NZ618221B2 - Trpv4 antagonists - Google Patents
Trpv4 antagonists Download PDFInfo
- Publication number
- NZ618221B2 NZ618221B2 NZ618221A NZ61822112A NZ618221B2 NZ 618221 B2 NZ618221 B2 NZ 618221B2 NZ 618221 A NZ618221 A NZ 618221A NZ 61822112 A NZ61822112 A NZ 61822112A NZ 618221 B2 NZ618221 B2 NZ 618221B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- benzo
- benzimidazolecarbonitrile
- imidazolecarbonitrile
- alkyl
- Prior art date
Links
- 108060008568 TRPV4 Proteins 0.000 title abstract description 47
- 230000003042 antagnostic Effects 0.000 title abstract description 14
- 239000005557 antagonist Substances 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 239000011780 sodium chloride Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- -1 1-(((5S,7S)(3-(2-cyanopropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan- 7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile Chemical compound 0.000 claims description 509
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 377
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 373
- 125000000217 alkyl group Chemical group 0.000 claims description 166
- DIOQZVSQGTUSAI-UHFFFAOYSA-N Decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 124
- 125000004043 oxo group Chemical group O=* 0.000 claims description 61
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
- 125000005843 halogen group Chemical group 0.000 claims description 57
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 47
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 47
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000004076 pyridyl group Chemical group 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 28
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 22
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 22
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 201000006233 congestive heart failure Diseases 0.000 claims description 19
- 239000000546 pharmaceutic aid Substances 0.000 claims description 18
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- AHHWIHXENZJRFG-UHFFFAOYSA-N Oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001820 oxy group Chemical compound [*:1]O[*:2] 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 11
- YKRWCOVMFLQPQJ-UHFFFAOYSA-N 2-(2-chlorophenyl)oxetane Chemical compound ClC1=CC=CC=C1C1OCC1 YKRWCOVMFLQPQJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 208000009856 Lung Disease Diseases 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 206010069351 Acute lung injury Diseases 0.000 claims description 8
- 206010030113 Oedema Diseases 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 8
- 206010037423 Pulmonary oedema Diseases 0.000 claims description 8
- 230000004064 dysfunction Effects 0.000 claims description 8
- 230000002068 genetic Effects 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 7
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 claims description 6
- 230000000968 intestinal Effects 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
- 208000006673 Asthma Diseases 0.000 claims description 5
- 210000000988 Bone and Bones Anatomy 0.000 claims description 5
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 210000002161 Motor Neurons Anatomy 0.000 claims description 5
- 208000005333 Pulmonary Edema Diseases 0.000 claims description 5
- 208000005069 Pulmonary Fibrosis Diseases 0.000 claims description 5
- 208000010285 Ventilator-Induced Lung Injury Diseases 0.000 claims description 5
- 230000001684 chronic Effects 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 230000000414 obstructive Effects 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 201000009890 sinusitis Diseases 0.000 claims description 5
- GVFPRYAPMFINSY-UHFFFAOYSA-N 1-dimethylphosphoryloxyethane Chemical compound CCOP(C)(C)=O GVFPRYAPMFINSY-UHFFFAOYSA-N 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- 206010016807 Fluid retention Diseases 0.000 claims description 4
- 206010058061 Gastrointestinal oedema Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 4
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 4
- 206010039083 Rhinitis Diseases 0.000 claims description 4
- 230000003187 abdominal Effects 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 201000001320 atherosclerosis Diseases 0.000 claims description 4
- 230000000268 renotropic Effects 0.000 claims description 4
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 3
- 206010009839 Coeliac disease Diseases 0.000 claims description 3
- 206010009887 Colitis Diseases 0.000 claims description 3
- 206010010774 Constipation Diseases 0.000 claims description 3
- 206010011401 Crohn's disease Diseases 0.000 claims description 3
- 206010012735 Diarrhoea Diseases 0.000 claims description 3
- 206010016092 Faecal incontinence Diseases 0.000 claims description 3
- 206010016766 Flatulence Diseases 0.000 claims description 3
- 201000008286 diarrhea Diseases 0.000 claims description 3
- 230000035874 hyperreactivity Effects 0.000 claims description 3
- 201000010538 lactose intolerance Diseases 0.000 claims description 3
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical compound 0.000 claims description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 102000003567 TRPV4 Human genes 0.000 abstract description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 248
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 208
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 164
- 239000000243 solution Substances 0.000 description 133
- 239000000203 mixture Substances 0.000 description 132
