Pharmaceutical compounds
11773090 · 2023-10-03
Assignee
Inventors
- Giles Albert Brown (Cambridge, GB)
- Barry John Teobald (Cambridge, GB)
- Benjamin Gerald Tehan (Cambridge, GB)
Cpc classification
A61P25/28
HUMAN NECESSITIES
C07D451/14
CHEMISTRY; METALLURGY
International classification
C07D451/14
CHEMISTRY; METALLURGY
Abstract
This invention relates to compounds that are agonists of the muscarinic M.sub.1 and/or M.sub.4 receptor and which are useful in the treatment of diseases mediated by the muscarinic M.sub.1 and M.sub.4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula ##STR00001##
where Y, R.sup.1, R.sup.2 and R.sup.4 are as defined herein.
Claims
1. A compound of the formula (1): ##STR00076## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is CONR.sup.8R.sup.9; R.sup.2 is selected from hydrogen; fluorine; cyano; hydroxy; amino; and a C.sub.1-3 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one of the carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidized forms thereof; R.sup.4 is H or a C.sub.1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof; R.sup.8 is hydrogen, a non-aromatic C.sub.1-6 hydrocarbon group optionally substituted with one or more fluorine atoms, or R.sup.8 can be joined together with R.sup.9 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, and R.sup.9 is a non-aromatic C.sub.1-6 hydrocarbon group optionally substituted with one or more fluorine atoms, or R.sup.9 can be joined together with R.sup.8 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is H.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or methyl.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is hydrogen and R.sup.1 is selected from the group consisting of: ##STR00077##
5. The compound according to claim 1, which is selected from the group consisting of: Ethyl 7-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl 7-{4-[(2-methylpropyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl 7-{4-[(cyclobutylmethyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl 7-[4-(azepan-1-ylcarbonyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; Methyl 7-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; Methyl 7-{4-[(2-methylpropyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; Methyl 7-{4-[(cyclobutylmethyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; and Methyl 7-[4-(azepan-1-ylcarbonyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
7. A method of treating a cognitive disorder or psychotic disorder or for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
8. The method according to claim 7, wherein the cognitive disorder is Alzheimer's disease.
9. The method according to claim 7, wherein the cognitive disorder is dementia with Lewy bodies.
10. The method according to claim 7, wherein the cognitive disorder is schizophrenia.
Description
EXAMPLES
(1) The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.
Examples 1-1 to 8-25
(2) Some of the compounds of Examples 1-1 to 8-25 shown in Table 1 below have been prepared. Their NMR and LCMS properties and the methods used to prepare them are set out in Table 3. The starting materials for each of the Examples are listed in Table 2.
(3) TABLE-US-00001 TABLE 1
General Procedures
(4) Where no preparative routes are included, the relevant intermediate is commercially available. Commercial reagents were utilized without further purification. Room temperature (rt) refers to approximately 20-27° C. .sup.1H NMR spectra were recorded at 400 MHz on either a Bruker or Jeol instrument. Chemical shift values are expressed in parts per million (ppm), i.e. (δ)-values. The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=triplet of triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets, ddt=doublet of doublet of triplets, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Chromatography refers to column chromatography performed using 60-120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. TLC for monitoring reactions refers to TLC run using the specified mobile phase and the Silica gel F254 as a stationary phase from Merck. Microwave-mediated reactions were performed in Biotage Initiator or CEM Discover microwave reactors.
(5) LCMS Analysis
(6) LCMS analysis of compounds was performed under electrospray conditions using the instruments and methods given in the tables below:
(7) TABLE-US-00002 System ID Instrument Name LC Detector Mass Detector 1 Waters 2695 Photo Diode Array ZQ-2000 Detector 2 Waters Acquity H Class Photo Diode Array SQ Detector 3 Shimadzu Nexera Photo Diode Array LCMS-2020 4 Agilent 1290 RRLC Photo Diode Array Agilent 6120 with Agilent 6120 Mass detector
(8) TABLE-US-00003 Method Solvent UV Mass Column Flow Rate Name System Column used Gradient Range Range Temp. ° C. ml/min A (A) 5 mM BEH C18 2.1 × 95:5 at 0.01 min up to 0.40 min, 65:35 at 200-400 100-1200 Ambient 0.55 ammonium 50 mm, 1.7 μm or 0.80 min, 45:55 at 1.20 min, 0:100 at nm amu acetate + 0.1% equivalent 2.50 min up to 3.30 min, 95:5 at 3.31 formic acid in min up to 4.00 min water (B) 0.1% formic acid in acetonitrile B (A) 20 mM X-Bridge C18 4.6 × 90:10 at 0.01 min, 10:90 at 5.00 min, 200-400 60-1000 Ambient 1.00 ammonium 150 mm, 5 μm 0:100 at 7.00 min up to 11.00 min, 90:10 nm amu acetate in water or equivalent at 11.01 min up to 12.00 min (B) methanol C (A) 0.1% X-Bridge 018 4.6 × 95:5 at 0.01 min, 10:90 at 5.00 min, 5:95 200-400 60-1000 Ambient 1.00 ammonia in 50 mm, 3.5 μm at 5.80 min up to 7.20 min, 95:5 at 7.21 nm amu water or equivalent min up to 10.00 min (B) 0.1% ammonia in acetonitrile D (A) 5 mM X-Bridge C18 4.6 × 95:5 at 0.01 min, 10:90 at 5.00 min, 5:95 200-400 60-1000 Ambient 1.00 ammonium 50 mm, 3.5 μm at 5.80 min up to 7.20 min, 95:5 at 7.21 nm amu bicarbonate in or equivalent min up to 10.00 min water (B) acetonitrile
(9) LCMS data in the experimental section and Tables 2 and 3 are given in the format: (Instrument system, Method): Mass ion, retention time, UV detection wavelength.
(10) Compound Purification
(11) Final purification of compounds was performed by preparative reversed phase HPLC, chiral HPLC or chiral SFC using the instruments and methods detailed below where data is given in the following format: Purification technique: [phase (column description, column length×internal diameter, particle size), solvent flow-rate, gradient—given as % of mobile phase B in mobile phase A (over time), mobile phase (A), mobile phase (B)].
(12) Preparative HPLC Purification:
(13) Shimadzu LC-20AP binary system with SPD-20A UV detector
(14) Chiral HPLC Purification:
(15) Shimadzu LC-20AP binary system with SPD-20A UV detector
(16) Chiral SFC Purification:
(17) Waters SFC 200
(18) Purification Method A
(19) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (85:15) (over 10 mins)]
(20) Purification Method B
(21) Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 5-40% (over 35 min), 40% (over 2 min), 100% (over 2 min), then 100-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(22) Purification Method C
(23) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 20-35% (over 30 min), 100% (over 2 min), then 100-20% (over 2 min), mobile phase (A): 0.1% formic acid in water, (B) 100% acetonitrile]
(24) Purification Method D
(25) SFC: [(CHIRALPAK IB, 250×21 mm, 5 μm), 75 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in MeOH, Isocratic (A:B) (90:10) (over 8 min)]
(26) Purification Method E
(27) SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (75:25) (over 13 mins)]
(28) Purification Method F
(29) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 18 mL per min, gradient 5-65% (over 20 min), 100% (over 2 min), then 100-5% (over 3 min), mobile phase (A): mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(30) Purification Method G
(31) SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA, Isocratic (A:B) (75:25) (over 20 mins)]
(32) Purification Method H
(33) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 5-55% (over 18 min), 100% (over 2 min), then 100-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(34) Purification Method I
(35) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.2% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (75:25) (over 9 mins)]
(36) Purification Method J
(37) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL per min, gradient 0-50% (over 33 min), 100% (over 2 min), then 100-0% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(38) Purification Method K
(39) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 75 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in MeOH, Isocratic (A:B) (85:15) (over 14.0 mins)]
(40) Purification Method L
(41) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 17 mL per min, gradient 35-45% (over 17 min), 100% (over 2 min), then 100-35% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(42) Purification Method M
(43) SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 75 mL per min, mobile phase (A): 100% liquid CO2, (B): 0.1% diethylamine in MeOH, Isocratic (A:B) (85:15) (over 20 mins)]
(44) Purification Method N
(45) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL per min, gradient 25% (over 46 min), 100% (over 3 min), then 100-25% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]
(46) Purification Method O
(47) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (75:25) (over 17.0 mins)]
(48) Purification Method P
(49) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 5-20% (over 35 min), 100% (over 2 min), then 100-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]
(50) Purification Method Q
(51) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (85:15) (over 9 mins)]
(52) Purification Method R
(53) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 13 mL per min, gradient 15-40% (over 20 min), 100% (over 2 min), then 100-15% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(54) Purification Method S
(55) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine MeOH, Isocratic (A:B) (75:25) (over 8 min)]
(56) Purification Method T
(57) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 20-30% (over 25 min), 30% (over 5 min), 100% (over 2 min), then 100-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B): 100% acetonitrile]
(58) Purification Method U
(59) Chiral HPLC [Normal Phase (CHIRALPAK AD-H 250×21 mm, 5 μm), 18 mL per min, mobile phase (A): 0.1% diethylamine in hexane, B) 0.1% diethylamine in IPA:MeOH (25:75), Isocratic (A:B) (80:20) (over 25 min)]
(60) Purification Method V
(61) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 10-35% (over 30 min), 35% (over 14 min), 100% (over 2 min), then 100-10% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B): 100% acetonitrile]
