyanoacetate
(4.1 ml, 46.7 mmol), ammonium acetate (780 mg, 10.1 mmol), acetic acid (0.44 ml, 7.8
mmol) and benzene (40 ml). The mixture was refluxed until no more water collected in
the Dean-Stark (2 hours), cooled, benzene (30 ml) added and the organic washed with
water (50 ml). The aqueous layer was extracted with CH Cl (3x50 ml). The combined
organic phase was washed with sat. NaHCO (100 ml), brine (100 ml) dried (MgSO ),
filtered and concentrated. Purified by normal phase SiO chromatography (7% to 60%
EtOAc/hexanes) to give methyl 2-cyano[(9Z)oxaspiro[4.5]decanylidene]acetate
as a colorless oil (8.93g, 97.5%, m/z 235.1 [M + H] observed).
By the procedure for the preparation of intermediate 8 substituting 2,2-diethyloxanone
for 6-oxaspiro[4.5]decanone, methyl 2-cyano[(4Z)-2,2-diethyloxan
ylidene]acetate was prepared (m/z 237.1 [M + H] observed).
By the procedure for the preparation of intermediate 8 substituting 1-
oxaspiro[5.5]undecanone for 6-oxaspiro[4.5]decanone, methyl 2-cyano[(4Z)
oxaspiro[5.5]undecanylidene]acetate was prepared (m/z 249.1 [M + H] observed).
Intermediate 9: methyl 2-cyano[9-(4-fluorophenyl)oxaspiro[4.5]decan
yl]acetate
A round bottom flask was equipped with a condenser, addition funnel and rubber septum
with nitrogen inlet was charged with a solution of 4-fluoromagnesium bromide (2.0 M in
diethyl ether, 7.5 ml, 12.5 mmol) and CuI (200 mg, 1.0 mmol) in 35 ml dry diethyl ether.
Methyl 2-cyano[(9Z)oxaspiro[4.5]decanylidene]acetate (2.5g, 10.5 mmol) in
diethyl ether (35 ml) was added drop-wise over 30 min while cooling the reaction flask in
an ice bath. The mixture was then stirred at room temperature for 1h. The reaction
mixture was poured into a 25 g ice/1 N HCl (20 ml) mixture. The product was extracted
with Et O (3x50 ml), washed with brine (50 ml), dried (NA SO ) and concentrated.
2 2 4
Purified by normal phase SiO chromatography (8% to 60% EtOAc/hexanes) to give
methyl 2-cyano[9-(4-fluorophenyl)oxaspiro[4.5]decanyl]acetate as a colorless
oil (3.24 g, 93%, m/z 331.2 [M + H] observed).
By the procedure described in the preparation of intermediate 9 substituting methyl 2-
cyano[(4Z)-2,2-diethyloxanylidene]acetate for methyl 2-cyano[(9Z)
oxaspiro[4.5]decanylidene]acetate, methyl 2-cyano[2,2-diethyl(4-
fluorophenyl)oxanyl]acetate was prepared (m/z 333.2 [M + H] observed).
By the procedure described in the preparation of intermediate 9 substituting methyl 2-
cyano[(4Z)oxaspiro[5.5]undecanylidene]acetate for methyl 2-cyano[(9Z)
oxaspiro[4.5]decanylidene]acetate, methyl 2-cyano[4-(4-fluorophenyl)
oxaspiro[5.5]undecanyl]acetate was prepared (m/z 345.2 [M + H] observed).
Intermediate 10: 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]acetonitrile
To a pre-dissolved solution of KOH (1.1g, 19.5 mmol) in ethylene glycol (50 ml) was
added methyl 2-cyano[9-(4-fluorophenyl)oxaspiro[4.5]decanyl]acetate (3.24 g,
9.8 mmol). The mixture was heated to 120 C for 3 h, then cooled. H O was added (50
ml), the product extracted with Et O (3x50 ml), washed with H O (50 ml), dried over
NA SO , filtered and concentrated. (7% to 60% EtOAc/hexanes) to give methyl 2-cyano-
2-[9-(4-fluorophenyl)oxaspiro[4.5]decanyl]acetate (1.96 g, 73%, m/z 273.2 [M +
H] observed).
1.96 g of the enantionmers were separated by SFC on an AD-3 column using 15% MeOH
(0.05% DEA) as a modifier to give 2-[(9S)(4-fluorophenyl)oxaspiro[4.5]decan
yl]acetonitrile as a colorless oil (faster eluting enantiomer, 635 mg, 24%, m/z 274.2 [M +
H] observed) and 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]acetonitrile as a
colorless oil (slower eluting enantiomer, 703 mg, 26%, m/z 273.2 [M + H] observed).
By the procedure described in the preparation of intermediate 10 substituting methyl 2-
cyano[2,2-diethyl(4-fluorophenyl)oxanyl]acetate for methyl 2-cyano[9-(4-
fluorophenyl)oxaspiro[4.5]decanyl]acetate, 2-[2,2-diethyl(4-fluorophenyl)oxan-
4-yl]acetonitrile was prepared (m/z 275.2 [M + H] observed).
By the procedure described in the preparation of intermediate 10 substituting methyl 2-
cyano[4-(4-fluorophenyl)oxaspiro[5.5]undecanyl]acetate for methyl 2-cyano
[9-(4-fluorophenyl)oxaspiro[4.5]decanyl]acetate, 2-[4-(4-fluorophenyl)
oxaspiro[5.5]undecanyl]acetonitrile was prepared (m/z 287.2 [M + H] observed).
Intermediate 11: 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]ethan
amine
To a solution of 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]acetonitrile (500
mg, 1.8 mmol) in anhydrous ether (30 ml) at 0 C was added dropwise LAH (1.0 M in
Et O, 3.7 ml, 3.7 mmol). The reaction was then warmed up to room temperature. After 2h
the reaction was quenched with 1 ml H O, 0.2 ml 15% NaOH and then 1 ml H O. The
reaction mixture was extracted with Et O (3x30 ml), dried over NA SO and
2 2 4
concentrated to give 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]ethan
amine as an yellow oil, which used without further purification (500 mg, 100%, m/z
277.2 [M + H] observed).
By the procedure described in the preparation of intermediate 11 substituting 2-[2,2-
diethyl(4-fluorophenyl)oxanyl]acetonitrile for 2-[(9R)(4-fluorophenyl)
oxaspiro[4.5]decanyl]acetonitrile, 2-[2,2-diethyl(4-fluorophenyl)oxanyl]ethan-
1-amine was prepared (m/z 279.2 [M + H] observed).
By the procedure described in the preparation of intermediate 11 substituting 2-[4-(4-
fluorophenyl)oxaspiro[5.5]undecanyl]acetonitrile for 2-[(9R)(4-fluorophenyl)
oxaspiro[4.5]decanyl]acetonitrile, 2-[4-(4-fluorophenyl)oxaspiro[5.5]undecan
yl]ethanamine was prepared (m/z 291.2 [M + H] observed).
Example 4: benzyl({2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decan
yl]ethyl})amine (Compound 81)
To a solution of amine 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]ethan
amine (100 mg, 0.361 mmol) in anhydrous CH Cl (6 ml) and NA SO (256 mg, 1.80
2 2 2 4
mmol) at rt was added benzaldehyde (0.055 ml; 0.541 mmol). The reaction was stirred
overnight. The reaction mixture was filtered and concentrated. The residue was dissolved
in 6 ml MeOH at 0 C and NaBH added in one portion (16 mg, 0.433 mmol). The
reaction was stirred at 0 C for 1 h. The solution was then quenched with H O (20 ml),
extracted with CH Cl (3x30 ml), washed with brine (10 ml) and dried over NA SO . The
2 2 2 4
mixture was purified by HPLC to give benzyl({2-[(9R)(4-fluorophenyl)
oxaspiro[4.5]decanyl]ethyl})amine as a white solid (121 mg, 92%, m/z 368.3 [M +
H] observed).
Intermediate 12: 2,2-diethyloxanol.
To a mixture of 3-buteneol (19.8 ml; 233mmol) and 3-pentenone (12.3 ml; 116 mmol)
was added 75% sulfuric acid (19.8; 334 mmol; prepared by diluting 79 ml of conc.
sulfuric acid to 100 ml with distilled water) drop-wise at 0 C. The reaction was allowed
to warm to room temperature and stirred overnight. Water (70 ml) was added to the
mixture then neutralized with NaOH (pellets) to pH 8 and extracted with diethyl ether
(3x150 ml). The ether extract was washed with an aqueous sodium bisulfite solution (40
ml), dried over K CO and the ether evaporated in vacuo. The residue was distilled under
reduced pressure to give 2,2-diethyloxanol (4.89 g, 27%, B. Pt. 65-70 C at 1mm Hg).
H NMR (400 MHz, CDCl ) δ 4.04 – 3.86 (m, 1H), 3.84 – 3.66 (m, 1H), 3.65 – 3.38 (m,
1H), 2.06 – 1.95 (m, 1H), 1.92 – 1.76 (m, 2H), 1.78 – 1.63 (m, 1H), 1.63 – 1.50 (m, 1H),
1.51 – 1.31 (m, 3H), 1.28 – 1.10 (m, 1H), 0.92 – 0.68 (m, 6H).
Intermediate 13: 2,2-diethyloxanone
To a solution of crude 2,2-diethyloxanol (500mg, 3.2 mmol) in CH Cl (10 ml) were
added NMO (750 mg, 6.41 mmol) and 4A moleculat sieves(2g). The solution was stirred
for 30 mins and then TPAP (34 mg, 0.096 mmol) was added in one portion. The reaction
was allowed to stir for 10 h. After checking the TLC, the alcohol was gone. It was filtered
through a short pad of SiO . The filtrate was concentrated and purified by normal phase
SiO chromatography (0% to 50% EtOAc/hexanes) to give 2,2-diethyloxanone (365
mg, 73%).
H NMR (400 MHz, CDCl ) δ 3.75 – 3.66 (m, 2H), 3.44 – 3.29 (m, 2H), 2.51 – 2.31 (m,
4H), 1.25-1.4 (m, 4H), 0.75 (m, 6H).
Intermediate 14: 2-(bromomagnesio)pyridine
Into a flask was placed isopropylmagnesium chloride 2.0M in THF (6 mL, 12 mmole), 2-
bromopyridine (1.2 mL, 12 mmol) in anhydrous Et O (4 ml) added dropwise. The
reaction mixture was stirred at rt. for 3h. The resulting mixture was used as is as 1M
Grignard solution.
Example 5: dibenzyl({2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decan
yl]ethyl})amine (Compound 225)
To a solution of 2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]acetonitrile (30
mg, 0.13 mmol) in anhydrous CH Cl (3 ml) and NA SO (92.3 mg, 0.65 mmol) at rt was
2 2 2 4
added 2.3 eq benzaldehyde (0.032 ml, 0.32 mmol); The reaction was stirred overnight.
NaBH(OAc) (6.6 mg, 0.31 mmol) added in one portion. The solution was then quenched
with H O (10 ml), extracted with CH Cl (3x20 ml), washed with brine (10 ml) and dried
2 2 2
over NA SO . The solvent was evaporated in vacuo and the residue was purified by
HPLC to obtain dibenzyl({2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decan
yl]ethyl})amine (37.4 mg, 50%, m/z 458.3 [M + H] observed).
Example 6: {2-[(9R)(4-fluorophenyl)oxaspiro[4.5]decanyl]ethyl}[(3-
methylphenyl)methyl]amine (Compound 122)
Following an analogueous procedure described for Compound 81, Compound 122
was obtained from the corresponding intermediate after a chiral HPLC separation (The
slower moving fraction on AD-3 column. The absolute configurationof Ex. 122 was
determined by an X-ray crystallography.
Example 7: {2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]ethyl}[2-(pyridin
yl)ethyl]amine (Compound 75)
1.0 M DIBAL solution in toluene (3.0 ml, 3 mmol) was added drop-wise to a solution of
2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]acetonitrile (350 mg, 1.4 mmol) in 7
mL toluene at -78 oC. The resulting mixture was stirred at -78 oC until completion (1.5
h). The reaction was then quenched with 5 eq of MeOH (0.28 mL) and 0.1 mL water, stir
while warming, 175 mg NA SO4 added, stir at room temp. 2h to give 310 mg (80%) of
2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]acetaldehyde. LCMS m/z 250.6 (M
+ 1) observed.
To a solution of 2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]acetaldehyde (50 mg,
0.19 mmole), 5 mL DCM and NA SO (134 mg, 0.95 mmole) was added 2-(pyridin
yl)ethanamine (31 mg, 0.25 mmole) and the reaction was stirred overnight. NaBH
(9.5 mg, 0.25 mmole) added, stir 10 minutes, 2 drops MeOH added, stir 1h, quenched
with water, organics separated off and evaporated. The residue was passed through a
Gilson reverse phase HPLC to give {2-[(9R)(pyridinyl)oxaspiro[4.5]decan
yl]ethyl}[2-(pyridinyl)ethyl]amine, 65.3 mg (71%). LCMS m/z 367.1 (M + 1)
observed.
Example 8: 2-[(9R)(2-{4H,5H,6H-thieno[2,3-c]pyrrolyl}ethyl)
oxaspiro[4.5]decanyl]pyridine (Compound 82)
To a stirred solution of 2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]ethanamine
(0.030 g, 0.115 mmol; prepared by following a sequence described for Compound 81 in
dried ACN (5.8 mL) was added 2,3-bis(bromomethyl)thiophene (31.1 mg, 0.115 mmol)
followed by addition of K CO (79.62 mg, 0.576 mmol). After 30 min, LCMS showed
that the reaction was done and the major peak had the corresponding mass to the desired
product. It was then subjected to HPLC purification. HPLC purification method: Luna
acid medium column, 10-50% acetonitrile in H O over 15 min, followed by flashing with
100% acetonitrile, 0.1% TFA modifier was employed. The fractions containing the
desired product were pooled, basified with 2N NaOH and extracted with DCM (3x20
mL). The combined organics were concentrated and purified with flash chromatography
(10 g silica gel column, eluted by 0-10% MeOH in DCM, based upon TLC measurement:
DCM/MeOH (10/1) Rf = 0.60) to afford 5 mg of 2-[(9R)(2-{4H,5H,6H-thieno[2,3-
c]pyrrolyl}ethyl)oxaspiro[4.5]decanyl]pyridine as a colorless oil in 12% yield.
LCMS m/z 369 (M + 1) observed.
Example 9: {2-[9-(1H-pyrazolyl)oxaspiro[4.5]decanyl]ethyl}(thiophen
ylmethyl)amine (Compound 26)
An oven-dried flask equipped with a Dean-Stork apparatus and condenser was cooled to
rt under a stream of N and was charged with 6-oxaspiro[4.5]decanone (0.50 g, 3.24
mmol), (tert-butoxy)carbohydrazide (0.42 g, 3.24 mmol) and hexane (10 mL). The
resulting solution was heated to reflux overnight.
It was cooled to rt and the solid collected by vacuum filtration. The solid was washed
with hexane and air-dried to give (tert-butoxy)-N'-[(9Z)oxaspiro[4.5]decan
ylidene]carbohydrazide (0.84 g, 96% yield). LCMS m/z 213 (M + 1-t-butyl) observed.
An oven-dried flask was charged with (tert-butoxy)-N'-[(9Z)oxaspiro[4.5]decan
ylidene]carbohydrazide (0.42 g, 1.56 mmol) and THF. The solution was cooled to 0 ºC
and allylmagnesiumchloride (2.0 M, 1.60 mL) was added dropwise. The reaction was
stirred at 0 ºC for 1h and the warmed to rt overnight. LC-MS indicated the reaction didn’t
go to completion. Another 2 equivalent of allylmagnesiumchloride was added at rt. The
solution was stirred for 1h before it was quenched with MeOH. The solution was diluted
with DCM (60 mL) and H O (20 mL). A lot of precipitates were formed and the solid
was filtered through a pad of celite. The organic was then separated and the aqueous layer
was extracted with 10 mL of EtOAc. The combined organic layers were concentrated and
the residue was purified on 25 g Snap column (0-20% tOAc in Hex, 12 CV) to give (tert-
butoxy)-N'-[9-(propenyl)oxaspiro[4.5]decanyl]carbohydrazide (0.33 g, 68%
yield). LCMS m/z 333 (M + Na) observed.
A solution of (tert-butoxy)-N'-[9-(propenyl)oxaspiro[4.5]decan
yl]carbohydrazide (0.33 g, 1.06 mmol) in 4 mL of EtOAc was added 4M HCl in dioxane
at rt. The solution was stirred at rt until reaction completion, monitored by LC-MS (30 h).
The solvent was then removed to give [9-(propenyl)oxaspiro[4.5]decan
yl]hydrazine (250 mg). LCMS m/z 211.1 (M + 1) observed.
A solution of [9-(propenyl)oxaspiro[4.5]decanyl]hydrazine (250 mg, 1.0
mmol) in 4 mL of i-PrOH were added Et3N and 3-dimethylaminoacrolein. The solution
was refluxed for 3h and then at 50 oC for 2d. The solvent removed and the residue was
purified on 25 g Biotage snap column, eluted with 0-18% EtOAc in Hex (12CV) to give
1-[9-(propenyl)oxaspiro[4.5]decanyl]-1H-pyrazole (80 mg, 31% yield).
LCMS m/z 247.1 (M + 1) observed.
To a solution of 1-[9-(propenyl)oxaspiro[4.5]decanyl]-1H-pyrazole (80 mg,
0.32 mmol) in DCM (5 mL) at -78 ºC was bubbled with O until the solution turned blue.
The resulting solution was bubbled with N for 5 min. To it was added PPh3 (168 mg,
0.64 mmol). And the solution was stirred for 4h at rt. After removal of the solvent, the
residue was purified by flash column chromatography to give 2-[9-(1H-pyrazolyl)
oxaspiro[4.5]decanyl]acetaldehyde (15 mg, 23 % yield). LCMS m/z 249 (M + 1)
observed.
To a mixture of 2-[9-(1H-pyrazolyl)oxaspiro[4.5]decanyl]acetaldehyde (15 mg,
0.06 mmol) and thiophenylmethanamine (19 uL, 0.18 mmol) was stirred ar rt for 1h
before NaBH(OAc) (25.4 mg, .12 mmol) was added. The solution stirred overnight.
After removal of solvent, the residue was purified by HPLC to provide {2-[9-(1H-
pyrazolyl)oxaspiro[4.5]decanyl]ethyl}(thiophenylmethyl)amine (17 mg, 61%
yield) as a TFA salt. LCMS m/z 346 (M + 1) observed.
Example 10: Basic Procedure for making compounds of the formula:
Following Scheme 8 2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]ethanamine ,
which can be prepared by following a sequence as described for Compound 81
(Compound 4) and a sequence similar to for Intermediate 11 reacts with an appropriately
substituted heteroaromatic aldehyde or appropriately substituted aromatic aldehyde (1
equivalent) in the presence of an organic solvent (i.e. DCM, MeOH, EtOH) to form a
corresponding imine, which is reduced by an appropriate reducing agent the compound.
The (R) and the R refers to the optional substituents Additionally, the phenyl groups
can be replaced with other cycles or aryl groups as described herein.
Example 11: Basic procedures for making compounds of the formula:
Following Scheme 9, 9-1, which can be prepared by following a sequence described for
Compound 81 (Compound 4) and a sequence similar to for Intermediate 11, reacts with
an appropriately substituted heteroaromatic aldehyde or appropriately substituted
aromatic aldehyde (1 equivalent) in the presence of an organic solvent (i.e. DCM, MeOH,
EtOH and etc) to form a corresponding imine, which is reduced by an appropriate
reducing agent (i.e. NaBH ) to give the compound. The (R) and the R refers to the
4 n m
optional substituents Additionally, the phenyl groups can be replaced with other cycles
or aryl groups as described herein.
Example 12: Opioid Receptor Ligands
The opioid receptor ligands and compounds listed in the following tables can be or were
prepared according to the procedures described above from appropriate starting materials
and appropriate reagents. Compounds that have been made lists NMR data and prophetic
examples do not list NMR data.
Table 1: Compounds with chemical name and characterization data
Compoun
Name (m/z) 1H NMR
[M+H]
δ 8.58 (ddd, J = 4.8, 1.9, 0.9, 1H), 7.63 (m, 1H),
7.30 (m, 1H), 7.12 (ddd, J = 7.4, 4.8, 1.0, 1H),
2-[9-(pyridinyl)
3.76 (m, 2H), 2.55 (td, J = 11.6, 5.1, 1H), 2.46
oxaspiro[4.5]decan-
1 261.1 (ddd, J = 13.7, 5.1, 2.7, 1H), 2.37 (dd, J = 13.7,
2.1, 1H), 2.14 (td, J = 11.6, 5.0, 1H), 1.92 (m,
yl]ethanamine
2H), 1.70 (m, 4H), 1.46 (m, 4H), 1.13 (m, 1H),
0.71 (dt, J = 13.4, 8.8, 1H).
2-[(9R)(pyridin δ 8.58 (ddd, J = 4.8, 1.7, 0.7, 1H), 7.64 (td, J =
yl) 7.8, 1.9, 1H), 7.28 (m, 1H), 7.12 (ddd, J = 7.4,
2 oxaspiro[4.5]decan- 261.2 4.8, 0.9, 1H), 3.76 (m, 2H), 2.55 (m, 1H), 2.46
9- (ddd, J = 13.7, 5.1, 2.7, 1H), 2.37 (m, 1H), 2.14
yl]ethanamine (m, 1H), 1.91 (m, 2H), 1.71 (m, 4H), 1.47 (m,
4H), 1.13 (m, 1H), 0.71 (m, 1H).
δ 7.60 (d, J = 6.8, 1H), 7.60 (d, J = 6.8, 1H),
7.21 (s, 2H), 6.79 (d, J = 332.9, 3H), 6.54 (m,
5H), 6.37 (s, 1H), 6.29 (d, J = 6.5, 1H), 5.97 (m,
2-[9-(2-aminoethyl)- 6H), 4.84 (d, J = 169.9, 3H), 3.69 (dt, J = 23.7,
6- 11.7, 3H), 3.69 (dt, J = 23.7, 11.7, 3H), 3.40 (s,
3 oxaspiro[4.5]decan- 277.1 2H), 3.40 (s, 2H), 2.64 (s, 1H), 2.64 (s, 1H),
9- 2.32 (d, J = 12.0, 1H), 2.26 (dd, J = 46.7, 13.0,
yl]pyridinol 2H), 2.20 (d, J = 13.9, 1H), 2.09 (d, J = 13.8,
1H), 2.09 (d, J = 13.8, 1H), 1.84 (t, J = 15.9,
2H), 1.60 (m, 15H), 1.55 (m, 11H), 0.89 (m,
2H), 0.89 (m, 1H).
δ 8.05 (m, 1H), 7.01 (d, J = 8.6, 1H), 6.87 (dd, J
6-[9-(2-aminoethyl)- = 8.6, 2.9, 1H), 5.37 (s, 2H), 3.66 (dd, J = 13.7,
6- 7.2, 2H), 2.60 (ddd, J = 12.3, 10.1, 5.6, 1H),
4 oxaspiro[4.5]decan- 277.1 2.22 (m, 3H), 1.88 (tt, J = 10.0, 7.9, 1H), 1.77
9- (d, J = 13.6, 1H), 1.58 (m, 4H), 1.37 (m, 5H),
yl]pyridinol 1.08 (dd, J = 15.4, 4.9, 1H), 0.63 (dt, J = 13.7,
8.9, 1H).
6-[9-(2-aminoethyl)-
δ 7.38 (dd, J = 9.0, 7.1, 1H), 6.40 (d, J = 9.0,
1H), 6.09 (d, J = 7.1, 1H), 5.28 (s, 1H), 3.73 (s,
oxaspiro[4.5]decan- 277.1
2H), 2.69 (m, 1H), 2.37 (m, 2H), 2.13 (m, 2H),
1.66 (m, 12H), 0.97 (dt, J = 12.4, 7.6, 1H).
yl]pyridinol
2-[(9R)(2- δ 8.23 (m, 1H), 7.31 (dd, J = 5.8, 2.0, 2H), 7.23
aminoethyl) (m, 1H), 4.03 (s, 2H), 3.81 (s, 2H), 3.27 (d, J =
oxaspiro[4.5]decan- 13.9, 1H), 2.95 (td, J = 12.8, 5.1, 1H), 2.65 (td, J
6 277.1
9- = 11.8, 5.1, 1H), 2.25 (s, 2H), 1.65 (ddd, J =
yl]oxidopyridin 38.7, 17.6, 11.7, 9H), 1.24 (s, 1H), 0.84 (dt, J =
ium 13.1, 8.8, 1H).
δ 9.72 (t, J = 1.5, 1H), 7.91 (m, 2H), 7.23 (m,
benzyl({2-[1-(4- 3H), 7.06 (m, 2H), 6.92 (m, 2H), 2.91 (t, J = 6.9,
7 fluorophenyl)cyclohe 312.2 2H), 2.44 (m, 4H), 2.09 (dd, J = 13.2, 5.3, 2H),
xyl]ethyl})amine 1.68 (m, 4H), 1.46 (m, 1H), 1.33 (dd, J = 15.4,
6.7, 4H).
δ 7.38 – 7.16 (m, 7H), 7.09 – 6.99 (m, 2H),
benzyl({2-[4-(4- 3.79 (ddd, J = 11.5, 5.7, 3.6, 2H), 3.64 (s, 2H),
8 fluorophenyl)oxan 314.2 3.56 (ddd, J = 11.6, 8.8, 2.8, 2H), 2.39 – 2.29
yl]ethyl})amine (m, 2H), 2.24 – 2.01 (m, 4H), 1.86 (ddd, J =
13.8, 7.9, 3.5, 2H).
[(2-
δ 7.16 (m, 8H), 3.79 (ddd, J = 11.5, 5.2, 3.8,
methylphenyl)methyl
2H), 3.58 (m, 4H), 2.41 (m, 2H), 2.36 (s, 3H),
9 ]({2-[4-(4- 324.2
2.27 (s, 3H), 2.16 (m, 2H), 1.86 (ddd, J = 12.3,
methylphenyl)oxan-
8.6, 4.6, 4H), 1.58 (s, 1H)
4-yl]ethyl})amine
N-{2-[2,2-dimethyl- 324.3 δ 7.25 (dt, J = 5.9, 2.9, 3H), 7.11 (m, 2H), 6.98
4-(4- (dd, J = 25.0, 8.2, 4H), 3.65 (dd, J = 8.9, 6.7,
methylphenyl)oxan- 2H), 2.95 (d, J = 4.6, 1H), 2.50 (d, J = 4.7, 1H),
4- 2.23 (s, 3H), 2.10 (d, J = 13.9, 1H), 1.89 (m,
yl]ethyl}aniline 3H), 1.43 (m, 2H), 1.21 (m, 1H), 1.05 (s, 3H),
0.53 (s, 3H).
2-[({2-[4-(4-
δ 7.15 (m, 5H), 6.88 (dd, J = 7.4, 1.3, 1H), 6.79
methylphenyl)oxan-
(dd, J = 8.1, 1.0, 1H), 6.73 (td, J = 7.4, 1.1, 1H),
11 4- 326.2
3.76 (m, 4H), 3.54 (ddd, J = 11.7, 9.4, 2.5, 2H),
yl]ethyl}amino)meth
2.37 (m, 5H), 2.13 (m, 2H), 1.82 (m, 4H)
yl]phenol
δ 8.26 (s, 2H), 7.07 (m, 3H), 6.95 (dd, J = 14.3,
2-[({2-[4-(4- 5.8, 2H), 6.86 (d, J = 6.3, 1H), 6.78 (d, J = 8.1,
fluorophenyl)oxan 1H), 6.71 (t, J = 7.4, 1H), 3.96 (d, J = 7.0, 2H),
12 330.2
yl]ethyl}amino)meth 3.80 (s, 2H), 3.64 (dt, J = 8.8, 3.9, 2H), 3.41 (t, J
yl]phenol = 9.3, 2H), 2.45 (s, 2H), 1.95 (d, J = 14.7, 2H),
1.85 (m, 2H), 1.67 (m, 2H).
δ 9.76 (s, 2H), 8.59 (d, J = 4.7, 1H), 8.11 (t, J =
7.8, 1H), 7.69 (d, J = 8.1, 1H), 7.63 – 7.52 (m,
benzyl({2-[3-
1H), 7.35 (s, 5H), 4.13 (d, J = 9.7, 1H), 4.03 (s,
(pyridinyl)
2H), 3.91 (d, J = 9.7, 1H), 2.92 (d, J = 26.5, 2H),
13 oxaspiro[4.4]nonan- 337.1
2.53 (ddd, J = 14.6, 9.5, 5.4, 1H), 2.38 (dd, J =
19.0, 8.5, 2H), 2.28 (d, J = 13.6, 1H), 1.99 –
yl]ethyl})amine
1.81 (m, 1H), 1.84 – 1.52 (m, 6H), 1.51 – 1.35
(m, 1H).
δ 8.54 (d, J = 226.0, 2H), 7.22 (q, J = 6.7, 3H),
benzyl({2-[2,2-
7.03 (dd, J = 19.0, 8.3, 6H), 6.23 (d, J = 186.3,
dimethyl(4-
2H), 3.69 (m, 4H), 2.66 (s, 1H), 2.25 (s, 4H),
14 methylphenyl)oxan- 338.3
2.10 (dd, J = 22.7, 13.3, 2H), 1.83 (m, 1H), 1.64
(m, 1H), 1.49 (m, 2H), 1.11 (s, 3H), 0.57 (s,
yl]ethyl})amine
3H).
δ 8.48 (dd, J = 5.2, 0.9, 1H), 8.26 (s, 1H), 7.98
{2-[2,2-dimethyl
(dd, J = 7.8, 1.6, 1H), 7.59 (d, J = 7.9, 1H), 7.54
(m, 1H), 7.07 (s, 4H), 4.17 (q, J = 13.9, 2H),
methylphenyl)oxan-
339.3 3.73 (m, 2H), 2.88 (d, J = 4.8, 1H), 2.42 (d, J =
4.8, 1H), 2.21 (m, 4H), 2.10 (dd, J = 13.9, 2.1,
yl]ethyl}(pyridin
1H), 2.00 (d, J = 4.6, 1H), 1.78 (d, J = 4.6, 1H),
ylmethyl)amine
1.58 (m, 2H), 1.12 (s, 3H), 0.59 (s, 3H).
δ 8.92 (s, 1H), 8.52 (s, 1H), 8.25 (d, J = 8.0,
{2-[2,2-dimethyl
1H), 7.67 (m, 1H), 7.08 (m, 4H), 5.92 (s, 4H),
4.09 (s, 2H), 3.71 (m, 2H), 2.85 (dd, J = 12.0,
methylphenyl)oxan-
16 339.3 7.9, 1H), 2.34 (m, 1H), 2.23 (m, 4H), 2.10 (d, J
= 13.9, 1H), 1.94 (m, 1H), 1.74 (dd, J = 12.5,
yl]ethyl}(pyridin
4.3, 1H), 1.55 (m, 2H), 1.10 (s, 3H), 0.57 (s,
ylmethyl)amine
3H).
[(2- δ 7.21 (m, 1H), 7.13 (s, 4H), 7.07 (dd, J = 7.4,
17 340.2
methoxyphenyl)meth 1.7, 1H), 6.84 (ddd, J = 12.1, 9.3, 4.6, 2H), 3.78
yl]({2-[4-(4- (m, 5H), 3.63 (s, 2H), 3.54 (ddd, J = 11.6, 9.1,
methylphenyl)oxan- 2.7, 2H), 2.38 (d, J = 1.3, 1H), 2.32 (m, 5H),
4-yl]ethyl})amine 2.10 (m, 2H), 1.84 (m, 4H)
δ 8.72 (d, J = 4.6, 1H), 8.23 (t, J = 7.3, 1H), 7.84
– 7.57 (m, 2H), 7.46 (s, 1H), 7.38 (t, J = 1.6,
(furan 1H), 7.28 (s, 1H), 3.89 (s, 2H), 3.82 (dt, J =
ylmethyl)({2-[(9R)- 12.4, 4.2, 1H), 3.72 (dd, J = 16.1, 6.2, 1H), 2.96
18 9-(pyridinyl) 341.1 (d, J = 4.4, 1H), 2.40 (ddd, J = 36.0, 24.7, 12.8,
oxaspiro[4.5]decan- 4H), 2.20 (dd, J = 12.7, 4.8, 1H), 2.01 (d, J =
9-yl]ethyl})amine 14.2, 1H), 1.95 – 1.77 (m, 2H), 1.69 (dd, J = 9.6,
4.4, 1H), 1.63 – 1.39 (m, 4H), 1.21 – 1.08 (m,
1H), 0.91 – 0.60 (m, 1H).
δ 8.70 (d, J = 5.1, 1H), 8.40 (t, J = 7.9, 1H), 7.92
(d, J = 8.2, 1H), 7.87 – 7.74 (m, 1H), 7.31 (d, J =
(1H-imidazol
18.0, 2H), 4.66 (d, J = 14.3, 1H), 4.49 (d, J =
ylmethyl)({2-[(9R)-
14.3, 1H), 4.02 – 3.81 (m, 1H), 3.74 (d, J = 9.7,
19 9-(pyridinyl) 341.1
1H), 3.10 (d, J = 4.9, 1H), 2.84 – 2.48 (m, 2H),
oxaspiro[4.5]decan-
2.37 (t, J = 12.7, 3H), 2.17 – 2.00 (m, 1H), 2.00
9-yl]ethyl})amine
– 1.82 (m, 2H), 1.70 (s, 1H), 1.65 – 1.41 (m,
4H), 1.21 (s, 1H), 0.82 (d, J = 13.1, 1H).
δ 8.77 (dd, J = 5.5, 1.4, 1H), 8.26 (td, J = 8.0,
1.7, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.79 – 7.60
(1,3-oxazol
(m, 2H), 4.08 (s, 2H), 3.86 (d, J = 12.9, 1H),
ylmethyl)({2-[(9R)-
3.81 – 3.66 (m, 1H), 3.13 (d, J = 5.6, 1H), 2.76 –
9-(pyridinyl) 342.1
2.60 (m, 1H), 2.48 (s, 1H), 2.42 – 2.25 (m, 3H),
oxaspiro[4.5]decan-
2.16 – 2.01 (m, 1H), 1.89 (dd, J = 9.6, 4.0, 2H),
9-yl]ethyl})amine
1.79 – 1.63 (m, 1H), 1.63 – 1.35 (m, 4H), 1.19
(s, 1H), 0.80 (d, J = 13.2, 1H).
δ 10.01 (s, 3H), 8.62 (d, J = 4.5, 1H), 8.11 (td, J
= 8.0, 1.4, 1H), 7.70 (d, J = 8.1, 1H), 7.63 – 7.46
{2-[3-(pyridinyl)- (m, 1H), 7.33 (dd, J = 5.1, 1.0, 1H), 7.16 (d, J =
1- 2.8, 1H), 7.00 (dd, J = 5.1, 3.6, 1H), 4.29 (s,
21 oxaspiro[4.4]nonan- 343 2H), 4.14 (d, J = 9.7, 1H), 3.92 (d, J = 9.7, 1H),
3-yl]ethyl}(thiophen- 2.97 (qd, J = 18.1, 12.2, 2H), 2.53 (ddd, J =
2-ylmethyl)amine 14.4, 9.0, 5.7, 1H), 2.45 – 2.21 (m, 3H), 2.00 –
1.82 (m, 1H), 1.67 (tt, J = 22.6, 8.0, 6H), 1.44
(dd, J = 14.3, 10.0, 1H).
δ 11.15 (s, 2H), 9.70 (s, 2H), 8.64 (d, J = 4.4,
1H), 8.17 (td, J = 8.0, 1.5, 1H), 7.74 (d, J = 8.1,
{2-[3-(pyridinyl)-
1H), 7.63 (dd, J = 6.7, 5.7, 1H), 7.40 (dd, J =
2.8, 1.1, 1H), 7.33 (dd, J = 5.0, 3.0, 1H), 7.10
oxaspiro[4.4]nonan-
22 343 (dd, J = 5.0, 1.2, 1H), 4.23 – 4.07 (m, 3H), 3.94
(d, J = 9.8, 1H), 2.90 (d, J = 33.7, 2H), 2.67 –
yl]ethyl}(thiophen
2.50 (m, 1H), 2.50 – 2.24 (m, 3H), 1.91 (dd, J =
ylmethyl)amine
13.7, 4.9, 1H), 1.83 – 1.52 (m, 6H), 1.43 (td, J =
7.7, 3.9, 1H).
δ 8.77 (d, J = 4.6, 2H), 8.26 (t, J = 7.6, 1H), 7.89
(cyclopentylmethyl)(
– 7.60 (m, 2H), 3.85 (dd, J = 8.5, 4.2, 1H), 3.73
{2-[(9R)(pyridin-
(t, J = 10.1, 1H), 3.00 (s, 1H), 2.81 (s, 2H), 2.42
23 2-yl) 343.3
(dt, J = 23.0, 9.5, 4H), 2.25 (t, J = 10.8, 1H),
oxaspiro[4.5]decan-
2.19 – 1.98 (m, 2H), 1.98 – 1.33 (m, 13H), 1.16
9-yl]ethyl})amine
(s, 3H), 0.76 (dt, J = 13.1, 8.9, 1H).
{2-[2,2-dimethyl
δ 8.87 (d, J = 194.4, 2H), 3.91 (s, 3H), 3.69 (m,
2H), 2.66 (d, J = 7.9, 1H), 2.24 (m, 4H), 2.10
methylphenyl)oxan-
24 344.2 (ddd, J = 30.6, 14.0, 2.1, 2H), 1.84 (td, J = 12.5,
4.9, 1H), 1.65 (m, 1H), 1.49 (m, 2H), 1.11 (d, J
yl]ethyl}(thiophen
= 6.1, 3H), 0.57 (s, 3H).
ylmethyl)amine
{2-[4-(4- δ 7.20 (ddd, J = 7.6, 4.8, 2.0, 3H), 7.03 (m, 3H),
fluorophenyl)oxan 6.84 (ddd, J = 11.7, 9.1, 4.5, 2H), 3.77 (m, 5H),
yl]ethyl}[(2- 344.2 3.61 (s, 2H), 3.54 (ddd, J = 11.6, 8.8, 2.8, 2H),
methoxyphenyl)meth 2.27 (m, 2H), 2.08 (m, 2H), 1.84 (ddd, J = 10.5,
yl]amine 8.4, 3.0, 4H), 1.58 (s, 1H)
δ 9.87 (s, 1H), 9.00 (d, J = 145.4, 2H), 7.46 (dd,
J = 12.7, 2.1, 2H), 7.28 (dd, J = 5.1, 1.1, 1H),
{2-[9-(1H-pyrazol 7.01 (d, J = 0.8, 1H), 6.93 (dd, J = 5.1, 3.5, 1H),
yl) 6.34 – 6.24 (m, 1H), 5.22 (s, 1H), 4.10 (q, J =
oxaspiro[4.5]decan- 14.2, 2H), 3.68 (d, J = 2.7, 2H), 2.94 (s, 1H),
26 346
9- 2.50 (s, 1H), 2.31 (s, 2H), 2.24 – 2.08 (m, 1H),
yl]ethyl}(thiophen 1.99 (dt, J = 14.7, 7.3, 1H), 1.93 – 1.76 (m, 2H),
ylmethyl)amine 1.75 – 1.63 (m, 1H), 1.57 (ddd, J = 23.2, 14.0,
8.1, 1H), 1.51 (s, 4H), 1.17 – 1.04 (m, 1H), 0.69
(dt, J = 13.3, 8.7, 1H).
δ 8.67 (d, J = 4.7, 1H), 8.17 (t, J = 7.7, 1H), 7.64
(m, 2H), 7.35 (m, 5H), 6.51 (s, 4H), 4.72 (s,
benzyl({2-[(9S)
1H), 3.94 (s, 2H), 3.75 (m, 2H), 2.95 (s, 1H),
(pyridinyl)
27 351.1 2.49 (s, 1H), 2.33 (m, 3H), 2.19 (m, 1H), 1.98
oxaspiro[4.5]decan-
(d, J = 14.1, 1H), 1.81 (dt, J = 13.4, 7.5, 2H),
9-yl]ethyl})amine
1.68 (m, 1H), 1.49 (ddd, J = 20.8, 14.7, 7.2, 4H),
1.15 (s, 1H), 0.75 (m, 1H).