- 238000006243 chemical reaction Methods 0.000 description 113
- 239000007787 solid Substances 0.000 description 108
- 239000011541 reaction mixture Substances 0.000 description 86
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- 239000000047 product Substances 0.000 description 79
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 59
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 56
- 239000008079 hexane Substances 0.000 description 48
- 239000010410 layer Substances 0.000 description 45
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 44
- 238000003756 stirring Methods 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 210000004027 cells Anatomy 0.000 description 39
- 239000012044 organic layer Substances 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 35
- 239000003921 oil Substances 0.000 description 34
- 235000019198 oils Nutrition 0.000 description 34
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 34
- 238000000034 method Methods 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
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- 239000000377 silicon dioxide Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 25
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 23
- 239000007858 starting material Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 239000002002 slurry Substances 0.000 description 21
- VEKMJKMSTPFHQD-UHFFFAOYSA-N 1H-benzimidazole-2-carbonitrile Chemical compound C1=CC=C2NC(C#N)=NC2=C1 VEKMJKMSTPFHQD-UHFFFAOYSA-N 0.000 description 20
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 20
- PYOKUURKVVELLB-UHFFFAOYSA-N Trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000000463 material Substances 0.000 description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000003643 water by type Substances 0.000 description 18
- 235000019253 formic acid Nutrition 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 238000004007 reversed phase HPLC Methods 0.000 description 13
- 125000004429 atoms Chemical group 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
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- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
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- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 10
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- 210000001132 Macrophages, Alveolar Anatomy 0.000 description 9
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 8
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Abstract
The present disclosure relates to spirocarbamate compounds of Formula (I) in which R1, (R2)Y, R3, R4, X and A have the meanings given in the specification. The disclosure further provides pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and relates to their use of these compounds as TRPV4 antagonists in treating or preventing conditions associated with TRPV4 imbalance. their use of these compounds as TRPV4 antagonists in treating or preventing conditions associated with TRPV4 imbalance.
Description
PU64638
TRPV4 ANTAGONISTS
FIELD OF THE INVENTION
The present invention relates to spirocarbamate analogs, pharmaceutical compositions
containing them and their use as TRPV4 antagonists.
BACKGROUND OF THE INVENTION
TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation
channels and is activated by heat, demonstrating spontaneous activity at physiological
temperatures (Guler et al., 2002. J Neurosci 22: 6408-6414). Consistent with its polymodal
activation property TRPV4 is also activated by hypotonicity and physical cell stress/pressure
(Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanism involving
phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid generation (Vriens
et al., 2004. Proc Natl Acad Sci U S A 101: 396-401), In addition, amongst other mechanisms
proposed, tyrosine kinase activity may also regulate TRPV4 (Wegierski et al., 2009. J Biol
Chem. 284: 2923-33).
Heart failure results in the decreased ability of the left ventricle to pump blood into the
peripheral circulation as indicated by a reduced ejection fraction and/or left ventricular dialation.
This increases the left ventricular end diastolic pressure resulting in enhanced pulmonary blood
pressures. This places the septal barrier, which separates the circulatory aqueous environment
and the alveolar airspaces of the lung, at risk. Increased pulmonary pressure results in the flow
of fluid from the pulmonary circulation into the alveolar space resulting in lung
edema/congestion, as is observed in patients with congestive heart failure.
TRPV4 is expressed in the lung (Delany et al., 2001. Physiol. Genomics 4: 165-174) and
has been shown to mediate Ca entry in isolated endothelial cells and in intact lungs (Jian et
al., 2009 Am J Respir Cell Mol Biol 38: 386-92). Endothelial cells are responsible for forming the
capillary vessels that mediate oxygen/carbon dioxide exchange and contribute to the septal
barrier in the lung. Activation of TRPV4 channels results in contraction of endothelial cells in
culture and cardiovascular collapse in vivo (Willette et al., 2008 J Pharmacol Exp Ther 325: 466-
74), at least partially due to the enhanced filtration at the septal barrier evoking lung edema and
hemorrage (Alvarez et al., 2006. Circ Res 99: 988-95). Indeed filtration at the septal barrier is
increased in response to increased vascular and/or airway pressures and this response is
dependent on the activity of TRPV4 channels (Jian et al., 2008 Am J Respir Cell Mol Biol 38:
386-92). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of
heart failure associated lung congestion.