(62) Purification Method W
(63) Chiral HPLC: [Normal Phase (CHIRALPAK AD-H 250×21 mm, 5 μm), 18 mL per min, mobile phase (A): 0.1% diethylamine in hexane, B) 0.1% diethylamine in IPA:MeOH (30:70), Isocratic (A:B) (85:15) (over 20 min)]
(64) Purification Method X
(65) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL per min, gradient 10-40% (over 25 min), 40% (over 5 min), 100% (over 2 min), then 100-10% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B): 100% acetonitrile]
(66) Purification Method Y
(67) Chiral HPLC [Normal Phase (CHIRALPAK AD-H 250×21 mm, 5 μm), 18 mL per min, mobile phase (A): 0.1% diethylamine in hexane, B) 0.1% diethylamine in IPA, Isocratic (A:B) (90:10) (over 37 min)]
(68) Purification Method Z
(69) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 20-50% (over 23 min), 100% (over 2 min), then 100-20% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(70) Purification Method AA
(71) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in MeOH, Isocratic (A:B) (85:15) (over 7 min)]
(72) Purification Method AB
(73) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 20-45% (over 20 min), 100% (over 2 min), then 100-20% (over 5 min) mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(74) Purification Method AC
(75) Chiral HPLC [Normal Phase (CHIRALPAK AD-H 250×21 mm, 5 μm), 18 mL per min, mobile phase (A): 0.1% diethylamine in hexane, B) 0.1% diethylamine in IPA:MeOH (25:75), Isocratic (A:B) (80:20) (over 50 min)]
(76) Purification Method AD
(77) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 0-28% (over 25 min), 28% (over 5 min), 100% (over 2 min), then 100-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]
(78) Purification Method AE
(79) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (80:20) (over 10 mins)]
(80) Purification Method AF
(81) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 5-27% (over 42 min), 27% (over 6 min), 100% (over 2 min), then 100-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]
(82) Purification Method AG
(83) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (70:30) (over 6 mins)]
(84) Purification Method AN
(85) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 15-35% (over 20 min), 35% (over 3 min), 100% (over 2 min), then 100-15% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(86) Purification Method AI
(87) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (85:15) (over 8 mins)]
(88) Purification Method AJ
(89) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 0-38% (over 28 min), 100% (over 2 min), then 100-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(90) Purification Method AK
(91) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% ammonia in IPA:MeOH (50:50), Isocratic (A:B) (88:12) (over 20 mins)]
(92) Purification Method AL
(93) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 0-40% (over 24 min), 40% (over 4 min), 100% (over 4 min), then 100-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(94) Purification Method AM
(95) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (87:13) (over 12 mins)]
(96) Purification Method AN
(97) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm, 13 mL per min, gradient 0-30% (over 55 min), 30% (over 20 min), 100% (over 2 min), then 100-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]
(98) Purification Method AO
(99) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 80 mL per min, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in IPA:MeOH (50:50), Isocratic (A:B) (85:15) (over 9 mins)]
(100) Purification Method AP
(101) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm, 10 mL per min, gradient 10-70% (over 20 min), 70% (over 2 min), 100% (over 2 min), then 100-10% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(102) Purification Method AQ
(103) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm, 14 mL per min, gradient 15-30% (over 35 min), 70% (over 16 min), 100% (over 2 min), then 100-15% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
(104) Purification Method AR
(105) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm, 16 mL per min, gradient 20% (over 60 min), 100% (over 2 min), then 100-20% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]
Abbreviations
(106) atm.=atmosphere conc.=concentrated DCM=dichloromethane DMF=dimethylformamide ES(I)=electro spray ionisation EtOAc=ethyl acetate h=hour(s) H.sub.2O=water HCl=hydrogen chloride, hydrochloric acid HPLC=high performance liquid chromatography IPA=isopropanol (propan-2-ol) LC=liquid chromatography MeOH=Methanol min(s)=minute(s) MS=mass spectrometry nm=nanometre(s) NMR=nuclear magnetic resonance SFC=supercritical fluid chromatography TEA=triethylamine TFA=trifluoroacetic acid TLC=thin layer chromatography
(107) Prefixes n-, s-, i-, t- and tert-have their usual meanings: normal, secondary, iso, and tertiary.
(108) Synthesis of Intermediates:
(109) Route 1
Typical Procedure for the Preparation of Ketones, as Exemplified by the Preparation of Intermediate 3, ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
(110) ##STR00068##
(111) tert-Butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Intermediate 1) (200 mg, 0.83 mmol) was dissolved in DCM (8 mL) and the solution was cooled down to 0° C. TFA (1 mL) was added drop wise, and the resulting reaction mixture was stirred at 25° C. for 6 h. The solvents were removed in-vacuo and the residue was purified by triturating with diethyl ether (3×1 mL) to give the crude 3-oxa-9-azabicyclo[3.3.1]nonan-7-one trifluoroacetate (115 mg, 98%) as a white solid.
(112) LCMS (System 4, Method C): m/z 142 (M+H)+ (ESI+ve), at 0.59-0.80 min, 202 nm.
(113) Triethylamine (0.3 mL, 2.44 mmol) was added to a solution of the crude 3-oxa-9-azabicyclo[3.3.1]nonan-7-one trifluoroacetate (115 mg, 0.82 mmol) in DCM (10 mL), and the mixture was cooled to 0° C. and stirred for 20 min. Ethyl chloroformate (Intermediate 2) (0.13 mL, 1.22 mmol) was then added drop wise at 0° C., and the resulting reaction mixture was stirred at 25° C. for 1 h. The solvents were removed in-vacuo, and the residue was partitioned between H.sub.2O (80 mL) and EtOAc (60 mL). The aqueous layer was further extracted with EtOAc (2×60 mL), and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvents were removed in-vacuo to give ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Intermediate 3) as a gum (170 mg, 98%), which was used without further purification.
(114) The data for Intermediate 3 are in Table 2
(115) Route 2
Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 9, 2-methoxy-6-(piperidin-4-yl)pyridine Hydrochloride
(116) ##STR00069##
(117) tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 7) (395 mg, 1.28 mmol) and CS.sub.2CO.sub.3 (1.03 g, 3.19 mmol) were added to a solution of 2-iodo-6-methoxypyridine (Intermediate 8) (300 mg, 1.28 mmol) in 1,4-dioxane (10 mL) and the resulting mixture was degassed under a nitrogen atmosphere for 20 min. (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos, 36 mg, 0.06 mmol) and palladium(II) acetate (29 mg, 0.13 mmol) were added and the resulting reaction mixture was stirred at 80° C. for 18 h. The solvents were removed in-vacuo and residue was partitioned between H.sub.2O (80 mL) and EtOAc (60 mL). The aqueous layer was further extracted with EtOAc (60 mL) and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified by column chromatography (normal phase neutral activated alumina, 10% to 12% EtOAc in hexane) to give tert-butyl 6-methoxy-3′,6′-dihydro-2,4′-bipyridine-1′(2′H)-carboxylate (310 mg, 84%) as a gum.
(118) LCMS (System 3, Method D): m/z 291 (M+H).sup.+ (ESI+ve), at 5.73 min, 202 nm. 10% Palladium on carbon (50% moisture, 100 mg) was added to a solution of tert-butyl 6-methoxy-3′,6′-dihydro-2,4′-bipyridine-1′(2′H)-carboxylate (300 mg, 1.03 mmol) in MeOH (20 mL) and the resulting mixture was stirred under an atmosphere of hydrogen (1 atm pressure) at 70° C. for 40 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in-vacuo. The crude product was triturated with pentane to give tert-butyl 4-(6-methoxypyridin-2-yl)piperidine-1-carboxylate (240 mg, 79%) as a gum.
(119) LCMS (System 3, Method D): m/z 293 (M+H).sup.+ (ESI+ve), at 5.05 min, 202 nm.
(120) tert-Butyl 4-(6-methoxypyridin-2-yl)piperidine-1-carboxylate (240 mg, 0.82 mmol) was dissolved in 1,4-dioxane (5 mL) and cooled to 0° C. HCl solution in 1,4-dioxane (4 M, 5 mL) was added drop wise and the resulting reaction mixture was stirred at 25° C. for 8 h. The solvents were removed in-vacuo, and the residue was purified by trituration with pentane (3×2 mL) to give 2-methoxy-6-(piperidin-4-yl)pyridine hydrochloride (Intermediate 9) (130 mg, 82%) as a solid.
(121) The data for Intermediate 9 are in Table 2.
(122) Route 3
Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 21, N-(2-methylpropyl)-N-(piperidin-4-yl)acetamide Hydrochloride
(123) ##STR00070##
(124) tert-Butyl 4-oxopiperidine-1-carboxylate (Intermediate 19) (5.0 g, 25.1 mmol) was dissolved in MeOH (50 mL) and 2-methylpropan-1-amine (Intermediate 20) (1.83 g, 25.1 mmol) was added. 10% Palladium hydroxide on carbon (50% moisture, 500 mg) was then added, and the resulting reaction mixture was stirred under an atmosphere of hydrogen (1 atm pressure) at 25° C. for 17 h. The mixture was filtered through Celite and the filtrate was concentrated in-vacuo to give tert-butyl 4-[(2-methylpropyl)amino]piperidine-1-carboxylate (5.0 g, 78%) as a gum.
(125) LCMS (System 3, Method D): m/z 257 (M+H).sup.+ (ESI+ve), at 3.39 min, 202 nm.
(126) tert-Butyl 4-[(2-methylpropyl)amino]piperidine-1-carboxylate (5.0 g, 19.5 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. Triethylamine (2.7 mL, 19.5 mmol) was added drop wise at 0-5° C. and the mixture was stirred at 0-5° C. for 10 min. Acetic anhydride (2.3 g, 23.4 mmol) was then added drop wise at 0-5° C., and the resulting reaction mixture was stirred at 25° C. for 2 h. The solvents were removed in-vacuo to give tert-butyl 4-[acetyl(2-methylpropyl)amino]piperidine-1-carboxylate (5.5 g, 89%) as a liquid.
(127) LCMS (System 3, Method D): m/z 597 (2M+H)+, 284 (M-Me+H).sup.+ (ESI+ve), at 4.03 min, 202 nm.
(128) tert-butyl 4-[acetyl(2-methylpropyl)amino]piperidine-1-carboxylate (5.0 g, 15.8 mmol) was slowly dissolved in HCl solution in 1,4-dioxane (4 M, 50 mL), then the resulting mixture was stirred at 25° C. for 16 h. The solvents were removed in-vacuo, and the residue was purified by trituration with diethyl ether (3×250 mL) to give N-(2-methylpropyl)-N-(piperidin-4-yl)acetamide hydrochloride (Intermediate 21) (3.0 g, 88%) as a gum.
(129) The data for Intermediate 21 are in Table 2.