δ 8.61 (s, 1H), 8.18 (t, J = 7.7, 1H), 7.65 (m,
2H), 7.26 (m, 5H), 6.90 (d, J = 26.0, 4H), 3.88
benzyl({2-[(9R)
(s, 2H), 3.72 (d, J = 12.7, 1H), 3.60 (t, J = 10.0,
(pyridinyl)
28 351.1 1H), 2.90 (s, 1H), 2.39 (d, J = 34.6, 2H), 2.20 (t,
oxaspiro[4.5]decan-
J = 13.3, 3H), 1.92 (d, J = 14.8, 2H), 1.75 (m,
9-yl]ethyl})amine
2H), 1.59 (d, J = 4.9, 1H), 1.41 (m, 4H), 1.08 (s,
1H), 0.68 (dt, J = 13.2, 9.0, 1H).
benzyl({2-[3- δ 9.67 (s, 2H), 8.61 (s, 1H), 8.19 (t, J = 7.5,
(pyridinyl) 1H), 7.80 (d, J = 8.1, 1H), 7.64 (s, 1H), 7.36 (s,
29 oxaspiro[4.5]decan- 351.1 5H), 4.22 (d, J = 10.0, 1H), 4.05 (s, 2H), 3.98 (d,
3- J = 10.0, 1H), 3.00 (s, 1H), 2.84 (s, 1H), 2.64 (s,
yl]ethyl})amine 1H), 2.39 (d, J = 8.7, 1H), 2.18 (d, J = 13.6, 1H),
2.09 (d, J = 13.6, 1H), 1.75 – 1.52 (m, 4H), 1.33
(dd, J = 28.9, 16.2, 7H).
δ 8.49 (s, 1H), 8.03 (s, 1H), 7.53 (d, J = 8.0,
2H), 7.18 (m, 5H), 3.82 (s, 2H), 3.63 (s, 1H),
benzyl({2-[9-
3.53 (dd, J = 23.8, 13.7, 1H), 2.84 (s, 1H), 2.38
(pyridinyl)
351.2 (s, 1H), 2.27 (d, J = 7.4, 1H), 2.13 (d, J = 14.1,
oxaspiro[4.5]decan-
3H), 1.84 (d, J = 14.2, 1H), 1.67 (m, 2H), 1.52
9-yl]ethyl})amine
(d, J = 5.0, 1H), 1.32 (m, 4H), 1.01 (s, 1H), 0.61
(dt, J = 13.0, 8.9, 1H).
{2-[2,2-dimethyl
(4- δ 7.09 (d, J = 8.3, 2H), 7.02 (ddd, J = 8.1, 6.1,
methylphenyl)oxan- 3.3, 6H), 3.69 (m, 2H), 3.47 (s, 2H), 2.41 (td, J
31 4- 352.2 = 10.8, 5.4, 1H), 2.25 (m, 4H), 2.11 (m, 5H),
yl]ethyl}[(2- 1.75 (ddd, J = 13.2, 10.4, 5.2, 1H), 1.56 (m, 4H),
methylphenyl)methyl 1.11 (s, 3H), 0.59 (s, 3H).
]amine
{2-[2,2-dimethyl
δ 9.13 (s, 1H), 8.69 (s, 1H), 7.04 (m, 6H), 6.86
methylphenyl)oxan-
(m, 2H), 3.65 (m, 6H), 2.59 (s, 1H), 2.12 (m,
32 4- 352.3
9H), 1.83 (td, J = 12.4, 4.5, 1H), 1.64 (m, 1H),
yl]ethyl}[(3-
1.48 (m, 2H), 1.10 (s, 3H), 0.57 (s, 3H).
methylphenyl)methyl
]amine
{2-[2,2-dimethyl
δ 8.68 (d, J = 205.9, 2H), 7.02 (dd, J = 16.8,
9.0, 6H), 6.93 (d, J = 8.1, 2H), 3.67 (dd, J = 6.6,
methylphenyl)oxan-
2.7, 2H), 3.57 (s, 2H), 3.44 (s, 3H), 2.61 (s, 1H),
33 4- 352.3
2.25 (d, J = 11.2, 3H), 2.17 (s, 3H), 2.08 (dd, J =
yl]ethyl}[(4-
.3, 14.0, 2H), 1.84 (m, 1H), 1.67 (d, J = 7.6,
methylphenyl)methyl
1H), 1.48 (m, 2H), 1.09 (s, 3H), 0.56 (s, 3H).
]amine
{2-[2,2-dimethyl δ 9.07 (dd, J = 228.2, 166.6, 2H), 7.24 (ddd, J =
(4- 9.3, 6.4, 3.4, 3H), 7.15 (m, 2H), 6.94 (m, 4H),
methylphenyl)oxan- 3.91 (s, 1H), 3.61 (dd, J = 7.0, 4.0, 2H), 2.42 (d,
34 352.3
4- J = 33.9, 1H), 2.21 (d, J = 11.7, 6H), 2.00 (m,
yl]ethyl}[(1R) 2H), 1.82 (m, 1H), 1.62 (dd, J = 8.6, 4.1, 1H),
phenylethyl]amine 1.42 (m, 5H), 1.05 (s, 3H), 0.53 (d, J = 3.4, 3H).
{2-[2,2-dimethyl δ 8.92 (dd, J = 238.8, 174.0, 2H), 7.24 (m, 3H),
(4- 7.14 (td, J = 7.5, 2.2, 2H), 6.95 (m, 4H), 3.89 (d,
methylphenyl)oxan- J = 19.3, 1H), 3.62 (m, 2H), 2.96 (s, 2H), 2.42
352.3
4- (m, 1H), 2.21 (d, J = 11.6, 3H), 2.00 (m, 3H),
yl]ethyl}[(1S) 1.82 (m, 1H), 1.63 (m, 1H), 1.40 (m, 5H), 1.06
phenylethyl]amine (s, 3H), 0.53 (d, J = 3.6, 3H).
benzyl({2-[2,2- δ 11.09 (s, 2H), 7.39 (m, 3H), 7.23 (m, 1H),
dimethyl(4- 7.15 (m, 5H), 4.19 (dd, J = 25.7, 12.6, 1H), 3.91
36 352.3
methylphenyl)oxan- (dd, J = 17.4, 8.4, 1H), 3.78 (m, 2H), 2.91 (d, J =
4- 127.4, 1H), 2.56 (dd, J = 17.7, 7.2, 3H), 2.37 (d,
yl]ethyl})methylamin J = 4.8, 3H), 2.24 (ddd, J = 22.0, 12.2, 2.2, 3H),
e 2.05 (m, 1H), 1.88 (td, J = 12.5, 4.7, 1H), 1.64
(m, 2H), 1.21 (s, 3H), 382.30.67 (d, J = 1.2, 3H).
{2-[2,2-dimethyl
δ 9.06 (d, J = 128.6, 2H), 7.17 (m, 3H), 7.02
(m, 6H), 3.68 (dd, J = 11.8, 10.1, 2H), 2.77 (dt, J
methylphenyl)oxan-
37 352.3 = 36.5, 30.4, 7H), 2.19 (m, 5H), 1.99 (m, 1H),
1.89 (td, J = 12.5, 4.6, 1H), 1.69 (m, 1H), 1.49
yl]ethyl}(2-
(m, 2H), 1.00 (s, 3H), 0.52 (s, 3H).
phenylethyl)amine
δ 8.79 (dd, J = 5.6, 1.4, 1H), 8.68 – 8.54 (m,
2H), 8.51 (dd, J = 2.3, 1.6, 1H), 8.32 (td, J = 8.0,
1.6, 1H), 7.93 – 7.66 (m, 3H), 4.30 (s, 2H), 3.85
(pyrazin
(dt, J = 12.3, 4.2, 1H), 3.72 (t, J = 9.9, 1H), 3.19
ylmethyl)({2-[(9R)-
(td, J = 11.7, 5.2, 1H), 2.72 (td, J = 11.8, 4.0,
38 9-(pyridinyl) 353.1
1H), 2.62 – 2.45 (m, 1H), 2.45 – 2.27 (m, 3H),
oxaspiro[4.5]decan-
2.10 (d, J = 14.2, 1H), 2.00 – 1.79 (m, 2H), 1.69
9-yl]ethyl})amine
(dt, J = 9.9, 6.6, 1H), 1.63 – 1.41 (m, 4H), 1.19
(dd, J = 12.6, 6.5, 1H), 0.78 (dt, J = 13.1, 8.9,
1H).
δ 8.71 (dd, J = 5.5, 1.4, 1H), 8.21 (td, J = 8.0,
1.7, 1H), 7.67 (m, 2H), 7.33 (m, 5H), 3.95 (s,
benzyl({2-[2,2-
2H), 3.79 (m, 1H), 3.67 (d, J = 10.8, 1H), 3.01
diethyl(pyridin
39 353.3 (d, J = 5.2, 1H), 2.40 (m, 4H), 2.10 (s, 1H), 1.73
yl)oxan
(t, J = 16.5, 2H), 1.55 (dd, J = 14.1, 7.5, 1H),
yl]ethyl})amine
1.39 (dd, J = 14.1, 7.4, 1H), 0.81 (m, 5H), 0.56
(t, J = 7.3, 3H).
benzyl({2-[2,2,6,6- δ 8.74 – 8.62 (m, 1H), 8.24 (td, J = 8.1, 1.5, 1H),
tetramethyl 7.87 (d, J = 8.2, 1H), 7.76 – 7.65 (m, 1H), 7.47 –
40 (pyridin 353.3 7.18 (m, 7H), 3.96 (s, 2H), 2.75 (s, 2H), 2.50 (d,
yl)oxan J = 14.7, 2H), 2.43 – 2.28 (m, 2H), 1.89 (d, J =
yl]ethyl})amine 14.8, 2H), 1.30 (s, 6H), 0.97 (s, 6H).
4-[({2-[2,2-dimethyl- δ 8.58 (d, J = 187.3, 2H), 7.05 (q, J = 8.3, 4H),
4-(4- 6.91 (d, J = 8.3, 2H), 6.58 (d, J = 8.4, 2H), 3.67
methylphenyl)oxan- (d, J = 10.4, 2H), 3.58 (s, 2H), 2.63 (d, J = 18.2,
41 354.2
4- 1H), 2.26 (s, 4H), 2.07 (d, J = 14.3, 4H), 1.84 (t,
yl]ethyl}amino)meth J = 10.2, 1H), 1.49 (d, J = 13.9, 3H), 1.09 (s,
yl]phenol 3H), 0.56 (s, 3H).
2-[({2-[2,2-dimethyl- δ 8.15 (d, J = 107.7, 2H), 7.03 (dt, J = 26.2, 8.3,
4-(4- 5H), 6.82 (m, 2H), 6.64 (t, J = 7.4, 1H), 3.68 (m,
methylphenyl)oxan- 6H), 2.58 (s, 1H), 2.24 (d, J = 6.8, 4H), 2.05 (dd,
42 354.3
4- J = 21.0, 14.9, 2H), 1.78 (d, J = 4.4, 1H), 1.58
yl]ethyl}amino)meth (s, 1H), 1.44 (dd, J = 21.2, 9.8, 2H), 1.10 (d, J =
yl]phenol 18.7, 3H), 0.57 (d, J = 24.3, 3H).
3-[({2-[2,2-dimethyl- δ 8.50 (d, J = 165.4, 2H), 7.02 (m, 5H), 6.68 (d,
43 4-(4- 354.3 J = 7.5, 2H), 6.47 (d, J = 7.4, 1H), 3.67 (d, J =
methylphenyl)oxan- 9.4, 2H), 3.59 (s, 2H), 2.63 (s, 2H), 2.23 (s, 4H),
4- 2.09 (dd, J = 27.3, 13.5, 2H), 1.84 (d, J = 7.8,
yl]ethyl}amino)meth 1H), 1.66 (d, J = 8.6, 1H), 1.52 (d, J = 13.9, 2H),
yl]phenol 1.09 (s, 3H), 0.56 (s, 3H).
δ 8.73 (d, J = 4.2, 1H), 8.18 (td, J = 8.0, 1.5,
[(5-methylfuran 1H), 7.80 – 7.53 (m, 2H), 7.29 (s, 1H), 4.00 (d, J
yl)methyl]({2-[(9R)- = 1.4, 2H), 3.83 (dt, J = 12.4, 4.3, 1H), 3.79 –
9-(pyridin 3.63 (m, 1H), 3.10 – 2.86 (m, 1H), 2.64 – 2.44
44 355.1
yl) (m, 1H), 2.45 – 2.27 (m, 3H), 2.27 – 2.11 (m,
oxaspiro[4.5]decan- 4H), 2.02 (d, J = 14.2, 1H), 1.95 – 1.77 (m, 2H),
9-yl]ethyl})amine 1.68 (dd, J = 9.5, 4.1, 1H), 1.62 – 1.39 (m, 4H),
1.26 – 1.05 (m, 1H), 0.77 (dt, J = 13.3, 9.0, 1H).
δ 8.66 (s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 6.27
[(5-methylfuran (d, J = 3.2, 1H), 6.05 – 5.83 (m, 1H), 3.94 (d, J =
yl)methyl]({2-[9- 1.9, 2H), 3.85 – 3.59 (m, 2H), 2.89 (d, J = 5.0,
45 (pyrazinyl) 356.1 1H), 2.49 (d, J = 5.1, 1H), 2.38 (t, J = 16.0, 2H),
oxaspiro[4.5]decan- 2.24 (s, 4H), 2.02 (dd, J = 18.2, 6.8, 2H), 1.96 –
9-yl]ethyl})amine 1.88 (m, 2H), 1.59 – 1.37 (m, 5H), 1.09 (s, 1H),
0.66 (d, J = 13.4, 1H).
δ 9.56 (s, 1H), 9.11 (s, 1H), 7.31 (m, 3H), 7.23
benzyl({2-[9- (m, 2H), 7.19 (dd, J = 5.1, 1.0, 1H), 6.91 (dd, J =
(thiophenyl) 5.1, 3.6, 1H), 6.74 (d, J = 3.5, 1H), 3.72 (m,
46 oxaspiro[4.5]decan- 356.2 4H), 2.74 (m, 1H), 2.44 (m, 1H), 2.01 (d, J =
9- 13.9, 2H), 1.95 (dd, J = 11.7, 5.0, 1H), 1.87 (m,
yl]ethyl})amine 2H), 1.73 (s, 5H), 1.66 (m, 2H), 1.50 (m, 3H),
1.00 (dd, J = 13.6, 8.5, 1H).
{2-[2,2-dimethyl
δ 7.15 (m, 1H), 7.06 (m, 5H), 6.94 (dt, J = 18.3,
8.1, 2H), 3.69 (t, J = 7.7, 2H), 3.60 (s, 2H), 2.44
methylphenyl)oxan-
(dd, J = 11.0, 5.2, 1H), 2.22 (d, J = 20.4, 4H),
47 4- 356.3
2.11 (m, 2H), 1.77 (dd, J = 6.6, 4.0, 1H), 1.57
yl]ethyl}[(2-
(qd, J = 10.9, 5.5, 3H), 1.11 (s, 3H), 0.59 (s,
fluorophenyl)methyl]
3H).
amine
δ 8.79 (d, J = 198.9, 2H), 7.19 (m, 2H), 7.05 (d,
{2-[2,2-dimethyl
J = 8.2, 2H), 7.00 (d, J = 8.4, 2H), 6.94 (td, J =
8.4, 2.2, 1H), 6.86 (d, J = 7.6, 1H), 6.79 (d, J =
methylphenyl)oxan-
48 356.3 8.9, 1H), 6.36 (s, 2H), 3.69 (m, 4H), 2.65 (s,
4-yl]ethyl}[(3-
1H), 2.24 (s, 3H), 2.11 (ddd, J = 18.3, 15.7,
fluorophenyl)methyl]
11.3, 3H), 1.81 (dt, J = 12.3, 6.2, 1H), 1.63 (m,
amine
1H), 1.48 (m, 2H), 1.10 (s, 3H), 0.56 (s, 3H).
{2-[2,2-dimethyl
(4- δ 8.73 (d, J = 173.6, 2H), 7.03 (m, 6H), 6.88 (t,
methylphenyl)oxan- J = 8.5, 2H), 5.32 (s, 2H), 3.68 (m, 4H), 2.61 (s,
49 4- 356.3 1H), 2.24 (s, 3H), 2.11 (m, 3H), 1.78 (dt, J =
yl]ethyl}[(4- 12.3, 6.2, 1H), 1.61 (m, 1H), 1.47 (m, 2H), 1.10
fluorophenyl)methyl] (s, 3H), 0.56 (s, 3H).
amine
benzyl(2-{9-
δ 9.09 (d, J = 38.9, 2H), 7.35 (m, 5H), 6.43 (s,
cyclohexyl
2H), 3.93 (s, 2H), 3.54 (m, 2H), 2.85 (s, 2H),
50 oxaspiro[4.5]decan- 356.3
1.63 (m, 16H), 1.10 (m, 7H), 0.84 (q, J = 11.8,
2H).
yl}ethyl)amine
δ 9.79 (s, 2H), 8.66 (s, 1H), 8.21 (t, J = 7.5,
{2-[3-(pyridinyl)- 1H), 7.80 (d, J = 8.1, 1H), 7.66 (s, 1H), 7.33 (d,
1- J = 5.0, 1H), 7.16 (s, 1H), 7.06 – 6.98 (m, 1H),
oxaspiro[4.5]decan- 4.29 (s, 2H), 4.23 (d, J = 9.9, 1H), 3.99 (d, J =
51 357
3- 10.0, 1H), 3.00 (s, 1H), 2.87 (s, 1H), 2.63 (t, J =
yl]ethyl}(thiophen 9.5, 1H), 2.39 (d, J = 8.6, 1H), 2.20 (d, J = 13.5,
ylmethyl)amine 1H), 2.10 (d, J = 13.6, 1H), 1.77 – 1.49 (m, 4H),
1.47 – 1.19 (m, 6H).
δ 9.72 (s, 2H), 8.64 (s, 1H), 8.21 (t, J = 7.5,
{2-[3-(pyridinyl)- 1H), 7.80 (d, J = 8.1, 1H), 7.66 (t, J = 5.9, 1H),
1- 7.44 – 7.31 (m, 2H), 7.09 (d, J = 4.8, 1H), 4.23
oxaspiro[4.5]decan- (d, J = 9.9, 1H), 4.10 (s, 2H), 3.99 (d, J = 10.0,
52 357
3- 1H), 2.95 (s, 1H), 2.80 (s, 1H), 2.64 (s, 1H),
yl]ethyl}(thiophen 2.39 (d, J = 8.7, 1H), 2.21 (d, J = 13.7, 1H), 2.10
ylmethyl)amine (d, J = 13.6, 1H), 1.77 – 1.50 (m, 4H), 1.49 –
1.22 (m, 6H).
δ 8.67 (d, J = 4.3, 1H), 8.14 (s, 1H), 7.66 (d, J =
8.2, 1H), 7.59 (s, 1H), 7.33 (dd, J = 5.1, 1.1,
{2-[9-(pyridinyl)-
1H), 7.12 (d, J = 2.7, 1H), 7.00 (dd, J = 5.1, 3.5,
1H), 4.22 (s, 2H), 3.80 (s, 1H), 3.72 (t, J = 9.8,
oxaspiro[4.5]decan-
53 357.1 1H), 3.33 – 2.70 (m, 1H), 2.70 – 2.50 (m, 1H),
2.30 (d, J = 14.0, 3H), 2.19 (dd, J = 18.0, 7.1,
yl]ethyl}(thiophen
1H), 1.98 (d, J = 14.1, 1H), 1.83 (d, J = 4.6, 2H),
ylmethyl)amine
1.76 – 1.62 (m, 1H), 1.50 (dd, J = 20.1, 13.3,
5H), 1.16 (s, 1H), 0.75 (dt, J = 13.1, 9.1, 1H).
δ 8.67 (d, J = 4.3, 1H), 8.14 (s, 1H), 7.66 (d, J =
8.2, 1H), 7.59 (s, 1H), 7.33 (dd, J = 5.1, 1.1,
{2-[(9R)(pyridin-
1H), 7.12 (d, J = 2.7, 1H), 7.00 (dd, J = 5.1, 3.5,
2-yl)
1H), 4.22 (s, 2H), 3.80 (s, 1H), 3.72 (t, J = 9.8,
oxaspiro[4.5]decan-
54 357.2 1H), 3.33 – 2.70 (m, 1H), 2.70 – 2.50 (m, 1H),
2.30 (d, J = 14.0, 3H), 2.19 (dd, J = 18.0, 7.1,
yl]ethyl}(thiophen
1H), 1.98 (d, J = 14.1, 1H), 1.83 (d, J = 4.6, 2H),
ylmethyl)amine
1.76 – 1.62 (m, 1H), 1.50 (dd, J = 20.1, 13.3,
5H), 1.16 (s, 1H), 0.75 (dt, J = 13.1, 9.1, 1H).
δ 8.73 (d, J = 5.0, 1H), 8.27 (t, J = 7.5, 2H), 7.88
{2-[(9R)(pyridin-
– 7.62 (m, 2H), 7.48 – 7.23 (m, 1H), 7.04 (dd, J
2-yl)
= 4.9, 1.0, 1H), 4.02 (s, 2H), 3.90 – 3.76 (m,
oxaspiro[4.5]decan-
55 357.2 1H), 3.69 (t, J = 10.0, 1H), 2.95 (s, 1H), 2.62 –
2.12 (m, 4H), 2.13 – 1.95 (m, 1H), 1.95 – 1.76
yl]ethyl}(thiophen
(m, 2H), 1.68 (dt, J = 13.5, 7.9, 1H), 1.62 – 1.30
ylmethyl)amine
(m, 5H), 1.16 (dd, J = 13.2, 6.6, 1H), 0.76 (dt, J
= 13.0, 8.9, 1H).
δ 8.77 (d, J = 4.3, 1H), 8.27 (t, J = 7.3, 1H), 7.86
– 7.65 (m, 2H), 7.43 (d, J = 3.1, 1H), 7.28 (s,
{2-[(9R)(pyridin-
1H), 4.56 – 4.39 (m, 2H), 3.79 (dddd, J = 21.9,
2-yl)
19.5, 10.8, 7.1, 2H), 3.19 (td, J = 11.5, 5.3, 1H),
oxaspiro[4.5]decan-
56 358 2.81 – 2.63 (m, 1H), 2.62 – 2.43 (m, 1H), 2.43 –
2.26 (m, 3H), 2.14 – 1.99 (m, 1H), 2.00 – 1.79
yl]ethyl}(1,3-thiazol-
(m, 2H), 1.79 – 1.63 (m, 1H), 1.63 – 1.38 (m,
2-ylmethyl)amine
4H), 1.20 (dd, J = 13.0, 6.5, 1H), 0.79 (dt, J =
13.0, 8.9, 1H).
δ 8.76 (d, J = 4.7, 1H), 8.37 (td, J = 8.1, 1.4,
{2-[(9R)(pyridin-
1H), 8.12 – 7.72 (m, 3H), 7.29 (s, 1H), 4.37 (s,
2-yl)
2H), 3.93 – 3.58 (m, 2H), 3.05 (td, J = 11.7, 5.1,
oxaspiro[4.5]decan-
57 358 1H), 2.66 – 2.43 (m, 2H), 2.42 – 2.22 (m, 3H),
2.18 – 1.96 (m, 1H), 1.96 – 1.79 (m, 2H), 1.79 –
yl]ethyl}(1,3-thiazol-
1.39 (m, 5H), 1.18 (dd, J = 12.1, 5.5, 1H), 0.77
-ylmethyl)amine
(dt, J = 12.9, 8.9, 1H).
δ 8.63 (s, 1H), 8.55 (s, 1H), 8.49 (d, J = 2.3,
{2-[9-(pyrazinyl)-
1H), 7.33 (dd, J = 5.1, 1.1, 1H), 7.08 (d, J = 2.6,
1H), 7.05 – 6.97 (m, 1H), 3.73 (d, J = 36.7, 2H),
oxaspiro[4.5]decan-
58 358 3.17 – 2.73 (m, 1H), 2.54 – 2.43 (m, 1H), 2.35
(d, J = 13.0, 2H), 2.24 – 2.11 (m, 1H), 2.05-2.15
yl]ethyl}(thiophen
(m, 4H), 1.51 (s, 5H), 1.14 – 1.01 (m, 1H), 0.66
ylmethyl)amine
(s, 1H).
δ 8.72 (dd, J = 5.5, 1.4, 1H), 8.21 (td, J = 8.0,
1.7, 1H), 7.68 (m, 2H), 7.35 (dd, J = 2.9, 1.2,
1H), 7.30 (m, 2H), 7.04 (dd, J = 5.0, 1.3, 1H),
{2-[2,2-diethyl
4.02 (s, 2H), 3.80 (dd, J = 10.0, 6.3, 1H), 3.68
(pyridinyl)oxan
59 359.2 (d, J = 10.8, 1H), 3.00 (m, 1H), 2.42 (m, 4H),
yl]ethyl}(thiophen
2.08 (d, J = 4.4, 1H), 1.78 (s, 1H), 1.71 (d, J =
ylmethyl)amine
14.5, 1H), 1.56 (dd, J = 14.1, 7.5, 1H), 1.40 (dd,
J = 14.1, 7.4, 1H), 0.81 (m, 5H), 0.57 (t, J = 7.3,
3H).
δ 8.70 (dd, J = 5.4, 1.4, 1H), 8.15 (d, J = 1.6,
1H), 7.66 (d, J = 8.2, 1H), 7.60 (dd, J = 6.7, 5.5,
1H), 7.33 (dd, J = 5.1, 1.2, 1H), 7.11 (d, J = 2.6,
{2-[2,2-diethyl 1H), 6.99 (dd, J = 5.1, 3.6, 1H), 3.73 (d, J =
(pyridinyl)oxan 44.0, 4H), 4.02 (s, 2H), 3.80 (dd, J = 10.0, 6.3,
60 359.2
yl]ethyl}(thiophen 1H), 3.68 (d, J = 10.8, 1H), 3.00 (m, 1H), 2.42
ylmethyl)amine (m, 4H), 2.08 (d, J = 4.4, 1H), 1.78 (s, 1H), 1.71
(d, J = 14.5, 1H), 1.56 (dd, J = 14.1, 7.5, 1H),
1.40 (dd, J = 14.1, 7.4, 1H), 0.81 (m, 5H), 0.57
(t, J = 7.3, 3H).
{2-[2,2,6,6- δ 8.63 (dd, J = 5.6, 1.3, 1H), 8.18 (td, J = 8.1,
61 tetramethyl 359.2 1.6, 1H), 7.81 (d, J = 8.2, 1H), 7.63 (dd, J = 6.8,
(pyridinyl)oxan 5.8, 1H), 7.36 – 7.16 (m, 2H), 7.05 – 6.96 (m,
yl]ethyl}(thiophen 2H), 6.88 (dd, J = 5.1, 3.6, 2H), 4.13 (s, 2H),
ylmethyl)amine 2.80 – 2.60 (m, 2H), 2.43 (d, J = 14.7, 2H), 2.33
– 2.17 (m, 2H), 1.81 (d, J = 14.8, 2H), 1.21 (d, J
= 12.2, 6H), 0.89 (s, 6H).
δ 8.62 (dd, J = 5.6, 1.4, 1H), 8.19 (td, J = 8.0,
{2-[2,2,6,6- 1.7, 1H), 7.81 (d, J = 8.2, 2H), 7.67 – 7.60 (m,
tetramethyl 1H), 7.27 (dd, J = 2.9, 1.2, 1H), 7.23 – 7.17 (m,
62 (pyridinyl)oxan 359.2 2H), 6.95 (dd, J = 5.0, 1.3, 1H), 3.95 (s, 2H),
yl]ethyl}(thiophen 2.62 (d, J = 8.1, 2H), 2.41 (d, J = 14.7, 2H), 2.34
ylmethyl)amine – 2.08 (m, 2H), 1.82 (d, J = 14.8, 2H), 1.21 (d, J
= 13.1, 6H), 0.89 (s, 6H).
δ 9.60 (s, 1H), 9.27 (s, 1H), 7.29 (dd, J = 5.1,
{2-[9-(thiophen
1.1, 2H), 7.21 (dd, J = 5.1, 1.0, 1H), 7.03 (d, J =
yl)
2.6, 1H), 6.94 (ddd, J = 9.9, 5.1, 3.6, 2H), 6.77
oxaspiro[4.5]decan-
63 362.2 (dd, J = 3.6, 1.1, 1H), 4.03 (s, 2H), 3.74 (m, 2H),
2.80 (td, J = 11.9, 4.9, 1H), 2.50 (td, J = 11.8,
yl]ethyl}(thiophen
.0, 1H), 1.96 (m, 4H), 1.71 (m, 4H), 1.48 (m,
ylmethyl)amine
6H), 1.00 (dt, J = 12.7, 8.1, 1H).
δ 9.46 (s, 1H), 9.23 (s, 1H), 7.27 (m, 2H), 7.21
{2-[9-(thiophen
(dd, J = 5.1, 1.0, 1H), 7.00 (dt, J = 7.5, 4.4, 1H),
yl)
6.93 (dd, J = 5.1, 3.5, 1H), 6.75 (dd, J = 3.6, 1.1,
oxaspiro[4.5]decan-
64 362.2 1H), 3.85 (s, 2H), 3.74 (m, 2H), 2.73 (m, 1H),
2.43 (s, 1H), 2.12 (m, 1H), 2.03 (m, 2H), 1.96
yl]ethyl}(thiophen
(dd, J = 12.4, 7.6, 1H), 1.87 (m, 2H), 1.70 (m,
ylmethyl)amine
3H), 1.48 (m, 5H), 1.00 (dt, J = 12.8, 8.1, 1H).
δ 9.23 (m, 1H), 8.73 (m, 1H), 7.25 (dd, J = 8.9,
(cyclopentylmethyl)( 5.2, 2H), 7.07 (t, J = 8.6, 2H), 3.73 (d, J = 10.9,
{2-[2,2-diethyl(4- 2H), 2.69 (s, 2H), 2.10 (m, 4H), 1.78 (d, J =
65 362.3
fluorophenyl)oxan 18.1, 3H), 1.64 (m, 7H), 1.38 (s, 2H), 1.28 (s,
yl]ethyl})amine 1H), 1.10 (d, J = 16.3, 3H), 0.84 (s, 4H), 0.53 (s,
3H).
(cyclopentylmethyl)( δ 8.64 (s, 2H), 7.22 (dd, J = 8.9, 5.1, 2H), 6.95
{2-[4-(4- (t, J = 8.6, 2H), 3.25 (s, 2H), 2.61 (s, 2H), 2.43
fluorophenyl)- (s, 2H), 2.24 (d, J = 14.3, 2H), 1.91 (m, 2H),
66 362.3
2,2,6,6- 1.68 (m, 2H), 1.60 (d, J = 14.3, 2H), 1.49 (m,
tetramethyloxan 4H), 1.18 (s, 6H), 1.03 (dd, J = 12.4, 7.3, 2H),
yl]ethyl})amine 0.93 (s, 6H).
(2-{9-cyclohexyl δ 9.21 (d, J = 25.7, 2H), 7.33 (dd, J = 5.1, 1.1,
oxaspiro[4.5]decan- 2H), 7.14 (d, J = 2.7, 1H), 7.00 (dd, J = 5.1, 3.6,
67 9- 362.3 1H), 4.19 (s, 2H), 3.56 (m, 2H), 2.92 (s, 2H),
yl}ethyl)(thiophen 1.65 (m, 17H), 1.12 (m, 7H), 0.87 (dd, J = 23.8,
ylmethyl)amine 11.9, 2H).
(2-{9-cyclohexyl δ 9.07 (d, J = 31.8, 2H), 7.37 (ddd, J = 7.9, 3.9,
oxaspiro[4.5]decan- 2.1, 2H), 7.10 (dd, J = 5.0, 1.3, 1H), 6.37 (s,
68 362.3
9- 2H), 4.04 (s, 2H), 3.55 (m, 2H), 2.87 (s, 2H),
yl}ethyl)(thiophen 1.64 (m, 16H), 1.12 (m, 7H), 0.85 (q, J = 11.8,
ylmethyl)amine 2H).
δ 8.77 (d, J = 4.0, 1H), 8.09 (td, J = 8.0, 1.7,
1H), 7.64 (d, J = 8.1, 1H), 7.55 (dd, J = 7.1, 5.8,
1H), 7.35 (dd, J = 5.6, 3.2, 2H), 7.24 (d, J = 3.6,
2-{2-[(9R)
2H), 4.76 (m, 4H), 4.21 (brs, 1H), 3.77 (m, 2H),
(pyridinyl)
3.30 (m, 1H), 2.80 (td, J = 12.3, 4.4, 1H), 2.49
69 oxaspiro[4.5]decan- 363.1
(td, J = 12.9, 4.5, 1H), 2.38 (t, J = 15.1, 2H),
9-yl]ethyl}-2,3-
2.23 (td, J = 12.9, 4.2, 1H), 2.07 (d, J = 14.0,
dihydro-1H-isoindole
1H), 1.87 (ddd, J = 24.1, 11.9, 7.1, 2H), 1.69 (m,
1H), 1.51 (dt, J = 24.2, 10.9, 4H), 1.15 (m, 1H),
0.78 (dt, J = 13.4, 9.0, 1H).
δ 11.44 (s, 1H), 7.28 (m, 2H), 7.10 (m, 2H),
{2-[2,2-diethyl(4-
3.75 (m, 2H), 2.88 (m, 5H), 2.27 (m, 3H), 1.97
fluorophenyl)oxan
70 364.4 (td, J = 12.7, 3.9, 1H), 1.80 (td, J = 12.6, 4.9,
yl]ethyl}dipropylami
1H), 1.66 (m, 2H), 1.46 (m, 6H), 1.04 (m, 1H),
0.88 (m, 10H), 0.55 (m, 3H).
δ 8.51 (dd, J = 5.3, 1.3, 1H), 8.04 (td, J = 7.9,
1.7, 1H), 7.56 (d, J = 8.1, 1H), 7.49 (dd, J = 7.1,
(2-phenylethyl)({2- 5.8, 1H), 7.25 – 7.12 (m, 6H), 7.10 – 7.03 (m,
[(9R)(pyridin 2H), 3.88 – 3.47 (m, 3H), 3.01 (d, J = 7.5, 2H),
71 yl) 365.1 2.85 (t, J = 7.8, 2H), 2.44 (s, 1H), 2.38 – 2.17
oxaspiro[4.5]decan- (m, 3H), 2.17 – 1.99 (m, 1H), 1.92 (d, J = 14.1,
9-yl]ethyl})amine 1H), 1.84 – 1.66 (m, 3H), 1.58 (d, J = 5.1, 1H),
1.40 (ddd, J = 15.2, 12.1, 8.9, 4H), 1.05 (d, J =
6.5, 1H), 0.65 (d, J = 13.4,1H).
δ 8.58 (d, J = 4.8, 1H), 8.07 (t, J = 7.9, 1H), 7.61
(s, 1H), 7.52 (dd, J = 12.0, 6.3, 1H), 7.27 (m,
(2-phenylethyl)({2- 3H), 7.20 (m, 2H), 4.04 (d, J = 3.2, 2H), 3.76
[9-(pyridinyl) (ddd, J = 19.4, 12.6, 8.9, 2H), 3.05 (s, 1H), 2.53
72 365.3
oxaspiro[4.5]decan- (m, 2H), 2.29 (d, J = 43.6, 5H), 1.96 (d, J =
9-yl]ethyl})amine 13.9, 1H), 1.80 (m, 2H), 1.68 (s, 1H), 1.50 (ddd,
J = 20.5, 13.1, 7.0, 4H), 1.17 (s, 1H), 0.75 (m,
1H).
δ 9.49 (s, 2H), 8.18 (t, J = 7.9, 1H), 7.55 (dd, J
= 23.1, 7.8, 2H), 7.35 (s, 5H), 5.87 (s, 3H), 4.00
(s, 2H), 3.88 – 3.66 (m, 2H), 3.00 (s, 1H), 2.80
benzyl({2-[9-(6-
(s, 3H), 2.65 (d, J = 12.5, 1H), 2.53 (s, 1H), 2.31
methylpyridinyl)-
(d, J = 14.3, 2H), 2.20 (d, J = 13.5, 1H), 2.11 –
73 6- 365.7
2.00 (m, 1H), 1.97 – 1.80 (m, 2H), 1.70 (d, J =
oxaspiro[4.5]decan-
.3, 1H), 1.52 (ddd, J = 29.7, 17.1, 7.4, 4H),
9-yl]ethyl})amine
1.28 (t, J = 7.1, 1H), 0.95 – 0.79 (m, 1H). (ddd, J
= 29.7, 17.1, 7.4, 4H), 1.28 (t, J = 7.1, 1H), 0.92
– 0.77 (m, 1H).
{2-[2,2-dimethyl 1H NMR (400 MHz324.3, CDCl3) δ 8.50 (d, J
74 (4- 366.3 = 223.4, 2H), 7.25 (s, 5H), 6.95 (d,338.3 J = 8.1,
methylphenyl)oxan- 2H), 6.87 (d, J = 8.3, 2H), 5.69 (s, 3H), 3.62 (dd,
4- J = 6.8, 2.5, 2H), 2.38 (dd, J = 15.7, 13.2, 1H),
yl]ethyl}(2- 2.22 (s, 3H), 1.98 (m, 2H), 1.80 (m, 2H), 1.63
phenylpropan (m, 1H), 1.56 (s, 3H), 1.51 (s, 3H), 1.47 (d, J =
yl)amine 14.1, 1H), 1.39 (dd, J = 10.5, 4.0, 1H), 1.06 (s,
3H), 0.53 (s, 3H).
δ 8.90 (s, 1H), 8.75 (d, J = 4.4, 1H), 8.61 (d, J =
{2-[(9R)(pyridin- 5.2, 1H), 8.41 – 8.28 (m, 2H), 7.87 – 7.70 (m,
2-yl) 3H), 3.81 (s, 1H), 3.71 (s, 1H), 3.29 (t, J = 10.5,
oxaspiro[4.5]decan- 3H), 2.97 (d, J = 7.3, 1H), 2.44 (s, 2H), 2.33 (t, J
75 367.1
9- = 11.9, 2H), 2.21 (dt, J = 24.1, 11.9, 1H), 2.07
yl]ethyl}[2-(pyridin- (d, J = 14.3, 1H), 1.88 (d, J = 10.3, 2H), 1.65
3-yl)ethyl]amine (dd, J = 16.4, 9.9, 1H), 1.60 – 1.44 (m, 5H), 1.19
(s, 1H), 0.81 (d, J = 13.1, 1H).
[(2-methylpyrimidin-
δ 8.57 (s, 2H), 7.83 – 7.66 (m, 1H), 7.33 (s, 4H),
-yl)methyl]({2-
7.21 (dt, J = 10.8, 2.9, 1H), 3.93 (s, 1H), 3.69 (s,
[(9R)
2H), 2.65 (s, 1H), 2.40 – 2.20 (m, 3H), 2.09 (s,
76 (pyridinyl) 367.1
2H), 1.87 (s, 2H), 1.76 – 1.50 (m, 3H), 1.42
oxaspiro[4.5]decan-
(ddd, J = 33.3, 13.0, 3.9, 2H), 1.22 (td, J = 7.3,
1.9, 1H), 1.02 (s, 1H), 0.71 – 0.54 (m, 1H).
yl]ethyl})amine
{2-[2,2-dimethyl
(4- δ 7.16 (m, 6H), 6.85 (dd, J = 18.0, 7.8, 2H),
methylphenyl)oxan- 3.80 (s, 3H), 3.61 (d, J = 1.9, 2H), 3.51 (s, 2H),
77 4- 368.3 2.45 (d, J = 5.2, 1H), 2.35 (s, 4H), 2.15 (m, 2H),
yl]ethyl}[(2- 1.81 (m, 1H), 1.66 (s, 4H), 1.20 (s, 3H), 0.69 (s,
methoxyphenyl)meth 3H).
yl]amine
{2-[2,2-dimethyl δ 9.28 (s, 1H), 8.80 (s, 1H), 7.10 (m, 1H), 7.01
(4- (q, J = 8.4, 4H), 6.74 (dd, J = 8.2, 2.0, 1H), 6.65
methylphenyl)oxan- (dd, J = 15.6, 4.8, 2H), 3.66 (m, 7H), 2.64 (s,
78 368.3
4-yl]ethyl}[(3- 4H), 2.24 (s, 3H), 2.09 (m, 3H), 1.82 (m, 1H),
methoxyphenyl)meth 1.64 (m, 1H), 1.48 (ddd, J = 13.4, 9.8, 8.8, 2H),
yl]amine 1.10 (s, 3H), 0.57 (s, 3H).
benzyl({2-[9-(4- δ 8.82 (d, J = 134.2, 2H), 7.31 (m, 3H), 7.16
fluorophenyl) (m, 4H), 7.00 (dd, J = 10.7, 6.5, 2H), 3.72 (m,
79 oxaspiro[4.5]decan- 368.3 4H), 2.70 (s, 1H), 2.28 (s, 1H), 1.92 (m, 6H),
9- 1.62 (m, 2H), 1.46 (m, 4H), 1.23 (m, 1H), 0.77
yl]ethyl})amine (dt, J = 13.6, 8.8, 1H)
δ 9.09 (s, 1H), 8.74 (s, 1H), 7.31 (m, 3H), 7.16
benzyl({2-[(9S)(4- (m, 4H), 7.00 (t, J = 8.6, 2H), 3.73 (m, 4H), 2.67
fluorophenyl) (s, 1H), 2.26 (s, 1H), 2.02 (s, 2H), 1.94 (td, J =
80 368.3
oxaspiro[4.5]decan- 12.6, 4.7, 1H), 1.85 (d, J = 13.9, 3H), 1.62 (s,
9-yl]ethyl})amine 2H), 1.46 (dd, J = 7.8, 4.0, 4H), 1.24 (d, J =
12.7, 1H), 0.77 (dt, J = 13.6, 8.7, 1H)
benzyl({2-[(9R) δ 7.24 – 7.17 (m, 2H), 7.16 – 7.09 (m, 3H),
81 368.3
(4-fluorophenyl) 7.01 (d, J = 7.8, 2H), 6.89 (d, J = 8.0, 2H), 3.68
oxaspiro[4.5]decan- (ddd, J = 11.8, 5.0, 1.3, 1H), 3.62 – 3.49 (m,
9-yl]ethyl})amine 3H), 2.32 (t, J = 7.3, 2H), 2.25 (s, 3H), 2.22 –
2.13 (m, 1H), 1.93 (dtd, J = 15.7, 7.7, 3.8, 1H),
1.81 – 1.66 (m, 2H), 1.65 – 1.56 (m, 1H), 1.37
(d, J = 20.2, 1H), 1.20 – 1.05 (m, 2H), 1.01-1.02
(m, 2H), 0.86 (t, J = 12.7, 1H).