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Additional benefit is suggested in inhibiting TRPV4 function in pulmonary-based
pathologies presenting with symptoms including lung edema/congestion, infection,
inflammation, pulmonary remodeling and/or altered airway reactivity. A genetic link between
TRPV4 and chronic obstructive pulmonary disorder (COPD) has recently been identified (Zhu et
al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potential efficacy for TRPV4 modulation
in treatment of COPD with or without coincident emphysema. Enhanced TRPV4 activity is also
a key driver in ventilator-induced lung injury (Hamanaka et al., 2007. Am J Physiol 293: L923-
32) and it is suggested that TRPV4 activation may underlie pathologies involved in acute
respiratory distress syndrome (ARDS), pulmonary fibrosis and asthma (Liedtke & Simon, 2004.
Am J Physiol 287: 269-71). A potential clinical benefit for TRPV4 blockers in the treatment of
sinusitis, as well as allergic and non-allergic rhinitis is also supported (Bhargave et al., 2008. Am
J Rhinol 22:7-12).
TRPV4 has been shown to be involved in Acute Lung Injury (ALI). Chemical activation of
TRPV4 disrupts the alvelor septal blood barrier potentially leading to pulmonary edema (Alvarez
et al, Circ Res. 2006 Oct 27;99(9):988-95. TRPV4 is a necessary step in a process known to
cause or worsen ALI in humans (Hamanaka et al, Am J Physiol Lung Cell Mol Physiol. 2007
Oct;293(4):L923-32).
Furthermore TRPV4 has in recent years been implicated in a number of other
physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide
significant clinical benefit. These include various aspects of pain (Todaka et al., 2004. J Biol
Chem 279: 35133-35138; Grant et al., 2007. J Physiol 578: 715-733; Alessandri-Haber et al.,
2006. J Neurosci 26: 3864-3874), genetic motor neuron disorders (Auer-Grumbach et al., 2009.
Nat Genet. PMID: 20037588; Deng et al., 2009. Nat Genet PMID: 20037587; Landouré et al.,
2009. Nat Genet PMID: 20037586), cardiovascular disease (Earley et al., 2005. Circ Res 97:
1270-9; Yang et al., 2006. Am. J Physiol. 290:L1267-L1276), and bone related disorders;
including osteoarthritis (Muramatsu et al., 2007. J. Biol. Chem. 282: 32158-67), genetic gain-of
function mutations (Krakow et al., 2009. Am J Hum Genet 84: 307-15; Rock et al., 2008 Nat
Genet 40: 999-1003) and osteoclast differentiation (Masuyama et al. 2008. Cell Metab 8: 257-
65).
SUMMARY OF THE INVENTION
In one aspect this invention provides for spirocarbamate analogs, pharmaceutically
acceptable salts thereof, and pharmaceutical compositions containing them.
Also described herein is the use of the compounds of Formula (I) as TRPV4 antagonists.
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Also described herein is the use of the compounds of Formula (I) for treating and
preventing conditions associated with TRPV4 imbalance.
In yet another aspect, this invention provides for the use of the compounds of Formula
(I) in the preparation of medicaments for the treatment or prevention of atherosclerosis,
disorders related to intestinal edema, post-surgical abdominal edema, local and systemic
edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and
congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator
induced lung injury, high altitude induced pulmonary edema, acute respiratory distress
syndrome, acute lung injury, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder,
pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal
dysfunction, osteoarthritis crohn's disease, colitis, diarrhea, intestinal irregularity
(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation,
intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence.
The TRPV4 antagonist may be administered alone or in conjunction with one or more
other therapeutic agents, eg. agents being selected from the group consisting of endothelin
receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor
antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta
blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel
modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, anti-
histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective β-
adrenoceptor and α -adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin
inhibitors.