(130) Route 4
Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 23, N-(2,2-dimethylpropyl)-N-(piperidin-4-yl)acetamide Trifluoroacetate
(131) ##STR00071##
(132) tert-Butyl 4-oxopiperidine-1-carboxylate (Intermediate 19) (3.0 g, 15.0 mmol), 2,2-dimethylpropan-1-amine (Intermediate 22) (1.5 g, 18 mmol), triethylamine (6.2 mL, 45 mmol) and ZnCl.sub.2 (0.7 mL, 0.07 mmol) were dissolved in MeOH (30 mL) and the reaction mixture was stirred at 65° C. for 6 h. To this was then added NaBH.sub.3CN (2.8 g, 45 mmol) portion wise at 0° C. The resulting reaction mixture was stirred at 25° C. for 17 h. The solvents were removed in-vacuo, and the residue was partitioned between H.sub.2O (100 mL) and DCM (80 mL). The aqueous layer was further extracted with DCM (2×80 mL) and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo to give tert-butyl 4-[(2,2-dimethylpropyl)amino]piperidine-1-carboxylate (3.5 g, 88%) as a yellow gum.
(133) LCMS (System 3, Method D): m/z 271 (M+H).sup.+, (ESI+ve), at 4.22 min, 202 nm.
(134) tert-Butyl 4-[(2,2-dimethylpropyl)amino]piperidine-1-carboxylate (3.5 g, 12 mmol) and triethylamine (5.3 mL, 30 mmol) were dissolved in DCM (20 mL) under nitrogen and stirred at 0° C. for 10 min. Acetyl chloride (1.3 mL, 19 mmol) was then added drop wise at 0-10° C. and the mixture was stirred at 25° C. for 2 h. The reaction mixture was partitioned between H.sub.2O (150 mL) and EtOAc (120 mL). The aqueous layer was further extracted with EtOAc (2×120 mL) and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo to give the crude product, which was purified by column chromatography (normal phase silica, 0 to 20% EtOAc in hexane to give tert-butyl 4-[acetyl(2,2-dimethylpropyl)amino]piperidine-1-carboxylate (3.1 g, 76%) as a yellow gum.
(135) LCMS (System 3, Method D): m/z 313 (M+H).sup.+, (ESI+ve), at 4.41 min, 202 nm.
(136) To a solution of tert-butyl 4-[acetyl(2,2-dimethylpropyl)amino]piperidine-1-carboxylate (3.1 g, 9 mmol) in DCM (14 mL) at 0° C. was added drop wise TFA (7.0 mL). The reaction was stirred at 25° C. for 6 h. The solvents were removed in-vacuo, and the residue was purified by triturating with pentane (3×1 mL) to give N-(2,2-dimethylpropyl)-N-(piperidin-4-yl)acetamide trifluoroacetate (Intermediate 23) (1.8 g, 86%) as a yellow gum.
(137) The data for Intermediate 23 are in Table 2.
(138) Route 5
Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 33, 1-(piperidin-4-yl)azepan-2-one Hydrochloride
(139) ##STR00072##
(140) tert-Butyl 4-aminopiperidine-1-carboxylate (Intermediate 31) (5.0 g, 25.0 mmol), was dissolved in DCM (50 mL) and triethylamine (4.17 mL, 30.0 mmol) was added. The mixture was cooled to 0° C. and then 6-bromohexanoyl chloride (Intermediate 32) (6.4 g, 30.0 mmol) was added. The resulting reaction mixture was stirred at 25° C. for 2 h and then the mixture was partitioned between H.sub.2O (100 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2×25 mL), the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give tert-butyl 4-[(6-bromohexanoyl)amino]piperidine-1-carboxylate (5.5 g, 78%) as a solid.
(141) LCMS (System 3, Method D): m/z 375/377 (M−H).sup.−, (ESI−ve), at 4.10 min, 202 nm.
(142) tert-Butyl 4-[(6-bromohexanoyl)amino]piperidine-1-carboxylate (5.0 g, 13.2 mmol) was dissolved in DMF (100 mL) and NaH suspension in mineral oil (60%, 638 mg, 15.9 mmol) was added portion wise at 0-5° C. The reaction mixture was then heated to 80° C. and stirred for 2 h. The reaction mixture was partitioned between H.sub.2O (100 mL) and EtOAc (100 mL) and the aqueous layer was further extracted with EtOAc (2×25 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo, and the crude product was purified by column chromatography (silica 60-120 mesh, 0% to 18% EtOAc in hexane) to give tert-butyl 4-(2-oxoazepan-1-yl)piperidine-1-carboxylate (1.0 g, 25%) as a gum.
(143) LCMS (System 3, Method D): m/z 297 (M+H).sup.+, 241 (M−56+H).sup.+ (ESI+ve), at 3.73 min, 202 nm.
(144) tert-Butyl 4-(2-oxoazepan-1-yl)piperidine-1-carboxylate (1.0 g, 3.37 mmol) was dissolved in HCl solution in 1,4-dioxane (4 M, 10 mL) and the resulting reaction mixture was stirred at 25° C. for 16 h. The solvents were removed in-vacuo and the residue was purified by trituration with diethyl ether (3×250 mL) to give 1-(piperidin-4-yl)azepan-2-one hydrochloride (Intermediate 33) (450 mg, 68%) as a gum.
(145) The data for Intermediate 33 are in Table 2.
(146) General Synthetic Procedures:
(147) Route A
Typical Procedure for the Preparation of Piperidines as Exemplified by the Preparation of Example 1-1, Ethyl 7-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
(148) ##STR00073##
(149) 4-(1H-Pyrazol-1-yl)piperidine (Intermediate 4) (150 mg, 0.9 mmol), ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Intermediate 3) (232 mg, 1.0 mmol), triethylamine (499 mg, 4.9 mmol) and zinc chloride solution (1 M in diethyl ether, 0.03 mL, 0.03 mmol) were dissolved in MeOH (5 mL) under nitrogen and stirred for 8 h at 50-60° C. After 8 h, NaBH.sub.3CN (184 mg, 2.9 mmol) was added portion wise at 0-10° C. and the resulting mixture was stirred at 50-60° C. until the reaction was complete. The reaction mixture was partitioned between H.sub.2O (20 mL) and EtOAc (30 mL), and the aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give the crude product, which was purified using purification method A to give ethyl 7-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate, Example 1-1 Isomer 1 (11 mg, 4%) as a gum and ethyl 7-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate, Isomer 2 (39 mg, 12%) as a gum.
(150) The data for Example 1-1 Isomer 1 are in Table 3.
(151) Route B
Typical Procedure for the Preparation of Pyridones from Methoxy Pyridines as Exemplified by the Preparation of Example 2-3, ethyl 7-[4-(2-oxo-1,2-dihydropyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
(152) ##STR00074##
(153) To a stirred solution of ethyl 7-[4-(2-methoxypyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Example 2-2) as a mixture of isomers (0.09 g, 2.31 mmol) in 1,4-dioxane (1.5 mL), were added H.sub.2O (1 mL) and conc. HCl (1 mL) and then the reaction mixture was stirred at 100° C. for 16 h. The solvents were removed in-vacuo, the residue was partitioned between H.sub.2O (2 mL) and EtOAc (10 mL), and the aqueous layer was further extracted with EtOAc (2×5 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo and the residue was purified using purification method H followed by purification method I to give ethyl 7-[4-(2-oxo-1,2-dihydropyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate, Example 2-3 Isomer 1 (2 mg, 2%) as a gum and ethyl 7-[4-(2-oxo-1,2-dihydropyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate, Example 2-3 Isomer 2 (20 mg, 23%) as a gum.
(154) The data for Example 2-3 Isomer 1 and Isomer 2 are in Table 3.
(155) Route C
Typical Procedure for the Preparation of Piperidine-4-Carboxamides as Exemplified by the Preparation of Example 7-1, ethyl 7-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
(156) ##STR00075##
(157) Ethyl piperidine-4-carboxylate (Intermediate 34) (1.0 g, 6.36 mmol), ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (Intermediate 3) (1.30 g, 6.36 mmol), triethylamine (2.7 mL, 19.1 mmol) and ZnCl.sub.2 (86 mg, 0.63 mmol) were dissolved in MeOH (20 mL) and the mixture was stirred at 70° C. for 8 h. The reaction mixture was then cooled to 0° C. and NaBH.sub.3CN (1.20 g, 19.1 mmol) was added portion wise. The resulting mixture was stirred at 70° C. for 150 h and then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (150 mL) and EtOAc (120 mL) and the aqueous layer was further extracted with EtOAc (2×120 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo, and the residue was purified by column chromatography (normal phase neutral activated alumina, 20% to 80% EtOAc in hexane) to give ethyl 7-[4-(ethoxycarbonyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (800 mg, 36%) as a gum.
(158) LCMS (System 3, Method D): m/z 341 (M−14+H).sup.+, (ESI+ve), at 2.87 min, 202 nm.
(159) 1-Methylcyclobutan-1-amine hydrochloride (Intermediate 35) (102 mg, 0.85 mmol) was dissolved in toluene (10 mL), triethylamine (0.3 mL, 1.69 mmol) was added and the mixture was cooled to −10° C. Trimethylaluminium solution in toluene (2 M, 0.8 mL, 1.69 mmol) was added and the reaction mixture was stirred at −10° C. for 20 min. Ethyl 7-[4-(ethoxycarbonyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (200 mg, 0.56 mmol) was then added at −10° C. and the resulting mixture was stirred at 80° C. for 18 h. The solvents were removed in-vacuo, and the residue was partitioned between H.sub.2O (80 mL) and DCM (60 mL). The aqueous layer was further extracted with DCM (2×60 mL) and the combined organic layers were dried (Na.sub.2SO.sub.4), and the solvent was removed in-vacuo. The residue (230 mg) was purified using purification method AH followed by purification method Al to give ethyl 7-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate, Example 7-1 Isomer 1 (6 mg, 3%) as a gum and ethyl 7-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate, Example 7-1 Isomer 2 (23 mg, 10%) as a gum.
(160) The data for Example 7-1 Isomer 1 and Isomer 2 are in Table 3.