δ 8.59 (ddd, J = 4.8, 1.9, 0.9, 1H), 7.64 (m, 1H),
2-[(9R)(2- 7.32 (t, J = 5.9, 1H), 7.15 (d, J = 4.9, 1H), 7.12
{4H,5H,6H- (ddd, J = 7.5, 4.8, 1.0, 1H), 6.74 (d, J = 4.9, 1H),
thieno[2,3-c]pyrrol- 3.80 (m, 4H), 3.68 (m, 2H), 2.63 (td, J = 11.6,
82 5- 369 5.1, 1H), 2.49 (dd, J = 13.8, 2.2, 1H), 2.37 (dd, J
yl}ethyl) = 13.7, 2.0, 1H), 2.16 (td, J = 11.6, 4.4, 1H),
oxaspiro[4.5]decan- 2.05 (m, 1H), 1.79 (m, 3H), 1.62 (d, J = 7.8,
9-yl]pyridine 2H), 1.50 (m, 3H), 1.40 (m, 1H), 1.14 (ddd, J =
9.7, 7.6, 3.2, 1H), 0.72 (dt, J = 13.4, 8.9, 1H).
δ 10.28 (brs, 1H), 9.39 (brs, 1H), 8.70 (d, J =
[(4,5-dimethylfuran-
4.6, 1H), 8.12 (t, J = 7.5, 1H), 7.65 (d, J = 8.1,
2-yl)methyl]({2-
1H), 7.58 (m, 1H), 6.14 (s, 1H), 3.91 (q, J =
[(9R)
14.4, 2H), 3.75 (m, 2H), 2.95 (dd, J = 10.9, 5.9,
83 (pyridinyl) 369.1
1H), 2.51 (t, J = 9.7, 1H), 2.33 (m, 3H), 2.10 (s,
oxaspiro[4.5]decan-
3H), 1.99 (d, J = 14.1, 1H), 1.82 (m, 5H), 1.68
(m, 1H), 1.48 (m, 4H), 1.15 (m, 1H), 0.74 (dt, J
yl]ethyl})amine
= 13.2, 8.9, 1H).
{2-[(9R)(4- δ 8.53 (s, 2H), 7.78 (s, 3H), 7.29 – 7.05 (m, 6H),
fluorophenyl) 6.96 (t, J = 8.4, 3H), 4.07 (s, 2H), 3.66 (d, J =
oxaspiro[4.5]decan- 12.5, 2H), 2.83 (s, 1H), 2.37 (s, 1H), 2.11 (d, J =
84 369.2
9- 13.7, 1H), 2.01 (d, J = 13.3, 2H), 1.83 (d, J =
yl]ethyl}(pyridin 14.0, 2H), 1.49 (t, J = 61.9, 9H), 1.17 (s, 2H),
ylmethyl)amine 0.70 (dt, J = 17.4, 8.9, 1H).
δ 8.05 (d, J = 152.9, 2H), 7.08 (m, 1H), 7.01 (d,
J = 8.9, 2H), 6.82 (m, 2H), 6.76 (d, J = 8.8, 2H),
2-[({2-[4-(4-
6.69 (t, J = 7.3, 1H), 4.00 (s, 2H), 3.77 (s, 2H),
methoxyphenyl)-2,2-
3.70 (s, 3H), 3.65 (dd, J = 6.9, 2.6, 2H), 2.61 (s,
85 dimethyloxan 370.3
1H), 2.23 (s, 1H), 2.04 (dd, J = 23.7, 13.9, 2H),
yl]ethyl}amino)meth
1.93 (s, 1H), 1.81 (td, J = 12.5, 4.9, 1H), 1.60
yl]phenol
(td, J = 12.7, 4.8, 1H), 1.48 (d, J = 13.9, 2H),
1.08 (s, 3H), 0.55 (s, 3H).
δ 7.26 – 7.14 (m, 3H), 7.13 – 7.02 (m, 4H), 6.91
(t, J = 8.6, 2H), 3.69 – 3.47 (m, 4H), 2.51 (td, J
benzyl({2-[2,2-
= 12.2, 4.7, 1H), 2.14 – 1.94 (m, 3H), 1.83 (td, J
diethyl(4-
86 370.3 = 12.7, 4.3, 1H), 1.64 (td, J = 12.6, 4.7, 1H),
fluorophenyl)oxan
1.56 – 1.35 (m, 3H), 1.27 (tt, J = 27.2, 13.7,
yl]ethyl})amine
1H), 0.95 (dq, J = 14.7, 7.4, 1H), 0.84 – 0.58 (m,
4H), 0.43 (t, J = 7.4, 3H).
benzyl({2-[4-(4- δ 9.15 (s, 2H), 7.32 (m, 3H), 7.25 (m, 2H), 7.18
87 370.3
fluorophenyl)- (dd, J = 7.3, 2.1, 2H), 6.99 (dd, J = 12.0, 5.3,
2,2,6,6- 2H), 3.72 (s, 2H), 2.34 (dd, J = 53.2, 23.4, 2H),
tetramethyloxan 1.91 (dd, J = 10.4, 6.5, 2H), 1.68 (d, J = 14.3,
yl]ethyl})amine 2H), 1.27 (s, 6H), 1.02 (s, 6H).
[(2,3- δ 7.13 (s, 4H), 6.95 (m, 1H), 6.80 (dd, J = 8.2,
dimethoxyphenyl)me 1.4, 1H), 6.72 (dd, J = 7.6, 1.4, 1H), 3.83 (s,
88 thyl]({2-[4-(4- 370.3 3H), 3.75 (m, 5H), 3.63 (s, 2H), 3.54 (ddd, J =
methylphenyl)oxan- 11.6, 9.1, 2.7, 2H), 2.31 (m, 5H), 2.10 (m, 3H),
4-yl]ethyl})amine 1.82 (ddd, J = 13.3, 8.3, 3.7, 4H)
[(3-methylthiophen- δ 9.68 (s, 1H), 8.75 (s, 1H), 8.16 (m, 1H), 7.74
2-yl)methyl]({2- (d, J = 27.0, 2H), 7.27 (d, J = 1.5, 1H), 6.85 (d, J
[(9R) = 5.1, 1H), 4.10 (m, 2H), 3.84 (d, J = 12.7, 1H),
89 (pyridinyl) 371.1 3.66 (d, J = 10.3, 1H), 2.96 (m, 1H), 2.69 (m,
oxaspiro[4.5]decan- 1H), 2.54 (m, 3H), 2.35 (m, 4H), 2.11 (d, J =
9- 14.0, 1H), 1.87 (d, J = 10.3, 3H), 1.57 (m, 5H),
yl]ethyl})amine 1.06 (m 1H), 0.78 (d, J = 12.8, 1H).
δ 8.80 – 8.66 (m, 1H), 8.45 – 8.25 (m, 1H), 7.84
{2-[(9R)(pyridin- – 7.63 (m, 2H), 7.16 (dd, J = 5.1, 1.1, 1H), 6.91
2-yl) (dd, J = 5.1, 3.5, 1H), 6.83 (dd, J = 3.4, 0.9, 1H),
oxaspiro[4.5]decan- 3.83 (tt, J = 13.7, 6.9, 1H), 3.69 (dd, J = 20.1,
90 9- 371.1 10.1, 1H), 3.16 (s, 4H), 3.02 (s, 1H), 2.61 – 2.22
yl]ethyl}[2- (m, 5H), 2.20 – 1.98 (m, 1H), 1.98 – 1.77 (m,
(thiophen 2H), 1.76 – 1.63 (m, 1H), 1.50 (tdd, J = 12.3,
yl)ethyl]amine 10.9, 5.3, 4H), 1.17 (dd, J = 7.9, 5.2, 1H), 0.76
(dt, J = 13.0, 8.8, 1H).
δ 8.68 (d, J = 5.4, 1H), 8.26 (s, 1H), 7.82 – 7.63
[(2-methylthiophen-
(m, 2H), 7.05 (t, J = 10.0, 1H), 6.94 (d, J = 5.3,
3-yl)methyl]({2-
1H), 3.96 (s, 2H), 3.82 (s, 1H), 3.72 (s, 1H),
[(9R)
3.03 (s, 1H), 2.50 (d, J = 15.9, 2H), 2.39 (s, 3H),
91 (pyridinyl) 371.1
2.30 (dd, J = 12.6, 7.5, 3H), 2.02 (d, J = 14.2,
oxaspiro[4.5]decan-
1H), 1.92 – 1.79 (m, 2H), 1.70 (dt, J = 14.5,
.2, 1H), 1.64 – 1.38 (m, 4H), 1.25 – 1.13 (m,
yl]ethyl})amine
1H), 0.79 (d, J = 13.2, 1H).
δ 8.71 (d, J = 4.7, 1H), 8.14 (t, J = 7.6, 1H), 7.78
[(5-methylthiophen-
– 7.48 (m, 2H), 6.86 (d, J = 3.4, 1H), 6.78 – 6.53
2-yl)methyl]({2-
(m, 1H), 4.09 (s, 2H), 3.76 (ddd, J = 40.6, 14.3,
[(9R)
7.2, 2H), 3.17 – 2.85 (m, 1H), 2.64 – 2.23 (m,
92 (pyridinyl) 371.2
4H), 2.16 (dd, J = 16.4, 8.6, 1H), 1.99 (d, J =
oxaspiro[4.5]decan-
14.2, 1H), 1.89 – 1.75 (m, 2H), 1.75 – 1.61 (m,
1H), 1.61 – 1.35 (m, 4H), 1.24 – 1.05 (m, 1H),
yl]ethyl})amine
0.74 (dt, J = 13.2, 8.9, 1H).
{2-[9-(6- δ 9.47 (d, J = 86.3, 2H), 8.17 (t, J = 8.0, 1H),
methylpyridinyl)- 7.58 (d, J = 8.0, 1H), 7.52 (d, J = 7.8, 1H), 7.39
6- (d, J = 1.9, 1H), 7.31 – 7.29 (m, 1H), 7.08 (dd, J
93 371.2
oxaspiro[4.5]decan- = 5.0, 1.0, 1H), 6.43 (s, 3H), 4.11 – 3.95 (m,
9- 2H), 3.91 – 3.67 (m, 2H), 2.97 (s, 1H), 2.81 (s,
yl]ethyl}(thiophen 3H), 2.61 (t, J = 12.6, 1H), 2.47 (t, J = 10.1, 1H),
ylmethyl)amine 2.43 – 2.15 (m, 3H), 2.15 – 1.99 (m, 1H), 1.87
(dd, J = 12.2, 6.8, 2H), 1.70 (dt, J = 12.7, 6.2,
1H), 1.63 – 1.40 (m, 4H), 1.28 – 1.20 (m, 1H),
0.84 (dt, J = 13.3, 9.0, 1H).
{2-[4-(4- δ 7.09 (dd, J = 8.9, 5.1, 2H), 6.93 (dd, J = 11.7,
fluorophenyl) 5.5, 2H), 6.71 (d, J = 2.3, 1H), 5.98 (s, 2H), 3.83
oxaspiro[5.5]undecan (s, 2H), 3.61 (m, 2H), 2.56 (m, 1H), 2.08 (t, J =
94 371.3
12.1, 3H), 1.68 (s, 3H), 1.48 (d, J = 14.6, 2H),
yl]ethyl}(1H-pyrrol- 1.40 (d, J = 14.1, 2H), 1.29 (m, 3H), 1.05 (m,
2-ylmethyl)amine 3H), 0.58 (s, 1H).
δ 9.48 (s, 1H), 8.08 (t, J = 7.9, 1H), 7.48 (d, J =
{2-[9-(6- 8.0, 1H), 7.42 (d, J = 7.8, 1H), 7.22 (dd, J = 5.1,
methylpyridinyl)- 0.8, 1H), 7.04 (d, J = 2.9, 1H), 6.88 (dd, J = 5.1,
6- 3.5, 1H), 5.95 (s, 3H), 4.13 (s, 2H), 3.66 (ddd, J
95 oxaspiro[4.5]decan- 371.3 = 18.7, 12.8, 9.1, 2H), 2.91 (s, 1H), 2.71 (s, 3H),
9- 2.60 – 2.40 (m, 2H), 2.18 (dd, J = 48.6, 14.1,
yl]ethyl}(thiophen 3H), 1.96 (d, J = 14.2, 1H), 1.88 – 1.68 (m, 2H),
ylmethyl)amine 1.71 – 1.54 (m, 1H), 1.56 – 1.31 (m, 4H), 1.20 –
1.05 (m, 1H), 0.83 – 0.63 (m, 1H).
δ 9.63 (s, 1H), 8.61 (d, J = 4.1, 1H), 8.08 (t, J =
[(4-methylthiophen- 7.8, 1H), 7.61 (d, J = 8.1, 1H), 7.53 (dd, J = 7.0,
2-yl)methyl]({2- 5.6, 1H), 6.91 (s, 1H), 6.88 (s, 1H), 4.14 (m,
[(9R)(pyridin 2H), 3.75 (dt, J = 19.0, 11.1, 2H), 3.02 (m, 1H),
96 371.3
yl) 2.61 (m, 1H), 2.40 (brs, 1H), 2.27 (m, 4H), 2.19
oxaspiro[4.5]decan- (d, J = 0.8, 3H), 1.95 (d, J = 14.0, 1H), 1.79 (m,
9-yl]ethyl})amine 2H), 1.66 (dd, J = 12.1, 5.9, 1H), 1.47 (m, 4H),
1.16 (m, 1H), 0.74 (dt, J = 13.1, 8.9, 1H).
δ 7.12 (dd, J = 8.9, 5.2, 2H), 6.94 (t, J = 8.6,
{2-[(9R)(4- 2H), 6.10 (d, J = 3.1, 1H), 5.79 (dd, J = 3.1, 0.9,
fluorophenyl) 1H), 3.77 (m, 2H), 3.72 – 3.49 (m, 2H), 2.63 (s,
oxaspiro[4.5]decan- 1H), 2.19 (s, 1H), 2.13 – 2.08 (m, 3H), 2.06 (s,
97 9- 372 1H), 1.98 (dd, J = 13.8, 1.3, 1H), 1.89 (td, J =
yl]ethyl}[(5- 12.7, 4.5, 1H), 1.80 (dd, J = 13.1, 7.1, 2H), 1.71
methylfuran (dd, J = 13.2, 6.0, 1H), 1.59 (ddd, J = 14.2, 9.4,
yl)methyl]amine 5.4, 2H), 1.50 – 1.28 (m, 4H), 1.25 – 1.09 (m,
1H), 0.71 (dt, J = 13.5, 8.8, 1H).
[(4-methyl-1,3- δ 8.68 (dd, J = 5.3, 1.2, 1H), 8.25 (s, 1H), 8.09
thiazol (td, J = 8.0, 1.7, 1H), 7.63 (d, J = 8.1, 1H), 7.54
yl)methyl]({2-[(9R)- (dd, J = 7.1, 5.7, 1H), 6.94 (d, J = 0.9, 1H), 4.37
9- (m, 2H), 3.76 (m, 2H), 3.14 (td, J = 11.2, 5.9,
98 372.1
(pyridinyl) 1H), 2.73 (td, J = 11.4, 4.7, 1H), 2.40 (m, 4H),
oxaspiro[4.5]decan- 2.27 (m, 3H), 2.00 (m, 1H), 1.83 (ddd, J = 13.8,
9- 9.3, 4.4, 2H), 1.66 (m, 1H), 1.49 (m, 4H), 1.19
yl]ethyl})amine (m, 1H), 0.78 (dt, J = 13.3, 9.0, 1H).
[(2-methyl-1,3- δ 8.71 (d, J = 4.3, 1H), 8.33 (td, J = 8.0, 1.5,
99 372.1
thiazol 1H), 7.77 (m, 2H), 7.69 (s, 1H), 5.53 (s, 1H),
yl)methyl]({2-[(9R)- 4.28 (m, 2H), 3.78 (m, 2H), 3.04 (td, J = 11.4,
9- 5.4, 1H), 2.73 (s, 3H), 2.56 (m, 2H), 2.30 (t, J =
(pyridinyl) 15.3, 3H), 2.04 (m, 1H), 1.88 (ddd, J = 19.6,
oxaspiro[4.5]decan- 11.5, 7.0, 2H), 1.68 (m, 1H), 1.49 (m, 4H), 1.18
9- (m, 1H), 0.77 (dt, J = 13.1, 9.0, 1H).
yl]ethyl})amine
[(4-methyl-1,3- δ 13.17 (s, 1H), 9.91 (s, 1H), 8.88 (s, 1H), 8.69
thiazol (d, J = 4.9, 1H), 8.31 (t, J = 7.4, 1H), 7.75 (t, J =
yl)methyl]({2-[(9R)- 7.9, 2H), 4.25 (m, 2H), 3.77 (m, 2H), 3.04 (td, J
9- = 11.5, 5.0, 1H), 2.57 (dt, J = 10.7, 7.9, 1H),
100 372.1
(pyridinyl) 2.34 (m, 7H), 2.02 (m, 1H), 1.86 (ddd, J = 26.5,
oxaspiro[4.5]decan- 13.3, 8.2, 2H), 1.66 (dt, J = 13.6, 8.4, 1H), 1.50
9- (m, 4H), 1.15 (dd, J = 13.2, 6.6, 1H), 0.73 (dt, J
yl]ethyl})amine = 13.0, 8.9, 1H).
[(2- δ 7.21 (m, 1H), 7.07 (m, 5H), 7.02 (d, J = 8.2,
chlorophenyl)methyl] 2H), 3.69 (m, 2H), 3.58 (d, J = 1.0, 2H), 2.37
({2-[2,2-dimethyl (td, J = 10.9, 5.3, 1H), 2.22 (m, 4H), 2.07 (ddd, J
101 372.2
(4- = 14.2, 9.9, 3.8, 2H), 1.74 (ddd, J = 13.2, 10.5,
methylphenyl)oxan- 5.1, 1H), 1.55 (m, 3H), 1.43 (s, 2H), 1.10 (s,
4-yl]ethyl})amine 3H), 0.58 (s, 3H).
[(3- δ 9.27 (d, J = 168.2, 2H), 7.19 (m, 2H), 7.11
chlorophenyl)methyl] (m, 2H), 7.04 (d, J = 8.2, 2H), 6.99 (d, J = 8.2,
({2-[2,2-dimethyl 3H), 3.67 (m, 2H), 3.58 (s, 2H), 2.57 (s, 1H),
102 372.2
(4- 2.33 (d, J = 12.1, 2H), 2.23 (s, 3H), 2.07 (m,
methylphenyl)oxan- 3H), 1.80 (td, J = 12.5, 4.6, 1H), 1.62 (m, 1H),
4-yl]ethyl})amine 1.47 (m, 2H), 1.09 (s, 3H), 0.56 (s, 3H).
[(4- δ 8.80 (d, J = 192.6, 2H), 7.19 (t, J = 4.2, 3H),
chlorophenyl)methyl] 7.02 (m, 6H), 4.06 (s, 3H), 3.68 (dd, J = 12.4,
({2-[2,2-dimethyl 10.2, 4H), 2.62 (s, 1H), 2.24 (d, J = 13.6, 3H),
103 372.2
(4- 2.11 (ddd, J = 21.2, 15.6, 7.6, 3H), 1.80 (dt, J =
methylphenyl)oxan- 12.3, 6.3, 1H), 1.64 (m, 1H), 1.49 (m, 2H), 1.11
4-yl]ethyl})amine (s, 3H), 0.57 (s, 3H).
1H NMR (400 MHz, CD3CN) δ 8.18 (t, J = 1.7,
1H), 8.11 (brs, 1H), 7.49 (dd, J = 5.1, 1.1, 1H),
6-[9-{2-[(thiophen 7.34 (d, J = 1.7, 2H), 7.18 (d, J = 2.7, 1H), 7.06
ylmethyl)amino]ethyl (dd, J = 5.1, 3.6, 1H), 4.24 (s, 2H), 3.67 (m, 2H),
104 } 373 2.95 (m, 1H), 2.73 (brs, 1H), 2.51 (d, J = 4.3,
oxaspiro[4.5]decan- 1H), 2.29 (t, J = 11.0, 2H), 2.08 (m, 2H), 1.84
9-yl]pyridinol (m, 2H), 1.72 (t, J = 8.5, 1H), 1.62 (dd, J = 14.4,
6.5, 2H), 1.48 (dt, J = 23.5, 7.0, 4H), 1.15 (m,
1H), 0.73 (dt, J = 12.7, 8.7, 1H).
6-[9-{2-[(thiophen δ 7.52 (d, J = 16.2, 1H), 7.29 (d, J = 1.1, 1H),
ylmethyl)amino]ethyl 7.12 (d, J = 2.7, 1H), 6.97 (dd, J = 5.1, 3.6, 1H),
105 } 373 6.51 (d, J = 8.9, 1H), 6.27 (d, J = 7.2, 1H), 4.16
oxaspiro[4.5]decan- (s, 2H), 3.71 (s, 2H), 2.85 (dd, J = 13.9, 7.6,
9-yl]pyridinol 1H), 2.68 (dd, J = 18.4, 9.5, 1H), 2.31 (m, 2H),
1.94 (d, J = 13.6, 2H), 1.59 (m, 10H), 0.90 (m,
1H).
δ 8.73 (dd, J = 5.5, 1.4, 2H), 8.24 (td, J = 8.0,
[(5-methylthiophen-
1.6, 1H), 7.87 (d, J = 8.2, 1H), 7.69 (dd, J = 7.0,
2-yl)methyl]({2-
6.1, 1H), 6.83 (dd, J = 20.2, 3.4, 1H), 6.67 –
[2,2,6,6-
106 373.2 6.48 (m, 1H), 4.09 (s, 2H), 2.83 – 2.69 (m, 2H),
tetramethyl
2.52 (dd, J = 19.1, 11.7, 3H), 2.41 (d, J = 0.5,
(pyridinyl)oxan
3H), 2.37 – 2.21 (m, 2H), 1.89 (d, J = 14.8, 2H),
yl]ethyl})amine
1.31 (s, 6H), 0.98 (s, 6H).
δ 9.46 (m, 2H), 7.95 (d, J = 6.6, 1H), 7.25 (d, J
2-(9-{2-[(thiophen
= 5.1, 1H), 7.10 (s, 1H), 7.03 (t, J = 5.8, 2H),
ylmethyl)amino]ethyl
6.90 (dd, J = 5.1, 3.6, 1H), 4.10 (s, 2H), 3.62 (m,
107 } 373.2
2H), 2.84 (s, 1H), 2.49 (s, 1H), 2.28 (s, 1H),
oxaspiro[4.5]decan-
2.06 (dd, J = 44.3, 14.1, 3H), 1.66 (m, 4H), 1.35
9-yl)pyridinol
(ddd, J = 72.6, 39.8, 18.9, 6H), 0.68 (s, 1H).
[(4-methylthiophen- δ 8.75 (d, J = 4.6, 1H), 8.35 (td, J = 8.1, 1.3,
2-yl)methyl]({2- 1H), 7.96 (d, J = 8.2, 1H), 7.86 – 7.74 (m, 1H),
[2,2,6,6- 6.95 – 6.80 (m, 2H), 4.14 (s, 2H), 2.87 – 2.68
108 373.3
tetramethyl (m, 2H), 2.52 (d, J = 14.8, 2H), 2.45 – 2.29 (m,
(pyridinyl)oxan 2H), 2.18 (d, J = 0.7, 3H), 1.93 (d, J = 14.9, 2H),
yl]ethyl})amine 1.31 (s, 6H), 0.98 (s, 6H).
δ 8.78 (d, J = 4.6, 1H), 8.05 (t, J = 7.5, 1H), 7.62
(d, J = 8.0, 1H), 7.50 (m, 1H), 3.80 (m, 2H),
dibutyl({2-[(9R)
3.06 (t, J = 10.5, 1H), 2.90 (s, 4H), 2.42 (m,
(pyridinyl)
109 373.4 4H), 2.02 (m, 2H), 1.83 (m, 2H), 1.68 (tt, J =
oxaspiro[4.5]decan-
13.3, 6.8, 1H), 1.43 (m, 12H), 1.15 (dd, J = 13.2,
9-yl]ethyl})amine
.7, 1H), 0.91 (dt, J = 11.8, 7.1, 6H), 0.72 (dt, J
= 13.3, 9.0, 1H).
{2-[(9R)(4- δ 7.33 – 7.23 (m, 7H), 7.19 (dd, J = 8.9, 5.2,
fluorophenyl) 2H), 7.04 (t, J = 8.6, 2H), 6.98 (dd, J = 5.0, 1.3,
oxaspiro[4.5]decan- 1H), 3.84 (s, 2H), 3.79 – 3.69 (m, 2H), 2.67 (s,
110 374.2
9- 1H), 2.19 – 1.74 (m, 22H), 1.66 (ddd, J = 14.0,
yl]ethyl}(thiophen 9.3, 4.6, 3H), 1.48 (ddd, J = 23.7, 15.2, 8.6, 4H),
ylmethyl)amine 1.28 (s, 1H), 0.99 – 0.64 (m, 1H).
δ 9.04 (d, J = 106.1, 2H), 7.21 (dd, J = 5.1, 1.1,
{2-[(9R)(4- 1H), 7.10 (m, 2H), 6.92 (m, 3H), 6.86 (dd, J =
fluorophenyl) 5.1, 3.6, 1H), 3.93 (s, 2H), 3.64 (m, 3H), 2.63
oxaspiro[4.5]decan- (d, J = 7.9, 1H), 2.22 (t, J = 9.7, 1H), 2.05 (d, J =
111 374.2
9- 14.1, 1H), 1.97 (d, J = 13.9, 1H), 1.88 (td, J =
yl]ethyl}(thiophen 12.7, 4.6, 1H), 1.75 (m, 3H), 1.57 (m, 2H), 1.38
ylmethyl)amine (m, 3H), 1.17 (dd, J = 14.1, 6.1, 1H), 0.70 (dt, J
= 13.6, 8.8, 1H).
(cyclopentylmethyl)( δ 7.15 (dd, J = 8.9, 5.2, 2H), 6.96 (s, 2H), 3.64
{2-[4-(4- (d, J = 13.0, 3H), 2.59 (s, 3H), 2.11 (m, 3H),
112 374.3
fluorophenyl) 1.94 (dd, J = 10.4, 5.7, 2H), 1.68 (dd, J = 12.4,
oxaspiro[5.5]undecan 4.8, 2H), 1.53 (m, 8H), 1.31 (d, J = 19.9, 4H),
yl]ethyl})amine 1.03 (s, 7H), 0.65 (m, 1H).
δ 7.20 – 7.13 (m, 8H), 7.09 (dd, J = 8.9, 5.2,
{2-[2,2-diethyl(4- 2H), 6.93 (t, J = 8.6, 2H), 6.87 (dd, J = 4.9, 1.3,
fluorophenyl)oxan 1H), 3.70 (s, 2H), 3.61 (d, J = 2.3, 2H), 2.56 (s,
113 376.2
yl]ethyl}(thiophen 1H), 2.02 (d, J = 14.1, 3H), 1.75 (s, 11H), 1.44
ylmethyl)amine (d, J = 14.2, 5H), 0.95 (dd, J = 14.5, 7.4, 1H),
0.73 (t, J = 7.5, 5H), 0.43 (t, J = 7.4, 4H).
δ 7.25 – 7.15 (m, 3H), 7.15 – 7.02 (m, 4H), 6.91
(t, J = 8.6, 2H), 3.82 – 3.36 (m, 4H), 2.51 (td, J
{2-[2,2-diethyl(4-
= 12.2, 4.7, 1H), 2.12 – 1.94 (m, 3H), 1.83 (td, J
fluorophenyl)oxan
114 376.2 = 12.7, 4.3, 1H), 1.64 (td, J = 12.6, 4.7, 1H),
yl]ethyl}(thiophen
1.55 – 1.35 (m, 3H), 1.28 (dq, J = 14.7, 7.4, 1H),
ylmethyl)amine
0.95 (dq, J = 14.7, 7.4, 1H), 0.80 – 0.64 (m, 4H),
0.43 (t, J = 7.4, 3H).
{2-[4-(4-
fluorophenyl)- δ 7.28 (m, 4H), 7.00 (ddd, J = 6.7, 6.3, 3.2, 3H),
2,2,6,6- 3.82 (s, 3H), 2.46 (s, 1H), 2.28 (d, J = 14.3, 1H),
115 376.2
tetramethyloxan 1.92 (m, 1H), 1.57 (m, 2H), 1.69 (d, J = 14.4,
yl]ethyl}(thiophen 2H), 1.28 (s, 6H), 1.02 (s, 6H).
ylmethyl)amine
{2-[4-(4-
fluorophenyl)- δ 7.29 (m, 3H), 7.01 (s, 4H), 3.98 (s, 2H), 2.50
2,2,6,6- (m, 2H), 2.30 (d, J = 14.2, 2H), 1.94 (m, 2H),
116 376.2
tetramethyloxan 1.69 (d, J = 14.4, 2H), 1.28 (s, 6H), 1.03 (s,
yl]ethyl}(thiophen 6H).
ylmethyl)amine
δ 8.86 (d, J = 149.6, 2H), 7.25 – 7.19 (m, 3H),
7.18 – 7.12 (m, 1H), 7.09 (dd, J = 7.4, 2.0, 2H),
benzyl({2-[9-(2-
6.96 (dd, J = 7.8, 1.5, 1H), 6.85 – 6.75 (m, 2H),
methoxyphenyl)
117 380.3 3.74 – 3.63 (m, 7H), 2.55 (dd, J = 15.6, 7.9, 3H),
oxaspiro[4.5]decan-
2.11 (d, J = 14.8, 2H), 1.75 – 1.46 (m, 5H), 1.46
9-yl]ethyl})amine
– 1.32 (m, 3H), 1.32 – 1.22 (m, 1H), 1.17 (d, J =
4.1, 1H), 0.74 – 0.60 (m, 1H).
δ 9.43 (s, 1H), 9.20 (s, 1H), 7.52 (m, 2H), 7.30
(dd, J = 5.1, 1.8, 3H), 7.21 (m, 2H), 6.78 (d, J =
benzyl({2-[9-(6-
7.3, 1H), 6.57 (d, J = 8.1, 1H), 3.83 (s, 3H), 3.77
methoxypyridin
(s, 2H), 3.71 (dd, J = 7.8, 2.7, 2H), 2.77 (s, 1H),
118 yl) 381.3
2.32 (d, J = 13.6, 2H), 2.25 (d, J = 11.5, 1H),
oxaspiro[4.5]decan-
2.06 (td, J = 11.9, 4.8, 1H), 1.76 (m, 3H), 1.59
9-yl]ethyl})amine
(m, 3H), 1.47 (m, 3H), 1.38 (m, 1H), 1.15 (m,
1H), 0.70 (m, 1H).
{2-[2,2-dimethyl δ 10.17 (m, 3H), 7.41 (tdd, J = 8.3, 4.8, 1.6,
(4- 1H), 7.13 (m, 5H), 6.93 (m, 2H), 4.20 (dd, J =
119 methylphenyl)oxan- 382.3 14.9, 5.8, 1H), 3.98 (ddd, J = 32.2, 12.9, 4.8,
4- 1H), 3.80 (dd, J = 7.4, 2.6, 5H), 2.94 (d, J =
yl]ethyl}[(2- 114.3, 1H), 2.35 (m, 9H), 2.05 (ddd, J = 17.1,
methoxyphenyl)meth 12.7, 6.5, 1H), 1.89 (dt, J = 12.8, 6.2, 1H), 1.67
yl]methylamine (ddd, J = 22.2, 14.2, 5.0, 2H), 1.23 (d, J = 10.7,
3H), 0.69 (t, J = 9.5, 3H).
{2-[9-(4-
fluorophenyl) δ 8.90 (d, J = 138.8, 2H), 7.15 (tt, J = 13.7, 7.6,
oxaspiro[4.5]decan- 4H), 6.97 (m, 4H), 3.70 (m, 4H), 2.67 (s, 1H),
120 9- 382.3 2.27 (s, 4H), 2.00 (m, 3H), 1.82 (m, 3H), 1.63
yl]ethyl}[(3- (m, 2H), 1.46 (m, 4H), 1.24 (d, J = 9.6, 1H),
methylphenyl)methyl 0.78 (dt, J = 13.6, 8.8, 1H)
]amine
{2-[(9S)(4-
δ 8.73 (d, J = 138.2, 2H), 7.16 (m, 4H), 7.00
fluorophenyl)
(dd, J = 10.5, 6.7, 2H), 6.94 (m, 2H), 3.72 (m,
oxaspiro[4.5]decan-
4H), 2.69 (m, 1H), 2.27 (s, 4H), 2.05 (m, 2H),
121 9- 382.3
1.94 (td, J = 12.6, 4.7, 1H), 1.83 (m, 3H), 1.63
yl]ethyl}[(3-
(ddd, J = 14.1, 9.6, 4.6, 2H), 1.47 (m, 4H), 1.23
methylphenyl)methyl
(m, 1H), 0.78 (dt, J = 13.9, 8.9, 1H)
]amine
{2-[(9R)(4-
δ 8.96 (d, J = 123.7, 2H), 7.15 (m, 4H), 6.98
fluorophenyl)
(m, 4H), 3.71 (m, 4H), 2.66 (s, 1H), 2.25 (d, J =
oxaspiro[4.5]decan-
14.0, 4H), 2.05 (m, 2H), 1.94 (td, J = 12.7, 4.6,
122 9- 382.3
1H), 1.81 (m, 3H), 1.63 (ddd, J = 14.2, 7.7, 3.4,
yl]ethyl}[(3-
2H), 1.47 (m, 4H), 1.23 (m, 1H), 0.77 (dt, J =
methylphenyl)methyl
13.7, 8.9, 1H)
]amine
δ 7.23 (m, 3H), 7.10 (dd, J = 4.6, 2.6, 4H), 6.92
benzyl({2-[4-(4-
(s, 2H), 3.64 (s, 2H), 2.63 (m, 1H), 2.07 (t, J =
fluorophenyl)
123 382.3 13.9, 3H), 1.74 (s, 2H), 1.48 (d, J = 8.3, 3H),
oxaspiro[5.5]undecan
1.40 (d, J = 14.0, 2H), 1.29 (m, 3H), 1.06 (m,
yl]ethyl})amine
4H), 0.57 (m, 1H).
{2-[(9R)(4- δ 7.47 – 7.32 (m, 3H), 7.31 – 7.22 (m, 2H), 7.11
fluorophenyl) (dd, J = 8.9, 5.2, 2H), 6.98 (t, J = 8.6, 2H), 6.28
oxaspiro[4.5]decan- (s, 2H), 4.03 (s, 1H), 3.79 – 3.58 (m, 2H), 2.51
124 382.3
9- (s, 1H), 2.19 (d, J = 14.5, 1H), 2.07 – 1.90 (m,
yl]ethyl}[(1R) 3H), 1.89 – 1.71 (m, 3H), 1.72 – 1.32 (m, 9H),
phenylethyl]amine 1.32 – 1.10 (m, 1H), 0.78 (dt, J = 13.6, 8.8, 1H).
{2-[(9R)(4- δ 7.47 – 7.32 (m, 3H), 7.31 – 7.22 (m, 2H), 7.11
fluorophenyl) (dd, J = 8.9, 5.2, 2H), 6.98 (t, J = 8.6, 2H), 6.28
oxaspiro[4.5]decan- (s, 2H), 4.03 (s, 1H), 3.79 – 3.58 (m, 2H), 2.51
125 382.3
9- (s, 1H), 2.19 (d, J = 14.5, 1H), 2.07 – 1.90 (m,
yl]ethyl}[(1S) 3H), 1.89 – 1.71 (m, 3H), 1.72 – 1.32 (m, 9H),
phenylethyl]amine 1.32 – 1.10 (m, 1H), 0.78 (dt, J = 13.6, 8.8, 1H).
{2-[2,2-dimethyl δ 7.94 (dd, J = 8.1, 1.2, 1H), 7.53 (td, J = 7.6,
(4- 1.3, 1H), 7.40 (m, 2H), 7.15 (m, 4H), 3.80 (m,
126 methylphenyl)oxan- 383.3 4H), 2.48 (td, J = 10.9, 5.4, 1H), 2.32 (m, 4H),
4- 2.18 (ddd, J = 12.7, 7.8, 3.7, 2H), 1.84 (ddd, J =
yl]ethyl}[(2- 13.2, 10.4, 5.1, 1H), 1.63 (m, 4H), 1.21 (s, 3H),
nitrophenyl)methyl]a 0.69 (s, 3H).
mine
{2-[2,2-dimethyl δ 9.09 (d, J = 219.1, 2H), 8.12 (dd, J = 8.2, 1.6,
(4- 1H), 8.01 (s, 1H), 7.45 (dt, J = 15.6, 7.7, 2H),
methylphenyl)oxan- 7.03 (q, J = 8.5, 4H), 3.87 (s, 2H), 3.69 (m, 2H),
127 4- 383.3 3.42 (s, 1H), 3.22 (s, 2H), 2.73 (d, J = 4.5, 1H),
yl]ethyl}[(3- 2.24 (d, J = 8.2, 4H), 2.12 (m, 2H), 1.85 (m,
nitrophenyl)methyl]a 1H), 1.69 (dd, J = 12.1, 4.5, 1H), 1.52 (m, 2H),
mine 1.11 (s, 3H), 0.57 (s, 3H).
2-[({2-[9-(4- δ 8.36 (d, J = 129.4, 2H), 7.20 (dd, J = 11.0,
fluorophenyl) 4.6, 1H), 7.14 (dd, J = 8.9, 5.1, 2H), 7.00 (t, J =
oxaspiro[4.5]decan- 8.6, 2H), 6.92 (m, 2H), 6.79 (t, J = 7.1, 1H),
128 384.2
9- 3.88 (s, 2H), 3.68 (m, 2H), 2.67 (m, 1H), 2.29
yl]ethyl}amino)meth (m, 1H), 1.98 (m, 3H), 1.79 (m, 3H), 1.51 (m,
yl]phenol 6H), 1.20 (s, 1H), 0.74 (dt, J = 13.8, 8.9, 1H)
δ 8.47 (d, J = 196.5, 2H), 7.36 (td, J = 8.3, 1.7,
{2-[4-(4- 1H), 7.12 (dd, J = 9.5, 2.6, 2H), 7.08 (dd, J =
methoxyphenyl)-2,2- 7.5, 1.6, 1H), 6.91 (td, J = 7.5, 0.8, 1H), 6.86 (d,
dimethyloxan J = 8.8, 3H), 5.77 (s, 2H), 3.91 (s, 2H), 3.82 (s,
129 384.3
yl]ethyl}[(2- 3H), 3.79 (s, 3H), 3.77 (m, 2H), 2.76 (s, 1H),
methoxyphenyl)meth 2.33 (s, 1H), 2.16 (m, 2H), 1.96 (d, J = 4.6, 1H),
yl]amine 1.77 (d, J = 4.7, 1H), 1.59 (m, 2H), 1.19 (s, 3H),
0.66 (s, 3H).