Other aspects and advantages of the present invention are described further in the
following detailed description of the preferred embodiments thereof.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for compounds of Formula (I):
(R )
Wherein:
R is hydrogen, C alkyl, CH OH, CH -O-CH , CH OCH Ph, CH CN, CN, halo or C(O)OCH ;
1 1-3 2 2 3 2 2 2 3
R is independently hydrogen, CN, CF , halo, SO C alkyl, C alkyl or CΞCH;
2 3 2 1-3 1-3
R is hydrogen, C alkyl, CF or OH;
3 1-2 3
R is hydrogen, halo or C alkyl;
4 1-3
X is CR or N;
A is (CH ) – Het;
or A is (CH ) -(CR R )-(CH ) -Het;
2 n a b 2 m
R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more
a 1-3 1-3
halos;
R is C alkyl;
b 1-3
or R and R together with the carbon atom they are attached form a C cycloalkyl group;
a b 3-6
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with nitrogen to form a pyrrolidinyl or piperidinyl group;
Het is
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N N N
S O O
, , , , ,
N N N
N N N
N N N
N , N ,
, , , ,
S S ;
S N or
Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, CH(OH)-C alkyl, C(CH ) – R , C(O)N(CH ) ,
3 1-3 1-5 3 2 5 3 p
N(C alkyl) , NH , C(O)NH , oxetane, oxetane-CH , tetrahydrofuryl, tetrahydropyranyl,
1-3 p 2 2 3
morpholinyl, or pyrazolyl;
wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further
substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
R is CN, O-C alkyl, (CH ) – OH, (CH ) – O – C(O) - O – C alkyl, or O-(CH ) -O –R ;
1-4 2 m 2 p 1-5 2 p 6
R is C alkyl or P(O) (CH ) ;
6 1-4 2 3 2
n is independently 0, 1 or 2;
m is independently 0, 1 or 2;
p is independently 1 or 2; and
y is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
“Alkyl” refers to a monovalent saturated hydrocarbon chain having the specified number
of carbon member atoms. For example, C alkyl refers to an alkyl group having from 1 to 4
carbon member atoms. Alkyl groups may be straight or branched. Representative branched
alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl, (n-propyl
and isopropyl), and butyl (n-butyl, isobutyl, s-butyl, and t-butyl).
“Cycloalkyl” refers to a monovalent saturated or unsaturated hydrocarbon ring having
the specified number of carbon member atoms. For example, C cycloalkyl refers to a
cycloalkyl group having from 3 to 6 carbon member atoms. Unsaturated cycloalkyl groups have
one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic.
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Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl,
cyclopentenyl, cyclohexyl, and cyclohexenyl.
When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and
iodine, and fluoro, chloro, bromo, and iodo, respectively.
"Substituted" in reference to a group indicates that one or more hydrogen atom attached
to a member atom within the group is replaced with a substituent selected from the group of
defined substituents. It should be understood that the term "substituted" includes the implicit
provision that such substitution be in accordance with the permitted valence of the substituted
atom and the substituent and that the substitution results in a stable compound (i.e. one that
does not spontaneously undergo transformation such as by rearrangement, cyclization, or
elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is
stated that a group may contain one or more substituents, one or more (as appropriate) member
atoms within the group may be substituted. In addition, a single member atom within the group
may be substituted with more than one substituent as long as such substitution is in accordance
with the permitted valence of the atom. Suitable substituents are defined herein for each
substituted or optionally substituted group.
With regard to stereoisomers, the compounds of Formula (I) may have one or more
asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual
enantiomers or diastereomers or diastereomeric mixtures. All such isomeric forms are included
within the present invention, including mixtures thereof.
As used herein, “pharmaceutically acceptable” refers to those compounds, materials,
compositions, and 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, or other problem or complication, commensurate with a reasonable benefit/risk
ratio.
The skilled artisan will appreciate that pharmaceutically acceptable salts of the
compounds according to Formula (I) may be prepared. These pharmaceutically acceptable
salts may be prepared in situ during the final isolation and purification of the compound, or by
separately treating the purified compound in its free acid or free base form with a suitable base
or acid, respectively.
In certain embodiments, compounds according to Formula (I) may contain an acidic
functional group and are, therefore, capable of forming pharmaceutically acceptable base
addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides,
carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium,
PU64638
and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic
amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine,
2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine,
diethanolamine, and cyclohexylamine.
In certain embodiments, compounds according to Formula (I) may contain a basic
functional group and are therefore capable of forming pharmaceutically acceptable acid addition
salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable
inorganic acids and organic acids. Representative pharmaceutically acceptable acids include
hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid,
acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid,
maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric
acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid,
methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
As used herein, the term “a compound of Formula (I)” or “the compound of Formula (I)”
refers to one or more compounds according to Formula (I). The compound of Formula (I) may
exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or
as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable
solvates may be formed from crystalline compounds wherein solvent molecules are
incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous
solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or
ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline
lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically
referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions
containing variable amounts of water. The invention includes all such solvates.