(161) TABLE-US-00004 TABLE 2 Starting Materials and Intermediates Table 2 Intermediate Synthetic Intermediates Number Name Route Used Data 1 tert-Butyl 7-oxo-3-oxa-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 280761-97-9 carboxylate 2 Ethyl chloroformate — — Commercially available, CAS: 541-41-3 3 Ethyl 7-oxo-3-oxa-9- 1 1 and 2 LCMS (System 2, Method A): m/z azabicyclo[3.3.1]nonane-9- 214 (M + H).sup.+ (ESI + ve), carboxylate at 1.53 min, 202 nm 4 4-(1H-Pyrazol-1-yl)piperidine — — Commercially available, CAS: 762240-09-5 5 4-(4-Chloro-1H-pyrazol-1- — — Commercially available, yl)piperidine CAS: 1251305-58-4 6 4-(4-methyl-1H-pyrazol-1- — — Commercially available, yl)piperidine CAS: 1211520-55-6 7 tert-Butyl 4-(4,4,5,5-tetramethyl- — — Commercially available, 1,3,2-dioxaborolan-2-yl)-3,6- CAS: 286961-14-6 dihydropyridine-1(2H)-carboxylate 8 2-Iodo-6-methoxypyridine — — Commercially available, CAS: 182275-70-3 9 2-Methoxy-6-(piperidin-4-yl)pyridine 2 7 and 8 LCMS (System 3, Method D): m/z hydrochloride 193 (M + H).sup.+ (ESI + ve), at 2.23 min, 202 nm See WO2015118342 10 3-Iodo-2-methoxypyridine — — Commercially available, CAS: 112197-15-6 11 2-Methoxy-3-(piperidin-4-yl)pyridine 2 7 and 10 LCMS (System 2, Method A): m/z hydrochloride 193 (M + H).sup.+ (ESI + ve), at 1.42 min, 273 nm See WO2015118342 12 4-(Pyridin-2-yl)piperidine-4- — — Commercially available, carbonitrile CAS: 767263-33-2 13 [(2R)-4,4-Difluoro-1-(piperidin-4- — — See WO2017021728 yl)pyrrolidin-2-yl]methanol 14 6-Azaspiro[2.5]octane — — Commercially available, CAS: 872-64-0 15 2,8-Diazaspiro[4.5]decan-3-one — — Commercially available, CAS: 561314-57-6 16 1-Oxa-3,8-diazaspiro[4.5]decan-2- — — Commercially available, one CAS: 5052-95-9 17 4-Ethyl-1-oxa-3,8- — — See WO2016147011 diazaspiro[4.5]decan-2-one 18 Spiro[indole-3,4′-piperidin]-2(1H)-one — — Commercially available, CAS: 252882-61-4 19 tert-Butyl 4-oxopiperidine-1- — — Commercially available, carboxylate CAS: 79099-07-3 20 2-Methylpropan-1-amine — — Commercially available, CAS: 78-81-9 21 N-(2-Methylpropyl)-N-(piperidin-4- 3 19 and 20 LCMS (System 1, Method B): m/z yl)acetamide hydrochloride 199 (M + H).sup.+ (ESI + ve), at 4.09 min, 220 nm 22 2,2-Dimethylpropan-1-amine — — Commercially available, CAS: 5813-64-9 23 N-(2,2-Dimethylpropyl)-N-(piperidin- 4 19 and 22 LCMS (System 3, Method D): m/z 4-yl)acetamide trifluoroacetate 213 (M + H).sup.+, (ESI + ve), at 2.24 min, 202 nm 24 1-(1-Methylcyclopropyl)methanamine — — Commercially available, CAS: 98137-40-7 25 N-[(1-methylcyclopropyl)methyl]-N- 4 19 and 24 LCMS (System 3, Method D): m/z (piperidin-4-yl)acetamide 211 (M + H).sup.+, (ESI + ve), trifluoroacetate at 2.00 min, 202 nm 26 1-(1-Methylcyclobutyl)methanamine — — Commercially available, CAS: 933722-69-1 27 N-[(1-methylcyclobutyl)methyl]-N- 4 19 and 26 LCMS (System 3, Method D): m/z (piperidin-4-yl)acetamide 225 (M + H).sup.+, (ESI + ve), trifluoroacetate at 2.24 min, 202 nm 28 1-Phenylmethanamine — — Commercially available, CAS: 100-46-9 29 N-Benzyl-N-(piperidin-4-yl)acetamide 3 19 and 28 LCMS (System 3, Method D): m/z hydrochloride 233 (M + H).sup.+ (ESI + ve), at 1.99 min, 202 nm 30 [1,4′-bipiperidin]-2-one — — Commercially available, CAS: 159874-26-7 31 tert-Butyl 4-aminopiperidine-1- — — Commercially available, carboxylate CAS: 87120-72-7 32 6-Bromohexanoyl chloride — — Commercially available, CAS: 22809-37-6 33 1-(Piperidin-4-yl)azepan-2-one 5 31 and 32 LCMS (System 3, Method D): m/z hydrochloride 197 (M + H).sup.+, 393 (2M + H).sup.+, (ESI + ve), at 1.55 min, 202 nm 34 Ethyl piperidine-4-carboxylate — — Commercially available, CAS: 1126-09-6 35 1-Methylcyclobutan-1-amine — — Commercially available, hydrochloride CAS: 174886-05-6 36 1-Cyclobutylmethanamine — — Commercially available, CAS: 4415-83-2 37 Azepane — — Commercially available, CAS: 111-49-9 38 Methyl chloroformate — — Commercially available, CAS: 79-22-1 39 Methyl 7-oxo-3-oxa-9- 1 1 and 38 LCMS (System 3, Method D): m/z azabicyclo[3.3.1]nonane-9- 200 (M + H).sup.+ (ESI + ve), carboxylate at 1.68 min, 202 nm
(162) TABLE-US-00005 TABLE 3 NMR and LCMS properties and the methods used to prepare and purify compounds represented by Examples 1-8-2 Synthetic LCMS Method and Analysis Ex. Intermediates Purification System and No. Name Used Method .sup.1H NMR Method LCMS data 1-1 Isomer 1: Ethyl 7-[4-(1H- A A .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 349 (M + H).sup.+ pyrazol-1-yl)piperidin-1-yl]- 3 and 4 ppm 1.24-1.32 (m, 3 H), 1.62-1.77 (m, 2 H), D (ESI.sup.+), at 3.28 3-oxa-9- 1.94-2.07 (m, 2 H), 2.07-2.18 (m, 2 H), 2.23- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.39 (m, 3 H), 2.39-2.52 (m, 2 H), 3.05-3.16 carboxylate (m, 2 H), 3.48-3.57 (m, 2 H), 3.57-3.68 (m, 2 H), 4.10-4.21 (m, 3 H), 4.21-4.34 (m, 2 H), 6.21-6.42 (m, 1 H), 7.42-7.57 (m, 1 H), 7.63- 7.79 (m, 1 H) 1-2 Isomer 1: Ethyl 7-[4-(4-chloro- A B .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 383, 385 1H-pyrazol-1-yl)piperidin-1- 3 and 5 ppm 1.22-1.33 (m, 3 H), 1.61-1.76 (m, 2 H), D (M + H).sup.+ (ESI.sup.+), yl]-3-oxa-9- 1.93-2.05 (m, 2 H), 2.05-2.13 (m, 2 H), 2.23- at 3.31 min, 202 azabicyclo[3.3.1]nonane-9- 2.37 (m, 3 H), 2.37-2.48 (m, 2 H), 3.03-3.16 nm carboxylate (m, 2 H), 3.47-3.56 (m, 2 H), 3.57-3.66 (m, 2 H), 4.07-4.20 (m, 3 H), 4.20-4.30 (m, 2 H), 7.43 (s, 1 H), 7.77 (s, 1 H) 1-2 Isomer 2: Ethyl 7-[4-(4-chloro- A B .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 383, 385 1H-pyrazol-1-yl)piperidin-1- 3 and 5 ppm 1.20-1.37 (m, 3 H), 1.65-1.81 (m, 2 H), D (M + H).sup.+ (ESI.sup.+), yl]-3-oxa-9- 1.90-2.21 (m, 6 H), 2.25-2.42 (m, 2 H), 3.07- at 3.32 min, 202 azabicyclo[3.3.1]nonane-9- 3.24 (m, 2 H), 3.61-3.78 (m, 3 H), 3.81-3.97 nm carboxylate (m, 2 H), 4.06-4.30 (m, 5 H), 7.43 (s, 1 H), 7.78 (s, 1 H) 1-3 Isomer 1: Ethyl 7-[4-(4- A C then D .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 363 (M + H).sup.+ methyl-1H-pyrazol-1- 3 and 6 ppm 1.27 (t, J = 7.1 Hz, 3 H), 1.61-1.79 (m, C (ESI.sup.+), at 3.04 yl)piperidin-1-yl]-3-oxa-9- 2 H), 1.87-2.17 (m, 6 H), 2.23-2.37 (m, 3 H), min, 202 nm azabicyclo[3.3.1]nonane-9- 2.37-2.51 (m, 2 H), 3.02-3.17 (m, 2 H), 3.47- carboxylate 3.72 (m, 5 H), 4.02-4.11 (m, 1 H), 4.15 (q, J = 7.1Hz, 2 H), 4.20-4.31 (m, 2 H), 7.26 (s, 1 H), 7.44 (s, 1 H) 1-3 Isomer 2: Ethyl 7-[4-(4- A C then D .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 363 (M + H).sup.