δ 8.73 (d, J = 4.6, 1H), 8.20 (t, J = 7.7, 2H), 7.80
– 7.55 (m, 2H), 6.88 (d, J = 3.4, 1H), 6.64 (d, J =
[(5-ethylthiophen 3.4, 1H), 4.11 (s, 2H), 3.81 (dd, J = 8.4, 4.3,
yl)methyl]({2-[(9R)- 1H), 3.70 (t, J = 10.0, 1H), 3.00 (d, J = 4.6, 1H),
9-(pyridin 2.86 – 2.70 (m, 2H), 2.53 (t, J = 10.1, 1H), 2.45
130 385.1
yl) – 2.25 (m, 3H), 2.18 (t, J = 10.0, 1H), 2.00 (d, J
oxaspiro[4.5]decan- = 14.2, 1H), 1.93 – 1.75 (m, 2H), 1.68 (dd, J =
9-yl]ethyl})amine 9.5, 4.4, 1H), 1.62 – 1.38 (m, 4H), 1.26 (t, J =
7.5, 3H), 1.20 – 1.07 (m, 1H), 0.75 (dt, J = 12.9,
8.8, 1H).
[(3,5- δ 9.45 (brs, 1H), 8.70 (d, J = 5.0, 1H), 8.26 (t, J
dimethylthiophen = 7.7, 1H), 7.75 (d, J = 8.1, 1H), 7.70 (m, 1H),
yl)methyl]({2-[(9R)- 6.46 (d, J = 0.8, 1H), 4.07 (s, 2H), 3.76 (ddd, J =
9- 44.9, 13.9, 7.2, 2H), 3.05 (m, 1H), 2.58 (m, 1H),
131 385.1
(pyridinyl) 2.43 (t, J = 10.6, 1H), 2.36 (d, J = 0.7, 3H), 2.24
oxaspiro[4.5]decan- (dd, J = 31.9, 17.7, 3H), 2.03 (m, 4H), 1.85 (m,
9- 2H), 1.66 (dd, J = 13.8, 8.8, 1H), 1.48 (m, 4H),
yl]ethyl})amine 1.15 (d, J = 7.9, 1H), 0.75 (dt, J = 13.1, 8.9, 1H).
{2-[2,2-diethyl(4- δ 8.84 (s, 1H), 8.24 (d, J = 8.2, 1H), 7.53 (d, J =
fluorophenyl)oxan 8.2, 1H), 7.17 (m, 3H), 6.96 (t, J = 8.6, 2H),
132 yl]ethyl}[(6- 385.3 4.08 (d, J = 13.9, 2H), 3.63 (d, J = 10.5, 2H),
methylpyridin 2.84 (dd, J = 12.0, 8.2, 1H), 2.68 (s, 3H), 2.24
yl)methyl]amine (m, 2H), 2.07 (d, J = 14.1, 1H), 1.96 (m, 1H),
1.74 (dd, J = 12.5, 8.6, 1H), 1.57 (m, 1H), 1.48
(d, J = 14.2, 1H), 1.41 (m, 1H), 1.28 (dd, J =
14.0, 7.4, 1H), 0.96 (dd, J = 14.5, 7.4, 1H), 0.73
(td, J = 7.3, 3.9, 4H), 0.44 (t, J = 7.4, 3H).
{2-[4-(4-
fluorophenyl)- δ 8.85 (s, 1H), 8.24 (d, J = 8.2, 1H), 7.54 (d, J =
2,2,6,6- 8.3, 2H), 7.24 (dd, J = 8.9, 5.1, 1H), 6.92 (m,
133 tetramethyloxan 385.3 2H), 4.12 (s, 2H), 2.61 (m, 5H), 2.25 (d, J =
yl]ethyl}[(6- 14.3, 2H), 1.91 (dd, J = 10.4, 6.2, 2H), 1.65 (d, J
methylpyridin = 14.4, 2H), 1.19 (d, J = 8.9, 6H), 0.94 (s, 6H).
yl)methyl]amine
[(4,5- δ 9.46 (s, 1H), 8.62 (d, J = 4.2, 1H), 8.07 (t, J =
dimethylthiophen 7.3, 1H), 7.60 (d, J = 8.1, 1H), 7.52 (m, 1H),
yl)methyl]({2-[(9R)- 6.76 (s, 1H), 4.06 (q, J = 13.9, 2H), 3.75 (m,
9- 2H), 3.01 (m, 1H), 2.57 (s, 1H), 2.29 (m, 7H),
134 385.3
(pyridinyl) 2.19 (m, 1H), 2.04 (s, 3H), 1.95 (d, J = 14.0,
oxaspiro[4.5]decan- 1H), 1.81 (m, 2H), 1.67 (d, J = 8.2, 1H), 1.47
9- (m, 4H), 1.15 (m, 1H), 0.74 (dt, J = 13.1, 8.8,
yl]ethyl})amine 1H).
[(2,4-dimethyl-1,3- δ 9.59 (s, 1H), 8.68 (dd, J = 5.6, 1.4, 1H), 8.35
thiazol (td, J = 8.0, 1.6, 1H), 7.80 (dd, J = 12.0, 7.0,
yl)methyl]({2-[(9R)- 2H), 4.22 (m, 2H), 3.83 (dt, J = 12.5, 4.4, 1H),
9- 3.72 (m, 1H), 3.05 (dt, J = 11.2, 5.6, 1H), 2.73
135 386.1
(pyridinyl) (s, 3H), 2.57 (m, 2H), 2.31 (m, 6H), 2.04 (m,
oxaspiro[4.5]decan- 1H), 1.88 (ddd, J = 19.2, 11.4, 6.9, 2H), 1.68 (m,
9- 1H), 1.52 (m, 4H), 1.19 (dd, J = 12.2, 5.9, 1H),
yl]ethyl})amine 0.76 (dt, J = 13.1, 8.9, 1H).
δ 8.90 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 6.60 (s,
{2-[9-(pyrazinyl)- 1H), 3.88 (d, J = 12.3, 2H), 3.79 – 3.66 (m, 1H),
6- 3.58 (dd, J = 16.8, 6.5, 1H), 2.81 (s, 1H), 2.40
oxaspiro[4.5]decan- (s, 1H), 2.35 – 2.22 (m, 2H), 2.16 (s, 3H), 2.12 –
136 386.1
9- 2.00 (m, 1H), 1.97 – 1.88 (m, 4H), 1.85 (t, J =
yl]ethyl}(thiophen 9.1, 1H), 1.75 – 1.49 (m, 3H), 1.49 – 1.27 (m,
ylmethyl)amine 4H), 0.98 (d, J = 11.4, 1H), 0.55 (dt, J = 13.3,
9.0, 1H).
[(4,5-dimethylfuran-
δ 9.14 (s, 1H), 8.85 (s, 1H), 7.24 (ddd, J = 11.5,
2-yl)methyl]({2-
6.2, 3.3, 2H), 7.05 (s, 2H), 6.06 (s, 1H), 3.89 –
[(9R)(4-
3.66 (m, 4H), 2.72 (s, 1H), 2.29 (s, 1H), 2.22 –
137 fluorophenyl) 386.1
2.13 (m, 1H), 2.11 (s, 4H), 1.85 (s, 7H), 1.76 –
oxaspiro[4.5]decan-
1.62 (m, 2H), 1.60 – 1.36 (m, 4H), 1.33 – 1.24
(m, 1H), 0.82 (dt, J = 13.6, 8.8, 1H).
yl]ethyl})amine
{2-[9-(2- δ 8.90 (d, J = 150.1, 2H), 7.19 (dd, J = 3.7, 1.4,
methoxyphenyl) 1H), 7.18 – 7.14 (m, 1H), 6.99 (dd, J = 7.8, 1.5,
138 386.2
oxaspiro[4.5]decan- 1H), 6.94 – 6.76 (m, 4H), 4.66 (s, 2H), 3.94 (s,
9- 2H), 3.80 – 3.63 (m, 5H), 2.73 – 2.45 (m, 3H),
yl]ethyl}(thiophen 2.30 – 2.08 (m, 2H), 1.76 – 1.48 (m, 5H), 1.39
ylmethyl)amine (dt, J = 7.0, 6.3, 3H), 1.30 (d, J = 5.2, 1H), 1.18
(d, J = 4.1, 1H), 0.68 (dd, J = 8.7, 5.0, 1H).
δ 9.28 (d, J = 95.5, 2H), 7.18 – 7.12 (m, 3H),
{2-[9-(2-
6.97 (dd, J = 7.8, 1.5, 1H), 6.93 – 6.86 (m, 1H),
methoxyphenyl)
6.86 – 6.71 (m, 2H), 3.80 – 3.61 (m, 7H), 2.55
oxaspiro[4.5]decan-
139 386.2 (dd, J = 19.5, 5.1, 3H), 2.12 (d, J = 12.8, 2H),
1.85 (s, 2H), 1.76 – 1.47 (m, 5H), 1.46 – 1.32
yl]ethyl}(thiophen
(m, 3H), 1.31 – 1.22 (m, 1H), 1.17 (d, J = 4.2,
ylmethyl)amine
1H), 0.74 – 0.60 (m, 1H).
δ 11.70 (brs, 1H), 9.14 (d, J = 66.6, 2H), 8.72
[(3-
(d, J = 4.3, 1H), 8.19 (td, J = 8.0, 1.4, 1H), 7.70
methoxythiophen
(d, J = 8.1, 1H), 7.63 (dd, J = 7.0, 5.8, 1H), 7.22
yl)methyl]({2-[(9R)-
(d, J = 5.5, 1H), 6.78 (d, J = 5.6, 1H), 4.08 (m,
140 387 2H), 3.80 (m, 4H), 3.69 (dd, J = 11.2, 8.7, 1H),
(pyridinyl)
2.99 (d, J = 4.8, 1H), 2.51 (t, J = 9.9, 1H), 2.35
oxaspiro[4.5]decan-
(m, 3H), 2.18 (td, J = 13.5, 5.4, 1H), 1.99 (d, J =
14.2, 1H), 1.82 (m, 2H), 1.65 (m, 1H), 1.47 (m,
yl]ethyl})amine
4H), 1.14 (m, 1H), 0.73 (dt, J = 13.2, 8.9, 1H).
δ 9.03 (d, J = 80.0, 2H), 8.75 (d, J = 5.3, 1H),
8.31 (t, J = 7.9, 1H), 7.76 (m, 2H), 7.26 (t, J =
[(3-
4.0, 1H), 6.81 (d, J = 5.6, 1H), 4.12 (s, 2H), 3.82
methoxythiophen
(s, 4H), 3.69 (dd, J = 24.9, 14.9, 1H), 3.04 (s,
yl)methyl]({2-[9-
141 387 1H), 2.56 (s, 1H), 2.45 (dd, J = 17.7, 7.6, 1H),
(pyridinyl)
2.29 (ddd, J = 17.8, 13.5, 5.8, 3H), 2.05 (d, J =
oxaspiro[4.5]decan-
14.3, 1H), 1.87 (dt, J = 14.4, 6.7, 2H), 1.67 (ddd,
9-yl]ethyl})amine
J = 27.6, 16.0, 6.9, 1H), 1.52 (m, 4H), 1.20 (m,
1H), 0.78 (dt, J = 13.0, 8.9, 1H).
δ 9.37 (s, 1H), 9.11 (s, 0H), 7.55 (dd, J = 8.2,
{2-[9-(6- 7.5, 1H), 7.30 (dd, J = 5.1, 1.1, 1H), 7.03 (d, J =
methoxypyridin 2.6, 1H), 6.96 (dd, J = 5.1, 3.6, 1H), 6.81 (d, J =
yl) 7.3, 1H), 6.60 (d, J = 8.0, 1H), 4.07 (s, 2H), 3.86
142 oxaspiro[4.5]decan- 387.2 (s, 3H), 3.73 (dd, J = 7.7, 2.7, 2H), 2.87 (m, 1H),
9- 2.75 (brs, 1H), 2.47 (m, 1H), 2.32 (dd, J = 24.5,
yl]ethyl}(thiophen 13.6, 2H), 2.09 (m, 1H), 1.80 (m, 3H), 1.63 (dt,
ylmethyl)amine J = 15.1, 7.4, 2H), 1.49 (m, 3H), 1.39 (d, J = 4.5,
1H), 1.16 (m, 1H), 0.72 (dt, J = 13.4, 8.8, 1H).
δ 9.40 (s, 1H), 9.21 (s, 1H), 7.53 (m, 1H), 7.28
{2-[9-(6-
(d, J = 3.0, 2H), 6.99 (dd, J = 4.8, 1.4, 1H), 6.80
methoxypyridin
(d, J = 7.4, 1H), 6.59 (d, J = 8.2, 1H), 3.86 (d, J
yl)
= 6.4, 5H), 3.72 (dd, J = 7.7, 2.7, 2H), 2.78 (m,
143 oxaspiro[4.5]decan- 387.2
1H), 2.30 (dd, J = 28.1, 12.5, 3H), 2.09 (m, 1H),
2.02 (brs, 1H), 1.79 (m, 3H), 1.61 (m, 2H), 1.47
yl]ethyl}(thiophen
(m, 4H), 1.16 (m, 1H), 0.71 (dt, J = 13.4, 8.7,
ylmethyl)amine
1H).
144 {2-[4-(4- 388.2 δ 8.48 (d, J = 152.7, 2H), 7.28 (td, J = 8.3, 1.7,
chlorophenyl)-2,2- 1H), 7.22 (dd, J = 6.6, 4.8, 2H), 7.06 (m, 2H),
dimethyloxan 6.97 (dd, J = 7.5, 1.6, 1H), 6.81 (ddd, J = 19.8,
yl]ethyl}[(2- 13.2, 4.6, 2H), 6.03 (s, 1H), 3.82 (s, 2H), 3.66
methoxyphenyl)meth (m, 5H), 2.64 (s, 1H), 2.15 (s, 1H), 2.05 (ddd, J
yl]amine = 22.5, 14.1, 2.1, 2H), 1.85 (m, 1H), 1.72 (dd, J
= 12.5, 4.7, 1H), 1.53 (m, 2H), 1.11 (s, 3H),
0.57 (s, 3H).
{2-[(9R)(4- δ 7.28 (s, 4H), 7.25 – 7.15 (m, 2H), 7.04 (t, J =
fluorophenyl) 8.6, 2H), 6.77 (d, J = 3.5, 1H), 6.59 (dd, J = 3.4,
oxaspiro[4.5]decan- 1.1, 1H), 3.91 (s, 2H), 3.85 – 3.64 (m, 2H), 2.73
145 9- 388.2 (t, J = 9.7, 1H), 2.41 (d, J = 0.7, 3H), 2.37 – 1.75
yl]ethyl}[(5- (m, 18H), 1.67 (dd, J = 11.7, 7.1, 2H), 1.59 –
methylthiophen 1.34 (m, 4H), 1.26 (s, 1H), 0.81 (dt, J = 14.0,
yl)methyl]amine 8.9, 1H).
{2-[4-(4- δ 7.18 (s, 1H), 7.15 (s, 1H), 7.10 (dd, J = 8.9,
fluorophenyl) 5.2, 2H), 6.92 (dd, J = 10.8, 6.4, 2H), 6.87 (m,
oxaspiro[5.5]undecan 1H), 3.67 (d, J = 35.8, 3H), 2.66 (m, 1H), 2.07
146 388.2
(s, 3H), 1.83 (m, 2H), 1.56 (s, 3H), 1.41 (d, J =
yl]ethyl}(thiophen 13.9, 2H), 1.33 (m, 3H), 1.02 (m, 4H), 0.58 (m,
ylmethyl)amine 1H).
{2-[(9R)(4- δ 9.01 (d, J = 137.9, 2H), 7.15 – 7.02 (m, 3H),
fluorophenyl) 6.94 (t, J = 8.6, 2H), 6.77 – 6.63 (m, 1H), 4.82
oxaspiro[4.5]decan- (s, 1H), 3.83 (d, J = 19.1, 2H), 3.73 – 3.54 (m,
147 9- 388.2 2H), 2.64 (s, 1H), 2.18 (d, J = 10.4, 1H), 2.12 –
yl]ethyl}[(3- 1.64 (m, 9H), 1.65 – 1.50 (m, 2H), 1.50 – 1.27
methylthiophen (m, 4H), 1.27 – 1.08 (m, 1H), 0.69 (dt, J = 13.5,
yl)methyl]amine 8.8, 1H).
δ 9.31 (d, J = 89.1, 2H), 7.15 – 7.05 (m, 2H),
{2-[(9R)(4-
6.93 (t, J = 8.6, 2H), 6.80 – 6.65 (m, 2H), 3.80
fluorophenyl)
(s, 2H), 3.73 – 3.57 (m, 2H), 2.93 (s, 1H), 2.60
oxaspiro[4.5]decan-
(s, 1H), 2.17 (s, 1H), 2.04 (dd, J = 16.0, 3.3,
148 9- 388.2
4H), 1.91 (ddd, J = 17.5, 16.7, 9.1, 2H), 1.84 –
yl]ethyl}[(4-
1.65 (m, 3H), 1.57 (ddd, J = 13.2, 9.0, 4.4, 2H),
methylthiophen
1.50 – 1.25 (m, 4H), 1.17 (dd, J = 14.9, 5.0, 1H),
yl)methyl]amine
0.70 (dt, J = 13.6, 8.8, 1H).
{2-[4-(4-
fluorophenyl) δ 7.28 (s, 3H), 7.22 (dd, J = 8.6, 4.9, 2H), 7.01
oxaspiro[5.5]undecan (m, 2H), 4.01 (s, 2H), 3.74 (s, 1H), 2.26 (m,
149 388.3
1H), 1.73 (m, 11H), 1.52 (d, J = 14.1, 2H), 1.39
yl]ethyl}(thiophen (m, 2H), 1.13 (s, 2H), 0.69 (m, 1H).
ylmethyl)amine
{2-[(9R)(4- δ 7.22 (dd, J = 8.9, 5.2, 2H), 7.02 (dd, J = 14.0,
fluorophenyl) 5.4, 2H), 6.92 (d, J = 0.9, 1H), 4.25 (q, J = 14.7,
150 oxaspiro[4.5]decan- 389 2H), 3.73 (m, 2H), 2.89 (td, J = 11.8, 4.8, 1H),
9-yl]ethyl}[(4- 2.50 (td, J = 11.7, 5.0, 1H), 2.38 (d, J = 0.8, 3H),
methyl-1,3-thiazol 2.15 (m, 1H), 2.08 (m, 2H), 1.98 (m, 1H), 1.91
yl)methyl]amine (d, J = 13.9, 1H), 1.79 (d, J = 9.3, 1H), 1.69 (m,
2H), 1.48 (m, 5H), 1.25 (m, 1H), 0.81 (dt, J =
13.3, 8.7, 1H).
δ 7.15 – 7.02 (m, 2H), 6.94 (t, J = 8.6, 2H), 6.67
{2-[2,2-diethyl(4- (d, J = 3.5, 1H), 6.49 (s, 1H), 3.78 (s, 2H), 3.62
fluorophenyl)oxan (dd, J = 10.4, 8.1, 3H), 2.61 (s, 1H), 2.30 (s,
151 yl]ethyl}[(5- 390.2 4H), 2.08 (dd, J = 31.6, 14.0, 4H), 1.88 (d, J =
methylthiophen 4.6, 1H), 1.79 – 1.34 (m, 19H), 1.29 (dd, J =
yl)methyl]amine 14.0, 7.4, 2H), 0.96 (dd, J = 14.5, 7.3, 1H), 0.74
(t, J = 7.5, 5H), 0.44 (t, J = 7.4, 4H).
δ 8.75 (d, J = 4.8, 1H), 8.24 (t, J = 7.7, 1H), 7.86
[(5-chlorothiophen
– 7.58 (m, 2H), 6.44 (d, J = 3.3, 1H), 6.28 (d, J =
yl)methyl]({2-[(9R)-
3.3, 1H), 4.07 (s, 2H), 3.94 – 3.79 (m, 1H), 3.72
(t, J = 10.1, 1H), 3.01 (dd, J = 11.1, 6.0, 1H),
152 (pyridinyl) 391
2.56 (t, J = 9.9, 1H), 2.49 – 2.11 (m, 4H), 2.05
oxaspiro[4.5]decan-
(d, J = 14.1, 1H), 1.88 (ddd, J = 18.8, 11.0, 6.5,
2H), 1.78 – 1.31 (m, 5H), 1.31 – 1.07 (m, 1H),
yl]ethyl})amine
0.77 (dt, J = 13.1, 8.9, 1H)
dibutyl({2-[4-(4- δ 7.37 (m, 2H), 7.07 (m, 2H), 2.83 (dd, J = 16.3,
fluorophenyl)- 9.4, 4H), 2.68 (m, 2H), 2.38 (d, J = 14.3, 2H),
153 2,2,6,6- 392.4 2.09 (s, 4H), 1.93 (m, 2H), 1.77 (d, J = 14.3,
tetramethyloxan 2H), 1.33 (m, 10H), 1.05 (d, J = 8.6, 6H), 0.91
yl]ethyl})amine (t, J = 7.2, 6H).
{2-[(9R)(4-
fluorophenyl) δ 7.37 (s, 5H), 7.28 (s, 0H), 7.17 – 6.99 (m, 3H),
oxaspiro[4.5]decan- 6.93 (t, J = 8.6, 2H), 3.81 – 3.57 (m, 2H), 2.45
154 9- 396.3 (d, J = 9.0, 1H), 2.04 – 1.72 (m, 7H), 1.66 (t, J =
yl]ethyl}(2- 10.7, 6H), 1.62 – 1.53 (m, 2H), 1.52 – 1.34 (m,
phenylpropan 4H), 1.23 (s, 1H), 0.78 (d, J = 13.8, 1H).
yl)amine
δ 9.57 (brs, 1H), 8.62 (d, J = 3.9, 1H), 8.02 (t, J
{4H,5H,6H- = 7.1, 1H), 7.57 (d, J = 8.1, 1H), 7.48 (dd, J =
cyclopenta[b]thiophe 6.9, 5.5, 1H), 6.80 (s, 1H), 5.30 (brs, 1H), 4.06
nylmethyl}({2- (q, J = 14.1, 2H), 3.74 (m, 2H), 2.99 (m, 1H),
[(9R)(pyridin 2.82 (t, J = 7.2, 2H), 2.65 (t, J = 7.2, 2H), 2.57
155 397.1
yl) (m, 1H), 2.34 (ddd, J = 33.3, 21.0, 10.4, 5H),
oxaspiro[4.5]decan- 2.16 (dd, J = 9.9, 5.6, 1H), 1.94 (d, J = 13.9,
9- 1H), 1.78 (m, 2H), 1.66 (d, J = 8.0, 1H), 1.46
yl]ethyl})amine (ddd, J = 16.6, 12.7, 5.7, 4H), 1.14 (m, 1H), 0.72
(dt, J = 13.4, 9.0, 1H).
{2-[4-(4- δ 8.22 (d, J = 8.0, 1H), 7.49 (t, J = 16.4, 1H),
fluorophenyl) 7.17 (m, 8H), 6.96 (t, J = 8.6, 2H), 4.09 (s, 2H),
oxaspiro[5.5]undecan 3.66 (s, 4H), 2.84 (s, 1H), 2.68 (s, 3H), 2.29 (s,
156 397.3
1H), 2.20 (d, J = 13.2, 1H), 2.10 (d, J = 14.1,
yl]ethyl}[(6- 1H), 1.93 (s, 1H), 1.73 (s, 1H), 1.59 (m, 1H),
methylpyridin 1.45 (d, J = 14.0, 3H), 1.30 (m, 2H), 1.10 (m,
yl)methyl]amine 3H), 0.62 (d, J = 11.1, 1H).
[(2,3-
δ 7.05 (dd, J = 19.6, 8.3, 4H), 6.88 (m, 1H),
dimethoxyphenyl)me
6.74 (dd, J = 8.2, 1.4, 1H), 6.62 (dd, J = 7.6, 1.4,
thyl]({2-[2,2-
1H), 3.77 (s, 3H), 3.68 (m, 5H), 3.55 (d, J = 2.3,
157 dimethyl 398.3
2H), 2.37 (m, 1H), 2.22 (m, 4H), 2.06 (ddd, J =
13.8, 8.6, 4.1, 2H), 1.73 (dd, J = 6.6, 4.3, 1H),
methylphenyl)oxan-
1.56 (m, 4H), 1.10 (s, 3H), 0.58 (s, 3H).
4-yl]ethyl})amine
[(2,4-
δ 8.09 (s, 1H), 7.68 (d, J = 33.5, 1H), 7.55 (s,
dimethoxyphenyl)me
1H), 7.02 (q, J = 8.4, 4H), 6.86 (m, 1H), 6.32
thyl]({2-[2,2-
(dd, J = 6.6, 2.2, 2H), 3.77 (d, J = 10.4, 2H),
158 dimethyl 398.3
3.69 (m, 8H), 2.67 (s, 1H), 2.24 (s, 4H), 2.10
(m, 2H), 1.87 (d, J = 4.5, 1H), 1.67 (d, J = 4.4,
methylphenyl)oxan-
1H), 1.51 (m, 2H), 1.10 (s, 3H), 0.57 (s, 3H).
4-yl]ethyl})amine
{2-[9-(4- δ 9.06 (d, J = 131.9, 2H), 7.17 (m, 2H), 7.08 (d,
fluorophenyl) J = 8.7, 2H), 7.00 (t, J = 8.6, 2H), 6.79 (d, J =
oxaspiro[4.5]decan- 8.7, 2H), 3.69 (m, 7H), 2.62 (s, 1H), 2.20 (s,
159 398.3
9-yl]ethyl}[(4- 1H), 1.99 (m, 3H), 1.81 (m, 3H), 1.62 (m, 2H),
methoxyphenyl)meth 1.46 (m, 4H), 1.24 (d, J = 9.5, 1H), 0.77 (dt, J =
yl]amine 13.4, 8.8, 1H)
δ 9.43 (s, 2H), 8.72 (d, J = 4.6, 1H), 8.21 (t, J =
[(5-propylthiophen-
7.3, 1H), 7.72 (d, J = 8.1, 2H), 6.88 (d, J = 3.5,
2-yl)methyl]({2-
1H), 6.63 (d, J = 3.5, 1H), 4.11 (s, 2H), 3.87 –
[(9R)
3.65 (m, 2H), 3.00 (s, 1H), 2.71 (t, J = 7.5, 2H),
160 (pyridinyl) 399.1
2.54 (s, 1H), 2.32 (s, 3H), 2.27 – 2.11 (m, 1H),
oxaspiro[4.5]decan-
2.02 (s, 1H), 1.84 (dd, J = 16.6, 7.3, 2H), 1.64
(dd, J = 15.0, 7.4, 7H), 1.22 – 1.10 (m, 1H), 0.95
yl]ethyl})amine
(t, J = 7.3, 3H), 0.83 – 0.72 (m, 1H).
δ 9.38 (s, 2H), 8.76 (d, J = 4.6, 1H), 8.29 (t, J =
1-{5-[({2-[(9R)
7.9, 1H), 7.84 – 7.69 (m, 2H), 6.92 – 6.74 (m,
(pyridinyl)
4H), 5.02 (d, J = 6.4, 1H), 4.13 (s, 2H), 3.87 –
oxaspiro[4.5]decan-
3.60 (m, 2H), 3.03 (s, 1H), 2.52 (s, 1H), 2.34 (t,
161 9- 401.1
J = 15.7, 3H), 2.20 (t, J = 12.6, 1H), 2.03 (dd, J
yl]ethyl}amino)meth
= 14.2, 4.7, 1H), 1.96 – 1.78 (m, 2H), 1.81 –
yl]thiophen
1.65 (m, 1H), 1.65 – 1.43 (m, 7H), 1.15 (s, 1H),
yl}ethanol
0.77 (s, 1H).
1H NMR (400 MHz, CD3CN) δ 8.18 (dd, J =
6-[9-(2-{[(4,5- 2.3, 1.2, 1H), 7.72 (s, 1H), 7.32 (d, J = 2.3, 2H),
dimethylthiophen 6.82 (s, 1H), 4.10 (s, 2H), 3.67 (m, 2H), 2.95
yl)methyl]amino}eth (m, 1H), 2.50 (m, 1H), 2.32 (s, 3H), 2.27 (d, J =
162 yl) 401.1 13.9, 2H), 2.09 (m, 4H), 2.03 (m, 1H), 1.88 (m,
oxaspiro[4.5]decan- 1H), 1.83 (t, J = 9.2, 2H), 1.71 (m, 1H), 1.63 (m,
9- 2H), 1.48 (ddd, J = 16.6, 12.3, 7.6, 4H), 1.13
yl]pyridinol (dd, J = 11.7, 5.4, 1H), 0.72 (dt, J = 13.7, 9.0,
1H).
6-[9-(2-{[(4,5-
dimethylthiophen δ 7.49 (m, 1H), 6.76 (s, 1H), 6.51 (d, J = 8.9,
yl)methyl]amino}eth 1H), 6.25 (d, J = 7.0, 1H), 3.99 (s, 2H), 3.71 (m,
163 yl) 401.1 2H), 2.83 (dd, J = 16.5, 11.3, 1H), 2.61 (dd, J =
oxaspiro[4.5]decan- 17.0, 5.8, 1H), 2.27 (d, J = 21.1, 5H), 1.99 (m,
9- 6H), 1.65 (m, 10H), 0.98 (dd, J = 18.1, 5.5, 1H).
yl]pyridinol
2-[9-(2-{[(4,5-
δ 9.21 (d, J = 64.7, 2H), 8.00 (s, 1H), 7.07 (m,
dimethylthiophen
2H), 6.67 (s, 1H), 3.95 (s, 2H), 3.62 (m, 2H),
yl)methyl]amino}eth
2.84 (s, 1H), 2.44 (s, 1H), 2.27 (d, J = 12.2, 1H),
164 yl) 401.2
2.16 (s, 4H), 2.03 (d, J = 13.5, 2H), 1.94 (s, 3H),
oxaspiro[4.5]decan-
1.83 (d, J = 13.9, 1H), 1.65 (m, 3H), 1.37 (m,
5H), 0.75 (s, 1H).
yl]pyridinol
δ 8.59 (d, J = 4.0, 1H), 8.15 (t, J = 7.0, 1H),
[(5-nitrothiophen 7.79 (d, J = 4.1, 1H), 7.66 (d, J = 8.2, 1H), 7.60
yl)methyl]({2-[(9R)- (m, 1H), 7.16 (d, J = 4.2, 1H), 4.23 (s, 2H), 3.78
9-(pyridin (m, 2H), 3.04 (d, J = 6.0, 1H), 2.65 (m, 1H),
165 402
yl) 2.43 (d, J = 9.8, 1H), 2.29 (m, 3H), 1.98 (d, J =
oxaspiro[4.5]decan- 14.1, 1H), 1.83 (d, J = 5.4, 2H), 1.67 (m, 1H),
9-yl]ethyl})amine 1.48 (m, 4H), 1.16 (m, 1H), 0.75 (d, J = 13.2,
1H).
[(3,5- δ 7.19 (dd, J = 8.9, 5.1, 2H), 7.01 (dd, J = 13.7,
dimethylthiophen 5.0, 2H), 6.43 (s, 1H), 3.87 (m, 2H), 3.72 (m,
yl)methyl]({2-[(9R)- 2H), 3.02 (s, 1H), 2.72 (dd, J = 14.6, 8.9, 1H),
9-(4- 2.31 (dd, J = 31.1, 10.4, 4H), 2.15 (d, J = 13.8,
166 402.1
fluorophenyl) 1H), 2.05 (d, J = 14.0, 1H), 1.98 (m, 4H), 1.87
oxaspiro[4.5]decan- (m, 2H), 1.77 (d, J = 9.7, 1H), 1.67 (ddd, J =
9- 15.6, 10.3, 5.4, 2H), 1.46 (m, 4H), 1.25 (t, J =
yl]ethyl})amine 7.1, 1H), 0.79 (dt, J = 13.7, 8.9, 1H).
δ 7.21 (dd, J = 8.9, 5.2, 2H), 7.04 (t, J = 8.6,
[(5-ethylthiophen
2H), 6.79 (d, J = 3.5, 1H), 6.62 (d, J = 3.5, 1H),
yl)methyl]({2-[(9R)-
3.92 (s, 2H), 3.80 – 3.67 (m, 3H), 2.82 – 2.67
9-(4-
(m, 2H), 2.32 (s, 1H), 2.16 (d, J = 14.3, 1H),
167 fluorophenyl) 402.1
2.06 (s, 1H), 2.00 (td, J = 12.8, 4.9, 1H), 1.91 (d,
oxaspiro[4.5]decan-
J = 13.9, 2H), 1.84 – 1.75 (m, 1H), 1.69 (s, 2H),
1.50 (d, J = 3.7, 4H), 1.25 (t, J = 7.5, 4H), 0.81
yl]ethyl})amine
(dt, J = 13.4, 8.7, 1H).
{2-[4-(4-
δ 7.12 (m, 2H), 6.93 (s, 2H), 6.66 (d, J = 3.4,
fluorophenyl)
1H), 6.49 (d, J = 2.5, 1H), 3.80 (s, 2H), 3.63 (s,
oxaspiro[5.5]undecan
168 402.3 2H), 2.65 (m, 1H), 2.31 (s, 3H), 2.12 (m, 2H),
yl]ethyl}[(5-
1.85 (m, 1H), 1.61 (s, 3H), 1.43 (d, J = 14.0,
methylthiophen
2H), 1.33 (m, 3H), 1.03 (s, 4H), 0.59 (m, 1H).
yl)methyl]amine
[(4,5- δ 8.92 (d, J = 108.6, 2H), 7.15 – 7.05 (m, 2H),
169 402.3
dimethylthiophen 6.93 (t, J = 8.6, 2H), 6.51 (s, 1H), 5.31 (s, 1H),
yl)methyl]({2-[(9R)- 3.75 (s, 2H), 3.69 – 3.54 (m, 2H), 2.63 (s, 1H),
9-(4- 2.27 – 2.10 (m, 4H), 2.06 (d, J = 14.0, 1H), 1.98
fluorophenyl) (d, J = 13.9, 1H), 1.93 – 1.84 (m, 4H), 1.84 –
oxaspiro[4.5]decan- 1.65 (m, 3H), 1.58 (ddd, J = 17.0, 8.4, 3.8, 2H),
9- 1.51 – 1.27 (m, 4H), 1.17 (dd, J = 13.9, 6.2, 1H),
yl]ethyl})amine 0.71 (dt, J = 13.6, 8.8, 1H).
{[5- δ 9.54 (s, 1H), 8.71 (d, J = 4.5, 1H), 8.26 (t, J =
(methylsulfanyl)thiop 7.2, 2H), 7.80 – 7.67 (m, 2H), 6.92 (dd, J = 21.5,
henyl]methyl}({2- 3.6, 2H), 4.15 (s, 2H), 3.76 (d, J = 40.3, 2H),
[(9R) 3.02 (td, J = 11.4, 5.3, 1H), 2.62 – 2.51 (m, 1H),
170 403
(pyridinyl) 2.48 (s, 3H), 2.42 (s, 1H), 2.31 (t, J = 13.3, 3H),
oxaspiro[4.5]decan- 2.03 (d, J = 14.2, 1H), 1.92 – 1.78 (m, 2H), 1.78
9- – 1.63 (m, 1H), 1.64 – 1.36 (m, 4H), 1.25 – 1.12
yl]ethyl})amine (m, 1H), 0.79 (s, 1H).
1H NMR (400 MHz, CD3CN) δ 8.15 (d, J = 1.5,
6-[9-(2-{[(3-
1H), 7.60 (s, 1H), 7.43 (d, J = 5.6, 1H), 7.31 (m,
methoxythiophen
2H), 6.97 (d, J = 5.6, 1H), 4.11 (s, 2H), 3.86 (s,
yl)methyl]amino}eth
3H), 3.66 (dd, J = 7.8, 2.9, 2H), 2.97 (m, 1H),
171 yl) 403
2.51 (m, 1H), 2.28 (m, 2H), 2.02 (m, 1H), 1.87
oxaspiro[4.5]decan-
(m, 2H), 1.80 (d, J = 13.5, 2H), 1.70 (d, J = 9.8,
1H), 1.61 (dd, J = 13.8, 7.1, 2H), 1.49 (m, 4H),
yl]pyridinol
1.12 (m, 1H), 0.71 (d, J = 13.5, 1H).
6-[9-(2-{[(3- δ 9.47 (brs, 1H), 7.51 (dd, J = 9.0, 7.2, 1H),
methoxythiophen 7.23 (d, J = 5.6, 1H), 6.80 (d, J = 5.5, 1H), 6.52
yl)methyl]amino}eth (d, J = 8.9, 1H), 6.27 (d, J = 7.1, 1H), 4.10 (s,
172 yl) 403 2H), 3.82 (s, 3H), 3.73 (dd, J = 6.8, 3.4, 2H),
oxaspiro[4.5]decan- 2.83 (dd, J = 11.9, 5.7, 1H), 2.60 (t, J = 10.0,
9- 1H), 2.27 (t, J = 15.0, 2H), 2.00 (t, J = 12.3, 2H),
yl]pyridinol 1.65 (m, 10H), 0.97 (d, J = 13.4, 1H).
δ 9.84 (s, 1H), 8.76 (s, 1H), 8.32 (d, J = 5.3,
2-[(9R)(2-{[(3- 1H), 7.60 (t, J = 7.7, 1H), 7.52 (m, 1H), 7.41 (m,
methoxythiophen 1H), 7.25 (d, J = 5.5, 1H), 6.81 (d, J = 5.5, 1H),
yl)methyl]amino}eth 4.16 (m, 2H), 3.82 (m, 4H), 3.71 (m, 1H), 3.05
173 yl) 403.2 (d, J = 13.4, 2H), 2.85 (d, J = 9.1, 1H), 2.53 (s,
oxaspiro[4.5]decan- 1H), 2.27 (d, J = 14.3, 1H), 2.14 (m, 1H), 1.99
9-yl] (t, J = 11.3, 1H), 1.85 (m, 2H), 1.66 (ddd, J =
oxidopyridinium 18.0, 10.0, 5.8, 1H), 1.51 (m, 4H), 1.22 (dd, J =
12.3, 6.0, 1H), 0.90 (dt, J = 13.0, 8.7, 1H).
2-[9-(2-{[(3-
methoxythiophen δ 9.17 (d, J = 50.2, 2H), 8.00 (d, J = 6.5, 1H),
yl)methyl]amino}eth 7.16 (d, J = 5.6, 3H), 6.72 (d, J = 5.6, 1H), 4.00
174 yl) 403.2 (s, 2H), 3.73 (s, 5H), 2.82 (s, 1H), 2.34 (d, J =
oxaspiro[4.5]decan- 39.9, 2H), 2.11 (dd, J = 51.0, 13.1, 3H), 1.84 (d,
9- J = 13.9, 1H), 1.43 (m, 9H), 0.75 (s, 1H).
yl]pyridinol
175 {2-[(9R)(4- 404 δ 7.24 (s, 3H), 7.03 (dd, J = 11.7, 5.6, 2H), 6.80
fluorophenyl) (d, J = 5.5, 1H), 4.00 (s, 2H), 3.81 (m, 5H), 2.78
oxaspiro[4.5]decan- (m, 1H), 2.39 (m, 1H), 2.17 (m, 1H), 2.06 (s,
9- 2H), 1.86 (m, 2H), 1.66 (m, 3H), 1.51 (m, 3H),
yl]ethyl}[(3- 1.26 (m, 2H), 0.80 (m, 1H).
methoxythiophen
yl)methyl]amine
{2-[2,2-dimethyl
δ 9.43 (d, J = 141.7, 2H), 7.47 (d, J = 7.2, 1H),
7.39 (s, 1H), 7.31 (m, 2H), 6.99 (q, J = 8.3, 4H),
methylphenyl)oxan-
3.67 (m, 4H), 2.54 (d, J = 8.4, 1H), 2.20 (d, J =
176 4- 406.3
7.1, 3H), 2.06 (m, 3H), 1.92 (s, 2H), 1.60 (td, J
yl]ethyl}({[3-
= 12.5, 4.7, 1H), 1.46 (m, 2H), 1.08 (s, 3H),
(trifluoromethyl)phen
0.55 (s, 3H).
yl]methyl})amine
δ 8.51 (dd, J = 5.5, 1.3, 1H), 8.02 (d, J = 1.4,
1H), 7.73 – 7.52 (m, 3H), 7.43 (d, J = 1.0, 1H),
(1-benzothiophen
7.35 – 7.23 (m, 3H), 3.67 (s, 3H), 2.96 (td, J =
ylmethyl)({2-[(9R)-
11.5, 5.7, 1H), 2.56 – 2.43 (m, 1H), 2.43 – 2.28
177 9-(pyridinyl) 407.1
(m, 1H), 2.16 (d, J = 13.6, 3H), 1.89 (d, J = 14.2,
oxaspiro[4.5]decan-
1H), 1.73 (ddd, J = 19.7, 11.9, 7.2, 2H), 1.55 (dt,
9-yl]ethyl})amine
J = 15.0, 5.7, 1H), 1.48 – 1.22 (m, 4H), 1.06 (s,
1H), 0.66 (dt, J = 13.2, 8.9, 1H).