The skilled artisan will further appreciate that certain compounds of the invention that
exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e.
the capacity to occur in different crystalline structures). These different crystalline forms are
typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs
have the same chemical composition but differ in packing, geometrical arrangement, and other
descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different
physical properties such as shape, density, hardness, deformability, stability, and dissolution
properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder
diffraction patterns, which may be used for identification. The skilled artisan will appreciate that
different polymorphs may be produced, for example, by changing or adjusting the reaction
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conditions or reagents, used in making the compound. For example, changes in temperature,
pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously
convert to another polymorph under certain conditions.
The subject invention also includes isotopically-labelled compounds, which are identical
to those recited in formula (I) and following, but for the fact that one or more atoms are replaced
by an atom having an atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be incorporated into compounds
of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as H, H,
11 13 14 15 17 18 31 32 35 18 36 123 125
C, C, C, N, O, O, P, P, S, F, Cl, I and I.
Compounds of the present invention and pharmaceutically acceptable salts of said
compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are
within the scope of the present invention. Isotopically-labelled compounds of the present
3 14
invention, for example those into which radioactive isotopes such as H, C are incorporated,
are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H, and carbon-14,
14 11
i.e., C, isotopes are particularly preferred for their ease of preparation and detectability. C
18 125
and F isotopes are particularly useful in PET (positron emission tomography), and I isotopes
are particularly useful in SPECT (single photon emission computerized tomography), all useful
in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., H, can
afford certain therapeutic advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in
some circumstances. Isotopically labelled compounds of formula I and following of this invention
can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in
the Examples below, by substituting a readily available isotopically labelled reagent for a non-
isotopically labelled reagent.
Representative Embodiments
In one embodiment:
R is hydrogen, C alkyl, CH OH, CH -O-CH , CH OCH Ph, CH CN, CN, halo or C(O)OCH ;
1 1-3 2 2 3 2 2 2 3
R is independently hydrogen, CN, CF , halo, SO C alkyl, C alkyl or CΞCH;
2 3 2 1-3 1-3
R is hydrogen, C alkyl, CF or OH;
3 1-2 3
R is hydrogen, halo or C alkyl;
4 1-3
X is CR or N;
A is (CH ) – Het;
or A is (CH ) -(CR R )-(CH ) -Het;
2 n a b 2 m
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R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more
a 1-3 1-3
halos;
R is C alkyl;
b 1-3
or R and R together with the carbon atom they are attached form a C cycloalkyl group;
a b 3-6
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with nitrogen to form a pyrrolidinyl or piperidinyl group;
Het is
, , , , ,
N N N
N N N
N , N ,
, , , ,
S S ;
S N or
Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, CH(OH)-C alkyl, C(CH ) – R , C(O)N(CH ) ,
3 1-3 1-5 3 2 5 3 p
N(C alkyl) , NH , C(O)NH , oxetane, oxetane-CH , tetrahydrofuryl, tetrahydropyranyl,
1-3 p 2 2 3
morpholinyl, or pyrazolyl;
wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further
substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
R is CN, O-C alkyl, (CH ) – OH, (CH ) – O – C(O) - O – C alkyl, or O-(CH ) -O –R ;
1-4 2 m 2 p 1-5 2 p 6
R is C alkyl or P(O) (CH ) ;
6 1-4 2 3 2
n is independently 0, 1 or 2;
m is independently 0, 1 or 2;
p is independently 1 or 2; and
y is 1, 2 or 3.
In another embodiment:
R is hydrogen, C alkyl, CH OH, CH -O-CH , CH OCH Ph, CH CN, CN, halo or C(O)OCH ;
1 1-3 2 2 3 2 2 2 3
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R is independently hydrogen, CN, CF , halo, SO C alkyl, C alkyl or CΞCH;
2 3 2 1-3 1-3
R is hydrogen, C alkyl, CF or OH;
3 1-2 3
R is hydrogen, halo or C alkyl;
4 1-3
X is CR or N;
A is (CH ) – Het;
or A is (CH ) -(CR R )-(CH ) -Het;
2 n a b 2 m
R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more
a 1-3 1-3
halos;
R is C alkyl;
b 1-3
or R and R together with the carbon atom they are attached form a C cycloalkyl group;
a b 3-6
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with nitrogen to form a pyrrolidinyl or piperidinyl group;
Het is
S O O
, , , , ,
N N N
N N N
N N , N ,
, , , ,
S S ;
S N or
Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN,
3 1-3 3 2 3 2 3 3 2
C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH ,
3 2 2 3 2 2 1-5 3 p 1-3 p 2 2
oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl;
wherein the phenyl and pyridyl substituent on the Het may be further substituted by one
or two substituents chosen from: halo, CN, OCH , C alkyl or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
n is independently 0, 1 or 2;
m is independently 0, 1 or 2;
p is independently 1 or 2; and
y is 1, 2 or 3.