+ methyl-1H-pyrazol-1- 3 and 6 ppm 1.21-1.33 (m, 3 H), 1.65-1.78 (m, 2 H), C (ESI.sup.+), at 2.98 yl)piperidin-1-yl]-3-oxa-9- 1.88-2.01 (m, 2 H), 2.02-2.16 (m, 7 H), 2.25- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.40 (m, 2 H), 3.06-3.21 (m, 2 H), 3.61-3.76 carboxylate (m, 3 H), 3.80-3.92 (m, 2 H), 4.02-4.23 (m, 5 H), 7.26 (s, 1 H), 7.44 (s, 1 H) 2-1 Isomer 1: Ethyl 7-[4-(6- A C then E .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 390 (M + H).sup.+ methoxypyridin-2- 3 and 9 ppm 1.21-1.37 (m, 3 H), 1.67-1.80 (m, 2 H), D (ESI.sup.+), at 3.62 yl)piperidin-1-yl]-3-oxa-9- 1.83-1.98 (m, 4 H), 2.07-2.19 (m, 2 H), 2.20- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.35 (m, 2 H), 2.54-2.71 (m, 1 H), 3.09-3.21 carboxylate (m, 2 H), 3.59-3.75 (m, 3 H), 3.79-3.95 (m, 5 H), 4.08-4.24 (m, 4 H), 6.50-6.63 (m, 1 H), 6.73-6.86 (m, 1 H), 7.47-7.61 (m, 1 H) 2-1 Isomer 2: Ethyl 7-[4-(6- A C then E .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 390 (M + H).sup.+ methoxypyridin-2- 3 and 9 ppm 1.23-1.35 (m, 3 H), 1.66-1.79 (m, 2 H), D (ESI.sup.+), at 3.52 yl)piperidin-1-yl]-3-oxa-9- 1.84-1.99 (m, 4 H), 2.22-2.47 (m, 5 H), 2.56- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.69 (m, 1 H), 3.04-3.18 (m, 2 H), 3.49-3.57 carboxylate (m, 2 H), 3.58-3.68 (m, 2 H), 3.89 (s, 3 H), 4.11-4.21 (m, 2 H), 4.22-4.32 (m, 2 H), 6.52- 6.63 (m, 1 H), 6.75-6.83 (m, 1 H), 7.50-7.60 (m, 1 H) 2-2 Isomer 1: Ethyl 7-[4-(2- A F then G .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 390 (M + H).sup.+ methoxypyridin-3- 3 and 11 ppm 1.21-1.39 (m, 3 H), 1.64-1.79 (m, 4 H), D (ESI.sup.+), at 3.31 yl)piperidin-1-yl]-3-oxa-9- 1.80-1.92 (m, 2 H), 2.20-2.48 (m, 5 H), 2.77- min, 272 nm azabicyclo[3.3.1]nonane-9- 2.91 (m, 1 H), 3.03-3.16 (m, 2 H), 3.47-3.73 carboxylate (m, 4 H), 3.92 (s, 3 H), 4.11-4.21 (m, 2 H), 4.22-4.32 (m, 2 H), 6.82-6.99 (m, 1 H), 7.49- 7.59 (m, 1 H), 7.89-8.01 (m, 1 H) 2-2 Isomer 2: Ethyl 7-[4-(2- A F then G .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 390 (M + H).sup.+ methoxypyridin-3- 3 and 11 ppm 1.24-1.34 (m, 3 H), 1.63-1.80 (m, 4 H), D (ESI.sup.+), at 3.23 yl)piperidin-1-yl]-3-oxa-9- 1.82-1.93 (m, 2 H), 2.08-2.20 (m, 2 H), 2.23- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.36 (m, 2 H), 2.78-2.91 (m, 1 H), 3.12-3.24 carboxylate (m, 2 H), 3.62-3.76 (m, 3 H), 3.81-3.99 (m, 5 H), 4.09-4.23 (m, 4 H), 6.85-6.97 (m, 1 H), 7.49-7.60 (m, 1 H), 7.92-8.01 (m, 1 H) 2-3 Isomer 1: Ethyl 7-[4-(2-oxo- B H then I .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 376 (M + H).sup.+ 1,2-dihydropyridin-3- Example ppm 1.22-1.40 (m, 3 H), 1.52-1.77 (m, 4 H), D (ESI.sup.+), at 2.27 yl)piperidin-1-yl]-3-oxa-9- 2-2 1.84-1.96 (m, 2 H), 2.38 (d, J = 11.7 Hz, 4 min, 202 nm azabicyclo[3.3.1]nonane-9- H), 2.74-2.87 (m, 1 H), 3.03-3.16 (m, 2 H), carboxylate 3.47-3.73 (m, 5 H), 4.11-4.21 (m, 2 H), 4.22- 4.32 (m, 2 H), 6.35-6.45 (m, 1 H), 7.26-7.34 (m, 1 H), 7.40-7.48 (m, 1 H) 2-3 Isomer 2: Ethyl 7-[4-(2-oxo- B H then I .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 376 (M + H).sup.+ 1,2-dihydropyridin-3- Example ppm 1.22-1.35 (m, 3 H), 1.51-1.65 (m, 2 H), D (ESI.sup.+), at 2.20 yl)piperidin-1-yl]-3-oxa-9- 2-2 1.68-1.81 (m, 2 H), 1.85-1.97 (m, 2 H), 2.08- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.19 (m, 2 H), 2.23-2.36 (m, 2 H), 2.75-2.89 carboxylate (m, 1 H), 3.11-3.23 (m, 2 H), 3.63-3.74 (m, 3 H), 3.81-3.95 (m, 2 H), 4.09-4.24 (m, 4 H), 6.34-6.43 (m, 1 H), 7.23-7.32 (m, 1 H), 7.39- 7.48 (m, 1 H) 3-1 Isomer 1: Ethyl 7-[4-cyano-4- A J then K .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 385 (M + H).sup.+ (pyridin-2-yl)piperidin-1-yl]- 3 and 12 ppm 1.28 (t, J = 7.3 Hz, 3 H), 1.67-1.85 (m, D (ESI.sup.+), at 3.33 3-oxa-9- 2 H), 2.13-2.45 (m, 7 H), 2.63-2.82 (m, 2 H), min, 202 nm azabicyclo[3.3.1]nonane-9- 3.05-3.20 (m, 2 H), 3.50-3.58 (m, 2 H), 3.59- carboxylate 3.74 (m, 2 H), 4.17 (q, J = 7.3 Hz, 2 H), 4.23-4.37 (m, 2 H), 7.28-7.48 (m, 1 H), 7.57- 7.71 (m, 1 H), 7.82-7.95 (m, 1 H), 8.51-8.67 (m, 1 H) 3-1 Isomer 2: Ethyl 7-[4-cyano-4- A J then K .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 385 (M + H).sup.+ (pyridin-2-yl)piperidin-1-yl]- 3 and 12 ppm 1.22-1.46 (m, 3 H), 1.67-1.86 (m, 2 H), D (ESI.sup.+), at 3.33 3-oxa-9- 2.06-2.38 (m, 6 H), 2.49-2.72 (m, 2 H), 3.11- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.25 (m, 2 H), 3.63-4.00 (m, 5 H), 4.09-4.31 carboxylate (m, 4 H), 7.26-7.47 (m, 1 H), 7.56-7.72 (m, 1 H), 7.81-7.94 (m, 1 H), 8.52-8.67 (m, 1 H) 4-1 Isomer 1: Ethyl 7-{4-[(2R)- A L then M .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 418 (M + H).sup.+ 4,4-difluoro-2- 3 and 13 ppm 1.20-1.38 (m, 3 H), 1.45-1.57 (m, 2 H), D (ESI.sup.+), at 3.01 (hydroxymethyl)pyrrolidin-1- 1.61-1.72 (m, 2 H), 1.77-1.87 (m, 2 H), 2.10- min, 202 nm yl]piperidin-1-yl}-3-oxa-9- 2.41 (m, 7 H), 2.64-2.77 (m, 1 H), 2.94-3.11 azabicyclo[3.3.1]nonane-9- (m, 3 H), 3.14-3.28 (m, 2 H), 3.45-3.68 (m, 6 carboxylate H), 4.10-4.19 (m, 2 H), 4.19-4.29 (m, 2 H) 4-1 Isomer 2: Ethyl 7-{4-[(2R)- A L then M .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 418 (M + H).sup.+ 4,4-difluoro-2- 3 and 13 ppm 1.20-1.36 (m, 3 H), 1.42-1.60 (m, 2 H), D (ESI.sup.+), at 2.93 (hydroxymethyl)pyrrolidin-1- 1.63-1.75 (m, 2 H), 1.77-1.88 (m, 2 H), 2.03- min, 202 nm yl]piperidin-1-yl}-3-oxa-9- 2.25 (m, 5 H), 2.26-2.43 (m, 1 H), 2.62-2.78 azabicyclo[3.3.1]nonane-9- (m, 1 H), 3.01-3.14 (m, 3 H), 3.15-3.26 (m, 2 carboxylate H), 3.44-3.73 (m, 5 H), 3.78-3.92 (m, 2 H), 4.05-4.23 (m, 4 H) 5-1 Isomer 1: Ethyl 7-(6- A N .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 309 (M + H).sup.+ azaspiro[2.5]oct-6-yl)-3-oxa- 3 and 14 ppm 0.21-0.38 (m, 4 H), 1.21-1.33 (m, 3 H), D (ESI.sup.+), at 3.46 9-azabicyclo[3.3.1]nonane-9- 1.37-1.55 (m, 4 H), 1.66-1.83 (m, 2 H), 2.03- min, 202 nm carboxylate 2.18 (m, 2 H), 2.53-2.74 (m, 4 H), 3.60-3.75 (m, 3 H), 3.79-3.93 (m, 2 H), 4.06-4.22 (m, 4 H) 5-1 Isomer 2: Ethyl 7-(6- A N .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 309 (M + H).sup.+ azaspiro[2.5]oct-6-yl)-3-oxa- 3 and 14 ppm 0.24-0.36 (m, 4 H), 1.20-1.33 (m, 3 H), D (ESI.sup.+), at 3.61 9-azabicyclo[3.3.1]nonane-9- 1.37-1.54 (m, 4 H), 1.66-1.79 (m, 2 H), 2.20- min, 202 nm carboxylate 2.40 (m, 3 H), 2.58-2.76 (m, 4 H), 3.47-3.55 (m, 2 H), 3.57-3.69 (m, 2 H), 4.10-4.19 (m, 2 H), 4.20-4.32 (m, 2 H) 5-2 Isomer 1: Ethyl 7-(3-oxo-2,8- A O .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 352 (M + H).sup.