δ 11.71 (s, 2H), 9.34 (d, J = 85.8, 1H), 8.48 (d,
J = 5.0, 1H), 8.10 (s, 1H), 7.71 (dd, J = 6.2, 2.8,
(1-benzothiophen
1H), 7.58 (ddd, J = 22.1, 9.6, 4.3, 3H), 7.47 (s,
ylmethyl)({2-[(9R)-
1H), 7.36 – 7.24 (m, 2H), 4.12 (s, 2H), 3.64 (s,
9-(pyridin
178 407.1 2H), 2.93 (s, 1H), 2.51 – 2.23 (m, 2H), 2.13 (t, J
yl)
= 14.3, 3H), 1.94 – 1.83 (m, 1H), 1.80 – 1.64
oxaspiro[4.5]decan-
(m, 2H), 1.62 – 1.49 (m, 1H), 1.37 (dd, J = 39.4,
9-yl]ethyl})amine
7.2, 4H), 1.06 (d, J = 13.0, 1H), 0.64 (dt, J =
13.1, 9.0, 1H).
[(5-chlorothiophen
δ 7.11 (dd, J = 8.9, 5.2, 2H), 6.94 (dd, J = 15.9,
yl)methyl]({2-[(9R)-
7.2, 2H), 6.75 – 6.56 (m, 2H), 3.79 (s, 2H), 3.71
9-(4-
– 3.52 (m, 2H), 2.61 (s, 1H), 2.18 (s, 1H), 1.84
179 fluorophenyl) 408.2
(dddd, J = 31.4, 25.9, 23.7, 13.1, 12H), 1.58 (td,
oxaspiro[4.5]decan-
J = 9.4, 4.6, 2H), 1.39 (ddd, J = 23.7, 14.8, 9.2,
5H), 1.17 (s, 2H), 0.69 (dd, J = 8.7, 5.1, 1H).
yl]ethyl})amine
2-{[(2-{2,2- δ 8.34 (d, J = 45.4, 2H), 7.50 (d, J = 8.3, 2H),
dimethyl[4- 7.24 (d, J = 8.2, 2H), 7.10 (s, 1H), 6.77 (m, 3H),
(trifluoromethyl)phen 3.80 (s, 2H), 3.66 (d, J = 12.3, 2H), 3.31 (s, 3H),
180 408.3
yl]oxan 2.63 (s, 1H), 2.09 (dd, J = 26.1, 13.9, 3H), 1.87
yl}ethyl)amino]meth (t, J = 10.4, 1H), 1.71 (t, J = 10.4, 1H), 1.58 (d, J
yl}phenol = 14.0, 2H), 1.10 (s, 3H), 0.53 (s, 3H).
[(5-chlorothiophen δ 7.12 (dd, J = 8.9, 5.2, 2H), 6.96 (t, J = 8.6,
181 yl)methyl]({2-[2,2- 410.1 2H), 6.69 (q, J = 3.8, 2H), 3.79 (s, 2H), 3.63 (dd,
diethyl J = 12.2, 7.1, 2H), 2.63 (dd, J = 12.2, 7.5, 1H),
(4- 2.29 – 1.77 (m, 8H), 1.67 (td, J = 12.5, 4.7, 1H),
fluorophenyl)oxan 1.44 (dd, J = 24.5, 10.8, 3H), 1.31 (d, J = 7.5,
yl]ethyl})amine 1H), 0.95 (s, 1H), 0.74 (t, J = 7.5, 4H), 0.44 (t, J
= 7.4, 3H).
δ 9.56 (brs, 1H), 8.66 (d, J = 4.7, 1H), 8.09 (t, J
{[5-(2-
= 7.5, 1H), 7.62 (d, J = 8.1, 1H), 7.55 (m, 1H),
methylpropyl)thiophe
6.87 (d, J = 3.4, 1H), 6.59 (d, J = 3.4, 1H), 4.08
nyl]methyl}({2-
(m, 2H), 3.75 (m, 2H), 2.96 (d, J = 4.8, 1H),
[(9R)
182 413.1 2.57 (d, J = 7.0, 2H), 2.50 (t, J = 9.6, 1H), 2.31
(pyridinyl)
(m, 3H), 2.14 (td, J = 13.5, 5.4, 1H), 1.96 (d, J =
oxaspiro[4.5]decan-
14.1, 1H), 1.80 (m, 3H), 1.66 (m, 1H), 1.47 (m,
4H), 1.14 (d, J = 13.0, 1H), 0.89 (d, J = 6.6, 6H),
yl]ethyl})amine
0.73 (dt, J = 13.6, 9.0, 1H).
δ 10.87 (brs, 1H), 9.42 (brs, 1H), 8.70 (d, J =
4.8, 1H), 8.17 (t, J = 7.7, 1H), 7.68 (d, J = 8.1,
[(5-butylthiophen 1H), 7.62 (m, 1H), 6.85 (d, J = 3.5, 1H), 6.60 (d,
yl)methyl]({2-[(9R)- J = 3.4, 1H), 4.08 (s, 2H), 3.79 (m, 1H), 3.67 (t,
9-(pyridin J = 10.0, 1H), 2.97 (d, J = 4.3, 1H), 2.70 (t, J =
183 413.1
yl) 7.6, 2H), 2.50 (t, J = 9.9, 1H), 2.33 (m, 3H),
oxaspiro[4.5]decan- 2.16 (td, J = 13.1, 5.0, 1H), 1.98 (t, J = 9.4, 1H),
9-yl]ethyl})amine 1.80 (t, J = 9.6, 2H), 1.54 (m, 7H), 1.33 (dq, J =
14.5, 7.3, 2H), 1.14 (m, 1H), 0.90 (t, J = 7.3,
3H), 0.73 (dt, J = 13.0, 8.9, 1H).
{4H,5H,6H- δ 7.20 (m, 2H), 7.01 (dd, J = 13.5, 4.7, 2H),
cyclopenta[b]thiophe 6.65 (s, 1H), 3.88 (s, 2H), 3.72 (m, 3H), 2.78 (t,
nylmethyl}({2- J = 7.2, 3H), 2.61 (t, J = 7.2, 2H), 2.34 (dt, J =
[(9R)(4- 14.5, 7.3, 3H), 2.15 (d, J = 14.1, 1H), 2.06 (d, J
184 414
fluorophenyl) = 13.9, 1H), 1.99 (m, 1H), 1.89 (m, 2H), 1.78
oxaspiro[4.5]decan- (m, 1H), 1.67 (ddd, J = 18.6, 11.9, 7.0, 2H), 1.46
9- (m, 4H), 1.25 (m, 1H), 0.79 (dt, J = 13.4, 8.7,
yl]ethyl})amine 1H).
δ 9.37 (s, 1H), 8.65 (dd, J = 5.3, 1.3, 1H), 8.12
{2-[(9R)(pyridin-
(td, J = 7.9, 1.6, 1H), 7.65 (d, J = 8.2, 1H), 7.56
2-yl)
(dd, J = 7.1, 5.7, 1H), 6.34 (s, 1H), 5.94 (s, 1H),
oxaspiro[4.5]decan-
4.16 (dt, J = 8.2, 6.0, 4H), 4.05 (m, 2H), 3.77
185 415 (m, 2H), 3.06 (dd, J = 17.1, 11.1, 1H), 2.61 (t, J
yl]ethyl}({2H,3H-
= 8.9, 1H), 2.29 (m, 4H), 1.99 (t, J = 8.8, 1H),
thieno[3,4-
1.82 (ddd, J = 13.6, 9.4, 4.3, 2H), 1.67 (m, 1H),
b][1,4]dioxin
1.48 (ddd, J = 14.5, 12.7, 6.9, 4H), 1.19 (m, 1H),
ylmethyl})amine
0.74 (dt, J = 13.3, 9.0, 1H).
{2-[2,2-dimethyl δ 8.66 (d, J = 167.7, 2H), 7.92 (m, 1H), 7.52
(4- (m, 3H), 7.05 (s, 4H), 4.21 (s, 2H), 3.71 (m,
methylphenyl)oxan- 2H), 3.49 (s, 1H), 3.06 (s, 3H), 2.85 (s, 1H),
186 416.3
4-yl]ethyl}[(2- 2.47 (d, J = 4.8, 1H), 2.20 (m, 4H), 2.09 (dd, J =
methanesulfonylphen 13.9, 2.1, 1H), 1.94 (d, J = 4.6, 1H), 1.72 (s,
yl)methyl]amine 1H), 1.55 (m, 2H), 1.10 (s, 3H), 0.57 (s, 3H).
δ 9.52 (s, 1H), 8.77 (s, 1H), 8.38 (s, 1H), 7.83
[(4-bromofuran
(d, J = 7.6, 2H), 7.40 (s, 1H), 6.51 (s, 1H), 4.09
yl)methyl]({2-[(9R)-
(s, 2H), 3.78 (d, J = 48.0, 2H), 3.03 (s, 1H), 2.63
9-(pyridin
187 419 – 2.41 (m, 2H), 2.33 (dd, J = 28.3, 13.9, 3H),
yl)
2.09 (d, J = 14.2, 1H), 1.90 (s, 2H), 1.82 – 1.63
oxaspiro[4.5]decan-
(m, 1H), 1.53 (ddd, J = 12.9, 10.9, 4.5, 4H), 1.19
9-yl]ethyl})amine
(s, 1H), 0.79 (dt, J = 13.0, 8.9, 1H).
{2-[(9R)(4- δ 7.22 (dd, J = 8.9, 5.2, 2H), 7.05 (t, J = 8.6,
fluorophenyl) 2H), 6.85 (dd, J = 10.8, 3.7, 2H), 3.95 (s, 2H),
oxaspiro[4.5]decan- 3.75 (d, J = 4.6, 2H), 2.75 (s, 1H), 2.47 (s, 3H),
9- 2.32 (s, 1H), 2.17 (d, J = 14.4, 1H), 2.09 (d, J =
188 420
yl]ethyl}({[5- 13.8, 1H), 1.99 (dt, J = 12.3, 6.4, 1H), 1.91 (d, J
(methylsulfanyl)thiop = 13.9, 2H), 1.80 (d, J = 10.5, 1H), 1.74 – 1.61
hen (m, 2H), 1.49 (dt, J = 18.7, 11.7, 4H), 1.26 (s,
yl]methyl})amine 1H), 0.89 – 0.75 (m, 1H).
δ 8.83 – 8.56 (m, 2H), 8.35 (t, J = 7.6, 1H), 7.96
{2-[(9R)(pyridin-
(dd, J = 19.3, 8.7, 1H), 7.87 – 7.75 (m, 2H), 7.71
2-yl)
(t, J = 9.2, 1H), 4.16 (s, 2H), 3.84 (dd, J = 8.5,
oxaspiro[4.5]decan-
4.4, 1H), 3.71 (t, J = 10.0, 1H), 3.07 (dd, J =
189 420.3 11.7, 6.8, 1H), 2.55 (dt, J = 25.6, 11.9, 2H), 2.43
yl]ethyl}({[6-
– 2.21 (m, 3H), 2.10 (d, J = 14.2, 1H), 1.90
(trifluoromethyl)pyri
(ddd, J = 26.1, 14.9, 6.7, 2H), 1.76 – 1.62 (m,
din
1H), 1.60 – 1.34 (m, 4H), 1.33 – 1.09 (m, 1H),
yl]methyl})amine
0.76 (dt, J = 12.8, 8.8, 1H).
δ 8.75 (d, J = 4.8, 1H), 8.24 (t, J = 7.7, 1H), 7.86
[(5-bromofuran – 7.58 (m, 2H), 6.44 (d, J = 3.3, 1H), 6.28 (d, J =
yl)methyl]({2-[(9R)- 3.3, 1H), 4.07 (s, 2H), 3.94 – 3.79 (m, 1H), 3.72
9-(pyridin (t, J = 10.1, 1H), 3.01 (dd, J = 11.1, 6.0, 1H),
190 421
yl) 2.56 (t, J = 9.9, 1H), 2.49 – 2.11 (m, 4H), 2.05
oxaspiro[4.5]decan- (d, J = 14.1, 1H), 1.88 (ddd, J = 18.8, 11.0, 6.5,
9-yl]ethyl})amine 2H), 1.78 – 1.31 (m, 5H), 1.31 – 1.07 (m, 1H),
0.77 (dt, J = 13.1, 8.9, 1H)
(2-{2,2-dimethyl δ 8.49 (d, J = 118.7, 2H), 7.50 (d, J = 8.3, 2H),
[4- 7.25 (dd, J = 10.3, 4.6, 3H), 6.96 (dd, J = 7.5,
(trifluoromethyl)phen 1.5, 1H), 6.79 (ddd, J = 22.1, 14.4, 4.4, 2H),
191 yl]oxan 422.3 6.08 (s, 1H), 3.84 (d, J = 9.2, 2H), 3.68 (m, 5H),
yl}ethyl)[(2- 2.64 (s, 1H), 2.09 (m, 3H), 1.90 (m, 1H), 1.77
methoxyphenyl)meth (dd, J = 12.7, 4.5, 1H), 1.58 (ddd, J = 14.0, 10.8,
yl]amine 10.1, 2H), 1.12 (s, 3H), 0.55 (s, 3H).
{2-[2,2,6,6-
tetramethyl δ 8.79 – 8.63 (m, 2H), 8.31 (t, J = 7.9, 1H), 8.05
(pyridinyl)oxan – 7.90 (m, 2H), 7.87 – 7.61 (m, 2H), 4.16 (s,
192 yl]ethyl}({[6- 422.3 2H), 2.82 (dd, J = 10.0, 6.6, 2H), 2.54 (d, J =
(trifluoromethyl)pyri 14.7, 2H), 2.46 – 2.30 (m, 2H), 1.95 (d, J = 14.8,
din 2H), 1.32 (s, 5H), 0.98 (s, 5H).
yl]methyl})amine
δ 9.59 (s, 1H), 8.56 (d, J = 4.7, 1H), 8.05 (t, J =
{[5-(furan 7.4, 1H), 7.57 (d, J = 8.1, 1H), 7.46 (dd, J =
yl)thiophen 12.2, 6.3, 1H), 7.35 – 7.26 (m, 1H), 6.93 (dd, J =
yl]methyl}({2-[(9R)- 19.9, 3.7, 2H), 6.46 – 6.30 (m, 2H), 4.08 (s, 2H),
9- 3.78 – 3.54 (m, 2H), 3.00 – 2.81 (m, 1H), 2.46
193 423.1
(pyridinyl) (t, J = 9.7, 1H), 2.30 (t, J = 10.6, 1H), 2.13 (ddd,
oxaspiro[4.5]decan- J = 17.3, 16.1, 9.3, 3H), 1.89 (d, J = 14.2, 1H),
9- 1.72 (ddd, J = 13.9, 9.5, 4.3, 2H), 1.54 (dd, J =
yl]ethyl})amine 21.6, 14.5, 1H), 1.48 – 1.23 (m, 4H), 1.06 (d, J =
13.2, 1H), 0.65 (dt, J = 13.3, 8.9, 1H).
[(5-chlorothiophen δ 7.13 (dd, J = 8.9, 5.1, 2H), 6.95 (dd, J = 15.5,
yl)methyl]({2-[4-(4- 6.8, 2H), 6.69 (q, J = 3.9, 2H), 3.81 (s, 2H), 3.62
fluorophenyl) (d, J = 13.8, 2H), 2.68 (m, 1H), 2.11 (dd, J =
194 423.2
oxaspiro[5.5]undecan 22.2, 13.8, 3H), 1.84 (m, 1H), 1.54 (m, 4H),
1.30 (m, 4H), 1.05 (d, J = 11.4, 4H), 0.63 (m,
yl]ethyl})amine 1H).
δ 9.53 (d, J = 105.8, 2H), 7.77 – 7.66 (m, 2H),
(1-benzothiophen
7.36 – 7.32 (m, 2H), 7.15 (dd, J = 8.8, 5.2, 3H),
ylmethyl)({2-[(9R)-
6.96 (t, J = 8.6, 2H), 3.96 (s, 2H), 3.75 – 3.63
195 9-(4-fluorophenyl) 424
(m, 2H), 2.75 (s, 1H), 2.33 (s, 1H), 2.19 – 2.16
oxaspiro[4.5]decan-
(m, 0H), 2.15 – 1.71 (m, 6H), 1.71 – 1.29 (m,
9-yl]ethyl})amine
6H), 1.22 (s, 1H), 0.77 (dt, J = 13.5, 9.0, 1H).
(1-benzothiophen δ 8.67 (d, J = 139.8, 2H), 7.76 – 7.61 (m, 1H),
ylmethyl)({2-[(9R)- 7.56 – 7.39 (m, 1H), 7.34 – 7.25 (m, 3H), 6.98
9-(4- (dd, J = 8.8, 5.1, 2H), 6.84 (t, J = 8.6, 2H), 3.89
196 fluorophenyl) 424 (s, 2H), 3.71 – 3.54 (m, 2H), 2.66 (s, 1H), 2.21
oxaspiro[4.5]decan- (s, 1H), 2.07 – 1.89 (m, 2H), 1.89 – 1.60 (m,
9- 4H), 1.60 – 1.45 (m, 2H), 1.44 – 1.24 (m, 4H),
yl]ethyl})amine 1.19 – 1.07 (m, 1H), 0.67 (dt, J = 13.8, 8.9, 1H).
[(5-fluoro δ 8.47 (s, 1H), 7.69 (s, 2H), 7.42 (d, J = 9.2,
benzothiophen 1H), 7.30 (dd, J = 10.5, 9.5, 3H), 7.13 (s, 2H),
yl)methyl]({2-[(9R)- 4.21 (d, J = 13.3, 2H), 3.73 (s, 2H), 3.16 – 2.91
9- (m, 1H), 2.82 – 2.52 (m, 1H), 2.27 (d, J = 14.8,
197 425
(pyridinyl) 2H), 2.21 – 2.09 (m, 1H), 2.08 – 1.94 (m, 1H),
oxaspiro[4.5]decan- 1.85 (d, J = 13.6, 1H), 1.65 (s, 4H), 1.43 (d, J =
9- 38.4, 3H), 1.18 – 1.02 (m, 1H), 0.75 – 0.60 (m,
yl]ethyl})amine 1H).
δ 12.19 – 12.13 (m, 0H), 8.69 (d, J = 4.7, 1H),
[(5-
8.18 (s, 1H), 7.80 – 7.59 (m, 2H), 6.90 (d, J =
cyclopentylthiophen-
3.5, 1H), 6.67 (d, J = 2.9, 1H), 4.14 (s, 2H), 3.82
2-yl)methyl]({2-
(d, J = 12.7, 2H), 3.73 (d, J = 9.7, 1H), 3.17 (t, J
[(9R)
198 425.1 = 8.3, 1H), 3.02 (s, 1H), 2.58 (s, 1H), 2.31 (d, J
(pyridinyl)
= 14.1, 4H), 2.05 (dd, J = 33.0, 10.0, 3H), 1.90 –
oxaspiro[4.5]decan-
1.74 (m, 4H), 1.68 (dt, J = 12.1, 9.1, 3H), 1.51
(ddd, J = 13.4, 10.8, 5.9, 6H), 1.18 (s, 1H), 0.79
yl]ethyl})amine
(s, 1H).
δ 8.59 (d, J = 4.9, 1H), 8.18 (t, J = 7.4, 1H), 7.75
– 7.52 (m, 2H), 7.47 – 7.38 (m, 4H), 7.35 – 7.29
[(4-
(m, 2H), 7.29 – 7.21 (m, 3H), 3.91 (s, 2H), 3.70
phenylphenyl)methyl
(dt, J = 12.3, 4.2, 1H), 3.57 (t, J = 9.7, 1H), 2.92
]({2-[(9R)
199 427.3 (s, 1H), 2.40 (dd, J = 26.0, 12.7, 2H), 2.30 –
(pyridinyl)
2.04 (m, 3H), 2.04 – 1.84 (m, 1H), 1.76 (ddd, J
oxaspiro[4.5]decan-
= 27.2, 15.3, 6.8, 2H), 1.65 – 1.21 (m, 5H), 1.07
9-yl]ethyl})amine
(dd, J = 14.4, 5.6, 1H), 0.67 (dt, J = 13.0, 9.0,
1H).
δ 8.44 (d, J = 4.1, 1H), 7.96 (t, J = 7.1, 1H), 7.53
[(3-
– 7.43 (m, 5H), 7.42 – 7.26 (m, 3H), 7.19 (s,
phenylphenyl)methyl
3H), 3.94 (s, 1H), 3.82 – 3.45 (m, 2H), 2.73 (s,
]({2-[(9R)
200 427.3 2H), 2.44 (s, 1H), 2.31 (d, J = 10.6, 1H), 2.15 (d,
(pyridinyl)
J = 13.2, 3H), 1.86 (d, J = 14.1, 1H), 1.70 (t, J =
oxaspiro[4.5]decan-
9.7, 2H), 1.56 (s, 1H), 1.50 – 1.22 (m, 5H), 1.06
9-yl]ethyl})amine
(s, 1H), 0.66 (dd, J = 13.3, 9.0, 1H).
δ 9.51 (s, 1H), 9.15 (s, 1H), 7.42 (d, J = 8.6,
benzyl({2-[9-(4- 2H), 7.30 (m, 3H), 7.16 (dd, J = 7.3, 2.1, 2H),
bromophenyl) 7.06 (d, J = 8.7, 2H), 3.68 (m, 4H), 2.62 (m,
201 oxaspiro[4.5]decan- 428.2 1H), 2.19 (m, 1H), 2.04 (dd, J = 22.4, 13.9, 2H),
9- 1.93 (m, 1H), 1.85 (m, 3H), 1.60 (m, 2H), 1.45
yl]ethyl})amine (ddd, J = 21.1, 16.1, 8.8, 5H), 1.25 (m, 2H), 0.77
(dt, J = 13.2, 8.7, 1H).
2-aminochloro
1H NMR (400 MHz, CD3CN) δ 8.57 (dd, J =
[({2-[(9R)
4.9, 1.0, 1H), 7.83 (m, 1H), 7.48 (d, J = 8.1,
(pyridinyl)
1H), 7.31 (ddd, J = 7.5, 4.9, 0.9, 1H), 6.13 (s,
oxaspiro[4.5]decan-
202 431 2H), 4.06 (s, 2H), 3.69 (m, 2H), 2.96 (m, 1H),
2.42 (m, 2H), 2.08 (m, 2H), 1.92 (m, 1H), 1.87
yl]ethyl}amino)meth
(d, J = 13.5, 1H), 1.57 (m, 8H), 1.10 (m, 1H),
yl]thiophene
0.71 (m, 1H).
carbonitrile
{2-[(9R)(4- δ 7.21 (dd, J = 9.0, 5.1, 2H), 7.03 (t, J = 8.6,
fluorophenyl) 2H), 6.33 (s, 1H), 4.13 (s, 4H), 3.90 (s, 2H),
oxaspiro[4.5]decan- 3.74 (m, 2H), 3.01 (brs, 1H), 2.77 (t, J = 13.7,
9- 1H), 2.35 (m, 1H), 2.17 (d, J = 14.0, 1H), 2.02
203 432
yl]ethyl}({2H,3H- (dt, J = 14.7, 9.5, 2H), 1.89 (m, 2H), 1.78 (d, J =
thieno[3,4- 10.1, 1H), 1.68 (ddd, J = 16.9, 10.6, 5.8, 2H),
b][1,4]dioxin 1.46 (ddd, J = 17.8, 10.0, 5.9, 4H), 1.25 (m, 1H),
ylmethyl})amine 0.79 (dt, J = 13.5, 8.8, 1H).
δ 9.71 (s, 4H), 8.53 (d, J = 5.0, 1H), 8.09 (t, J =
[(4-phenylthiophen-
7.6, 1H), 7.62 (d, J = 8.1, 1H), 7.54 – 7.44 (m,
2-yl)methyl]({2-
1H), 7.43 – 7.35 (m, 2H), 7.32 – 7.19 (m, 5H),
[(9R)(pyridin
204 433.1 4.12 (s, 2H), 3.77 – 3.52 (m, 2H), 3.00 – 2.76
yl)
(m, 1H), 2.41 (dt, J = 25.0, 11.5, 2H), 2.18 (t, J
oxaspiro[4.5]decan-
= 17.1, 3H), 1.90 (d, J = 14.1, 1H), 1.73 (ddd, J
9-yl]ethyl})amine
= 19.6, 11.4, 6.9, 2H), 1.55 (dd, J = 10.0, 4.9,
1H), 1.48 – 1.26 (m, 4H), 1.04 (s, 1H), 0.72 –
0.56 (m, 1H).
δ 9.74 (brs, 1H), 7.62 (d, J = 8.1, 1H), 7.50 (m,
[(5-phenylthiophen- 3H), 7.37 (m, 2H), 7.31 (m, 1H), 7.12 (d, J =
2-yl)methyl]({2- 3.7, 1H), 7.04 (d, J = 3.7, 1H), 5.23 (brs, 1H),
[(9R) 4.19 (mz, 2H), 3.72 (m, 2H), 3.02 (d, J = 6.5,
205 (pyridinyl) 433.1 1H), 2.59 (t, J = 9.1, 1H), 2.39 (t, J = 10.1, 1H),
oxaspiro[4.5]decan- 2.22 (dd, J = 29.2, 10.0, 3H), 1.96 (d, J = 14.1,
9- 1H), 1.80 (t, J = 11.0, 2H), 1.62 (dd, J = 14.1,
yl]ethyl})amine 7.4, 1H), 1.44 (ddd, J = 16.8, 16.4, 7.5, 4H),
1.13 (m, 1H), 0.73 (dt, J = 12.7, 8.8, 1H).
[(5- δ 8.67 (d, J = 5.0, 1H), 8.32 (t, J = 8.0, 1H), 7.79
methanesulfonylthiop (d, J = 7.9, 2H), 7.59 (d, J = 3.8, 1H), 7.22 (d, J
henyl)methyl]({2- = 3.8, 1H), 4.31 (d, J = 6.2, 2H), 3.84 (s, 1H),
[(9R) 3.74 (s, 1H), 3.18 (s, 1H), 3.05 (s, 2H), 2.54 (t, J
206 435
(pyridinyl) = 10.3, 2H), 2.31 (d, J = 13.3, 2H), 2.14 – 2.00
oxaspiro[4.5]decan- (m, 2H), 1.89 (d, J = 13.8, 3H), 1.81 – 1.64 (m,
9- 1H), 1.64 – 1.37 (m, 3H), 1.28 (s, 2H), 0.81 (d, J
yl]ethyl})amine = 13.2, 1H).
δ 11.51 (s, 1H), 9.44 (s, 1H), 8.69 – 8.58 (m,
1H), 8.14 (td, J = 8.0, 1.6, 1H), 7.68 – 7.56 (m,
[(4-bromothiophen-
2H), 7.52 (d, J = 3.4, 1H), 7.21 (d, J = 3.3, 1H),
3-yl)methyl]({2-
4.01 (s, 2H), 3.82 – 3.54 (m, 2H), 2.97 (td, J =
[(9R)(pyridin
207 435 11.5, 5.7, 1H), 2.62 – 2.43 (m, 1H), 2.41 – 2.12
yl)
(m, 4H), 2.02 – 1.89 (m, 1H), 1.78 (ddd, J =
oxaspiro[4.5]decan-
18.6, 11.9, 6.5, 2H), 1.60 (dt, J = 13.5, 7.7, 1H),
9-yl]ethyl})amine
1.55 – 1.30 (m, 4H), 1.10 (d, J = 4.1, 0H), 0.67
(dt, J = 13.1, 8.9, 1H).
δ 8.59 (d, J = 4.0, 1H), 8.13 (t, J = 7.1, 1H),
[(4-bromothiophen- 7.65 (d, J = 8.2, 1H), 7.59 (m, 1H), 7.23 (d, J =
2-yl)methyl]({2- 1.4, 1H), 7.04 (d, J = 1.2, 1H), 4.19 (s, 2H), 3.75
[(9R)(pyridin (m, 2H), 3.01 (m, 1H), 2.84 (s, 1H), 2.60 (m,
208 435.1
yl) 1H), 2.40 (m, 1H), 2.25 (d, J = 13.0, 3H), 1.97
oxaspiro[4.5]decan- (d, J = 14.0, 1H), 1.83 (d, J = 9.4, 2H), 1.67 (m,
9-yl]ethyl})amine 1H), 1.48 (dd, J = 24.0, 15.8, 4H), 1.17 (brs,
1H), 0.77 (m, 1H).
δ 8.61 (d, J = 4.3, 1H), 8.14 (t, J = 7.9, 1H),
[(5-bromothiophen- 7.65 (d, J = 8.1, 1H), 7.60 (m, 1H), 6.94 (d, J =
2-yl)methyl]({2- 3.8, 1H), 6.89 (d, J = 3.8, 1H), 4.14 (s, 2H), 3.76
[(9R)(pyridin (m, 3H), 2.99 (m, 1H), 2.58 (m, 1H), 2.38 (d, J =
209 435.1
yl) 9.8, 1H), 2.26 (d, J = 13.9, 3H), 1.97 (d, J =
oxaspiro[4.5]decan- 14.1, 1H), 1.82 (t, J = 9.7, 2H), 1.67 (s, 1H),
9-yl]ethyl})amine 1.47 (m, 4H), 1.16 (s, 1H), 0.75 (dt, J = 13.4,
9.2, 1H).
[(2-bromothiophen- δ 8.66 (d, J = 5.3, 1H), 8.21 (d, J = 7.2, 1H),
210 436
3-yl)methyl]({2- 7.85 – 7.58 (m, 2H), 7.33 (d, J = 5.7, 1H), 7.09
[(9R)(pyridin (d, J = 5.7, 1H), 4.02 – 3.63 (m, 3H), 3.10 – 2.97
yl) (m, 2H), 2.61 (t, J = 9.1, 1H), 2.43 (d, J = 11.0,
oxaspiro[4.5]decan- 1H), 2.30 (d, J = 13.6, 3H), 2.04 (s, 1H), 1.94 –
9-yl]ethyl})amine 1.80 (m, 2H), 1.69 (s, 1H), 1.64 – 1.40 (m, 4H),
1.20 (s, 1H), 0.86 – 0.68 (m, 1H).
[(5-bromofuran δ 9.07 (d, J = 116.7, 2H), 7.16 – 7.06 (m, 2H),
yl)methyl]({2-[(9R)- 7.01 – 6.89 (m, 2H), 6.25 (d, J = 3.4, 1H), 6.17
9-(4- (s, 1H), 3.83 (s, 2H), 3.76 – 3.58 (m, 2H), 2.66
211 fluorophenyl) 436 (s, 1H), 2.23 (s, 1H), 2.09 (d, J = 14.0, 1H), 2.04
oxaspiro[4.5]decan- – 1.96 (m, 1H), 1.95 – 1.66 (m, 4H), 1.66 – 1.50
9- (m, 2H), 1.50 – 1.28 (m, 4H), 1.28 – 1.13 (m,
yl]ethyl})amine 1H), 0.71 (dt, J = 13.6, 8.8, 1H).
{2-[(9R)(4-
δ 8.63 (s, 1H), 7.83 (d, J = 8.3, 1H), 7.68 (d, J =
fluorophenyl)
8.0, 1H), 7.29 (s, 1H), 7.21 (dd, J = 8.9, 5.1,
oxaspiro[4.5]decan-
3H), 7.05 (s, 2H), 3.93 (s, 2H), 3.75 (dd, J =
212 437.2 11.3, 7.3, 2H), 2.84 – 2.58 (m, 1H), 2.44 – 2.04
yl]ethyl}({[6-
(m, 10H), 2.02 – 1.75 (m, 5H), 1.74 – 1.56 (m,
(trifluoromethyl)pyri
3H), 1.59 – 1.33 (m, 5H), 1.33 – 1.19 (m, 1H),
din
0.78 (d, J = 13.6, 1H).
yl]methyl})amine
δ 7.38 (d, J = 0.6, 1H), 7.28 (s, 1H), 7.22 (d, J =
.2, 2H), 7.08 (d, J = 8.5, 2H), 3.75 (dd, J =
[(4-bromofuran
11.7, 7.1, 2H), 2.73 (s, 1H), 2.30 (d, J = 4.5,
yl)methyl]({2-[(9R)-
2H), 2.17 (d, J = 13.5, 1H), 2.10 (d, J = 13.9,
213 9-(4-fluorophenyl) 437.9
1H), 2.05 – 1.95 (m, 1H), 1.94 (s, 2H), 1.79 (d, J
oxaspiro[4.5]decan-
= 9.8, 1H), 1.74 – 1.62 (m, 2H), 1.49 (dt, J =
9-yl]ethyl})amine
16.4, 10.6, 4H), 1.28 (s, 2H), 0.80 (d, J = 13.7,
1H).
{2-[(9R)(pyridin- δ 8.52 (d, J = 5.3, 1H), 7.96 (t, J = 7.9, 1H), 7.50
2-yl) (d, J = 8.1, 1H), 7.40 (dd, J = 16.2, 10.4, 1H),
oxaspiro[4.5]decan- 7.24 – 7.10 (m, 1H), 7.03 (dd, J = 3.6, 1.0, 1H),
9- 6.98 – 6.81 (m, 3H), 4.07 (s, 2H), 3.80 – 3.49
214 439
yl]ethyl}({[5- (m, 2H), 2.90 (d, J = 11.1, 2H), 2.16 (s, 5H),
(thiophen 1.87 (d, J = 14.0, 1H), 1.71 (dd, J = 11.5, 7.2,
yl)thiophen 2H), 1.54 (d, J = 6.1, 1H), 1.36 (ddd, J = 16.8,
yl]methyl})amine 12.9, 6.1, 5H), 1.05 (s, 1H), 0.82 – 0.54 (m, 1H).
{2-[2,2-diethyl(4- δ 8.62 (s, 1H), 7.84 (d, J = 8.2, 1H), 7.66 (d, J =
fluorophenyl)oxan 8.2, 1H), 7.20 (m, 1H), 7.04 (s, 2H), 3.90 (s,
yl]ethyl}({[6- 2H), 3.71 (d, J = 12.1, 2H), 2.77 (m, 1H), 2.19
215 439.3
(trifluoromethyl)pyri (m, 3H), 1.98 (m, 1H), 1.68 (M, 3H), 1.40 (d, J
din = 7.6, 2H), 1.04 (s, 1H), 0.83 (t, J = 7.5, 4H),
yl]methyl})amine 0.54 (d, J = 7.3, 3H).
[(5-chloro δ 8.61 (d, J = 4.9, 1H), 8.44 (s, 1H), 8.17 (s,
benzothiophen 1H), 7.93 (d, J = 5.5, 1H), 7.69 (d, J = 8.1, 1H),
216 442
yl)methyl]({2-[(9R)- 7.60 (s, 1H), 7.50 (d, J = 5.5, 1H), 7.28 (s, 1H),
9- 3.82 (s, 3H), 3.17 (dd, J = 16.8, 10.9, 1H), 2.75
(pyridinyl) (t, J = 8.9, 1H), 2.47 (t, J = 9.7, 1H), 2.32 (d, J =
oxaspiro[4.5]decan- 13.9, 3H), 2.10 – 1.98 (m, 1H), 1.87 (dd, J =
9- 12.1, 7.1, 2H), 1.78 – 1.62 (m, 1H), 1.48 (dd, J =
yl]ethyl})amine 23.5, 18.9, 5H), 1.18 (s, 1H), 0.77 (dt, J = 13.2,
9.0, 1H).
δ 10.10 – 9.21 (m, 1H), 8.53 (d, J = 3.9, 1H),
[(5-bromo
7.90 (td, J = 7.9, 1.6, 1H), 7.45 (d, J = 8.1, 1H),
methylthiophen
7.38 (dd, J = 7.0, 5.4, 1H), 6.69 (s, 1H), 4.02 –
yl)methyl]({2-[(9R)-
3.86 (m, 2H), 3.74 – 3.55 (m, 2H), 2.85 (dd, J =
217 449 11.4, 5.9, 1H), 2.47 – 2.33 (m, 1H), 2.31 – 2.09
(pyridinyl)
(m, 3H), 2.09 – 1.93 (m, 4H), 1.87 (d, J = 14.0,
oxaspiro[4.5]decan-
1H), 1.69 (dt, J = 14.4, 6.1, 2H), 1.57 (d, J = 5.4,
1H), 1.38 (ddd, J = 26.7, 14.6, 8.4, 4H), 1.04 (s,
yl]ethyl})amine
1H), 0.73 – 0.56 (m, 1H).
[(4-bromo
δ 8.72 (d, J = 4.9, 1H), 8.26 (d, J = 7.7, 1H),
methylthiophen
7.74 (dd, J = 16.7, 7.1, 2H), 6.92 (s, 1H), 4.21
yl)methyl]({2-[(9R)-
(d, 1H), 3.90 – 3.78 (m, 2H), 3.74 (d, J = 9.6,
218 449 1H), 3.02 (s, 1H), 2.51 (dd, J = 52.4, 11.0, 2H),
(pyridinyl)
2.39 – 2.16 (m, 6H), 2.05 (d, J = 13.8, 1H), 1.87
oxaspiro[4.5]decan-
(d, J = 9.5, 2H), 1.69 (s, 1H), 1.63 – 1.41 (m,
4H), 1.24 (d, J = 30.9, 1H), 0.81 (s, 1H).
yl]ethyl})amine
[(3-bromo
δ 8.61 (d, J = 4.9, 1H), 8.02 (d, J = 7.9, 1H),
methylthiophen
7.69 – 7.41 (m, 2H), 6.68 (d, J = 1.0, 1H), 4.23
yl)methyl]({2-[(9R)-
(q, J = 14.2, 2H), 3.90 – 3.59 (m, 2H), 3.10 (s,
219 449 1H), 2.75 (m, 2H), 2.36 – 2.13 (m, 5H), 1.96 (d,
(pyridinyl)
J = 13.9, 1H), 1.82 (d, J = 9.9, 2H), 1.75 – 1.62
oxaspiro[4.5]decan-
(m, 1H), 1.62 – 1.38 (m, 4H), 1.24 – 1.05 (m,
1H), 0.74 (d, J = 13.2, 1H).
yl]ethyl})amine
[(4-bromo
δ 8.61 (d, J = 5.2, 1H), 8.09 (t, J = 7.7, 1H), 7.71
methylthiophen
– 7.49 (m, 2H), 7.30 (s, 1H), 4.21 (d, J = 4.3,
yl)methyl]({2-[(9R)-
2H), 4.00 – 3.59 (m, 2H), 3.05 (s, 1H), 2.64 (s,
220 449 1H), 2.31 (d, J = 14.5, 2H), 2.25 (d, J = 13.7,
(pyridinyl)
2H), 2.18 (s, 3H), 1.96 (d, J = 13.9, 1H), 1.82
oxaspiro[4.5]decan-
(dd, J = 12.0, 7.2, 2H), 1.68 (s, 1H), 1.61 – 1.40
(m, 4H), 1.17 (s, 1H), 0.92 – 0.64 (m, 1H).
yl]ethyl})amine
{2-[4-(4-
fluorophenyl) δ 8.52 (s, 1H), 7.73 (d, J = 9.6, 1H), 7.57 (d, J =
oxaspiro[5.5]undecan 8.0, 1H), 7.11 (dd, J = 9.0, 5.2, 2H), 6.94 (t, J =
8.4, 2H), 3.83 (s, 2H), 3.63 (d, J = 18.0, 2H),
221 451.2
yl]ethyl}({[6- 2.69 (m, 1H), 2.12 (t, J = 13.9, 3H), 1.70 (m,
(trifluoromethyl)pyri 5H), 1.31 (d, J = 18.3, 4H), 1.03 (s, 4H), 0.57
din (m, 1H).
yl]methyl})amine
δ 9.26 (d, J = 136.7, 2H), 7.39 (dd, J = 22.6,
[(4-bromothiophen- 19.3, 2H), 7.10 (dd, J = 8.8, 5.2, 2H), 6.92 (dd, J
3-yl)methyl]({2- = 10.6, 6.6, 2H), 3.82 (s, 2H), 3.71 – 3.53 (m,
[(9R)(4- 2H), 2.64 (s, 1H), 2.20 (s, 1H), 2.05 (d, J = 14.1,
222 451.9
fluorophenyl) 1H), 1.97 (d, J = 13.9, 1H), 1.89 (td, J = 12.6,
oxaspiro[4.5]decan- 4.6, 1H), 1.83 – 1.64 (m, 3H), 1.57 (ddd, J =
9-yl]ethyl})amine 14.0, 9.6, 4.7, 2H), 1.49 – 1.25 (m, 4H), 1.17 (d,
J = 13.2, 1H), 0.69 (dt, J = 13.8, 8.8, 1H).