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In another embodiment:
R is hydrogen, C alkyl or CH OH;
1 1-3 2
R is CN;
R is hydrogen;
X is N;
A is (CH ) – Het;
or A is (CH ) -(CR R )-(CH ) -Het;
2 n a b 2 m
R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more
a 1-3 1-3
halos;
R is C alkyl;
b 1-3
or R and R together with the carbon atom they are attached form a C cycloalkyl group;
a b 3-6
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with nitrogen to form a pyrrolidinyl or piperidinyl group;
Het is
S O O
, , ,
N N N
N N N N
N N N
, N ,
, , , ,
S S ;
S N or
Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN,
3 1-3 3 2 3 2 3 3 2
C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH ,
3 2 2 3 2 2 1-5 3 p 1-3 p 2 2
oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl;
wherein the phenyl and pyridyl substituent on the Het may be further substituted by one
or two substituents chosen from: halo, CN, OCH , C alkyl or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
n is independently 0 or 1;
m is independently 0 or 1;
p is independently 1 or 2; and
y is 1 or 2.
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In yet another embodiment:
R is hydrogen, C alkyl or CH OH;
1 1-3 2
R is CN;
R is hydrogen;
X is N;
A is (CH ) – Het;
or A is (CH ) -(CR R )-(CH ) -Het;
2 n a b 2 m
R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more
a 1-3 1-3
halos;
R is C alkyl;
b 1-3
or R and R together with the carbon atom they are attached form a C cycloalkyl group;
a b 3-6
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group;
or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced
3-6 a b
with nitrogen to form a pyrrolidinyl or piperidinyl group;
Het is
, , , ,
N N N
N N N N
S N N
, N , or
Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN,
3 1-3 3 2 3 2 3 3 2
C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH ,
3 2 2 3 2 2 1-5 3 p 1-3 p 2 2
oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl;
wherein the phenyl and pyridyl substituent on the Het may be further substituted by one
or two substituents chosen from: halo, CN, OCH , C alkyl, or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
n is independently 0 or 1;
m is independently 0 or 1;
p is independently 1 or 2;and
y is 1 or 2;
In yet another embodiment:
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R is hydrogen, C alkyl or CH OH;
1 1-3 2
R is CN;
R is hydrogen;
X is N;
A is (CH ) – Het;
Het is
N N N
O , ,
, or ;
, N N
Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN,
3 1-3 3 2 3 2 3 3 2
C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH ,
3 2 2 3 2 2 1-5 3 p 1-3 p 2 2
oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl;
wherein the phenyl and pyridyl substituent on the Het may be further substituted by one
or two substituents chosen from: halo, CN, OCH , C alkyl, or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
n is independently 0 or 1;
p is independently 1 or 2; and
y is 1 or 2.
In yet another embodiment:
R is hydrogen, C alkyl or CH OH;
1 1-3 2
R is CN;
R is hydrogen;
X is N;
A is (CH ) – Het;
Het is
N N N
, or ;
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Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl,
CN, CH F, CHF , CF , C cycloalkyl, , (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl,
2 2 3 3-6 2 n 1-3 2 n 2 n
pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN,
3 1-3 3 2 3 2 3 3 2
C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH ,
3 2 2 3 2 2 1-5 3 p 1-3 p 2 2
oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl;
wherein the phenyl and pyridyl substituent on the Het may be further substituted by one
or two substituents chosen from: halo, CN, OCH , C alkyl, or CF ;
3 1-3 3
and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by
1-5 3-6
CN or OH;
n is 0;
p is independently 1 or 2; and
y is 1 or 2.
It is to be understood that the present invention covers all combinations of particular
groups described hereinabove.