+ diazaspiro[4.5]dec-8-yl)-3- 3 and 15 ppm 1.20-1.36 (m, 4 H), 1.60-1.76 (m, 6 H), D (ESI.sup.+), at 2.56 oxa-9- 2.18-2.24 (m, 2 H), 2.27-2.39 (m, 2 H), 2.50- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.72 (m, 4 H), 3.16-3.22 (m, 2 H), 3.47-3.55 carboxylate (m, 2 H), 3.56-3.67 (m, 2 H), 4.09-4.19 (m, 2 H), 4.20-4.31 (m, 2 H) 5-2 Isomer 2: Ethyl 7-(3-oxo-2,8- A O .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 1 m/z 352 (M + H).sup.+ diazaspiro[4.5]dec-8-yl)-3- 3 and 15 ppm 1.17-1.36 (m, 4 H), 1.56-1.79 (m, 5 H), D (ESI.sup.+), at 2.56 oxa-9- 2.01-2.15 (m, 2 H), 2.18-2.27 (m, 2 H), 2.42- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.73 (m, 4 H), 3.11-3.25 (m, 2 H), 3.51-3.75 carboxylate (m, 3 H), 3.77-3.94 (m, 2 H), 4.02-4.25 (m, 4 H) 5-3 Isomer 1: Ethyl 7-(2-oxo-1- A P then Q .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 354 (M + H).sup.+ oxa-3,8-diazaspiro[4.5]dec-8- 3 and 16 ppm 1.22-1.33 (m, 3 H), 1.62-1.74 (m, 2 H), D (ESI.sup.+), at 2.10 yl)-3-oxa-9- 1.77-1.88 (m, 2 H), 1.92-2.03 (m, 2 H), 2.23- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.37 (m, 3 H), 2.65-2.77 (m, 4 H), 3.34-3.38 carboxylate (m, 2 H), 3.47-3.56 (m, 2 H), 3.57-3.67 (m, 2 H), 4.10-4.20 (m, 2 H), 4.21-4.31 (m, 2 H) 5-3 Isomer 2: Ethyl 7-(2-oxo-1- A P then Q .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 354 (M + H).sup.+ oxa-3,8-diazaspiro[4.5]dec-8- 3 and 6 ppm 1.22-1.33 (m, 3 H), 1.63-1.76 (m, 2 H), D (ESI.sup.+), at 2.21 yl)-3-oxa-9- 1.77-1.88 (m, 2 H), 1.91-2.02 (m, 2 H), 2.06- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.15 (m, 2 H), 2.56-2.81 (m, 4 H), 3.34-3.39 carboxylate (m, 2 H), 3.62-3.73 (m, 3 H), 3.79-3.92 (m, 2 H), 4.08-4.21 (m, 4 H) 5-4 Isomer 1a: Ethyl 7-(4-ethyl-2- A R then S .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 382 (M + H).sup.+ oxo-1-oxa-3,8- 3 and 17 ppm 0.93-1.03 (m, 3 H), 1.21-1.35 (m, 3 H), D (ESI.sup.+), at 2.49 diazaspiro[4.5]dec-8-yl)-3- 1.37-1.51 (m, 1 H), 1.52-1.96 (m, 7 H), 2.17- min, 202 nm oxa-9- 2.37 (m, 3 H), 2.49-2.67 (m, 2 H), 2.79-2.94 azabicyclo[3.3.1]nonane-9- (m, 2 H), 3.33-3.40 (m, 1 H), 3.47-3.55 (m, 2 carboxylate H), 3.56-3.68 (m, 2 H), 4.09-4.19 (m, 2 H), 4.20-4.31 (m, 2 H) 5-4 Isomer 1b: Ethyl 7-(4-ethyl-2- A R then S .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 382 (M + H).sup.+ oxo-1-oxa-3,8- 3 and 17 ppm 0.94-1.05(m, 3 H), 1.20-1.36 (m, 3 H), D (ESI.sup.+), at 2.50 diazaspiro[4.5]dec-8-yl)-3- 1.39-1.51 (m, 1 H), 1.52-1.96 (m, 7 H), 2.19- min, 202 nm oxa-9-azabicyclo[3.3.1] 2.41 (m, 3 H), 2.49-2.68 (m, 2 H), 2.78-2.94 nonane-9-carboxylate (m, 2 H), 3.34-3.41 (m, 1 H), 3.46-3.56 (m, 2 H), 3.56-3.68 (m, 2 H), 4.10-4.19 (m, 2 H), 4.20-4.31 (m, 2 H) 5-4 Isomer 2a: Ethyl 7-(4-ethyl-2- A R then S .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 382 (M + H).sup.+ oxo-1-oxa-3,8- 3 and 17 ppm 0.92-1.06 (m, 3 H), 1.19-1.35 (m, 3 H), D (ESI.sup.+), at 2.48 diazaspiro[4.5]dec-8-yl)-3- 1.38-1.51 (m, 1 H), 1.52-1.98 (m, 7 H), 2.03- min, 202 nm oxa-9-azabicyclo[3.3.1] 2.19 (m, 2 H), 2.40-2.62 (m, 2 H), 2.83-3.03 nonane-9-carboxylate (m, 2 H), 3.33-3.43 (m, 1 H), 3.59-3.76 (m, 3 H), 3.80-3.94 (m, 2 H), 4.06-4.26 (m, 4 H) 5-4 Isomer 2b: Ethyl 7-(4-ethyl-2- A R then S .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 382 (M + H).sup.+ oxo-1-oxa-3,8- 3 and 17 ppm 0.91-1.06 (m, 3 H), 1.21-1.35 (m, 3 H), D (ESI.sup.+), at 2.49 diazaspiro[4.5]dec-8-yl)-3- 1.39-1.52 (m, 1 H), 1.53-1.98 (m, 7 H), 2.03- min, 202 nm oxa-9-azabicyclo[3.3.1] 2.18 (m, 2 H), 2.42-2.61 (m, 2 H), 2.85-2.99 nonane-9-carboxylate (m, 2 H), 3.33-3.41 (m, 1 H), 3.60-3.75 (m, 3 H), 3.79-3.94 (m, 2 H), 4.05-4.23 (m, 4 H) 5-5 Isomer 1: Ethyl 7-(2-oxo-1,2- A T .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 400 (M + H).sup.+ dihydro-1′H-spiro[indole-3,4′- 3 and 18 ppm 1.20-1.38 (m, 3 H), 1.69-2.02 (m, 6 H), D (ESI.sup.+), at 3.01 piperidin]-1′-yl)-3-oxa-9- 2.32-2.53 (m, 2 H), 2.83-3.00 (m, 2 H), 3.06- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.25 (m, 2 H), 3.46-3.78 (m, 5 H), 4.11-4.23 carboxylate (m, 2 H), 4.24-4.38 (m, 2 H), 6.84-6.96 (m, 1 H), 6.97-7.08 (m, 1 H), 7.16-7.27 (m, 1 H), 7.33-7.44 (m, 1 H) 5-5 Isomer 2: Ethyl 7-(2-oxo-1,2- A T .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 400 (M + H).sup.+ dihydro-1′H-spiro[indole-3,4′- 3 and 18 ppm 1.22-1.35 (m, 3 H), 1.70-2.01 (m, 6 H), D (ESI.sup.+), at 3.01 piperidin]-1′-yl)-3-oxa-9- 2.13-2.24 (m, 2 H), 2.80-2.96 (m, 2 H), 3.07- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.18 (m, 2 H), 3.66-3.75 (m, 2 H), 3.77-3.96 carboxylate (m, 3 H), 4.07-4.23 (m, 4 H), 6.86-6.96 (m, 1 H), 6.98-7.08 (m, 1 H), 7.14-7.24 (m, 1 H), 7.34-7.45 (m, 1 H) 6-1 Isomer 1: A U .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 396 (M + H).sup.+ Ethyl 7-{4-[acetyl(2- 3 and 21 ppm 0.79-1.04 (m, 6 H), 1.22-1.37 (m, 3 H), D (ESI.sup.+), at 2.99 methylpropyl)amino]piperidin- 1.61-1.86 (m, 5 H), 1.87-2.34 (m, 9 H), 3.01- min, 220 nm 1-yl}-3-oxa-9- 3.23 (m, 4 H), 3.52-4.02 (m, 6 H), 4.05-4.24 azabicyclo[3.3.1]nonane-9- (m, 4 H) carboxylate 6-1 Isomer 2: A U .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 396 (M + H).sup.+ Ethyl 7-{4-[acetyl(2- 3 and 21 ppm 0.79-1.03 (m, 6 H), 1.26 (t, J = 7.0 Hz, D (ESI.sup.+), at 3.02 methylpropyl)amino]piperidin- 3 H), 1.59-2.47 (m, 14 H), 2.98-3.20 (m, 4 min, 220 nm 1-yl}-3-oxa-9-azabicyclo H), 3.44-3.95 (m, 6 H), 4.15 (q, J = 6.9 Hz, 2 [3.3.1]nonane-9-carboxylate H), 4.20-4.31 (m, 2 H) 6-2 Isomer 1: Ethyl 7-{4-[acetyl(2,2- A V then W .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 410 (M + H).sup.+ dimethylpropyl)amino]piperidin- 3 and 23 ppm 0.88-1.08 (m, 9 H), 1.20-1.35 (m, 3 H), D (ESI.sup.+), at 3.33 1-yl}-3-oxa-9- 1.60-1.94 (m, 5 H), 1.99-2.31 (m, 7 H), 2.59- min, 220 nm azabicyclo[3.3.1]nonane-9- 2.78 (m, 1 H), 2.89-3.02 (m, 1 H), 3.05-3.16 carboxylate (m, 2 H), 3.17-3.23 (m, 2 H), 3.53-3.73 (m, 3 H), 3.76-3.91 (m, 2 H), 4.05-4.23 (m, 4 H) 6-3 Isomer 1: Ethyl 7-(4- A X then Y .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 408 (M + H).sup.+ {acetyl[(1-methylcyclopropyl) 3 and 25 ppm 0.29-0.63 (m, 4 H), 0.94-1.16 (m, 3 H), D (ESI.sup.+), at 3.10 methyl]amino}piperidin- 1.19-1.45 (m, 7 H), 1.85 (br. s., 3 H), 2.08- min, 202 nm 1-yl)-3-oxa-9- 2.25 (m, 3 H), 2.27-2.85 (m, 6 H), 3.12-3.26 azabicyclo[3.3.1]nonane-9- (m, 1 H), 3.37-3.45 (m, 1 H), 3.50-3.79 (m, 5 carboxylate H), 4.11-4.21 (m, 2 H), 4.23-4.35 (m, 2 H) 6-3 Isomer 2: Ethyl 7-(4- A X then Y .