[(4-bromothiophen- δ 9.38 (d, J = 89.0, 2H), 7.16 – 7.03 (m, 3H),
2-yl)methyl]({2- 6.96 (t, J = 8.6, 2H), 6.84 (d, J = 1.3, 1H), 3.86
[(9R)(4- (s, 2H), 3.70 – 3.55 (m, 2H), 2.62 (dd, J = 12.1,
223 fluorophenyl) 452.1 7.7, 1H), 2.18 (dd, J = 11.9, 7.8, 1H), 2.02 (dd, J
oxaspiro[4.5]decan- = 32.5, 14.0, 2H), 1.91 – 1.63 (m, 4H), 1.64 –
9- 1.50 (m, 2H), 1.49 – 1.25 (m, 4H), 1.16 (dd, J =
yl]ethyl})amine 14.0, 6.1, 1H), 0.69 (dt, J = 13.5, 8.8, 1H).
δ 9.31 (d, J = 92.6, 2H), 7.15 – 7.04 (m, 2H),
[(5-bromothiophen- 6.95 (t, J = 8.6, 2H), 6.82 (d, J = 3.8, 1H), 6.67
2-yl)methyl]({2- (d, J = 3.8, 1H), 3.82 (s, 2H), 3.70 – 3.53 (m,
[(9R)(4- 2H), 3.44 (s, 1H), 2.62 (dd, J = 12.0, 7.6, 1H),
224 fluorophenyl) 452.1 2.18 (dd, J = 11.8, 7.9, 1H), 2.02 (dd, J = 31.6,
oxaspiro[4.5]decan- 14.0, 2H), 1.93 – 1.64 (m, 4H), 1.57 (ddd, J =
9- 12.1, 8.5, 3.8, 2H), 1.52 – 1.25 (m, 4H), 1.16
yl]ethyl})amine (dd, J = 14.9, 5.1, 1H), 0.69 (dt, J = 13.6, 8.8,
1H).
δ 7.27 (m, 17H), 7.00 (dd, J = 8.9, 5.2, 2H), 6.86
dibenzyl({2-[(9R) (t, J = 8.6, 2H), 4.24 (s, 2H), 3.90 (m, 2H), 3.55
(4-fluorophenyl) (d, J = 3.4, 2H), 2.59 (m, 1H), 2.22 (m, 12H),
225 458.3
oxaspiro[4.5]decan- 1.86 (dd, J = 75.2, 14.8, 7H), 1.59 (dd, J = 44.5,
9-yl]ethyl})amine 9.1, 2H), 1.38 (m, 6H), 1.18 (s, 1H), 1.11 (s,
1H), 0.68 (m, 1H).
δ 7.27 (d, J = 34.4, 7H), 7.18 (s, 4H), 6.98 (dd, J
= 8.9, 5.2, 2H), 6.84 (t, J = 8.6, 2H), 4.25 (s,
dibenzyl({2-[2,2-
2H), 3.85 (d, J = 46.4, 2H), 3.53 (m, 2H), 2.57
diethyl(4-
226 460.3 (d, J = 4.7, 2H), 2.12 (d, J = 4.0, 2H), 1.97 (m,
fluorophenyl)oxan
3H), 1.73 (d, J = 4.8, 1H), 1.44 (s, 1H), 1.38 (dd,
yl]ethyl})amine
J = 13.8, 7.5, 3H), 1.23 (m, 1H), 0.90 (m, 1H),
0.70 (dt, J = 10.8, 7.4, 4H), 0.40 (t, J = 7.4, 3H).
[(4-bromo
methylthiophen
δ 7.19 (dd, J = 8.9, 5.1, 2H), 7.04 (t, J = 8.6,
yl)methyl]({2-[(9R)-
2H), 3.94 (d, J = 16.3, 2H), 3.72 (m, 2H), 2.72
227 465.9 (dd, J = 13.8, 6.5, 1H), 2.31 (m, 1H), 2.15 (d, J =
(4-fluorophenyl)
12.1, 2H), 2.07 (s, 3H), 1.90 (m, 5H), 1.65 (m,
oxaspiro[4.5]decan-
2H), 1.47 (m, 4H), 1.25 (s, 1H), 0.78 (m, 1H).
yl]ethyl})amine
228 [(4-bromo 465.9 δ 9.06 (d, J = 100.4, 2H), 7.15 – 7.04 (m, 2H),
methylthiophen 6.95 (s, 2H), 6.68 (s, 1H), 3.80 (s, 2H), 3.73 –
yl)methyl]({2-[(9R)- 3.57 (m, 2H), 2.64 (s, 1H), 2.21 (s, 4H), 2.07 (d,
9- J = 14.1, 1H), 1.99 (d, J = 13.9, 1H), 1.94 – 1.64
(4-fluorophenyl) (m, 4H), 1.64 – 1.51 (m, 2H), 1.51 – 1.26 (m,
oxaspiro[4.5]decan- 4H), 1.17 (dd, J = 13.9, 6.3, 1H), 0.70 (dt, J =
9- 13.7, 8.8, 1H).
yl]ethyl})amine
[(3-bromo δ 7.20 (m, 2H), 7.01 (dd, J = 11.1, 6.1, 2H),
methylthiophen 6.61 (d, J = 1.1, 1H), 4.01 (s, 2H), 3.72 (m, 2H),
yl)methyl]({2-[(9R)- 2.75 (m, 1H), 2.61 (brs, 1H), 2.41 (d, J = 0.9,
9- 3H), 2.32 (m, 1H), 2.15 (d, J = 14.2, 1H), 2.07
229 466
(4-fluorophenyl) (d, J = 13.9, 1H), 1.99 (m, 1H), 1.89 (m, 2H),
oxaspiro[4.5]decan- 1.77 (m, 1H), 1.67 (ddd, J = 17.0, 10.6, 5.6, 2H),
9- 1.46 (m, 4H), 1.25 (m, 1H), 0.78 (dt, J = 13.9,
yl]ethyl})amine 8.9, 1H).
[(5-bromo
methylthiophen δ 7.20 (d, J = 5.2, 2H), 7.06 (d, J = 8.5, 2H),
yl)methyl]({2-[(9R)- 6.85 (t, J = 3.6, 1H), 3.91 (s, 2H), 3.81 – 3.62
9- (m, 2H), 2.71 (s, 1H), 2.28 (s, 1H), 2.07 (s, 6H),
230 466.9
(4-fluorophenyl) 1.91 (d, J = 13.8, 2H), 1.79 (d, J = 10.3, 1H),
oxaspiro[4.5]decan- 1.69 (ddd, J = 14.1, 9.4, 4.7, 2H), 1.59 – 1.37
9- (m, 4H), 1.28 (s, 1H), 0.80 (dd, J = 8.8, 4.9, 1H).
yl]ethyl})amine
δ 7.31 (d, J = 4.9, 2H), 7.07 (dd, J = 8.9, 5.2,
2H), 6.99 (s, 2H), 6.95 (d, J = 4.5, 2H), 6.89 (t, J
{2-[2,2-diethyl(4-
= 8.6, 2H), 4.24 (s, 2H), 3.58 (dt, J = 23.8, 6.6,
fluorophenyl)oxan
231 472.2 2H), 2.66 (m, 1H), 2.06 (d, J = 14.0, 4H), 1.82
yl]ethyl}bis(thiophen
(m, 2H), 1.51 (d, J = 14.3, 3H), 1.25 (m, 2H),
ylmethyl)amine
0.94 (dd, J = 14.6, 7.4, 1H), 0.74 (t, J = 7.5, 4H),
0.42 (t, J = 7.4, 3H).
δ 8.61 (dd, J = 5.3, 1.3, 1H), 8.13 (td, J = 8.0,
[(4,5-
1.7, 1H), 7.64 (d, J = 8.2, 1H), 7.60 (m, 1H),
dibromothiophen
6.94 (s, 1H), 4.40 (brs, 1H), 4.11 (s, 2H), 3.77
yl)methyl]({2-[(9R)-
(ddd, J = 36.9, 13.7, 7.2, 2H), 2.98 (td, J = 11.3,
232 514.8 6.0, 1H), 2.54 (td, J = 11.2, 4.3, 1H), 2.38 (m,
(pyridinyl)
1H), 2.22 (m, 3H), 1.98 (d, J = 14.0, 1H), 1.83
oxaspiro[4.5]decan-
(dt, J = 18.5, 9.2, 2H), 1.68 (m, 1H), 1.48 (m,
4H), 1.21 (d, J = 37.1, 1H), 0.75 (dt, J = 13.1,
yl]ethyl})amine
9.0, 1H).
[(3,4- δ 8.39 (d, J = 4.0, 1H), 7.67 (t, J = 7.0, 1H), 7.38
dibromothiophen (s, 1H), 7.28 (d, J = 8.1, 1H), 7.18 (s, 1H), 4.22
yl)methyl]({2-[(9R)- (d, J = 18.2, 2H), 3.65 (dd, J = 11.2, 7.1, 2H),
233 9- 514.8 3.09 – 2.85 (m, 1H), 2.60 (s, 1H), 2.22 (dd, J =
(pyridinyl) 25.9, 13.8, 2H), 2.10 – 1.83 (m, 2H), 1.87 – 1.50
oxaspiro[4.5]decan- (m, 4H), 1.36 (dd, J = 18.7, 10.7, 3H), 1.02 (s,
9- 2H), 0.68 – 0.50 (m, 1H).
yl]ethyl})amine
[(4,5-
δ 7.20 (m, 2H), 7.05 (t, J = 8.6, 2H), 6.81 (s,
dibromothiophen
1H), 3.91 (s, 2H), 3.74 (m, 2H), 3.60 (brs, 1H),
yl)methyl]({2-[(9R)-
2.74 (m, 1H), 2.31 (td, J = 12.1, 4.7, 1H), 2.15
9-(4-
234 531.8 (d, J = 14.1, 1H), 2.08 (d, J = 13.9, 1H), 1.88 (m,
fluorophenyl)
4H), 1.67 (ddd, J = 15.1, 10.2, 5.0, 2H), 1.46
oxaspiro[4.5]decan-
(ddd, J = 27.4, 14.5, 7.2, 4H), 1.24 (dd, J = 10.5,
.6, 1H), 0.78 (dt, J = 13.5, 8.8, 1H).
yl]ethyl})amine
[(3,4-
δ 7.35 (s, 1H), 7.11 – 7.06 (m, 2H), 6.94 (dd, J
dibromothiophen
= 14.3, 5.7, 2H), 4.05 (s, 2H), 3.75 – 3.56 (m,
yl)methyl]({2-[(9R)-
2H), 2.70 (dd, J = 11.9, 7.4, 1H), 2.25 (dd, J =
9-(4-
235 531.8 11.7, 7.3, 1H), 2.08 (d, J = 14.7, 1H), 1.99 (d, J
fluorophenyl)
= 13.9, 1H), 1.95 – 1.65 (m, 4H), 1.65 – 1.50
oxaspiro[4.5]decan-
(m, 2H), 1.50 – 1.29 (m, 4H), 1.16 (dd, J = 14.8,
7.3, 1H), 0.70 (dt, J = 13.6, 8.8, 1H).
yl]ethyl})amine
[(2- δ 8.82 (s, 2H), 8.61 (dd, J = 4.8, 1.2, 1H), 7.85
fluorophenyl)methyl] (td, J = 7.8, 1.8, 1H), 7.51 (m, 3H), 7.30 (m,
({2-[(9R)(pyridin- 3H), 5.22 (s, 2H), 4.12 (d, J = 5.3, 2H), 3.66 (m,
236 369
2-yl) 2H), 2.90 (d, J = 4.5, 1H), 2.39 (m, 3H), 2.08
oxaspiro[4.5]decan- (td, J = 12.8, 4.4, 1H), 1.54 (m, 7H), 1.02 (dd, J
9-yl]ethyl})amine = 12.3, 5.8, 1H), 0.68 (dt, J = 13.3, 8.9, 1H).
δ 8.93 (s, 2H), 8.60 (dd, J = 4.8, 1.2, 1H), 7.83
[(2-
(td, J = 7.8, 1.9, 1H), 7.71 (dd, J = 8.0, 1.1, 1H),
bromophenyl)methyl
7.50 (m, 3H), 7.33 (m, 2H), 4.18 (s, 2H), 3.65
]({2-[(9R)
237 429 (m, 2H), 2.94 (s, 1H), 2.43 (t, J = 12.2, 3H),
(pyridinyl)
2.11 (td, J = 12.8, 4.4, 1H), 1.89 (m, 2H), 1.55
oxaspiro[4.5]decan-
(m, 7H), 1.01 (m, 1H), 0.67 (dt, J = 13.3, 8.9,
9-yl]ethyl})amine
1H).
δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.52 (s, 3H), 8.22
[(2- (td, J = 8.0, 1.7, 1H), 7.77 (d, J = 8.2, 1H), 7.67
chlorophenyl)methyl] (ddd, J = 7.5, 5.4, 0.9, 1H), 7.42 (m, 4H), 4.20
({2-[(9R)(pyridin- (d, J = 14.0, 2H), 3.72 (m, 2H), 3.05 (td, J =
238 385
2-yl) 12.0, 5.1, 1H), 2.53 (td, J = 12.0, 4.4, 1H), 2.36
oxaspiro[4.5]decan- (m, 3H), 2.17 (m, 1H), 2.01 (d, J = 14.2, 1H),
9-yl]ethyl})amine 1.79 (ddd, J = 9.3, 6.7, 3.4, 2H), 1.52 (m, 5H),
1.17 (m, 1H), 0.78 (dt, J = 12.9, 8.8, 1H).
δ 8.81 (dd, J = 5.7, 1.3, 1H), 8.43 (td, J = 8.0,
[(2- 1.7, 1H), 7.98 (s, 1H), 7.92 (d, J = 8.2, 1H), 7.86
methylphenyl)methyl (ddd, J = 7.6, 5.7, 1.0, 1H), 7.27 (m, 2H), 7.18
]({2-[(9R) (m, 2H), 3.98 (s, 2H), 3.75 (m, 2H), 2.98 (d, J =
239 365.1
(pyridinyl) 4.4, 1H), 2.44 (m, 2H), 2.36 (m, 5H), 2.25 (dd, J
oxaspiro[4.5]decan- = 13.5, 5.4, 1H), 2.07 (d, J = 14.3, 1H), 1.84 (m,
9-yl]ethyl})amine 2H), 1.55 (m, 5H), 1.23 (m, 1H), 0.83 (dt, J =
13.0, 8.8, 1H).
δ 8.71 (dd, J = 5.3, 1.2, 1H), 8.18 (td, J = 8.0,
{2-[(9R)(pyridin-
1.7, 1H), 7.79 (d, J = 7.8, 1H), 7.75 (d, J = 8.2,
2-yl)
1H), 7.70 (m, 2H), 7.62 (ddd, J = 13.7, 6.8, 1.2,
oxaspiro[4.5]decan-
2H), 6.71 (s, 3H), 4.23 (s, 2H), 3.75 (ddd, J =
240 9- 419.1
17.6, 8.8, 3.7, 2H), 3.08 (m, 1H), 2.56 (m, 1H),
yl]ethyl}({[2-
2.36 (m, 3H), 2.19 (m, 1H), 1.79 (dq, J = 7.2,
(trifluoromethyl)phen
4.7, 2H), 1.53 (m, 5H), 1.19 (m, 1H), 0.79 (m,
yl]methyl})amine
1H).
δ 8.74 (m, 1H), 8.21 (td, J = 8.0, 1.8, 1H), 7.75
2-[({2-[(9R)
(d, J = 8.2, 1H), 7.66 (ddd, J = 7.6, 5.4, 1.0, 1H),
(pyridinyl)
7.27 (m, 1H), 7.20 (dd, J = 7.6, 1.6, 1H), 6.90
oxaspiro[4.5]decan-
241 367 (m, 4H), 4.05 (s, 2H), 3.72 (ddd, J = 12.4, 11.1,
.4, 2H), 2.96 (d, J = 5.2, 1H), 2.35 (m, 4H),
yl]ethyl}amino)meth
2.13 (m, 1H), 1.78 (m, 2H), 1.51 (m, 5H), 1.15
yl]phenol
(dd, J = 4.0, 2.0, 1H), 0.78 (m, 1H).
δ 9.66 (s, 3H), 8.80 (dd, J = 5.5, 1.2, 1H), 8.31
[(2- (td, J = 8.0, 1.7, 1H), 7.77 (m, 3H), 7.42 (ddd, J
methoxyphenyl)meth = 15.9, 8.0, 1.6, 1H), 7.25 (dd, J = 7.5, 1.6, 1H),
yl]({2-[(9R) 7.04 (m, 1H), 6.96 (td, J = 7.5, 1.0, 1H), 4.04 (s,
242 (pyridin 381.1 2H), 3.85 (m, 4H), 3.73 (m, 2H), 2.97 (d, J =
yl) 4.9, 1H), 2.37 (m, 4H), 2.19 (dd, J = 13.2, 5.2,
oxaspiro[4.5]decan- 1H), 2.04 (d, J = 14.1, 1H), 1.81 (ddd, J = 14.0,
9-yl]ethyl})amine 9.5, 4.5, 2H), 1.81 (ddd, J = 14.0, 9.5, 4.5, 2H),
1.54 (m, 5H), 1.18 (m, 1H), 0.80 (m, 1H).
δ 8.77 (dd, J = 5.4, 1.5, 1H), 8.38 (s, 1H), 8.29
(td, J = 8.0, 1.7, 1H), 7.82 (d, J = 8.2, 1H), 7.74
[(3-
(dd, J = 7.1, 6.1, 1H), 7.43 (ddd, J = 13.8, 7.5,
fluorophenyl)methyl]
1.4, 1H), 7.19 (m, 3H), 6.90 (s, 3H), 4.03 (d, J =
({2-[(9R)(pyridin-
243 369 2.0, 2H), 3.74 (m, 2H), 2.98 (dt, J = 11.4, 5.6,
2-yl)
1H), 2.42 (ddd, J = 29.2, 13.0, 3.8, 4H), 2.18 (m,
oxaspiro[4.5]decan-
1H), 2.03 (d, J = 14.1, 1H), 1.81 (ddd, J = 13.9,
9-yl]ethyl})amine
9.4, 4.5, 2H), 1.55 (m, 5H), 1.20 (ddd, J = 9.9,
6.9, 2.4, 1H), 0.80 (dt, J = 12.9, 8.8, 1H).
δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.41 (s, 1H), 8.25
(td, J = 8.0, 1.8, 1H), 7.79 (d, J = 8.2, 1H), 7.70
[(3-
(ddd, J = 7.6, 5.5, 0.9, 1H), 7.59 (m, 2H), 7.36
bromophenyl)methyl
(ddd, J = 22.8, 10.9, 4.6, 2H), 6.76 (s, 3H), 4.01
]({2-[(9R)
244 431 (d, J = 2.3, 2H), 3.74 (ddd, J = 12.3, 11.0, 5.4,
(pyridinyl)
2H), 2.97 (d, J = 5.0, 1H), 2.38 (m, 4H), 2.16
oxaspiro[4.5]decan-
(m, 1H), 2.00 (m, 1H), 1.79 (ddd, J = 8.6, 7.8,
9-yl]ethyl})amine
4.7, 2H), 1.53 (m, 5H), 1.20 (m, 1H), 0.80 (m,
1H).
[(3- δ 8.72 (dd, J = 5.4, 1.1, 1H), 8.57 (s, 1H), 8.19
chlorophenyl)methyl] (td, J = 8.0, 1.8, 1H), 7.74 (d, J = 8.2, 1H), 7.64
245 385
({2-[(9R)(pyridin- (ddd, J = 7.6, 5.4, 0.9, 1H), 7.37 (m, 5H), 3.99
2-yl) (d, J = 2.3, 2H), 3.70 (m, 2H), 2.95 (m, 1H),
oxaspiro[4.5]decan- 2.36 (m, 4H), 2.12 (td, J = 12.9, 5.1, 1H), 1.76
9-yl]ethyl})amine (ddd, J = 14.2, 9.3, 5.1, 2H), 1.50 (m, 5H), 0.77
(dt, J = 13.0, 8.9, 1H).
δ 8.81 (dd, J = 5.7, 1.3, 1H), 8.43 (td, J = 8.0,
[(3- 1.7, 1H), 7.98 (s, 1H), 7.92 (d, J = 8.2, 1H), 7.86
methylphenyl)methyl (ddd, J = 7.6, 5.7, 1.0, 1H), 7.24 (dq, J = 19.8,
]({2-[(9R) 7.4, 4H), 3.98 (s, 2H), 3.75 (m, 2H), 2.98 (d, J =
246 365
(pyridinyl) 4.4, 1H), 2.44 (m, 2H), 2.36 (m, 5H), 2.25 (dd, J
oxaspiro[4.5]decan- = 13.5, 5.4, 1H), 2.07 (d, J = 14.3, 1H), 1.84 (m,
9-yl]ethyl})amine 2H), 1.55 (m, 5H), 1.23 (m, 1H), 0.83 (dt, J =
13.0, 8.8, 1H).
δ 8.78 (dd, J = 5.5, 1.3, 1H), 8.33 (td, J = 8.0,
1.7, 1H), 8.24 (s, 1H), 8.04 (m, 2H), 7.85 (d, J =
methyl 3-[({2-[(9R)-
8.2, 1H), 7.78 (m, 1H), 7.63 (m, 2H), 7.55 (d, J
9-(pyridinyl)
= 7.7, 1H), 4.10 (d, J = 2.0, 2H), 3.90 (s, 3H),
oxaspiro[4.5]decan-
247 409.1 3.75 (ddd, J = 12.2, 11.0, 5.4, 2H), 3.00 (dd, J =
11.5, 7.1, 1H), 2.40 (m, 4H), 2.21 (m, 1H), 2.04
yl]ethyl}amino)meth
(d, J = 14.2, 1H), 1.83 (ddd, J = 13.9, 9.2, 4.3,
yl]benzoate
2H), 1.51 (dddd, J = 17.6, 10.1, 8.1, 3.0, 5H),
1.21 (s, 1H), 0.82 (dd, J = 15.6, 6.6, 1H).
δ 8.77 (dd, J = 5.5, 1.2, 1H), 8.30 (td, J = 8.0,
1.7, 1H), 7.81 (s, 1H), 7.75 (ddd, J = 7.6, 5.5,
3-[({2-[(9R)
1.0, 1H), 7.23 (t, J = 8.1, 1H), 6.85 (dt, J = 3.2,
(pyridinyl)
2.1, 3H), 6.65 (s, 3H), 3.96 (s, 2H), 3.73 (dd, J =
oxaspiro[4.5]decan-
248 367 13.8, 7.3, 2H), 2.96 (s, 1H), 2.36 (m, 4H), 2.15
(ddd, J = 9.9, 8.5, 4.7, 1H), 2.03 (d, J = 14.2,
yl]ethyl}amino)meth
1H), 1.80 (dt, J = 11.2, 4.8, 2H), 1.52 (ddd, J =
yl]phenol
21.7, 12.8, 7.4, 5H), 1.20 (m, 1H), 0.80 (d, J =
13.3, 1H).
{2-[(9R)(pyridin-
δ 8.66 (m, 1H), 8.07 (td, J = 7.9, 1.8, 1H), 7.72
2-yl)
(m, 2H), 7.65 (m, 2H), 7.54 (m, 2H), 6.22 (s,
oxaspiro[4.5]decan-
2H), 4.08 (d, J = 3.1, 2H), 3.71 (m, 2H), 2.97 (d,
249 9- 419.1
J = 5.0, 1H), 2.34 (dddd, J = 25.4, 19.6, 16.7,
yl]ethyl}({[3-
4.4, 4H), 2.09 (m, 1H), 1.74 (m, 2H), 1.49 (m,
(trifluoromethyl)phen
5H), 0.76 (m, 1H).
yl]methyl})amine
N-methyl[({2- δ 8.78 (dd, J = 5.6, 1.3, 1H), 8.36 (td, J = 8.0,
[(9R)(pyridin 1.7, 1H), 7.86 (d, J = 8.2, 1H), 7.79 (ddd, J =
yl) 7.6, 5.6, 1.0, 1H), 7.38 (d, J = 3.8, 1H), 7.14 (d,
oxaspiro[4.5]decan- J = 3.8, 1H), 7.06 (d, J = 3.9, 1H), 4.21 (s, 2H),
250 414.1
9- 3.72 (m, 2H), 2.97 (td, J = 12.0, 5.1, 1H), 2.84
yl]ethyl}amino)meth (d, J = 4.7, 3H), 2.34 (m, 4H), 2.16 (m, 1H),
yl]thiophene 2.03 (d, J = 14.2, 1H), 1.80 (dd, J = 12.2, 3.0,
carboxamide 2H), 1.50 (m, 5H), 1.20 (m, 1H), 0.82 (s, 1H).
N-ethyl[({2-[(9R)- δ 8.78 (dd, J = 5.6, 1.2, 1H), 8.35 (td, J = 8.0,
251 428.1
9-(pyridinyl) 1.7, 1H), 7.86 (d, J = 8.2, 1H), 7.79 (ddd, J =
oxaspiro[4.5]decan- 7.6, 5.6, 0.9, 1H), 7.40 (d, J = 3.8, 1H), 7.14 (t, J
9- = 10.7, 2H), 6.20 (s, 4H), 4.21 (d, J = 1.2, 2H),
yl]ethyl}amino)meth 3.72 (m, 2H), 3.34 (m, 2H), 2.97 (m, 1H), 2.39
yl]thiophene (m, 4H), 2.18 (m, 1H), 2.03 (d, J = 14.2, 1H),
carboxamide 1.81 (m, 2H), 1.52 (m, 5H), 1.19 (m, 4H), 0.80
(m, 1H).
δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.24 (td, J = 8.0,
N-methyl[({2- 1.7, 1H), 7.89 (s, 1H), 7.77 (m, 2H), 7.69 (ddd, J
[(9R)(pyridin = 7.6, 5.5, 0.9, 1H), 7.49 (ddd, J = 18.3, 10.6,
yl) 4.6, 2H), 7.33 (s, 1H), 4.07 (s, 2H), 3.73 (m,
252 oxaspiro[4.5]decan- 408.1 2H), 2.98 (m, 1H), 2.88 (d, J = 4.6, 3H), 2.47 (t,
9- J = 10.7, 1H), 2.36 (dd, J = 12.8, 7.5, 3H), 2.16
yl]ethyl}amino)meth (d, J = 4.8, 1H), 1.79 (m, 2H), 1.50 (ddd, J =
yl]benzamide 18.7, 13.3, 6.9, 5H), 1.19 (ddd, J = 8.3, 7.0, 1.8,
1H), 0.80 (d, J = 13.3, 1H).
δ 8.70 (dd, J = 5.3, 1.2, 1H), 8.43 (s, 1H), 8.14
(td, J = 7.9, 1.8, 1H), 7.89 (d, J = 1.4, 1H), 7.76
N-ethyl[({2-[(9R)-
(dt, J = 7.3, 1.6, 1H), 7.71 (d, J = 8.2, 1H), 7.59
9-(pyridinyl)
(ddd, J = 7.6, 5.3, 0.9, 1H), 7.46 (m, 2H), 7.37
oxaspiro[4.5]decan-
253 422.1 (s, 1H), 6.55 (s, 3H), 4.05 (s, 2H), 3.70 (m, 2H),
3.36 (qd, J = 7.2, 5.7, 2H), 2.96 (d, J = 7.9, 1H),
yl]ethyl}amino)meth
2.45 (t, J = 10.2, 1H), 2.32 (dd, J = 21.2, 8.7,
yl]benzamide
3H), 2.11 (d, J = 5.2, 1H), 1.77 (m, 2H), 1.47
(m, 5H), 1.19 (m, 4H), 0.76 (d, J = 13.3, 1H).
δ 9.09 (d, J = 86.1, 2H), 8.69 (d, J = 5.0, 1H),
[(4-
8.29 (t, J = 7.7, 1H), 8.06 (s, 3H), 7.75 (m, 2H),
methoxyphenyl)meth
7.20 (d, J = 8.6, 2H), 6.81 (d, J = 8.6, 2H), 3.89
yl]({2-[(9R)
(s, 2H), 3.79 (m, 4H), 3.66 (m, 1H), 2.96 (s,
254 (pyridin 381.1
1H), 2.43 (dd, J = 23.4, 11.5, 2H), 2.27 (t, J =
yl)
16.0, 3H), 2.01 (d, J = 14.2, 1H), 1.83 (dd, J =
oxaspiro[4.5]decan-
19.3, 9.5, 2H), 1.66 (m, 1H), 1.47 (m, 4H), 1.14
9-yl]ethyl})amine
(d, J = 7.0, 1H), 0.75 (m, 1H).
δ 8.76 (dd, J = 5.5, 1.2, 1H), 8.26 (m, 1H), 7.80
4-[({2-[(9R)
(d, J = 8.2, 1H), 7.72 (ddd, J = 7.6, 5.5, 0.9, 1H),
(pyridinyl)
7.65 (s, 1H), 7.22 (m, 2H), 6.82 (m, 2H), 3.93
oxaspiro[4.5]decan-
255 367 (s, 2H), 3.73 (dd, J = 10.7, 7.6, 2H), 2.94 (dd, J
= 11.1, 5.9, 1H), 2.36 (m, 4H), 2.13 (m, 1H),
yl]ethyl}amino)meth
2.01 (m, 1H), 1.80 (d, J = 3.6, 2H), 1.51 (dd, J =
yl]phenol
9.7, 5.6, 5H), 1.19 (m, 1H), 0.81 (s, 1H).
[(2,3- δ 8.75 (dd, J = 5.4, 1.3, 1H), 8.26 (td, J = 8.0,
difluorophenyl)meth 1.7, 1H), 7.80 (d, J = 8.2, 1H), 7.71 (ddd, J =
yl]({2-[(9R) 7.5, 5.5, 0.9, 1H), 7.34 (dtd, J = 10.0, 7.9, 1.9,
256 (pyridin 387 1H), 7.21 (m, 4H), 4.11 (s, 2H), 3.72 (m, 2H),
yl) 3.02 (td, J = 12.0, 5.1, 1H), 2.49 (td, J = 12.1,
oxaspiro[4.5]decan- 4.3, 1H), 2.35 (m, 3H), 2.16 (m, 1H), 2.01 (d, J
9-yl]ethyl})amine = 14.1, 1H), 1.79 (ddd, J = 11.2, 9.4, 4.1, 2H),
1.52 (m, 5H), 1.17 (m, 1H), 0.78 (dt, J = 12.9,
8.8, 1H).
δ 8.79 (dd, J = 5.5, 1.3, 1H), 8.38 (s, 1H), 8.32
[(2,4-
(m, 1H), 7.84 (d, J = 8.2, 1H), 7.76 (ddd, J = 7.6,
difluorophenyl)meth
.5, 0.9, 1H), 7.50 (dd, J = 14.8, 8.3, 1H), 7.03
yl]({2-[(9R)
(m, 2H), 4.08 (s, 2H), 3.74 (m, 2H), 3.02 (td, J =
257 (pyridin 387
12.0, 5.0, 1H), 2.42 (m, 4H), 2.18 (m, 1H), 2.03
yl)
(d, J = 14.2, 1H), 1.82 (ddd, J = 14.2, 9.6, 4.5,
oxaspiro[4.5]decan-
2H), 1.56 (m, 5H), 1.19 (ddd, J = 7.0, 6.2, 2.8,
9-yl]ethyl})amine
1H), 0.80 (dt, J = 12.9, 8.8, 1H).
δ 8.74 (dd, J = 5.4, 1.2, 1H), 8.26 (td, J = 8.0,
[(2,5-
1.7, 1H), 7.72 (m, 2H), 7.21 (dddd, J = 8.4, 7.0,
difluorophenyl)meth
4.8, 1.8, 3H), 6.45 (s, 3H), 4.07 (s, 2H), 3.73
yl]({2-[(9R)
(ddd, J = 12.2, 11.1, 5.5, 2H), 3.02 (d, J = 5.2,
258 (pyridin 387
1H), 2.49 (d, J = 4.3, 1H), 2.36 (dt, J = 11.8, 4.5,
yl)
3H), 2.18 (dd, J = 12.3, 5.2, 1H), 2.00 (m, 1H),
oxaspiro[4.5]decan-
1.79 (ddd, J = 13.9, 9.3, 4.4, 2H), 1.49 (m, 5H),
9-yl]ethyl})amine
1.18 (m, 1H), 0.78 (d, J = 13.3, 1H).
δ 8.79 (dd, J = 5.6, 1.3, 1H), 8.36 (m, 1H), 8.20
[(2,6-
(s, 4H), 7.86 (d, J = 8.2, 1H), 7.79 (ddd, J = 7.6,
difluorophenyl)meth
.6, 1.0, 1H), 7.50 (tt, J = 8.5, 6.6, 1H), 7.04 (m,
yl]({2-[(9R)
2H), 4.13 (s, 2H), 3.72 (m, 2H), 3.05 (td, J =
259 (pyridin 387.1
12.0, 5.1, 1H), 2.52 (td, J = 12.1, 4.2, 1H), 2.37
yl)
(m, 3H), 2.19 (m, 1H), 2.04 (d, J = 14.2, 1H),
oxaspiro[4.5]decan-
1.81 (m, 2H), 1.53 (m, 5H), 1.18 (m, 1H), 0.79
9-yl]ethyl})amine
(dt, J = 12.8, 8.8, 1H).
δ 8.84 (s, 1H), 8.79 (dd, J = 5.6, 1.3, 1H), 8.41
[(3,4-
(td, J = 8.0, 1.6, 1H), 8.25 (s, 1H), 7.86 (ddd, J =
difluorophenyl)meth
13.3, 7.6, 7.0, 2H), 7.30 (m, 3H), 3.99 (d, J =
yl]({2-[(9R)
1.7, 2H), 3.73 (m, 2H), 2.96 (dd, J = 12.1, 7.4,
260 (pyridin 387.1
1H), 2.38 (m, 4H), 2.21 (m, 1H), 2.05 (d, J =
yl)
14.2, 1H), 1.82 (ddd, J = 12.6, 9.0, 4.2, 2H),
oxaspiro[4.5]decan-
1.53 (m, 5H), 1.21 (m, 1H), 0.81 (dt, J = 12.9,
9-yl]ethyl})amine
8.8, 1H).
[(3,5- δ 8.77 (d, J = 5.4, 1H), 8.43 (s, 1H), 8.35 (d, J =
difluorophenyl)meth 7.7, 1H), 7.83 (m, 2H), 7.03 (m, 3H), 4.01 (s,
yl]({2-[(9R) 2H), 3.74 (ddd, J = 27.7, 13.8, 7.4, 2H), 2.96 (m,
261 (pyridin 387 1H), 2.39 (m, 4H), 2.23 (dd, J = 13.3, 5.1, 1H),
yl) 2.02 (m, 1H), 1.81 (m, 2H), 1.52 (m, 5H), 1.21
oxaspiro[4.5]decan- (dd, J = 9.4, 5.3, 1H), 0.80 (dt, J = 12.9, 8.9,
9-yl]ethyl})amine 1H).
[(2,3- δ 8.75 (dd, J = 5.4, 1.2, 1H), 8.21 (td, J = 8.0,
dimethoxyphenyl)me 1.8, 1H), 7.88 (s, 2H), 7.75 (d, J = 8.2, 1H), 7.66
262 thyl]({2-[(9R) 411.1 (ddd, J = 7.6, 5.4, 0.9, 1H), 7.08 (dd, J = 9.0,
(pyridin 5.6, 2H), 6.87 (dd, J = 6.2, 3.0, 1H), 4.05 (s,
yl) 2H), 3.86 (d, J = 6.3, 6H), 3.73 (ddd, J = 12.5,
oxaspiro[4.5]decan- 11.1, 5.4, 2H), 2.97 (s, 1H), 2.45 (s, 1H), 2.35
9-yl]ethyl})amine (m, 3H), 2.14 (m, 1H), 1.78 (ddd, J = 14.2, 6.0,
3.9, 2H), 1.49 (m, 5H), 1.16 (m, 1H), 0.77 (d, J
= 13.3, 1H).
δ 8.73 (dd, J = 5.5, 1.2, 1H), 8.24 (td, J = 8.0,
[(3,4-
1.7, 1H), 8.00 (s, 1H), 7.78 (d, J = 8.2, 1H), 7.69
dimethoxyphenyl)me
(ddd, J = 7.5, 5.5, 0.8, 1H), 6.96 (d, J = 1.0, 1H),
thyl]({2-[(9R)
6.88 (d, J = 1.7, 2H), 6.55 (s, 3H), 3.93 (s, 2H),
263 (pyridin 411.1
3.78 (t, J = 7.5, 6H), 3.72 (m, 2H), 2.92 (s, 1H),
yl)
2.35 (m, 4H), 2.15 (m, 1H), 1.99 (d, J = 14.2,
oxaspiro[4.5]decan-
1H), 1.79 (m, 2H), 1.49 (m, 5H), 1.18 (s, 1H),
9-yl]ethyl})amine
0.79 (dd, J = 15.6, 6.6, 1H).
2-methoxy[({2- δ 8.62 (dd, J = 5.0, 1.0, 1H), 7.94 (td, J = 7.9,
[(9R)(pyridin 1.8, 1H), 7.57 (d, J = 8.1, 1H), 7.42 (m, 1H),
yl) 7.00 (s, 1H), 6.81 (d, J = 0.8, 2H), 3.93 (s, 2H),
264 oxaspiro[4.5]decan- 397.1 3.84 (s, 3H), 3.70 (m, 3H), 2.93 (s, 1H), 2.36 (s,
9- 3H), 2.17 (m, 1H), 1.90 (d, J = 13.7, 1H), 1.74
yl]ethyl}amino)meth (m, 2H), 1.51 (s, 5H), 1.13 (m, 1H), 0.73 (dt, J =
yl]phenol 13.2, 8.9, 1H).
[(5-fluoropyridin δ 8.82 (s, 1H), 8.50 (dd, J = 34.5, 26.7, 3H),
yl)methyl]({2-[(9R)- 7.93 (m, 2H), 7.74 (t, J = 9.7, 1H), 4.12 (d, J =
9-(pyridin 10.8, 2H), 3.76 (dd, J = 25.7, 11.8, 2H), 3.03 (d,
265 370
yl) J = 7.9, 1H), 2.39 (m, 5H), 2.09 (t, J = 13.0, 1H),
oxaspiro[4.5]decan- 1.85 (d, J = 9.0, 2H), 1.60 (d, J = 44.8, 5H), 1.24
9-yl]ethyl})amine (s, 1H), 0.86 (d, J = 9.1, 1H).
[(5-bromopyridin δ 8.64 (m, 5H), 8.16 (s, 1H), 8.00 (d, J = 8.2,
yl)methyl]({2-[(9R)- 1H), 7.95 (m, 1H), 4.10 (m, 2H), 3.76 (m, 2H),
9-(pyridin 3.02 (td, J = 12.4, 5.0, 1H), 2.49 (m, 2H), 2.29
266 430
yl) (m, 3H), 2.12 (t, J = 10.2, 1H), 1.88 (ddd, J =
oxaspiro[4.5]decan- 25.8, 12.8, 8.1, 2H), 1.57 (m, 5H), 1.26 (m, 1H),
9-yl]ethyl})amine 0.86 (dt, J = 12.9, 8.9, 1H).
[(5-chloropyridin δ 8.80 (s, 1H), 8.63 (s, 1H), 8.49 (dd, J = 17.4,
yl)methyl]({2-[(9R)- 10.6, 3H), 7.93 (m, 3H), 4.08 (s, 2H), 3.75 (dd, J
9-(pyridin = 29.6, 6.9, 2H), 2.99 (d, J = 11.6, 1H), 2.45 (m,
267 386
yl) 2H), 2.28 (m, 3H), 2.08 (d, J = 14.3, 1H), 1.85
oxaspiro[4.5]decan- (d, J = 7.5, 2H), 1.60 (m, 5H), 1.23 (s, 1H), 0.84
9-yl]ethyl})amine (d, J = 5.6, 1H).