Specific examples of compounds of the present invention include the following:
1-({(5S,7S)[3-(1,1-dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-(((5S,7S)(3-(2-cyanopropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-({(5S,7S)[5-(1,1-dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)methyloxo(2-pyridinylmethyl)oxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile;
1-({(5S,7S)[2-methyl(5-phenyl-1,3,4-oxadiazolyl)propyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[2-(3-ethyl-1,2,4-oxadiazolyl)methylpropyl]oxooxaazaspiro[4.5]dec-
7-yl}methyl)-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[3-methyl(2-pyrimidinyl)pyrrolidinyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5S,7S)methyloxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec-
7-yl}methyl)-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)oxo({1-[5-(trifluoromethyl)pyridinyl]-1H-1,2,3-triazolyl}methyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
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1-({(5S,7S)[4-chloro(1,1-dimethylethyl)isoxazolyl]methyloxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)methyloxo[5-(trifluoromethyl)pyridinyl]oxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[6-(ethyloxy)pyridinyl]methyloxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-(((5S,7S)(6-methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-ethoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(1-ethylmethyl-1H-pyrazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((7S)(5-methoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-chloropyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-(dimethylamino)pyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
tert-butyl (2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa
azaspiro[4.5]decanyl)isoxazolyl)methylpropyl) carbonate;
1-(((5S,7S)(3-(1-hydroxymethylpropanyl)isoxazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(4,6-dimethoxypyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-ethoxymethylpyridazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyloxo(2-(trifluoromethyl)pyrimidinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyloxo(3-(trifluoromethyl)pyridinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
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1-({(5S,7S)[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-{[(5S,7S)(2-{3-[1-(ethyloxy)ethyl]-1,2,4-oxadiazolyl}methylpropyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)methyl(5-methylpyridinyl)oxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile;
1-({(5S,7S)methyl[3-(1-methylethyl)isoxazolyl]oxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)methyl[3-(2-methylpropyl)isoxazolyl]oxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)(1-tert-butyl-1H-pyrazolyl)methyloxooxaazaspiro[4.5]dec
yl]methyl}-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)(3-ethylisoxazolyl)methyloxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile;
1-{[(5S,7S)(3-cyclopropylisoxazolyl)methyloxooxaazaspiro[4.5]decyl]methyl}-
1H-benzimidazolecarbonitrile;
1-{[(5S,7S)methyloxo(3-phenylisoxazolyl)oxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile;
1-({(5S,7S)[3-(1,1-dimethylethyl)methyl-1H-pyrazolyl]methyloxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)methyloxo[3-(trifluoromethyl)isoxazolyl]oxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[3-(1-cyanocyclopropyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-(((5S,7S)(3-(2-fluoropropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-cyclobutylisoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-(tert-butyl)methylisoxazolyl)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(4-(tert-butyl)oxazolyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(1-(tert-butyl)-1H-pyrazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
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1-(((5S,7S)(3-(tert-butyl)fluoroisoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-(1,1-difluoroethyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-(tert-butyl)methylisoxazolyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-(tert-butyl)fluoroisoxazolyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-(tert-butyl)pyridazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(tert-butyl)pyrimidinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-(tert-butyl)-2H-1,2,3-triazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyl(3-(1-methyl-1H-pyrazolyl)isoxazolyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(1-(tert-butyl)-1H-1,2,3-triazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(tert-butyl)pyrazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyloxo(5-(trifluoromethyl)pyrimidinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-(2-methoxypropanyl)pyridinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyloxo(3-(propenyl)isoxazolyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3,4-dimethylisoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3,4-dimethylisoxazolyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-({3-[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-
indolecarbonitrile;
1-({3-[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)
(trifluoromethyl)-1H-benzimidazolecarbonitrile;
PU64638
1-({3-[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile;
1-{[3-(1-benzothienylmethyl)oxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole-
6-carbonitrile;
1-({(5S,7S)oxo[(2-phenyl-1,3-thiazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-({(5S,7S)oxo[(6-phenylpyridinyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile;
1-[((5S,7S){2-methyl[3-(tetrahydro-2H-pyranyl)-1,2,4-oxadiazolyl]propyl}oxo
oxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5S,7S)oxo[(4-phenyl-1,3-thiazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-[((5S,7S){[3-(4-chlorophenyl)isoxazolyl]methyl}oxooxaazaspiro[4.5]dec
yl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5S,7S)oxo[(3-phenylisoxazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile;
