NZ615993B2 - Opioid receptor ligands and methods of using and making same - Google Patents

Opioid receptor ligands and methods of using and making same Download PDF

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Publication number
NZ615993B2
NZ615993B2 NZ615993A NZ61599312A NZ615993B2 NZ 615993 B2 NZ615993 B2 NZ 615993B2 NZ 615993 A NZ615993 A NZ 615993A NZ 61599312 A NZ61599312 A NZ 61599312A NZ 615993 B2 NZ615993 B2 NZ 615993B2
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New Zealand
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ethyl
oxaspiro
amine
decan
methyl
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NZ615993A
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NZ615993A (en
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Xiaotao Chen
Dimitar Gotchev
Guodong Liu
Philip Pitis
Dennis Yamashita
Catherine Ck Yuan
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Trevena Inc
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Priority to NZ713143A priority Critical patent/NZ713143B2/en
Priority claimed from PCT/US2012/030327 external-priority patent/WO2012129495A1/en
Publication of NZ615993A publication Critical patent/NZ615993A/en
Publication of NZ615993B2 publication Critical patent/NZ615993B2/en

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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.
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. [0123a] Specific embodiments Specific embodiments of the present disclosure are represented by the following items: 1. A compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: D is an optionally substituted aryl; and B is an optionally substituted pyridyl. 2. The compound of item 1, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted pyridyl. 3. The compound of item 1, or a pharmaceutically acceptable salt thereof, wherein D is pyridyl. 4. The compound of any one of items 1-3, wherein the compound has the formula of or a pharmaceutically acceptable salt thereof.
. The compound of any one of items 1-4, or a pharmaceutically acceptable salt thereof, wherein B is , , or , wherein R , R and R are each independently H, OH, cycle, aryl, branched or 23 24, 30 unbranched alkyl alcohol, halo, branched or unbranched alkyl, amino or substituted amino, amide, ester, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitro, or alkylsulfanyl. 6. The compound of item 5, or a pharmaceutically acceptable salt thereof, wherein R , R , and R are each independently H, NH , OH, Cl, Br, F, I, OMe, CN, 23 24 30 2 CH , phenyl, C -C carbocycle, methanesulfonyl, CF , , 3 3 6 3 , or , wherein R is H or an alkyl. 7. The compound of item 5, or a pharmaceutically acceptable salt thereof, wherein one of R , R , and R is H. 23 24 30 8. The compound of item 5, or a pharmaceutically acceptable salt thereof, wherein two of R , R , and R are H. 23 24 30 9. The compound of item 6, or a pharmaceutically acceptable salt thereof, wherein R is F.
. The compound of item 8, or a pharmaceutically acceptable salt thereof, wherein R is F, and R and R are H. 23 24 30 11. The compound of item 1, wherein the optionally substituted pyridyl is a halo substituted pyridyl. 12. The compound of item 11, or a pharmaceutically acceptable salt thereof, wherein the halo substituted pyridyl is a fluoro substituted pyridyl. 13. The compound of item 1, having the formula or a pharmaceutically acceptable salt thereof. 14. The compound of item 1, having the formula or a pharmaceutically acceptable salt thereof.
. A pharmaceutical composition comprising a compound of item 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition of item 15 further comprising at least one additional analgesic or non-opioid analgesic. 17. The pharmaceutical composition of item 15 further comprising at least one anti- constipation agent. 18. A pharmaceutical composition comprising a compound of item 13, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition of item 18 further comprising at least one additional analgesic or non-opioid analgesic.
. The pharmaceutical composition of item 18 further comprising at least one anti- constipation agent. 21. The pharmaceutical composition of item 18, wherein the composition is substantially free of the S-enantiomer of or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition comprising a compound of item 14, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 23. Use of a compound having the formula of: or a pharmaceutically acceptable salt thereof, wherein: D is an optionally substituted aryl; and B is an optionally substituted pyridyl; in the preparation of a medicament for the treatment of pain. 24. The use of item 23, wherein the medicament is prepared for simultaneous or sequential use with an additional analgesic or non-opioid analgesic.
. The use of item 23, wherein the medicament is prepared for simultaneous or sequential use with an anti-constipation agent. 26. The use of item 23, wherein the compound has the formula or a pharmaceutically acceptable salt thereof. 27. The pharmaceutical composition of item 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 90% of or pharmaceutically acceptable salt thereof. 28. The pharmaceutical composition of item 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 95% of or pharmaceutically acceptable salt thereof. 29. The pharmaceutical composition of item 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 98% of or pharmaceutically acceptable salt thereof.
. The pharmaceutical composition of item 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 99% of or pharmaceutically acceptable salt thereof.
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 (30)

1. A compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: D is an optionally substituted aryl; and B is an optionally substituted pyridyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted pyridyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D is pyridyl.
4. The compound of any one of claims 1-3, wherein the compound has the formula of or a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1-4, 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, or alkylsulfanyl.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R , R , and R are each independently H, NH , OH, Cl, Br, F, I, OMe, CN, CH , 23 24 30 2 3 phenyl, C -C carbocycle, methanesulfonyl, CF , , , 3 6 3 or , wherein R is H or an alkyl.
7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein one of R , R , and R is H. 23 24 30
8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein two of R , R , and R are H. 23 24 30
9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R is F.
10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R is F, and R and R are H. 24 30
11. The compound of claim 1, wherein the optionally substituted pyridyl is a halo substituted pyridyl.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the halo substituted pyridyl is a fluoro substituted pyridyl.
13. The compound of claim 1, having the formula or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1, having the formula or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 further comprising at least one additional analgesic or non-opioid analgesic.
17. The pharmaceutical composition of claim 15 further comprising at least one anti- constipation agent.
18. A pharmaceutical composition comprising a compound of claim 13, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 18 further comprising at least one additional analgesic or non-opioid analgesic.
20. The pharmaceutical composition of claim 18 further comprising at least one anti- constipation agent.
21. The pharmaceutical composition of claim 18, wherein the composition is substantially free of the S-enantiomer of or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of claim 14, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
23. Use of a compound having the formula of: or a pharmaceutically acceptable salt thereof, wherein: D is an optionally substituted aryl; and B is an optionally substituted pyridyl; in the preparation of a medicament for the treatment of pain.
24. The use of claim 23, wherein the medicament is prepared for simultaneous or sequential use with an additional analgesic or non-opioid analgesic.
25. The use of claim 23, wherein the medicament is prepared for simultaneous or sequential use with an anti-constipation agent.
26. The use of claim 23, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.
27. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 90% of or pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 95% of or pharmaceutically acceptable salt thereof.
29. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 98% of or pharmaceutically acceptable salt thereof.
30. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises an enantiomeric excess of at least 99% of or pharmaceutically acceptable salt thereof.
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