[(5-methoxypyridin-
δ 8.81 (d, J = 5.5, 1H), 8.48 (m, 3H), 7.95 (m,
3-yl)methyl]({2-
3H), 4.22 (d, J = 13.4, 2H), 3.98 (s, 3H), 3.75
[(9R)
(ddd, J = 19.2, 12.7, 9.3, 2H), 3.04 (td, J = 11.6,
268 (pyridinyl) 382.1
4.8, 1H), 2.42 (m, 7H), 2.09 (d, J = 14.3, 1H),
oxaspiro[4.5]decan-
1.88 (m, 2H), 1.57 (m, 6H), 1.26 (d, J = 10.9,
1H), 0.85 (dt, J = 12.4, 8.7, 1H).
yl]ethyl})amine
-[({2-[(9R) δ 8.96 (d, J = 15.0, 1H), 8.83 (t, J = 10.5, 2H),
269 377.1
(pyridinyl) 8.53 (dt, J = 15.9, 8.0, 2H), 8.23 (d, J = 15.0,
oxaspiro[4.5]decan- 1H), 7.97 (ddd, J = 13.4, 11.9, 7.5, 2H), 4.13 (m,
9- 2H), 3.77 (m, 2H), 3.02 (m, 1H), 2.50 (ddd, J =
yl]ethyl}amino)meth 26.3, 14.4, 3.7, 2H), 2.31 (m, 3H), 2.13 (dd, J =
yl]pyridine 19.3, 11.3, 1H), 1.88 (ddd, J = 17.2, 11.0, 7.0,
carbonitrile 2H), 1.58 (m, 5H), 1.27 (m, 1H), 0.85 (dt, J =
12.8, 8.7, 1H).
[(5-methylpyridin δ 8.71 (dd, J = 50.6, 19.3, 3H), 8.37 (m, 2H),
yl)methyl]({2-[(9R)- 7.85 (m, 2H), 4.20 (d, J = 13.3, 2H), 3.74 (ddd, J
9-(pyridin = 11.9, 11.1, 5.6, 2H), 3.02 (m, 1H), 2.44 (m,
270 366
yl) 7H), 2.25 (dd, J = 12.5, 5.0, 1H), 1.84 (m, 2H),
oxaspiro[4.5]decan- 1.57 (tdd, J = 24.6, 15.7, 8.5, 5H), 1.22 (d, J =
9-yl]ethyl})amine 9.3, 1H), 0.83 (m, 1H).
{2-[(9R)(pyridin-
δ 8.96 (s, 1H), 8.81 (m, 2H), 8.45 (td, J = 8.1,
2-yl)
1.6, 2H), 8.21 (s, 1H), 7.90 (m, 2H), 4.16 (m,
oxaspiro[4.5]decan-
2H), 3.77 (dtd, J = 12.7, 9.5, 5.3, 2H), 3.04 (td, J
271 420.1 = 12.2, 5.1, 1H), 2.50 (m, 2H), 2.31 (ddd, J =
yl]ethyl}({[5-
21.7, 14.1, 7.0, 3H), 2.12 (d, J = 12.6, 1H), 1.87
(trifluoromethyl)pyri
(ddd, J = 20.7, 12.7, 7.7, 2H), 1.58 (m, 5H), 1.26
din
(m, 1H), 0.85 (m, 1H).
yl]methyl})amine
δ 8.70 (m, 1H), 8.60 (d, J = 2.1, 1H), 8.28 (d, J =
{[6-chloro 2.2, 1H), 8.16 (td, J = 7.9, 1.8, 1H), 7.73 (d, J =
(trifluoromethyl)pyri 8.2, 1H), 7.62 (ddd, J = 7.6, 5.3, 1.0, 1H), 4.12
din (m, 2H), 3.73 (m, 2H), 3.18 (brs, 1H), 2.99 (td, J
272 yl]methyl}({2-[(9R)- 454.1 = 12.0, 5.1, 2H), 2.49 (td, J = 12.0, 4.4, 1H),
9-(pyridinyl) 2.35 (dd, J = 14.1, 1.9, 3H), 2.13 (ddd, J = 14.2,
oxaspiro[4.5]decan- 12.1, 5.2, 1H), 1.79 (dd, J = 5.6, 3.7, 2H), 1.62
9-yl]ethyl})amine (dd, J = 7.8, 2.8, 1H), 1.51 (dd, J = 7.9, 4.1, 4H),
1.18 (m, 1H), 0.78 (dt, J = 13.2, 8.9, 1H).
δ 8.73 (dd, J = 5.3, 1.2, 1H), 8.62 (s, 1H), 8.35
(dd, J = 8.5, 2.3, 1H), 8.22 (td, J = 8.0, 1.6, 1H),
{[2-fluoro
7.78 (d, J = 8.2, 1H), 7.67 (dd, J = 6.9, 5.8, 1H),
(trifluoromethyl)pyri
4.25 (brs, 1H), 4.13 (m, 2H), 3.74 (ddd, J =
din
12.3, 11.0, 5.5, 2H), 3.05 (td, J = 11.9, 5.1, 1H),
273 yl]methyl}({2-[(9R)- 438.1
2.54 (td, J = 12.0, 4.4, 1H), 2.35 (dt, J = 9.7, 5.3,
9-(pyridinyl)
3H), 2.16 (ddd, J = 9.9, 8.8, 3.8, 1H), 2.01 (d, J
oxaspiro[4.5]decan-
= 14.1, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.49
9-yl]ethyl})amine
(m, 4H), 1.19 (m, 1H), 0.79 (dt, J = 13.1, 8.8,
1H).
{[6-fluoro δ 8.58 (d, J = 4.0, 1H), 8.45 (s, 1H), 8.35 (d, J =
(trifluoromethyl)pyri 9.0, 1H), 7.85 (m, 1H), 7.51 (d, J = 8.1, 1H),
din 7.33 (dd, J = 7.4, 4.9, 1H), 4.12 (m, 2H), 3.70
274 yl]methyl}({2-[(9R)- 438.1 (dd, J = 8.8, 2.9, 2H), 2.98 (m, 2H), 2.47 (dd, J =
9-(pyridinyl) 12.1, 7.4, 2H), 2.38 (t, J = 11.7, 2H), 2.18 (dd, J
oxaspiro[4.5]decan- = 12.9, 4.8, 1H), 1.90 (d, J = 13.7, 1H), 1.70 (m,
9-yl]ethyl})amine 2H), 1.60 (m, 1H), 1.50 (dt, J = 39.4, 20.7, 4H),
1.11 (m, 1H), 0.73 (dt, J = 13.5, 9.1, 1H).
δ 9.29 (brs, 1H), 8.90 (s, 1H), 8.86 (d, J = 5.1,
{2-[(9R)(pyridin- 1H), 8.80 (dd, J = 5.7, 1.2, 1H), 8.49 (td, J = 8.0,
2-yl) 1.7, 1H), 7.98 (d, J = 8.2, 1H), 7.91 (ddd, J =
oxaspiro[4.5]decan- 7.6, 5.7, 1.0, 1H), 7.74 (d, J = 5.1, 1H), 4.27 (m,
9- 2H), 3.81 (dt, J = 12.8, 4.6, 1H), 3.72 (m, 1H),
275 420.1
yl]ethyl}({[3- 3.13 (td, J = 12.1, 5.1, 1H), 2.60 (td, J = 12.3,
(trifluoromethyl)pyri 4.1, 1H), 2.49 (m, 1H), 2.33 (m, 3H), 2.10 (d, J
din = 14.3, 1H), 1.85 (m, 2H), 1.65 (m, 1H), 1.52
yl]methyl})amine (m, 4H), 1.25 (m, 1H), 0.84 (dt, J = 12.8, 8.8,
1H).
δ 8.81 (dd, J = 5.5, 1.2, 1H), 8.75 (d, J = 4.4,
{2-[(9R)(pyridin- 1H), 8.32 (td, J = 8.0, 1.7, 1H), 8.16 (dd, J = 8.0,
2-yl) 0.7, 1H), 7.86 (d, J = 8.2, 1H), 7.77 (ddd, J =
oxaspiro[4.5]decan- 7.6, 5.5, 1.0, 1H), 7.59 (dd, J = 7.5, 5.0, 1H),
9- 4.40 (m, 2H), 3.75 (m, 2H), 3.13 (td, J = 12.0,
276 420.1
yl]ethyl}({[4- 5.3, 1H), 2.66 (td, J = 12.1, 4.5, 1H), 2.49 (ddd,
(trifluoromethyl)pyri J = 13.7, 11.9, 4.5, 1H), 2.41 (m, 1H), 2.32 (m,
din 2H), 2.07 (d, J = 14.0, 1H), 1.85 (ddd, J = 9.3,
yl]methyl})amine 7.7, 4.5, 2H), 1.64 (m, 1H), 1.51 (m, 4H), 1.22
(m, 1H), 0.82 (dt, J = 13.1, 8.9, 1H).
{2-[(9R)(pyridin- δ 8.80 (dd, J = 5.5, 1.3, 1H), 8.75 (d, J = 5.0,
2-yl) 1H), 8.31 (td, J = 8.0, 1.7, 1H), 7.84 (d, J = 8.2,
oxaspiro[4.5]decan- 1H), 7.75 (ddd, J = 7.6, 5.5, 0.9, 1H), 7.65 (M,
9- 2H), 4.31 (m, 2H), 3.74 (m, 2H), 3.09 (td, J =
277 420.1
yl]ethyl}({[4- 12.0, 5.2, 1H), 2.60 (td, J = 12.1, 4.4, 1H), 2.36
(trifluoromethyl)pyri (m, 4H), 2.05 (d, J = 14.1, 1H), 1.82 (m, 2H),
din 1.64 (m, 1H), 1.50 (m, 4H), 1.20 (m, 1H), 0.81
yl]methyl})amine (dt, J = 12.8, 8.8, 1H).
500 [(4-
chlorophenyl)methyl]
({2-[4-(4-
methoxyphenyl)-
2,2-dimethyloxan
yl]ethyl})amine
501 [(3,4-
dimethoxyphenyl)me
thyl][2-(2,2-
dimethyl
phenyloxan
yl)ethyl]amine
502 2-[({2-[2-ethyl
methyl(4-
methylphenyl)oxan-
yl]ethyl}amino)meth
yl]phenol
503 [2-(2,2-dimethyl
phenyloxan
yl)ethyl][(2-
fluorophenyl)methyl]
amine
504 4-[({2-[4-(2-
methoxyphenyl)-2,2-
dimethyloxan
yl]ethyl}amino)meth
yl]-N,N-
dimethylaniline
505 2-[({2-[2-ethyl(4-
fluorophenyl)
methyloxan
yl]ethyl}amino)meth
yl]phenol
Example 13: Opioid Receptor Ligands
The following compounds in Table 2 can also be prepared according to the procedures
described above from appropriate starting materials and appropriate reagents and would be
expected to also have similar properties and therapeutic effects as other compounds described
herein. In addition to the specific structure shown the other isomers or enantiomers are included
with the description herein. Compounds that have been made lists NMR data and prophetic
examples do not list NMR data.
Table 2: Examples with chemical name and/or characterization data
Compoun Name Structure and/or NMR Spectrum
506. {2-[(9R)(pyridinyl) MS: 353.2
oxaspiro[4.5]decan H NMR (400 MHz, CD3CN) δ 9.16 (s,
1H), 8.78 (s, 2H), 8.70 (dd, J = 5.3, 1.1,
yl]ethyl}(pyrimidin
1H), 8.16 (td, J = 8.0, 1.8, 1H), 7.74 (d, J =
ylmethyl)amine 8.2, 1H), 7.62 (ddd, J = 7.6, 5.4, 0.9, 1H),
4.27 (brs, 1H), 4.04 (t, J = 7.7, 2H), 3.73
(m, 2H), 3.01 (td, J = 12.0, 5.1, 1H), 2.50
(td, J = 12.0, 4.4, 1H), 2.33 (m, 3H), 2.12
(ddd, J = 19.0, 11.7, 5.2, 1H), 1.99 (d, J =
.1, 1H), 1.78 (m, 2H), 1.61 (m, 1H), 1.48
(m, 4H), 1.17 (m, 1H), 0.78 (dt, J = 13.1,
8.9, 1H).
Compoun Name Structure and/or NMR Spectrum
507. [(2-methylpyrimidin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
508. {2-[(9R)(pyridinyl)
oxaspiro[4.5]decanyl]ethyl}({[2-
(trifluoromethyl)pyrimidin
yl]methyl})amine
509. [(2-methoxypyrimidin MS: 383.3
yl)methyl]({2-[(9R) H NMR (400 MHz, CD3CN) δ 8.69 (dd, J
= 5.2, 1.1, 1H), 8.54 (s, 2H), 8.10 (td, J =
(pyridinyl)oxaspiro[4.5]decan-
7.9, 1.7, 1H), 7.69 (d, J = 8.1, 1H), 7.56 (dd,
9- J = 6.7, 5.3, 1H), 3.98 (s, 5H), 3.71 (m, 3H),
3.50 (brs, 1H), 2.98 (td, J = 12.0, 5.0, 1H),
yl]ethyl})amine
2.47 (td, J = 12.0, 4.3, 1H), 2.37 (m, 2H),
2.27 (m, 1H), 2.10 (m, 1H), 1.77 (m, 2H),
1.62 (m, 1H), 1.47 (dddd, J = 14.1, 12.4,
8.4, 4.9, 4H), 1.17 (m, 1H), 0.77 (dt, J =
13.1, 8.9, 1H).
Compoun Name Structure and/or NMR Spectrum
510. (pyridazinylmethyl)({2-[(9R)
(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
511. [(6-methylpyridazin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
512. {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[6-
(trifluoromethyl)pyridazin
yl]methyl})amine
513. [(6-methoxypyridazin
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
514. (pyrazinylmethyl)({2-[(9R) MS: 353.3
H NMR (400 MHz, CD3CN) δ 8.74 (dd, J
(pyridinyl)
= 5.3, 1.1, 1H), 8.60 (d, J = 1.6, 2H), 8.55
oxaspiro[4.5]decan
(m, 1H), 8.16 (td, J = 7.9, 1.7, 1H), 7.73 (d,
yl]ethyl})amine J = 8.2, 1H), 7.61 (ddd, J = 7.5, 5.3, 0.8,
1H), 7.13 (brs, 1H), 4.25 (m, 2H), 3.73 (m,
2H), 3.09 (td, J = 11.8, 5.4, 1H), 2.61 (td, J
= 11.9, 4.6, 1H), 2.37 (m, 3H), 2.18 (ddd, J
= 13.7, 11.6, 5.5, 1H), 1.99 (m, 1H), 1.77
(dd, J = 9.6, 4.4, 2H), 1.62 (m, 1H), 1.48
(m, 4H), 1.18 (m, 1H), 0.79 (dt, J = 13.1,
8.9, 1H).
Compoun Name Structure and/or NMR Spectrum
515. [(6-methylpyrazinyl)methyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
516. {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[6-
(trifluoromethyl)pyrazin
yl]methyl})amine
517. [(6-methoxypyrazin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
518. [(5-methylpyrazinyl)methyl]({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
519. {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyrazin
yl]methyl})amine
Compoun Name Structure and/or NMR Spectrum
520. [(5-methoxypyrazin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
521. {2-[(9R)(pyridinyl) MS: 402.3
H NMR (400 MHz, CD3CN) δ 9.90 (brs,
oxaspiro[4.5]decan
1H), 9.15 (d, J = 1.7, 1H), 8.89 (s, 1H), 8.77
yl]ethyl}(quinolinylmethyl)amine
(dd, J = 5.6, 1.3, 1H), 8.40 (td, J = 8.0, 1.6,
1H), 8.30 (d, J = 8.6, 1H), 8.16 (d, J = 8.2,
1H), 8.08 (ddd, J = 8.5, 7.0, 1.3, 1H), 7.90
(m, 2H), 7.81 (m, 1H), 4.36 (m, 2H), 3.74
(m, 2H), 3.06 (td, J = 12.0, 5.1, 1H), 2.57
(td, J = 12.2, 4.1, 1H), 2.45 (m, 1H), 2.29
(m, 3H), 2.08 (m, 1H), 1.98 (d, J = 2.5, 1H),
1.83 (m, 2H), 1.64 (ddd, J = 11.6, 8.7, 3.4,
1H), 1.50 (m, 4H), 1.23 (ddd, J = 10.4, 4.4,
2.4, 1H), 0.82 (dt, J = 12.9, 8.8, 1H).
522. (1H-pyrazolylmethyl)({2-[(9R) MS: 341.2
(pyridinyl) 1H NMR (400 MHz, CD3CN) δ 8.76 (dd, J
= 5.5, 1.2, 1H), 8.28 (td, J = 8.0, 1.7, 1H),
oxaspiro[4.5]decan
7.80 (d, J = 8.2, 1H), 7.73 (ddd, J = 7.6, 5.5,
yl]ethyl})amine 0.9, 1H), 7.61 (d, J = 2.3, 1H), 6.32 (d, J =
2.3, 1H), 5.78 (brs, 1H), 4.09 (m, 2H), 3.72
(m, 2H), 2.98 (td, J = 12.0, 5.2, 1H), 2.47
(td, J = 12.1, 4.3, 1H), 2.36 (m, 3H), 2.16
(m, 1H), 2.02 (d, J = 14.2, 1H), 1.79 (m,
2H), 1.62 (m, 1H), 1.49 (m, 4H), 1.19 (m,
1H), 0.79 (dt, J = 12.9, 8.8, 1H).
Compoun Name Structure and/or NMR Spectrum
523. [(1-methyl-1H-pyrazol MS: 355.3
yl)methyl]({2-[(9R)(pyridin 1H NMR (400 MHz, CD3CN) δ 8.98 (brs,
1H), 8.73 (dd, J = 5.3, 1.1, 1H), 8.73 (dd, J
yl)oxaspiro[4.5]decan
= 5.3, 1.1, 1H), 8.16 (m, 2H), 7.72 (d, J =
yl]ethyl})amine 8.2, 1H), 7.72 (d, J = 8.2, 1H), 7.62 (ddd, J
= 7.5, 5.4, 0.8, 1H), 7.62 (ddd, J = 7.5, 5.4,
0.8, 1H), 7.47 (d, J = 2.2, 1H), 7.47 (d, J =
2.2, 1H), 6.25 (d, J = 2.2, 1H), 6.25 (d, J =
2.2, 1H), 4.02 (m, 2H), 3.80 (s, 3H), 3.72
(m, 2H), 2.98 (td, J = 11.8, 5.2, 1H), 2.48
(td, J = 11.9, 4.2, 1H), 2.33 (m, 3H), 2.12
(ddd, J = 13.5, 11.9, 5.4, 1H), 1.99 (m, 1H),
1.77 (m, 2H), 1.62 (m, 1H), 1.48 (m, 4H),
1.17 (m, 1H), 0.78 (dt, J = 13.1, 8.9, 1H).
524. [(5-methyl-1H-pyrazol MS: 355.3
yl)methyl]({2-[(9R) 1H NMR (400 MHz, CD3CN) δ 8.78 (dd, J
= 5.5, 1.2, 1H), 8.34 (td, J = 8.0, 1.7, 1H),
(pyridinyl)oxaspiro[4.5]decan-
7.79 (m, 2H), 6.07 (s, 1H), 5.95 (brs, 1H),
9- 4.02 (m, 2H), 3.72 (m, 2H), 2.97 (td, J =
12.0, 5.1, 1H), 2.44 (ddd, J = 12.1, 10.0,
yl]ethyl})amine
4.2, 1H), 2.34 (m, 3H), 2.26 (s, 3H), 2.18
(td, J = 13.1, 5.2, 1H), 2.03 (d, J = 14.2,
1H), 1.81 (ddd, J = 8.7, 7.4, 3.8, 2H), 1.63
(ddd, J = 14.6, 10.4, 4.6, 1H), 1.49 (m, 4H),
1.20 (m, 1H), 0.81 (dt, J = 12.9, 8.9, 1H).
Compoun Name Structure and/or NMR Spectrum
525. [(1,5-dimethyl-1H-pyrazol MS: 369.3
1H NMR (400 MHz, CD3CN) δ 12.13 (brs,
yl)methyl]({2-[(9R)
1H), 8.77 (dd, J = 5.4, 1.2, 1H), 8.28 (td, J =
(pyridinyl)oxaspiro[4.5]decan-
8.0, 1.7, 1H), 8.00 (brs, 1H), 7.74 (m, 2H),
9- 6.03 (s, 1H), 3.96 (m, 2H), 3.73 (m, 5H),
2.96 (td, J = 12.0, 5.2, 1H), 2.47 (td, J =
yl]ethyl})amine
12.1, 4.2, 1H), 2.36 (m, 3H), 2.17 (m, 4H),
2.00 (m, 1H), 1.79 (m, 2H), 1.63 (ddd, J =
8.4, 7.6, 3.3, 1H), 1.50 (m, 4H), 1.19 (ddd, J
= 10.1, 6.6, 1.8, 1H), 0.81 (dt, J = 12.9, 8.9,
1H).
526. (1H-pyrazolylmethyl)({2-[(9R) MS: 341.2
(pyridinyl) 1H NMR (400 MHz, CD3CN) δ 8.73 (dd, J
= 5.3, 1.1, 1H), 8.21 (td, J = 8.0, 1.7, 2H),
oxaspiro[4.5]decan
7.75 (d, J = 8.2, 1H), 7.66 (m, 3H), 7.56 (s,
1H), 3.96 (s, 2H), 3.73 (m, 2H), 2.91 (m,
yl]ethyl})amine
1H), 2.32 (m, 4H), 2.08 (m, 1H), 1.99 (m,
1H), 1.78 (m, 2H), 1.62 (m, 1H), 1.49 (m,
4H), 1.19 (m, 1H), 0.78 (dt, J = 13.1, 8.8,
1H).
MS: 355.2
527. [(1-methyl-1H-pyrazol
1H NMR (400 MHz, CD3CN) δ 8.78 (dd, J
yl)methyl]({2-[(9R)
= 5.5, 1.3, 1H), 8.32 (td, J = 8.0, 1.7, 1H),
(pyridinyl)oxaspiro[4.5]decan- 7.84 (d, J = 8.2, 1H), 7.77 (ddd, J = 7.6, 5.5,
0.9, 1H), 7.71 (brs, 1H), 7.55 (s, 1H), 7.43
(s, 1H), 3.91 (s, 2H), 3.81 (d, J = 11.7, 3H),
yl]ethyl})amine 3.73 (m, 2H), 2.90 (dt, J = 11.7, 5.8, 1H),
2.35 (m, 4H), 2.14 (ddd, J = 10.8, 10.2, 5.2,
1H), 2.03 (d, J = 14.2, 1H), 1.80 (m, 2H),
1.62 (tdd, J = 8.7, 6.8, 2.7, 1H), 1.49 (m,
4H), 1.20 (m, 1H), 0.80 (dt, J = 12.9, 8.8,
Compoun Name Structure and/or NMR Spectrum
1H).
528. [(5-methyl-1H-pyrazol
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
529. [(1,5-dimethyl-1H-pyrazol
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
530. [(5,6-difluoropyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
531. [(5-chlorofluoropyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
532. [(5-bromofluoropyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
Compoun Name Structure and/or NMR Spectrum
533. [(6-fluoroiodopyridin
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
534. [(6-fluoromethylpyridin MS: 384.3
yl)methyl]({2-[(9R) 1H NMR (400 MHz, CD3CN) δ 8.73 (d, J =
4.4, 1H), 8.36 (s, 1H), 8.20 (d, J = 7.8, 1H),
(pyridinyl)oxaspiro[4.5]decan-
8.01 (s, 1H), 7.77 (t, J = 7.1, 2H), 7.66 (m,
9- 1H), 4.01 (s, 2H), 3.73 (m, 2H), 2.98 (dd, J
= 11.6, 6.9, 1H), 2.36 (m, 5H), 2.26 (s, 3H),
yl]ethyl})amine
2.16 (dd, J = 13.2, 5.1, 2H), 1.80 (m, 2H),
1.51 (m, 6H), 1.20 (dd, J = 8.7, 4.7, 1H),
0.79 (d, J = 13.3, 1H).
535. [(6-fluoromethoxypyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
536. 2-fluoro[({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
537. [(6-chlorofluoropyridin MS: 404.2
yl)methyl]({2-[(9R) 1H NMR (400 MHz, CD3CN) δ 8.68 (dd, J
= 5.2, 1.1, 1H), 8.24 (d, J = 1.9, 1H), 8.10
(pyridinyl)oxaspiro[4.5]decan-
(td, J = 7.9, 1.8, 1H), 7.78 (dd, J = 9.0, 2.0,
9- 1H), 7.69 (d, J = 8.2, 1H), 7.56 (ddd, J =
7.5, 5.3, 0.9, 1H), 4.75 (brs, 1H), 4.07 (m,
Compoun Name Structure and/or NMR Spectrum
yl]ethyl})amine 2H), 3.72 (m, 2H), 2.99 (td, J = 11.9, 5.2,
1H), 2.48 (td, J = 12.0, 4.5, 1H), 2.32 (m,
3H), 2.11 (m, 1H), 1.77 (m, 2H), 1.62 (m,
1H), 1.49 (m, 4H), 1.17 (m, 1H), 0.77 (dt, J
= 13.1, 8.9, 1H).
538. [(5,6-dichloropyridin MS: 422.2
yl)methyl]({2-[(9R)(pyridin 1H NMR (400 MHz, CD3CN) δ 8.51 (m,
1H), 8.33 (d, J = 2.1, 1H), 8.12 (d, J = 2.1,
yl)oxaspiro[4.5]decan
1H), 7.76 (t, J = 7.9, 1H), 7.49 (d, J = 8.1,
yl]ethyl})amine 1H), 7.23 (dd, J = 7.4, 4.9, 1H), 4.26 (d, J =
1.5, 2H), 3.57 (dd, J = 7.7, 3.0, 2H), 3.09
(td, J = 12.2, 4.6, 1H), 2.55 (td, J = 12.1,
4.6, 1H), 2.27 (dddd, J = 25.5, 17.3, 14.3,
3.4, 4H), 1.77 (m, 1H), 1.59 (m, 2H), 1.34
(m, 6H), 0.98 (dd, J = 11.4, 5.0, 1H), 0.60
(dt, J = 13.4, 9.0, 1H).
539. [(5-bromochloropyridin MS: 466.1
1H NMR (400 MHz, CD3CN) δ 8.64 (d, J =
yl)methyl]({2-[(9R)
.1, 1H), 8.36 (d, J = 2.1, 1H), 8.24 (d, J =
(pyridinyl)oxaspiro[4.5]decan- 2.1, 1H), 8.02 (m, 1H), 7.69 (d, J = 8.0, 1H),
7.47 (m, 1H), 3.59 (m, 2H), 3.17 (d, J = 4.7,
1H), 2.63 (d, J = 4.5, 1H), 2.34 (m, 4H),
yl]ethyl})amine 2.12 (d, J = 4.8, 1H), 1.85 (d, J = 13.8, 1H),
1.66 (m, 2H), 1.35 (m, 6H), 1.02 (m, 1H),
0.66 (s, 1H).
Compoun Name Structure and/or NMR Spectrum
540. [(6-chloroiodopyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
541. [(6-chloromethylpyridin MS: 400.2
1H NMR (400 MHz, CD3CN) δ 8.70 (dd, J
yl)methyl]({2-[(9R)
= 5.3, 1.2, 1H), 8.20 (t, J = 2.4, 1H), 8.17
(pyridinyl)oxaspiro[4.5]decan- (dd, J = 7.9, 1.7, 1H), 7.74 (t, J = 5.2, 2H),
7.63 (ddd, J = 7.5, 5.3, 0.9, 1H), 5.11 (s,
1H), 4.01 (m, 2H), 3.73 (m, 2H), 2.98 (td, J
= 11.9, 5.1, 1H), 2.46 (td, J = 12.0, 4.2, 1H),
yl]ethyl})amine
2.33 (m, 6H), 2.12 (ddd, J = 14.7, 10.5, 5.3,
1H), 1.99 (d, J = 6.9, 1H), 1.78 (m, 2H),
1.62 (m, 1H), 1.48 (m, 4H), 1.18 (m, 1H),
0.78 (dt, J = 13.1, 8.9, 1H).
MS: 416.2
542. [(6-chloromethoxypyridin
1H NMR (400 MHz, CD3CN) δ 8.73 (dd, J
yl)methyl]({2-[(9R)
= 5.4, 1.2, 1H), 8.26 (td, J = 7.9, 1.6, 1H),
(pyridinyl)oxaspiro[4.5]decan- 7.93 (d, J = 1.9, 1H), 7.80 (d, J = 8.2, 1H),
7.70 (dd, J = 7.1, 5.9, 1H), 7.52 (d, J = 1.9,
1H), 5.05 (brs, 1H), 4.04 (m, 2H), 3.90 (s,
yl]ethyl})amine 3H), 3.74 (m, 2H), 2.98 (td, J = 12.0, 5.1,
1H), 2.40 (dddd, J = 19.5, 12.3, 9.6, 4.7,
3H), 2.16 (m, 1H), 1.99 (m, 1H), 1.80 (m,
2H), 1.63 (ddd, J = 14.5, 7.2, 3.0, 1H), 1.49
(m, 4H), 1.20 (m, 1H), 0.80 (dt, J = 12.9,
8.8, 1H).
Compoun Name Structure and/or NMR Spectrum
543. 2-chloro[({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
544. 3-fluoro[({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
545. 3-chloro[({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
546. 3-bromo[({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
547. 3-iodo[({2-[(9R)(pyridinyl)-
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
548. 3-methyl[({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
Compoun Name Structure and/or NMR Spectrum
549. 3-methyl[({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
550. 5-[({2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine-2,3-
dicarbonitrile
551. 5-[({2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]
(trifluoromethyl)pyridine
carbonitrile
552. {[5-fluoro
(trifluoromethyl)pyridin
yl]methyl}({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl})amine
553. {[5-chloro
(trifluoromethyl)pyridin
yl]methyl}({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
Compoun Name Structure and/or NMR Spectrum
554. {[5-bromo MS: 498.1
1H NMR (400 MHz, CD3CN) δ 8.74 (dd, J
(trifluoromethyl)pyridin
= 5.4, 1.2, 1H), 8.64 (d, J = 1.6, 1H), 8.32
yl]methyl}({2-[(9R)(pyridin (d, J = 1.2, 1H), 8.26 (td, J = 8.0, 1.6, 1H),
7.81 (d, J = 8.2, 1H), 7.71 (dd, J = 7.1, 6.0,
yl)
1H), 4.12 (m, 3H), 3.74 (m, 3H), 3.00 (td, J
oxaspiro[4.5]decan = 12.0, 5.1, 1H), 2.49 (td, J = 12.1, 4.2, 1H),
2.37 (ddd, J = 14.0, 11.9, 5.0, 3H), 2.16 (m,
yl]ethyl})amine
1H), 2.02 (m, 1H), 1.81 (m, 2H), 1.63 (ddd,
J = 14.4, 8.7, 4.7, 1H), 1.49 (m, 4H), 1.21
(m, 1H), 0.80 (dt, J = 13.0, 8.9, 1H).
555. {[5-iodo(trifluoromethyl)pyridin-
yl]methyl}({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl})amine
556. {[5-methyl
(trifluoromethyl)pyridin
yl]methyl}({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl})amine
557. {[5-methoxy
(trifluoromethyl)pyridin
yl]methyl}({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl})amine
Compoun Name Structure and/or NMR Spectrum
558. 5-[({2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]
(trifluoromethyl)pyridine
carbonitrile
559. {[5,6-bis(trifluoromethyl)pyridin
yl]methyl}({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
560. [(5-fluoromethylpyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
561. [(5-chloromethylpyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
562. [(5-bromomethylpyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
Compoun Name Structure and/or NMR Spectrum
563. [(5-iodomethylpyridin
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
564. [(5,6-dimethylpyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
565. [(5-methoxymethylpyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
yl]ethyl})amine
566. 2-methyl[({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
567. {[6-methyl
(trifluoromethyl)pyridin
yl]methyl}({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl})amine
Compoun Name Structure and/or NMR Spectrum
568. [(5-fluoromethoxypyridin MS: 400.3
1H NMR (400 MHz, CD3CN) δ 8.63 (dd, J
yl)methyl]({2-[(9R)(pyridin
= 5.3, 1.2, 1H), 8.25 (s, 1H), 8.12 (td, J =
yl)oxaspiro[4.5]decan 8.0, 1.6, 1H), 7.83 (d, J = 1.9, 1H), 7.67 (d,
J = 8.2, 1H), 7.57 (dd, J = 6.8, 5.7, 1H),
yl]ethyl})amine
7.44 (dd, J = 11.1, 2.0, 1H), 3.88 (d, J = 6.7,
5H), 3.62 (m, 2H), 2.86 (dd, J = 11.5, 7.1,
1H), 2.26 (m, 4H), 2.05 (dd, J = 12.7, 5.0,
1H), 1.69 (ddd, J = 9.5, 8.0, 4.4, 2H), 1.69
(ddd, J = 9.5, 8.0, 4.4, 2H), 1.39 (m, 5H),
0.68 (d, J = 13.3, 1H).
MS: 416.2
569. [(5-chloromethoxypyridin
1H NMR (400 MHz, CD3CN) δ 8.65 (d, J =
yl)methyl]({2-[(9R)
.4, 1H), 8.21 (s, 1H), 8.18 (d, J = 8.0, 1H),
(pyridinyl)oxaspiro[4.5]decan- 7.96 (d, J = 2.1, 1H), 7.72 (m, 2H), 7.63 (t, J
= 6.4, 1H), 3.87 (m, 5H), 3.62 (m, 2H), 2.85
(dd, J = 11.5, 7.2, 1H), 2.27 (m, 4H), 2.07
yl]ethyl})amine (d, J = 4.9, 1H), 1.91 (d, J = 14.1, 1H), 1.69
(m, 2H), 1.39 (m, 5H), 1.10 (m, 1H), 0.69
(d, J = 13.2, 1H).
570. [(5-bromomethoxypyridin MS: 460.2
1H NMR (400 MHz, CDCl3) δ 8.79 (dd, J =
yl)methyl]({2-[(9R)
.7, 1.3, 1H), 8.43 (td, J = 8.0, 1.7, 1H),
(pyridinyl)oxaspiro[4.5]decan- 8.11 (d, J = 2.1, 1H), 7.98 (d, J = 2.1, 1H),
7.92 (d, J = 8.2, 1H), 7.86 (ddd, J = 7.6, 5.7,
1.0, 1H), 5.63 (brs, 1H), 3.97 (m, 5H), 3.75
yl]ethyl})amine (m, 2H), 2.96 (m, 1H), 2.42 (dq, J = 12.2,
4.1, 2H), 2.33 (d, J = 14.1, 2H), 2.21 (m,
1H), 2.06 (d, J = 14.2, 1H), 1.83 (m, 2H),
1.64 (ddd, J = 19.4, 10.1, 4.4, 1H), 1.50 (m,
4H), 1.23 (m, 1H), 0.82 (dt, J = 12.9, 8.9,
1H).
Compoun Name Structure and/or NMR Spectrum
571. [(5-iodomethoxypyridin
yl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decan-
l]ethyl})amine
572. [(6-methoxymethylpyridin MS: 396.3
1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J =
yl)methyl]({2-[(9R)
.6, 1.3, 1H), 8.38 (td, J = 8.0, 1.7, 1H),
(pyridinyl)oxaspiro[4.5]decan- 7.96 (d, J = 2.2, 1H), 7.88 (d, J = 8.2, 1H),
7.81 (ddd, J = 7.6, 5.6, 1.0, 1H), 7.49 (d, J =
1.5, 1H), 5.36 (brs, 1H), 3.93 (m, 5H), 3.74
yl]ethyl})amine (m, 2H), 2.95 (dd, J = 11.4, 7.7, 1H), 2.39
(m, 4H), 2.21 (dd, J = 13.2, 5.4, 1H), 2.14
(m, 3H), 2.05 (d, J = 14.2, 1H), 1.82 (m,
2H), 1.63 (m, 1H), 1.50 (m, 4H), 1.21 (ddd,
J = 10.5, 6.1, 2.5, 1H), 0.81 (dt, J = 12.9,
8.8, 1H).
573. [(5,6-dimethoxypyridin
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
Compoun Name Structure and/or NMR Spectrum
574. 2-methoxy[({2-[(9R)(pyridin-
2-yl)
oxaspiro[4.5]decan
yl]ethyl}amino)methyl]pyridine
carbonitrile
575. {[6-methoxy
(trifluoromethyl)pyridin
yl]methyl}({2-[(9R)(pyridin
yl)
oxaspiro[4.5]decan
yl]ethyl})amine
Example 14: Opioid Receptor Ligands
The following compounds in Table 3 can also be prepared according to the procedures
described above from appropriate starting materials and appropriate reagents and would be
expected to also have similar properties and therapeutic effects as other compounds described
herein. In addition to the specific structure shown the other isomers or enantiomers are included
with the description herein. Compounds that have been made lists NMR data and prophetic
examples do not list NMR data.
Table 3: Opioid Receptor Ligands
Compound Name Structure
Compound Name Structure
576 [(5-chloropyridin
yl)methyl]({2-[(9R)phenyl
oxaspiro[4.5]decan
yl]ethyl})amine
577 {2-[(9R)phenyl
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
578 {2-[(9R)phenyl
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
579 [(3,5-difluorophenyl)methyl]({2-
[(9R)phenyl
oxaspiro[4.5]decan
yl]ethyl})amine
580 [(3-methylphenyl)methyl]({2-
[(9R)phenyl
oxaspiro[4.5]decan
yl]ethyl})amine
581 [(5-chloropyridin
yl)methyl]({2-[(9R)(4-
fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl})amine
Compound Name Structure
582 {2-[(9R)(4-fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amin
583 {2-[(9R)(4-fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
584 [(3,5-difluorophenyl)methyl]({2-
[(9R)(4-
fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl})amine
585 [(5-chloropyridin
yl)methyl]({2-[(9R)[4-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
586 {2-[(9R)[4-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
587 {2-[(9R)[4-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
Compound Name Structure
588 [(3,5-difluorophenyl)methyl]({2-
[(9R)[4-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
589 [(3-methylphenyl)methyl]({2-
[(9R)[4-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
590 [(5-chloropyridin
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
591 {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
592 {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
593 [(3,5-difluorophenyl)methyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
Compound Name Structure
594 [(3-methylphenyl)methyl]({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
595 [(5-chloropyridin
yl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
596 {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
597 {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
598 [(3,5-difluorophenyl)methyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
599 [(3-methylphenyl)methyl]({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
Compound Name Structure
600 [(5-chloropyridin
yl)methyl]({2-[(9R)(3-
methylphenyl)
oxaspiro[4.5]decan
yl]ethyl})amine
601 {2-[(9R)(3-methylphenyl)
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
602 {2-[(9R)(3-methylphenyl)
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
603 [(3,5-difluorophenyl)methyl]({2-
[(9R)(3-
methylphenyl)
oxaspiro[4.5]decan
yl]ethyl})amine
604 {2-[(9R)(3-methylphenyl)
oxaspiro[4.5]decan
yl]ethyl}[(3-
methylphenyl)methyl]amine
605 [(5-chloropyridin
yl)methyl]({2-[(9R)[3-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
Compound Name Structure
606 {2-[(9R)[3-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
607 {2-[(9R)[3-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
608 [(3,5-difluorophenyl)methyl]({2-
[(9R)[3-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
609 [(3-methylphenyl)methyl]({2-
[(9R)[3-
(trifluoromethoxy)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
610 [(5-chloropyridin
yl)methyl]({2-[(9R)[4-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
611 {2-[(9R)[4-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
Compound Name Structure
612 {2-[(9R)[4-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
613 [(3,5-difluorophenyl)methyl]({2-
[(9R)[4-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
614 [(3-methylphenyl)methyl]({2-
[(9R)[4-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
615 [(5-chloropyridin
yl)methyl]({2-[(9R)(3-
fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl})amine
616 {2-[(9R)(3-fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
617 {2-[(9R)(3-fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
Compound Name Structure
618 [(3,5-difluorophenyl)methyl]({2-
[(9R)(3-
fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl})amine
619 {2-[(9R)(3-fluorophenyl)
oxaspiro[4.5]decan
yl]ethyl}[(3-
methylphenyl)methyl]amine
620 [(5-chloropyridin
yl)methyl]({2-[(9R)[3-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
621 {2-[(9R)[3-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[5-
(trifluoromethyl)pyridin
yl]methyl})amine
622 {2-[(9R)[3-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl}({[4-
(trifluoromethyl)pyridin
yl]methyl})amine
623 [(3,5-difluorophenyl)methyl]({2-
[(9R)[3-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
Compound Name Structure
624 [(3-methylphenyl)methyl]({2-
[(9R)[3-
(trifluoromethyl)phenyl]
oxaspiro[4.5]decan
yl]ethyl})amine
625 [(5-chloropyridin MS: 400.2
yl)methyl](methyl){2-[(9R)
1H NMR (400 MHz, CD3CN) δ 8.77 (dd, J
(pyridinyl)
= 5.6, 1.3, 1H), 8.67 (d, J = 2.0, 1H), 8.53
oxaspiro[4.5]decan
(s, 1H), 8.41 (td, J = 8.0, 1.6, 1H), 7.93 (m,
yl]ethyl}amine
2H), 7.85 (m, 1H), 4.18 (s, 2H), 3.76 (ddd, J
= 12.4, 11.3, 5.5, 2H), 3.09 (d, J = 5.1, 1H),
2.65 (s, 3H), 2.55 (m, 2H), 2.33 (m, 3H),
2.08 (d, J = 14.2, 1H), 1.84 (m, 2H), 1.53
(m, 5H), 1.21 (m, 1H), 0.77 (d, J = 13.2,
1H).