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 408 (M + H).sup.+ {acetyl[(1-methylcyclopropyl) 3 and 25 ppm 0.26-0.59 (m, 4 H), 0.93-1.13 (m, 3 H), D (ESI.sup.+), at 3.06 methyl]amino}piperidin- 1.20-1.38 (m, 3 H), 1.62-1.80 (m, 4 H), 1.89 min, 202 nm 1-yl)-3-oxa-9- (m, 1 H), 1.99-2.37 (m, 8 H), 3.06-3.21 (m, 2 azabicyclo[3.3.1]nonane-9- H), 3.22-3.29 (m, 2 H), 3.59-3.77 (m, 4 H), carboxylate 3.78-3.93 (m, 2 H), 4.06-4.24 (m, 4 H) 6-4 Isomer 1: Ethyl 7-(4- A Z then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 422 (M + H).sup.+ {acetyl[(1-methylcyclobutyl) 3 and 27 AA ppm 1.08-1.35 (m, 7 H), 1.54-1.84 (m, 8 H), D (ESI.sup.+), at 3.56 methyl]amino}piperidin- 1.97-2.20 (m, 5 H), 2.21-2.51 (m, 6 H), 3.01- min, 215 nm 1-yl)-3-oxa-9- 3.28 (m, 5 H), 3.47-3.55 (m, 2 H), 3.56-3.70 azabicyclo[3.3.1]nonane-9- (m, 2 H), 4.08-4.18 (m, 2 H), 4.20-4.29 (m, 2 carboxylate H) 6-4 Isomer 2: Ethyl 7-(4- A Z then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 422 (M + H).sup.+ {acetyl[(1-methylcyclobutyl) 3 and 27 AA ppm 1.05-1.36 (m, 7 H), 1.56-1.96 (m, 9 H), D (ESI.sup.+), at 3.54 methyl]amino}piperidin- 1.97-2.30 (m, 9 H), 2.31-2.49 (m, 1 H), 3.04- min, 215 nm 1-yl)-3-oxa-9- 3.17 (m, 2 H), 3.20-3.27 (m, 1 H), 3.34-3.45 azabicyclo[3.3.1]nonane-9- (m, 1 H), 3.59-3.75 (m, 3 H), 3.78-3.91 (m, 2 carboxylate H), 4.07-4.24 (m, 4 H) 6-5 Isomer 1: Ethyl 7-{4- A AB then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 430 (M + H).sup.+ [acetyl(benzyl)amino]piperidin- 3 and 29 AC ppm 1.09-1.38 (m, 3 H), 1.58-1.83 (m, 6 H), D (ESI.sup.+), at 3.05 1-yl}-3-oxa-9- 1.97-2.42 (m, 7 H), 2.97-3.16 (m, 2 H), 3.58- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.74 (m, 3 H), 3.77-3.91 (m, 2 H), 4.03-4.22 carboxylate (m, 4 H), 4.37-4.53 (m, 1 H), 4.55-4.67 (m, 2 H), 7.11-7.45 (m, 5 H) 6-5 Isomer 2: Ethyl 7-{4- A AB then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 430 (M + H).sup.+ [acetyl(benzyl)amino]piperidin- 3 and 29 AC ppm 1.16-1.35 (m, 3 H), 1.54-1.82 (m, 5 H), D (ESI.sup.+), at 3.06 1-yl}-3-oxa-9- 1.97-2.39 (m, 9 H), 2.87-3.04 (m, 2 H), 3.43- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.65 (m, 4 H), 3.73-4.51 (m, 5 H), 4.52-4.68 carboxylate (m, 2 H), 7.13-7.41 (m, 5 H) 6-6 Isomer 1: Ethyl 7-(2-oxo-1,4′- A AD then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 380 (M + H).sup.+ bipiperidin-1′-yl)-3-oxa-9- 3 and 30 AE ppm 1.26 (t, J = 7.0 Hz, 3 H), 1.57-1.71 (m, D (ESI.sup.+), at 3.06 azabicyclo[3.3.1]nonane-9- 4 H), 1.72-1.89 (m, 6 H), 2.18-2.45 (m, 7 H), min, 220 nm carboxylate 3.00-3.10 (m, 2 H), 3.23-3.29 (m, 2 H), 3.46- 3.55 (m, 2 H), 3.56-3.67 (m, 2 H), 4.15 (q, J = 7.0 Hz, 2 H), 4.20-4.30 (m, 2 H), 4.33- 4.45 (m, 1 H) 6-6 Isomer 2: Ethyl 7-(2-oxo-1,4′- A AD then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 380 (M + H).sup.+ bipiperidin-1′-yl)-3-oxa-9- 3 and 30 AE ppm 1.21-1.33 (m, 3 H), 1.57-1.86 (m, 10 D (ESI.sup.+), at 2.52 azabicyclo[3.3.1]nonane-9- H), 2.03-2.14 (m, 2 H), 2.19-2.31 (m, 2 H), min, 220 nm carboxylate 2.33-2.43 (m, 2 H), 3.08-3.19 (m, 2 H), 3.23- 3.28 (m, 2 H), 3.57-3.73 (m, 3 H), 3.79-3.92 (m, 2 H), 4.08-4.21 (m, 4 H), 4.34-4.47 (m, 1 H) 6-7 Isomer 1: Ethyl 7-[4-(2- A AF then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 394 (M + H).sup.+ oxoazepan-1-yl)piperidin-1- 3 and 33 AG ppm 1.18-1.35 (m, 3 H), 1.51-1.85 (m, 11 D (ESI.sup.+), at 2.76 yl]-3-oxa-9- H), 2.01-2.42 (m, 4 H), 2.48-2.61 (m, 2 H), min, 202 nm azabicyclo[3.3.1]nonane-9- 2.98-3.18 (m, 2 H), 3.33-3.43 (m, 2 H), 3.46- carboxylate 3.73 (m, 4 H), 3.79-3.91 (m, 2 H), 4.06-4.29 (m, 4 H), 4.33-4.47 (m, 1 H) 6-7 Isomer 2: Ethyl 7-[4-(2- A AF then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 394 (M + H).sup.+ oxoazepan-1-yl)piperidin-1- 3 and 33 AG ppm 1.22-1.34 (m, 3 H), 1.53-1.82 (m, 12 D (ESI.sup.+), at 2.71 yl]-3-oxa-9- H), 2.01-2.14 (m, 2 H), 2.17-2.28 (m, 2 H), min, 202 nm azabicyclo[3.3.1]nonane-9- 2.46-2.61 (m, 2 H), 3.04-3.16 (m, 2 H), 3.34- carboxylate 3.42 (m, 2 H), 3.56-3.75 (m, 3 H), 3.78-3.92 (m, 2 H), 4.06-4.22 (m, 4 H), 4.33-4.47 (m, 1 H) 7-1 Isomer 1: Ethyl 7-{4-[(1- C AH then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z (M + H).sup.+ methylcyclobutyl)carbamoyl] 3, 34 and AI ppm 1.20-1.34 (m, 3 H), 1.41 (s, 3 H), 1.62- D (ESI.sup.+), at 2.43 piperidin-1-yl}-3-oxa-9- 35 2.03 (m, 11 H), 2.07-2.44 (m, 8 H), 2.98- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.11 (m, 2 H), 3.47-3.56 (m, 2 H), 3.57-3.67 carboxylate (m, 2 H), 4.10-4.19 (m, 2 H), 4.20-4.30 (m, 2 H) 7-1 Isomer 2: Ethyl 7-{4-[(1- C AH then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 394 (M + H).sup.+ methylcyclobutyl)carbamoyl] 3, 34 and AI ppm 1.18-1.34 (m, 3 H), 1.41 (s, 3 H), 1.62- D (ESI.sup.+), at 2.83 piperidin-1-yl}-3-oxa-9- 35 1.90 (m, 8 H), 1.93-2.34 (m, 9 H), 2.86-2.99 min, 202 nm azabicyclo[3.3.1]nonane-9- (m, 1 H), 3.01-3.14 (m, 2 H), 3.54-3.73 (m, 3 carboxylate H), 3.77-3.90 (m, 2 H), 4.05-4.25 (m, 4 H) 7-2 Isomer 1: Ethyl 7-{4-[(2- C AJ then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 382 (M + H).sup.+ methylpropyl)carbamoyl] 3, 34 and AK ppm 0.85-0.96 (m, 6 H), 1.22-1.33 (m, 3 H), D (ESI.sup.+), at 2.81 piperidin-1-yl}-3-oxa-9- 20 1.61-1.85 (m, 7 H), 2.12-2.38 (m, 6 H), 2.93- min, 202 nm azabicyclo[3.3.1]nonane-9- 3.08 (m, 4 H), 3.48-3.56 (m, 2 H), 3.57-3.67 carboxylate (m, 2 H), 4.10-4.19 (m, 2 H), 4.20-4.29 (m, 2 H) 7-3 Isomer 1: Ethyl 7-{4- C AL then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 394 (M + H).sup.+ [(cyclobutylmethyl)carbamoyl] 3, 34 and AM ppm 1.22-1.33 (m, 3 H), 1.60-1.81 (m, 8 H), D (ESI.sup.+), at 2.95 piperidin-1-yl}-3-oxa-9- 36 1.82-1.96 (m, 2 H), 1.97-2.09 (m, 2 H), 2.11- min, 202 nm azabicyclo[3.3.1]nonane-9- 2.36 (m, 6 H), 2.41-2.55 (m, 1 H), 2.92-3.05 carboxylate (m, 2 H), 3.13-3.23 (m, 2 H), 3.45-3.54 (m, 2 H), 3.55-3.66 (m, 2 H), 4.10-4.18 (m, 2 H), 4.19-4.28 (m, 2 H) 7-4 Isomer 1: Ethyl 7-[4-(azepan- C AN then .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 3 m/z 408 (M + H).sup.+ 1-ylcarbonyl)piperidin-1-yl]-3- 3, 34 and AO ppm 1.20-1.40 (m, 5 H), 1.51-1.87 (m, 13 D (ESI.sup.+), at 3.28 oxa-9- 37 H), 2.14-2.38 (m, 5 H), 2.55-2.69 (m, 1 H), min, 202 nm azabicyclo[3.3.1]nonane-9- 2.95-3.06 (m, 2 H), 3.46-3.66 (m, 7 H), 4.10- carboxylate 4.18 (m, 2 H), 4.19-4.31 (m, 2 H) 8-1 Isomer 1: Methyl 7-(4-(N-((1- A AP then .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.28- 3 m/z 408 (M + H).sup.+ methylcyclobutyl)methyl) 27 and AQ 4.17 (m, 2H), 3.71 (s, 3H), 3.67-3.45 (m, D (ESI.sup.+), at 3.18 acetamido)piperidin-1-yl)-3-oxa- 39 6H), 3.09-2.98 (m, 2H), 2.44-2.19 (m, 6H), min, 202 nm 9-azabicyclo[3.3.1]nonane-9- 2.17 (s, 1.5H), 2.12-2.02 (m, 3H), 2.01 (s, carboxylate 1.5H), 1.83-1.55 (m, 9H), 1.23 (s, 1.5H), 1.12 (s, 1.5H). 8-1 Isomer 2: Methyl 7-(4-(N-((1- A AP .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.15- 3 m/z 408 (M + H).sup.+ methylcyclobutyl)methyl) 27 and 4.07 (m, 2H), 3.89-3.78 (m, 2H), 3.70-3.58 D (ESI.sup.+), at 3.10 acetamido)piperidin-1-yl)-3-oxa- 39 (m, 4H), 3.29 (s, 1H), 3.24 (s, 1H), 3.14-3.06 min, 202 nm 9-azabicyclo[3.3.1]nonane-9- (m, 2H), 2.44-2.30 (m, 1H), 2.29-2.19 (m, carboxylate 1H), 2.17 (s, 2H), 2.16-2.02 (m, 6H), 2.01 (s, 2H), 1.96-1.83 (m, 1H), 1.83-1.55 (m, 9H), 1.23 (s, 1.5H), 1.12 (s, 1.5H). 8-2 Isomer 1: Methyl 7-(4-(N- A AR .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.42- 3 m/z 416 (M + H).sup.+ benzylacetamido)piperidin-1- 39 and 7.33 (m, 1H), 7.31-7.13 (m, 4H), 4.65-4.54 C (ESI.sup.+), at 2.79 yl)-3-oxa-9- 29 (m, 2H), 4.50-4.36 (m, 1H), 4.27-4.14 (m, min, 202 nm azabicyclo[3.3.1]nonane-9- 2H), 3.89-3.77 (m, 1H), 3.69 (s, 3H), 3.63- carboxylate 3.45 (m, 4H), 3.02-2.92 (m, 2H), 2.41-2.13 (m, 4H), 2.28 (s, 1.5H), 2.04 (s, 1.5H), 1.84- 1.54 (m, 6H). 8-2 Isomer 2: Methyl 7-(4-(N- A AR .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.40- 3 m/z 416 (M + H).sup.+ benzylacetamido)piperidin-1- 39 and 7.33 (m, 1H), 7.31-7.15 (m, 4H), 4.66-4.56 C (ESI.sup.+), at 2.79 yl)-3-oxa-9- 29 (m, 2H), 4.49-4.39 (m, 1H), 4.14-4.04 (m, min, 202 nm azabicyclo[3.3.1]nonane-9- 2H), 3.89-3.76 (m, 2H), 3.70 (s, 3H), 3.68- carboxylate 3.55 (m, 3H), 3.08-2.99 (m, 2H), 2.28 (s, 1.5H), 2.25-2.15 (m, 2H), 2.08-1.99 (m, 2H), 2.05 (s, 1.5H), 1.81-1.57 (m, 6H).
Biological Activity
Example A
(163) Phospho-ERK1/2 Assays
(164) Functional assays were performed using the Alphascreen Surefire phospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High Throughput Screen, 2008). ERK1/2 phosphorylation is a downstream consequence of both Gq/11 and Gi/o protein coupled receptor activation, making it highly suitable for the assessment of M.sub.1, M.sub.3 (Gq/11 coupled) and M.sub.2, M.sub.4 receptors (Gi/o coupled), rather than using different assay formats for different receptor subtypes. CHO cells stably expressing the human muscarinic M.sub.1, M.sub.2, M.sub.3 or M.sub.4 receptor were plated (25K/well) onto 96-well tissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cells were serum-starved overnight. Agonist stimulation was performed by the addition of 5 μL agonist to the cells for 5 min (37° C.). Media was removed and 50 μL of lysis buffer added. After 15 min, a 4 μL sample was transferred to 384-well plate and 7 μL of detection mixture added. Plates were incubated for 2 h with gentle agitation in the dark and then read on a PHERAstar plate reader. pEC.sub.50 and E.sub.max figures were calculated from the resulting data for each receptor subtype and the results are set out in Table 4 below.
(165) For the vast majority of examples at least two diastereomers exist and these have been separated, unless otherwise stated, using the techniques of reversed phase HPLC, chiral HPLC or chiral SFC. Isomer assignment (Isomer 1, Isomer 2, etc.) is based on the retention time of the compound using the separation technique that was performed in the final purification step. By implication, this could be reversed phase HPLC, chiral HPLC or chiral SFC retention time, and this will vary from compound to compound.
(166) Analytical data for active isomers is reported in Table 3. Data for several weakly active compounds are included in Table 4 to highlight the preference for absolute stereochemistry.
(167) TABLE-US-00006 TABLE 4 Muscarinic Activity pEC.sub.50 M1 pEC.sub.50 M2 pEC.sub.50 M3 pEC.sub.50 M4 (% Emax cf. (% Emax cf. (% Emax cf. (% Emax cf. Ex. No. ACh) ACh) ACh) ACh) ACh 8.33 (102) 7.82 (105) 8.12 (115) 8.09 (110) 1-1 Isomer 1 6.37 (116) 6.24 (57) <4.70 (13) 7.28 (100) 1-2 Isomer 1 7.82 (96) 7.06 (69) <4.70 (2) 8.54 (78) 1-2 Isomer 2 7.11 (67) <4.70 (10) <4.70 (2) 7.88 (51) 1-3 Isomer 1 7.26 (124) 6.55 (112) 5.60 (40) 8.14 (99) 1-3 Isomer 2 6.50 (45) <4.70 (11) <4.70 (5) 6.95 (81) 2-1 Isomer 1 6.60 (44) NT NT <4.70 (17) 2-1 Isomer 2 6.80 (40) NT NT <4.70 (20) 2-2 Isomer 1 <4.70 (63) <4.70 (3) <4.70 (4) 7.44 (61) 2-2 Isomer 2 <4.70 (10) <4.70 (3) <4.70 (5) 6.95 (37) 2-3 Isomer 1 6.71 (77) 6.54 (45) <4.70 (9) 8.19 (99) 2-3 Isomer 2 6.76 (34) <4.70 (10) <4.70 (5) 7.94 (65) 3-1 Isomer 1 5.86 (97) NT NT 6.89 (94) 3-1 Isomer 2 5.86 (79) NT NT 6.51 (78) 4-1 Isomer 1 6.81 (108) 6.60 (87) <4.70 (11) 7.51 (114) 4-1 Isomer 2 6.40 (47) <4.70 (17) <4.70 (4) 7.00 (59) 5-1 Isomer 1 7.14 (47) <4.70 (8) <4.70 (0) <4.70 (13) 5-1 Isomer 2 6.85 (66) <4.70 (13) <4.70 (8) 7.47 (41) 5-2 Isomer 1 6.50 (82) NT NT 6.52 (36) 5-2 Isomer 2 7.36 (61) <4.70 (8) <4.70 (5) <4.70 (18) 5-3 Isomer 1 5.84 (75) NT NT 6.08 (33) 5-3 Isomer 2 6.90 (73) <4.70 (4) <4.70 (5) <4.70 (17) 5-4 Isomer 1a 5.83 (76) <4.70 (3) <4.70 (2) 6.84 (81) 5-4 Isomer 1b <4.70 (9) NT NT 6.50 (30) 5-4 Isomer 2a 6.01 (75) NT NT 6.70 (61) 5-4 Isomer 2b 7.13 (25) <4.70 (1) <4.70 (4) <4.70 (20) 5-5 Isomer 1 6.54 (75) 6.91 (24) <4.70 (4) 7.67 (99) 5-5 Isomer 2 7.27 (108) 7.12 (67) NT 8.07 (108) 6-1 Isomer 1 6.75 (93) <4.70 (26) <4.70 (7) 6.82 (77) 6-1 Isomer 2 7.21 (102) 6.49 (90) <4.70 (62) 7.76 (111) 6-2 Isomer 1 6.21 (71) NT NT 5.98 (45) 6-3 Isomer 1 6.92 (124) 6.45 (36) <4.70 (390) 7.22 (93) 6-3 Isomer 2 6.71 (90) <4.70 (11) <4.70 (9) 6.41 (44) 6-4 Isomer 1 7.84 (103) 6.44 (33) NT 7.37 (80) 6-4 Isomer 2 7.47 (72) <4.70 (15) <4.70 (19) 6.69 (38) 6-5 Isomer 1 6.78 (92) <4.70 (11) <4.70 (13) 6.52 (50) 6-5 Isomer 2 7.80 (91) 5.63 (68) 5.55 (83) 6.84 (73) 6-6 Isomer 1 6.60 (103) 6.47 (60) <4.70 (7) 7.72 (109) 6-6 Isomer 2 6.01 (50) <4.70 (6) <4.70 (3) 7.09 (48) 6-7 Isomer 1 6.19 (111) 5.99 (87) <4.70 (28) 7.12 (105) 6-7 Isomer 2 5.66 (41) <4.70 (5) <4.70 (2) 6.76 (52) 7-1 Isomer 1 6.42 (91) NT NT 6.49 (76) 7-1 Isomer 2 5.76 (62) NT NT <4.70 (54) 7-2 Isomer 1 7.10 (96) NT NT 6.34 (72) 7-3 Isomer 1 7.45 (100) 5.83 (62) <4.70 (57) 6.56 (97) 7-4 Isomer 1 6.26 (85) NT NT <4.70 (65) 8-1 Isomer 1 7.07 (123) NT NT 6.81 (77) 8-1 Isomer 2 6.63 (86) NT NT 6.24 (47) 8-2 Isomer 1 7.10 (99) NT NT 6.18 (54) 8-2 Isomer 2 6.22 (60) NT NT <4.70 (27)
EQUIVALENTS
(168) The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.