626 methyl({2-[(9R)(pyridinyl)- MS: 434.3
6-oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 8.99 (s,
yl]ethyl}){[5-
1H), 8.84 (s, 1H), 8.77 (m, 1H), 8.40 (td, J
(trifluoromethyl)pyridin
= 8.0, 1.6, 1H), 8.23 (s, 1H), 7.91 (d, J =
yl]methyl}amine
8.2, 1H), 7.84 (dd, J = 6.9, 6.3, 1H), 4.26 (s,
2H), 3.77 (m, 2H), 3.11 (d, J = 4.8, 1H),
2.65 (s, 3H), 2.57 (ddd, J = 17.4, 12.8, 8.9,
2H), 2.34 (dd, J = 19.0, 9.6, 3H), 2.09 (d, J
= 14.2, 1H), 1.86 (m, 2H), 1.54 (m, 5H),
1.20 (dd, J = 9.5, 3.8, 1H), 0.77 (dd, J = 9.0,
4.1, 1H).
Compound Name Structure
627 [(5-chloropyridinyl)methyl- MS: 388.2
(2H2)] {2-[(9R)(pyridinyl)-
1H NMR (400 MHz, CD3CN) δ 9.51 (s,
6-oxaspiro[4.5]decan
1H), 8.48 (d, J = 1.9, 1H), 8.45 (d, J = 2.3,
yl]ethyl}amine
1H), 8.42 (ddd, J = 4.8, 1.8, 0.8, 1H), 8.06
(m, 1H), 7.64 (td, J = 7.8, 1.8, 1H), 7.33 (d,
J = 8.1, 1H), 7.12 (ddd, J = 7.4, 4.8, 0.7,
1H), 3.57 (m, 2H), 2.74 (td, J = 12.0, 4.7,
1H), 2.21 (m, 4H), 1.96 (dt, J = 12.4, 6.1,
1H), 1.76 (d, J = 13.8, 1H), 1.63 (dd, J =
9.9, 5.9, 1H), 1.40 (m, 6H), 0.95 (m, 1H),
0.59 (m, 1H).
628 ({2-[(9R)(pyridinyl) MS: 422.3
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 9.44 (s,
yl]ethyl}){[5-
1H), 8.82 (d, J = 1.9, 1H), 8.78 (d, J = 1.2,
(trifluoromethyl)pyridin
1H), 8.40 (ddd, J = 4.8, 1.8, 0.9, 1H), 8.31
yl]methyl-(2H2)}amine
(m, 1H), 7.61 (m, 1H), 7.31 (m, 1H), 7.09
(ddd, J = 7.4, 4.8, 1.0, 1H), 3.57 (m, 2H),
2.74 (m, 1H), 2.24 (m, 3H), 2.10 (m, 1H),
1.95 (dd, J = 12.5, 4.7, 1H), 1.75 (d, J =
13.6, 1H), 1.44 (m, 7H), 0.96 (s, 1H), 0.59
(m, 1H).
Compound Name Structure
629 {2-[(9R)(pyridinyl) MS: 420.2
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 8.70 (dd, J
yl]ethyl}({[6-
= 5.2, 1.1, 1H), 8.53 (brs, 1H), 8.11 (td, J =
(trifluoromethyl)pyridin
7.9, 1.7, 1H), 8.05 (t, J = 7.9, 1H), 7.80 (d, J
yl]methyl})amine
= 7.8, 1H), 7.70 (d, J = 8.2, 1H), 7.57 (ddd,
J = 8.3, 7.5, 4.4, 2H), 6.58 (brs, 1H), 4.29
(m, 2H), 3.73 (m, 2H), 3.09 (td, J = 11.8,
.2, 1H), 2.60 (td, J = 11.9, 4.8, 1H), 2.36
(m, 3H), 2.16 (m, 1H), 1.99 (m, 1H), 1.77
(ddd, J = 14.0, 9.0, 5.1, 2H), 1.62 (m, 1H),
1.48 (m, 4H), 1.16 (ddd, J = 8.5, 7.0, 3.5,
1H), 0.78 (dt, J = 13.1, 8.9, 1H).
630 {2-[(9R)(pyridinyl) MS: 420.2
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 8.86 (d, J =
yl]ethyl}({[5- 0.8, 1H), 8.77 (dd, J = 5.4, 1.2, 1H), 8.20
(trifluoromethyl)pyridin (m, 1H), 8.11 (dd, J = 8.3, 1.9, 1H), 7.77 (d,
yl]methyl})amine J = 8.2, 1H), 7.66 (ddd, J = 7.6, 5.4, 0.9,
1H), 7.53 (d, J = 8.3, 1H), 4.31 (m, 2H),
3.73 (m, 2H), 3.09 (td, J = 11.9, 5.4, 1H),
2.60 (td, J = 11.9, 4.6, 1H), 2.39 (m, 3H),
2.21 (ddd, J = 13.6, 11.8, 5.4, 1H), 2.02 (d,
J = 14.0, 1H), 1.80 (ddd, J = 9.5, 8.3, 4.6,
2H), 1.63 (m, 1H), 1.49 (qdd, J = 13.9, 8.5,
3.5, 4H), 1.19 (m, 1H), 0.80 (dt, J = 13.1,
8.8, 1H).
Compound Name Structure
631 {2-[(9R)(pyridinyl) MS: 352.3
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 10.49 (s,
yl]ethyl}(pyridin 1H), 8.81 (dd, J = 5.5, 1.2, 1H), 8.55 (dd, J
ylmethyl)amine = 3.7, 0.8, 1H), 8.30 (td, J = 8.0, 1.7, 1H),
7.91 (td, J = 7.8, 1.7, 1H), 7.83 (d, J = 8.2,
1H), 7.75 (ddd, J = 7.6, 5.5, 1.0, 1H), 7.45
(dd, J = 11.3, 6.5, 2H), 4.24 (m, 2H), 3.73
(m, 2H), 3.06 (td, J = 12.0, 5.2, 1H), 2.57
(td, J = 12.1, 4.4, 1H), 2.39 (m, 3H), 2.24
(m, 1H), 2.04 (d, J = 14.0, 1H), 1.82 (m,
2H), 1.63 (m, 1H), 1.50 (m, 4H), 1.19 (m,
1H), 0.81 (dt, J = 12.9, 8.8, 1H).
632 {2-[(9R)(pyridinyl) MS: 352.3
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 8.81 (s,
yl]ethyl}(pyridin
1H), 8.74 (m, 2H), 8.32 (d, J = 8.1, 1H),
ylmethyl)amine
8.26 (td, J = 8.0, 1.7, 1H), 7.80 (m, 2H),
7.70 (m, 1H), 4.18 (m, 2H), 3.73 (m, 2H),
3.02 (td, J = 12.0, 5.1, 1H), 2.51 (td, J =
12.1, 4.3, 1H), 2.36 (m, 3H), 2.15 (m, 1H),
2.01 (d, J = 14.1, 1H), 1.80 (ddd, J = 9.8,
8.2, 4.7, 2H), 1.62 (m, 1H), 1.48 (m, 4H),
1.19 (m, 1H), 0.80 (dt, J = 13.0, 8.8, 1H).
Compound Name Structure
633 {2-[(9R)(pyridinyl) MS: 352.3
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 8.73 (m,
yl]ethyl}(pyridin
3H), 8.20 (td, J = 8.0, 1.7, 1H), 7.82 (d, J =
ylmethyl)amine
6.5, 2H), 7.76 (d, J = 8.2, 1H), 7.65 (m,
1H), 4.22 (m, 2H), 3.73 (m, 2H), 3.03 (td, J
= 12.0, 5.1, 1H), 2.53 (td, J = 12.1, 4.4, 1H),
2.37 (m, 3H), 2.16 (m, 1H), 2.00 (d, J =
14.2, 1H), 1.79 (m, 2H), 1.63 (ddd, J = 12.2,
8.8, 4.0, 1H), 1.49 (m, 4H), 1.19 (m, 1H),
0.80 (dt, J = 13.1, 8.9, 1H).
634 (1H-imidazolylmethyl)({2- MS: 341.2
[(9R)(pyridinyl)
1H NMR (400 MHz, CD3CN) δ 8.75 (dd, J
oxaspiro[4.5]decan
= 5.4, 1.2, 1H), 8.54 (d, J = 1.0, 1H), 8.22
yl]ethyl})amine
(td, J = 8.0, 1.6, 1H), 7.77 (d, J = 8.2, 1H),
7.67 (dd, J = 6.8, 5.6, 1H), 7.47 (s, 1H),
4.18 (s, 2H), 3.72 (m, 2H), 2.92 (td, J =
12.1, 5.0, 1H), 2.38 (m, 4H), 2.13 (m, 1H),
2.00 (m, 1H), 1.79 (m, 2H), 1.63 (m, 1H),
1.48 (m, 4H), 1.19 (m, 1H), 0.82 (dt, J =
13.1, 8.9, 1H).
635 [(2-methylpyridin MS: 366.3
yl)methyl]({2-[(9R)(pyridin
1H NMR (400 MHz, CD3CN) δ 8.71 (d, J =
yl)oxaspiro[4.5]decan
1.9, 1H), 8.65 (dd, J = 5.1, 1.0, 1H), 8.18
yl]ethyl})amine
(dd, J = 8.2, 2.1, 1H), 8.02 (td, J = 7.9, 1.8,
1H), 7.64 (d, J = 8.1, 2H), 7.49 (dd, J = 6.7,
.2, 1H), 4.13 (m, 2H), 3.71 (m, 2H), 3.00
(td, J = 11.8, 5.1, 1H), 2.71 (s, 3H), 2.50 (td,
Compound Name Structure
J = 11.9, 4.6, 1H), 2.37 (m, 2H), 2.23 (m,
1H), 2.06 (dd, J = 12.0, 5.1, 1H), 1.76 (ddt,
J = 14.1, 9.4, 3.8, 3H), 1.61 (dd, J = 16.6,
9.7, 1H), 1.49 (m, 4H), 1.16 (d, J = 11.3,
1H), 0.76 (dt, J = 13.1, 8.9, 1H).
636 {2-[(9R)(pyridinyl) MS: 420.2
oxaspiro[4.5]decan
1H NMR (400 MHz, CD3CN) δ 8.75 (d, J =
yl]ethyl}({[2-
.1, 2H), 8.30 (td, J = 8.1, 1.4, 1H), 7.84
(trifluoromethyl)pyridin
(m, 2H), 7.74 (m, 1H), 7.63 (d, J = 4.7, 1H),
yl]methyl})amine
4.13 (m, 2H), 3.73 (m, 2H), 3.01 (td, J =
11.9, 5.0, 1H), 2.45 (m, 4H), 2.22 (td, J =
13.0, 5.0, 1H), 2.03 (d, J = 14.1, 1H), 1.81
(m, 2H), 1.63 (m, 1H), 1.49 (m, 4H), 1.21
(dd, J = 9.4, 5.1, 1H), 0.81 (dt, J = 12.8, 8.8,
1H).
637 [(6-chloropyridin MS: 386.2
yl)methyl]({2-[(9R)(pyridin
1H NMR (400 MHz, CD3CN) δ 8.69 (m,
yl)oxaspiro[4.5]decan
1H), 8.38 (m, 1H), 8.12 (m, 1H), 7.81 (m,
yl]ethyl})amine
1H), 7.70 (m, 1H), 7.58 (m, 1H), 7.45 (m,
1H), 4.43 (s, 1H), 4.06 (d, J = 13.9, 2H),
3.72 (m, 2H), 2.98 (td, J = 11.9, 5.1, 1H),
2.48 (td, J = 12.0, 4.4, 1H), 2.32 (m, 3H),
2.10 (m, 1H), 1.98 (d, J = 2.4, 1H), 1.77 (m,
2H), 1.61 (ddd, J = 15.0, 8.2, 4.0, 1H), 1.48
(m, 4H), 1.16 (ddd, J = 8.7, 7.1, 4.1, 1H),
0.77 (dt, J = 13.2, 8.9, 1H).
Compound Name Structure
638 [(1-methyl-1H-imidazol MS: 355.3
yl)methyl]({2-[(9R)
1H NMR (400 MHz, CD3CN) δ 8.71 (ddd,
(pyridinyl)
J = 5.3, 1.7, 0.6, 1H), 8.14 (td, J = 8.0, 1.8,
oxaspiro[4.5]decan
1H), 7.73 (d, J = 8.2, 1H), 7.60 (ddd, J =
yl]ethyl})amine
7.6, 5.3, 1.0, 1H), 7.43 (d, J = 1.9, 1H), 7.35
(d, J = 1.9, 1H), 4.33 (s, 2H), 3.80 (m, 3H),
3.72 (ddt, J = 15.3, 9.3, 3.1, 2H), 3.03 (td, J
= 12.0, 4.9, 1H), 2.59 (td, J = 12.0, 4.6, 1H),
2.36 (m, 3H), 2.15 (m, 1H), 1.99 (m, 1H),
1.80 (m, 2H), 1.63 (ddd, J = 14.4, 9.9, 5.5,
1H), 1.49 (m, 4H), 1.19 (m, 1H), 0.83 (dt, J
= 13.1, 8.9, 1H).
639 (naphthalenylmethyl)({2- MS: 401.3
[(9R)(pyridinyl)
1H NMR (400 MHz, CD3CN) δ 8.57 (dd, J
oxaspiro[4.5]decan
= 5.0, 1.0, 1H), 7.90 (m, 5H), 7.59 (m, 2H),
yl]ethyl})amine
7.54 (d, J = 8.1, 1H), 7.48 (dd, J = 8.5, 1.7,
1H), 7.34 (m, 1H), 4.19 (s, 2H), 3.69 (dt, J
= 8.9, 5.1, 3H), 3.48 (brs, 1H), 3.02 (s, 1H),
2.52 (s, 1H), 2.33 (m, 2H), 2.19 (m, 1H),
2.02 (m, 1H), 1.89 (t, J = 9.4, 1H), 1.70 (dq,
J = 9.2, 5.1, 2H), 1.59 (m, 1H), 1.44 (m,
4H), 1.10 (m, 1H), 0.69 (dt, J = 13.1, 8.8,
1H).
Compound Name Structure
640 [(6-bromofluoropyridin MS: 448.2
yl)methyl]({2-[(9R)(pyridin
1H NMR (400 MHz, CD3CN) δ 8.68 (dd, J
yl)oxaspiro[4.5]decan
= 5.2, 1.2, 1H), 8.24 (d, J = 1.5, 1H), 8.12
yl]ethyl})amine
(td, J = 7.9, 1.7, 1H), 7.71 (m, 2H), 7.58
(dd, J = 7.1, 5.7, 1H), 4.88 (s, 1H), 4.08 (d,
J = 14.0, 2H), 3.72 (m, 2H), 2.98 (td, J =
11.9, 5.1, 1H), 2.48 (td, J = 12.0, 4.4, 1H),
2.32 (m, 3H), 2.11 (m, 1H), 1.98 (d, J = 2.5,
1H), 1.77 (m, 2H), 1.61 (m, 1H), 1.48 (m,
4H), 1.17 (m, 1H), 0.77 (dt, J = 13.1, 8.9,
1H).
641 [(5-methanesulfonylpyridin MS: 430.2
yl)methyl]({2-[(9R)(pyridin
1H NMR (400 MHz, CD3CN) δ 9.10 (d, J =
yl)oxaspiro[4.5]decan
2.0, 1H), 8.87 (d, J = 1.8, 1H), 8.71 (dd, J =
yl]ethyl})amine
.3, 1.1, 1H), 8.37 (t, J = 2.0, 1H), 8.18 (td,
J = 8.0, 1.8, 1H), 7.75 (d, J = 8.2, 1H), 7.63
(ddd, J = 7.6, 5.4, 0.9, 1H), 4.16 (m, 2H),
3.73 (m, 2H), 3.14 (s, 3H), 3.02 (td, J =
12.0, 5.2, 1H), 2.52 (m, 1H), 2.33 (m, 3H),
2.14 (m, 1H), 2.01 (m, 1H), 1.79 (m, 2H),
1.62 (m, 1H), 1.48 (m, 4H), 1.19 (m, 1H),
0.79 (dt, J = 13.1, 8.9, 1H).
Compound Name Structure
642 [2-(3-methylphenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
643 [2-(3-chlorophenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
644 [2-(3-bromophenyl)ethyl]({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
645 [2-(3-fluorophenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
646 {2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({2-[3-
(trifluoromethyl)phenyl]ethyl})a
mine
Compound Name Structure
647 [2-(3-methoxyphenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
648 [2-(4-methylphenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
[2-(4-chlorophenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
[2-(4-bromophenyl)ethyl]({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
[2-(4-fluorophenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
{2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({2-[4-
(trifluoromethyl)phenyl]ethyl})a
mine
Compound Name Structure
[2-(4-methoxyphenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
[2-(2-methylphenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
[2-(2-chlorophenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
[2-(2-bromophenyl)ethyl]({2-
[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl})amine
[2-(2-fluorophenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
{2-[(9R)(pyridinyl)
oxaspiro[4.5]decan
yl]ethyl}({2-[2-
(trifluoromethyl)phenyl]ethyl})a
mine
Compound Name Structure
[2-(2-methoxyphenyl)ethyl]({2-
[(9R)(pyridin
yl)oxaspiro[4.5]decan
yl]ethyl})amine
Example 15: Synthesis of [(3-methoxythiophenyl)methyl]({2-[(9R)
(pyridinyl)oxaspiro[4.5]decanyl]ethyl})amine (Compound 140).
Methyl 2-cyano[6-oxaspiro[4.5]decanylidene]acetate (mixture of E and Z isomers)
A mixture of 6-oxaspiro[4.5]decanone (13.74 g, 89.1 mmol), methylcyanoacetate (9.4
ml, 106.9 mmol), ammonium acetate (1.79 g, 26.17 mmol) and acetic acid (1.02 ml, 17.8
mmol) in benzene (75 ml) was heated at reflux in a 250 ml round bottom flask equipped
with a Dean-Stark and a reflux condenser. After 3h, TLC (25%EtOAc in hexane, PMA
stain) showed the reaction was completed. After cooling, benzene (50 ml) was added
and the layer was separated, the organic was washed by water (120 ml) and the aqueous
layer was extracted by CH Cl (3 x 120 ml). The combined organic was washed with
sat’d NaHCO , brine, dried and concentrated and the residual was purified by flash
chromatography (340 g silica gel column, eluted by EtOAc in hexane: 5% EtOAc, 2CV;
-25%, 14CV; 25-40%,8 CV) gave a mixture of E and Z isomers: methyl 2-cyano[6-
oxaspiro[4.5]decanylidene]acetate (18.37 g, 87.8 % yield, m/z 236.0 [M + H]
observed) as a clear oil.
Methyl 2-cyano[9-(pyridinyl)oxaspiro[4.5]decanyl]acetate
A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) was added
dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF) at 0 C under
N , the mixture was then stirred at rt for 3h, copper Iodide(2.59 g, 13.6 mmol) was added
and allowed to stir at rt for another 30 min before a solution of a mixture of E and Z
isomers of methyl 2-cyano[6-oxaspiro[4.5]decanylidene]acetate (16 g, 150 mmol)
in THF (60 ml) was added in 30 min. The mixture was then stirred at rt for 18h. The
reaction mixture was poured into a 200 g ice/2 N HCl (100 ml) mixture. The product was
extracted with Et O (3x300 ml), washed with brine (200 ml), dried (Na SO ) and
2 2 4
concentrated. The residual was purified by flash chromatography (100 g silica gel
column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV gave methyl
2-cyano[9-(pyridinyl)oxaspiro[4.5]decanyl]acetate (15.44 g, 72% yield, m/z
315.0 [M + H]+ observed) as an amber oil .
2-[9-(Pyridinyl)oxaspiro[4.5]decanyl]acetonitrile
Ethylene glycol (300 ml) was added to methyl 2-cyano[9-(pyridinyl)
oxaspiro[4.5]decanyl]acetate(15.43 g, 49 mmol) followed by potassium hydroxide (5.5
g , 98 mmol), the resulting mix was heated to 120oC, after 3 h, the reaction mix was
cooled and water (300 ml) was added, the product was extracted by Et2O(3 x 400 ml),
washed with water(200 ml), dried (Na2SO4) and concentrated, the residual was purified
by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 3% 2CV;
3-25%, 12 CV; 25-40% 6CV to give 2-[9-(Pyridinyl)oxaspiro[4.5]decan
yl]acetonitrile (10.37 g, 82% yield, m/z 257.0 [M + H]+ observed).
2-[(9R)(Pyridinyl)oxaspiro[4.5]decanyl]acetonitrile
The racemic 2-[9-(pyridinyl)oxaspiro[4.5]decanyl]acetonitrile
was separated by chiral HPLC column under the following preparative-SFC conditions:
Instrument: SFC-80 (Thar, Waters); Column: Chiralpak AD-H (Daicel); column
temperature: 40 ºC; Mobile phase: Methanol /CO2=40/60; Flow: 70 g/min; Back
pressure: 120 Bar; Cycle time of stack injection: 6.0min; Load per injection: 225 mg;
Under these conditions, 2-[9-(pyridinyl)oxaspiro[4.5]decanyl]acetonitrile (4.0 g)
was separated to provide the desired isomer, 2-[(9R)(Pyridinyl)
oxaspiro[4.5]decanyl]acetonitrile (2.0 g, >99.5% enantiomeric excess) as a slow-
moving fraction. The absolute (R) configuration of the desired isomer was later
determined by an X-ray crystal structure analysis of Compound 140.
2-[(9R)(Pyridinyl)oxaspiro[4.5]decanyl]ethanamine
LAH (1M in Et2O, 20ml, 20 mmol) was added to a solution of 2-[(9R)(pyridinyl)-
6-oxaspiro[4.5]decanyl]acetonitrile (2.56 g, 10 mmol) in Et2O (100 ml, 0.1M ) at 0oC
under N . The resulting mix was stirred and allowed to warm to room temperature. After
2 h, LCMS showed the reaction had completed. The reaction was cooled at 0oC and
quenched with water (1.12 ml), NaOH (10%, 2.24 ml) and another 3.36 ml of water.
Solid was filtered and filter pad was washed with ether (3 x 20 ml). The combined
organic was dried and concentrated to give 2-[(9R)(Pyridinyl)
oxaspiro[4.5]decanyl]ethanamine (2.44 g, 94% yield, m/z 260.6 [M + H]+
observed) as a light amber oil.
Alternatively, 2-[(9R)(Pyridinyl)oxaspiro[4.5]decanyl]ethanamine was
prepared by Raney-Nickel catalyzed hydrogenation.
An autoclave vessel was charged with 2-[(9R)(pyridinyl)oxaspiro[4,5]decan
yl] acetonitrile and ammonia (7N solution in methanol). The resulting solution was
stirred at ambient conditions for 15 minutes and treated with Raney 2800 Nickel, slurried
in water. The vessel was pressurized to 30 psi with nitrogen and agitated briefly. The
autoclave was vented and the nitrogen purge repeated additional two times. The vessel
was pressurized to 30 psi with hydrogen and agitated briefly. The vessel was vented and
purged with hydrogen two additional times. The vessel was pressurized to 85-90 psi with
hydrogen and the mixture was warmed to 25-35 C. The internal temperature was
increased to 45-50 C over 30-60 minutes. The reaction mixture was stirred at 45-50 C
for 3 days. The reaction was monitored by HPLC. Once reaction was deemed complete,
it was cooled to ambient temperature and filtered through celite. The filter cake was
washed with methanol (2 x). The combined filtrates were concentrated under reduced
pressure at 40-45 C. The resulting residue was co-evaporated with EtOH (3 x) and dried
to a thick syrupy of 2-[(9R)(pyridinyl)oxaspiro[4.5]decanyl]ethanamine.
[(3-Methoxythiophenyl)methyl]({2-[(9R)(pyridinyl)oxaspiro[4.5]decan
yl]ethyl})amine
Into a vial were added 2-[(9R)(Pyridinyl)oxaspiro[4.5]decanyl]ethanamine
(500 mg, 1.92 mmole), 18 mL CH2Cl2 and sodium sulfate (1.3 g, 9.6 mmole). The 3-
methoxythiophenecarboxaldehyde (354 mg, 2.4 mmole) was then added, and the
misture was stirred overnight. NaBH4 (94 mg, 2.4 mmole) was added to the reaction
mixture, stirred for 10 minutes, and then MeOH (6.0 mL) was added, stirred 1h, and
finally quenched with water. The organics were separated off and evaporated. The crude
residue was purified by a Gilson prep HPLC. The desired fractions collected and
concentrated and lyophilized. After lyophilization, residue was partitioned between
CH2Cl2 and 2N NaOH, and the organic layers were collected. After solvent was
concentrated to half of the volume, 1.0 eq of 1N HCl in Et2O was added,and majority of
solvent evaporated under reduced pressure. The solid obtained was washed several times
with Et2O and dried to provide [(3-methoxythiophenyl)methyl]({2-[(9R)(pyridin
yl)oxaspiro[4.5]decanyl]ethyl})amine monohydrochloride (336 mg, 41% yield, m/z
387.0 [M + H]+ observed) as a white solid. The NMR for Compound 140 is described
herein.
Example 16: Biological Example
Procedure for the Testing for Antinociception
The hot plate assay is adapted from the procedure originally described by O’Callaghan
and Holtzman (JPET, 192, 497, 1975) and is commonly used to determine the potential
analgesic efficacy of opioid agonists. The antinociceptive effect of the composition(s)
described herein in the hot plate is expressed in %MPE (Maximum Possible Effect).
Rats (175-250g) or mice (20-30g) acclimated to the vivarium for at least 48 hr prior to
behavioral testing. Test drugs were administered by the subcutaneous (SC) route.
Animals were placed on the hot plate, which the temperature was set at 50-56°C,
depending on the in vitro potency of the compound. A cutoff time of 30-60 seconds was
used depending on the temperature of the hot plate so that the paws of the animal
displaying analgesia, was not damaged by the heat stimulus. The cutoff time was
considered a 100% response to the thermal insult. Prior to drug treatment, each animal
was tested to determine the baseline response. Thirty minutes after drug administration,
animals were re-tested. Dose response experiments were performed to evaluate the
potency of the test compound when various doses were administered at the point when
maximal analgesia is observed.
The %MPE was calculated according to the following formula: %MPE = [(Post drug
latency – baseline latency) / (60 or 30 – baseline latency)] x 100
ED values were calculated from the mean %MPE values for each group using log dose-
response curves by least-squares regression analysis.
Table 4
COMPOUND ED50 or %MPE
Morphine 3.8 mg/kg SC
Compound 81 100% at 10 mg/kg SC
Compound 122 1.1 mg/kg SC
Compound 28 1.2 mg/kg SC
Compound 145 5.9 mg/kg SC
Results are shown in Table 4. Naïve or control mice typically exhibit reaction times in
the hot plate from 10-15 seconds. The ED50 for morphine in the mouse hot plate was 3.8
mg/kg with full efficacy observed at a dose of 10 mg/kg SC. For comparison, Compound
122 and Compound 28 produced potent efficacy with an ED50 of 1.1 and 1.2 mg/kg SC,
respectively. These results demonstrate that Compound 122 and Compound 28 produced
a more robust analgesic effect in the mouse hot plate assay compared to morphine.
Example 17: In vivo administration to humans (Prophetic Example)
One or more compounds will be administered in dosage range from 0.15 mg to 4 mg to
human subject. The compound(s) will be administered as a continuous infusion over one
hour. The dose may be escalated as deemed appropriate to obtain pain relief. Dose
escalation will usually not exceed 5-fold as compared to the previous dose. Dosage
amounts, however, may be repeated or decreased as deemed appropriate. The subjects
will be tested for their ability to withstand or not appreciate pain as compared to a control
(placebo) group.
The cold pain test has been shown to be a reproducible and sensitive measure of the
effect of opiates and other centrally acting drugs (Van F and Rolan PE. The utility of the
cold pain test to measure analgesia from intravenous morphine. Br. J. Clin. Pharmacol.
1996; 42: 663-664; ; Posner J. Pain Models in Healthy Volunteers. In: Nimmo WS,
Tucker G, eds. Clinical Measurement in Drug Evaluation. 1991, Wolfe Publishing
Limited, UK.; Wotherspoon HA, Kenny GNC, McArdle CS. Analgesic Efficacy of
Controlled-Release DihydroCodeine. Anaesthesia 1991; 46: 915-917.; Lamb RJ, Mercer
AJ, Posner J. The effect of lamotrigine (300 mg) and dipipanone (4 mg and 8 mg), alone
and in combination, on the cold-pain test in healthy volunteers. Br. J. Clin. Pharmacol.
1994; 39: 539-588P.). In the test a subject’s hand is immersed in cold water chilled to a
range of 1 to 3 ºC. The initial sensation of cold is replaced by a deep burning discomfort
in the hand which is mediated by nociceptors in veins. The discomfort gradually builds to
a plateau over approximately 90 seconds and then either persists or decreases slightly.
The stimulus is easily controlled and the response is reproducible. The technique has
been shown to be sensitive to different doses of analgesic drugs.
During the cold pain test, the subject will sit down and place his/her non-dominant hand
into a stirred, thermostatically controlled water bath at about 2 ºC. With the other hand
the subject can adjust a visual analogue scale on a computer screen using the arrow keys
on the keypad. The scale is labelled "no pain" at one end and "maximum pain" at the
other end. The pointer will initially be at the "no pain" end and the subject will move the
pointer across the line to rate their feelings continuously over the test period. At the end
of 2 minutes the computer will automatically instruct the subject to remove his/her hand
which can then be dried. The cold pain test has been used extensively in healthy
volunteer studies and is non-invasive.
It is expected that the administration of the compound(s) will enable the human subject to
feel no pain or less pain as compared to the control group.
While the compounds describd herein have been described with reference to examples,
those skilled in the art recognize that various modifications may be made without
departing from the spirit and scope thereof.
All of the above U.S. patents, U.S. patent application publications, U.S. patent
applications, foreign patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application Data Sheet are
incorporated herein by reference, in their entirety, including but not limited to, U.S.
Provisional Application No. 61/596,808 filed February 9, 2012, and U.S. Provisional
Application No. 61/466,809 filed March 23, 2011.
Claims (87)
1. A compound having a formula of or a pharmaceutically acceptable salt thereof, wherein: R and R are independently H or CH ; 21 22 3 D is an optionally substituted aryl; B is H or optionally substituted alkyl; and B is an optionally substituted thiophenyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D1 is an optionally substituted phenyl or an optionally substituted pyridyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D1 is pyridyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D1 is 2- pyridyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted thiophenyl selected from the group consisting of and .
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is or , wherein R , R , and R are each independently H, OH, cycle, aryl, branched or unbranched 23 24 30 alkyl alcohol, halo, branched or unbranched alkyl, amino or substituted amino, amide, ester, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitro, alkylsulfanyl; or R and R together form an aryl 23 24 or cycle that is attached to one or more of the atoms of B .
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R , R , and R are each independently H, NH , OH, Cl, Br, F, I, OMe, CN, CH , phenyl, C -C 24 30 2 3 3 6 carbocycle, methanesulfonyl, CF , , , or ,wherein R is H or an optionally substituted branched or unbranched alkyl.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is wherein R and R are each independently H, OH, cycle, aryl, branched or 23 24 unbranched alkyl alcohol, halo, branched or unbranched alkyl, amino or substituted amino, amide, ester, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitro, alkylsulfanyl; or R and R together 23 24 form an aryl or cycle that is attached to one or more of the atoms of B .
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is , wherein R is H, OH, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, or alkylsulfanyl.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R is alkoxy.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R is methoxy.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is H or C -C alkyl.
13. The compound of claim 1 having a formula of or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted aryl; B is H or optionally substituted alkyl B is an optionally substituted thiophenyl.
14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein D1 is an optionally substituted phenyl or an optionally substituted pyridyl.
15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein D is pyridyl.
16. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein D is 2-pyridyl.
17. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein B is wherein R and R are each independently H, OH, cycle, aryl, branched or 23 24 unbranched alkyl alcohol, halo, branched or unbranched alkyl, amino or substituted amino, amide, ester, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitro, alkylsulfanyl; or R and R together 23 24 form an aryl or cycle that is attached to one or more of the atoms of B .
18. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein B is , wherein R is H, OH, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amino or substituted amino, amide, ester, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitro, or alkylsulfanyl.
19 The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R is alkoxy.
20. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein B is H or C -C alkyl.
21. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein B is H or C -C alkyl.
22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein B is , wherein R is H, OH, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amino or substituted amino, amide, ester, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitro, or alkylsulfanyl.
23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R is alkoxy.
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R is methoxy.
25. A pharmaceutical composition comprising a compound of claim 23, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising a compound of claim 13, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier.
27. Use of a compound, or a pharmaceutically acceptable salt thereof, of claim 24, for the manufacture of a medicament for treating pain.
28. Use of a compound, or a pharmaceutically acceptable salt thereof, of claim 13, for the manufacture of a medicament for treating pain.
29. A compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.
30. A compound according to claim 1 or 29, having the formula or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising a compound of claim 29 and a pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 31 further comprising at least one additional analgesic or non-opioid analgesic.
33. The pharmaceutical composition of claim 31 or 32 further comprising at least one anti- constipation agent.
34. Use of a compound, or a pharmaceutically acceptable salt thereof, of claim 30, for the manufacture of a medicament for treating pain..
35. The use of claim 34, wherein the medicament further comprises an additional analgesic or non-opioid analgesic.
36. A pharmaceutical composition comprising a compound of claim 30 and a pharmaceutically acceptable carrier.
37. The pharmaceutical composition of claim 36 further comprising at least one additional analgesic or non-opioid analgesic.
38. The pharmaceutical composition of claim 36 or 37 further comprising at least one anti- constipation agent.
39. The pharmaceutical composition of any one of claims 36-38, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 90% of
40. The pharmaceutical composition of any one of claims 36-38, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 95% of
41. The pharmaceutical composition of any one of claims 36-38, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 98% of
42. The pharmaceutical composition of any one of claims 36-38, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 99% of
43. Use of the pharmaceutical composition of claim 36 for the manufacture of a medicament for treating pain .
44. Use of the pharmaceutical composition of claim 37 for the manufacture of a medicament for treating pain.
45. Use of the pharmaceutical composition of claim 38 for the manufacture of a medicament for treating pain..
46. Use of the pharmaceutical composition of claim 39 for the manufacture of a medicament for treating pain. .
47. Use of the pharmaceutical composition of claim 40 for the manufacture of a medicament for treating pain. .
48. Use of the pharmaceutical composition of claim 41 for the manufacture of a medicament for treating pain.
49. Use of the pharmaceutical composition of claim 42 for the manufacture of a medicament for treating pain.
50. Use of a compound according to claim 1, having a formula of or a pharmaceutically acceptable salt thereof, in the preparation of a medicament suitable for parenteral administration for the treatment of pain.
51 The use of claim 50, wherein the compound has a formula of , or a pharmaceutically acceptable salt thereof.
52. The use of claim 50, wherein the compound has a formula of , or a pharmaceutically acceptable salt thereof.
53. The use of claim 50, wherein the medicament suitable for parenteral administration is suitable for intravenous administration.
54. The use of claim 50, wherein medicament suitable for parenteral administration is suitable for intraperitoneal administration.
55. The use of claim 50, wherein medicament suitable for parenteral administration is suitable for intravesical administration.
56. The use of claim 50, wherein medicament suitable for parenteral administration is suitable for intrathecal administration.
57. The use of claim 50, wherein the pain is post-operative pain.
58. The use of claim 50, wherein the pain is neuropathic pain.
59. The use of claim 50, wherein the pain is inflammation pain.
60. The use of claim 50, wherein the pain is trauma pain.
61. The use of claim 50, wherein the medicament comprises 0.15 mg to 4 mg of the compound, or a pharmaceutically acceptable salt thereof.
62. The use of claim 51, wherein the medicament comprises 0.15 mg to 4 mg of the compound, or a pharmaceutically acceptable salt thereof.
63. The use of claim 52, wherein the medicament comprises 0.15 mg to 4 mg of the compound, or a pharmaceutically acceptable salt thereof.
64. The use of claim 50, wherein the medicament comprises, wherein the pharmaceutical composition comprises 0.1 mg to 200 mg of the compound, or a pharmaceutically acceptable salt thereof.
65. The use of claim 51, wherein the medicament comprises, wherein the pharmaceutical composition comprises 0.1 mg to 200 mg of the compound, or a pharmaceutically acceptable salt thereof.
66. The use of claim 52, wherein the medicament comprises, wherein the pharmaceutical composition comprises 0.1 mg to 200 mg of the compound, or a pharmaceutically acceptable salt thereof.
67. The use of claim 50, wherein the medicament comprises, wherein the pharmaceutical composition comprises 0.01 mg to about 250 mg of the compound, or a pharmaceutically acceptable salt thereof.
68. The use of claim 51, wherein the medicament comprises, wherein the pharmaceutical composition comprises 0.01 mg to about 250 mg of the compound, or a pharmaceutically acceptable salt thereof.
69. The use of claim 52, wherein the medicament comprises, wherein the pharmaceutical composition comprises 0.01 mg to about 250 mg of the compound, or a pharmaceutically acceptable salt thereof.
70. A pharmaceutical composition comprising about 0.01 mg to about 250 mg of a compound according to claim 1, wherein the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
71. The pharmaceutical composition of claim 70, wherein the pharmaceutical composition comprises 0.1 mg to 200 mg of the compound, or a pharmaceutically acceptable salt thereof.
72. The pharmaceutical composition of claim 70, wherein the pharmaceutical composition comprises 0.15 mg to 4 mg of the compound, or a pharmaceutically acceptable salt thereof.
73. The pharmaceutical composition of claim 70, wherein the pharmaceutical composition is suitable for parenteral administration.
74. The pharmaceutical composition of claim 71, wherein the pharmaceutical composition is suitable for parenteral administration.
75. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is suitable for parenteral administration.
76. The pharmaceutical composition of claim 70, wherein the pharmaceutical composition is suitable for intravenous administration.
77. The pharmaceutical composition of claim 71, wherein the pharmaceutical composition is suitable for intravenous administration.
78. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is suitable for intravenous administration.
79. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the compound is a fumaric salt of the compound.
80. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the compound is a fumaric salt of the compound.
81. The pharmaceutical composition of claim 31, wherein the compound is a fumaric salt of the compound.
82. The pharmaceutical composition of claim 36, wherein the compound is a fumaric salt of the compound.
83. The compound or pharmaceutically acceptable salt thereof according to claim 29 substanatially as herein before described with reference to any one of the Examples.
84. The compound or pharmaceutically acceptable salt thereof according to claim 30 substanatially as herein before described with reference to any one of the Examples.
85. The pharmaceutical composition according to claim 31 substanatially as herein before described with reference to any one of the Examples.
86. The pharmaceutical composition according to claim 36 substanatially as herein before described with reference to any one of the Examples.
87. The compound or pharmaceutically acceptable salt thereof according to claim 1 substanatially as herein before described with reference to any one of the Examples. 88 The pharmaceutical composition according to claim 26 substanatially as herein before described with reference to any one of the Examples. 89 The pharmaceutical composition according to claim 70 substanatially as herein before described with reference to any one of the Examples.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161466809P | 2011-03-23 | 2011-03-23 | |
US61/466,809 | 2011-03-23 | ||
US201261596808P | 2012-02-09 | 2012-02-09 | |
US61/596,808 | 2012-02-09 | ||
NZ615993A NZ615993B2 (en) | 2011-03-23 | 2012-03-23 | Opioid receptor ligands and methods of using and making same |
Publications (2)
Publication Number | Publication Date |
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NZ713143A NZ713143A (en) | 2017-05-26 |
NZ713143B2 true NZ713143B2 (en) | 2017-08-29 |
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