1-({(5S,7S)[(1-methylphenyl-1H-pyrazolyl)methyl]oxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)({4-[3-methyl(methyloxy)phenyl]-1,3-thiazolyl}methyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-({(5S,7S)oxo[(3-phenyl-1H-1,2,4-triazolyl)methyl]oxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)oxo[(5-phenylpyridinyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile trifluoroacetate;
4-chloro({(5S,7S)[2-methyl(3-phenyl-1,2,4-oxadiazolyl)propyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[2-methyl(3-methyl-1,2,4-oxadiazolyl)propyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[2-methyl(3-phenyl-1,2,4-oxadiazolyl)propyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-[((5S,7S){2-methyl[3-(1-methylethyl)-1,2,4-oxadiazolyl]propyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[2-(3-cyclopentyl-1,2,4-oxadiazolyl)methylpropyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
PU64638
1-[((5S,7S){2-methyl[3-(5-pyrimidinyl)-1,2,4-oxadiazolyl]propyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S){2-[3-(1,1-dimethylethyl)-1,2,4-oxadiazolyl]methylpropyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S){2-methyl[3-(trifluoromethyl)-1,2,4-oxadiazolyl]propyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)(2-methyl{3-[(methyloxy)methyl]-1,2,4-oxadiazolyl}propyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-[((5S,7S){2-methyl[3-(2-methylpropyl)-1,2,4-oxadiazolyl]propyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[2-methyl(3-{[(1-methylethyl)oxy]methyl}-1,2,4-oxadiazolyl)propyl]oxo
oxaazaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
4-chloro[((5S,7S)oxo{[4-(3-phenyl-1,2,4-oxadiazolyl)tetrahydro-2H-pyran
yl]methyl}oxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
4-chloro[((5S,7S){[4-(3-cyclopentyl-1,2,4-oxadiazolyl)tetrahydro-2H-pyranyl]methyl}-
2-oxooxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S)oxo{[1-(2-pyridinyl)pyrrolidinyl]methyl}oxaazaspiro[4.5]decyl)methyl]-
1H-benzimidazolecarbonitrile;
1-({(5S,7S)oxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(4-cyanophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(4-chlorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3-chlorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(4-methylphenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3-cyanophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)oxo({1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazolyl}methyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3-fluorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
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1-{[(5S,7S)({1-[3-(methyloxy)phenyl]-1H-1,2,3-triazolyl}methyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3-methylphenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[(1-cyclohexaneyl-1H-1,2,3-triazolyl)methyl]oxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)({1-[4-cyano(trifluoromethyl)phenyl]-1H-1,2,3-triazolyl}methyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3-chlorocyanophenyl)-1H-1,2,3-triazolyl]methyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)oxo({1-[2-(trifluoromethyl)pyridinyl]-1H-1,2,3-triazolyl}methyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3,5-difluorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-{[(5S,7S)oxo({1-[4-(trifluoromethyl)phenyl]-1H-1,2,3-triazolyl}methyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(3-cyanofluorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-[((5S,7S)methyl{[1-(1-methylethyl)-1H-1,2,3-triazolyl]methyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-({(5R,7S)methyloxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec-
7-yl}methyl)-1H-benzimidazolecarbonitrile;
1-[((5S,7S){[1-(5-chloropyridinyl)-1H-1,2,3-triazolyl]methyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile;
1-(((5S,7S)(4-chloro(2-cyanopropanyl)isoxazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-({(5S,7S)[4-bromo(1,1-dimethylethyl)isoxazolyl]methyloxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)methyl[2-(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-({(5S,7S)[2,6-bis(methyloxy)pyridinyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[4-methyl(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
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1-(((7S)(3,5-dichloropyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-ethoxypyrimidinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-chlorofluoropyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyloxo(5-(trifluoromethyl)pyrazinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-(tert-butyl)pyrimidinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyl(5-methylpyrazinyl)oxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-ethoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-chloromethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-chloromethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-chloromethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-chloromethoxypyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-chloromethoxypyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(4-methyl(trifluoromethyl)pyrimidinyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)
fluoro-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-chloromethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
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1-(((5S,7S)(3-ethylpyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3,5-dimethylpyrazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(3-methyl(trifluoromethyl)pyrazinyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-(2-cyanopropanyl)pyridinyl)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-(tert-butyl)pyrimidinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-({(5S,7S)methyl[5-(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-({(5S,7S)[6-(ethyloxy)pyridazinyl]methyloxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-{[(5S,7S)(3-chloropyridinyl)methyloxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile;
1-({(5S,7S)methyl[3-(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile;
1-({(5S,7S)methyloxo[6-(trifluoromethyl)pyridinyl]oxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile;
1-(((7S)methyl(6-methylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile;
1-({(5S,7S)[4,6-bis(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile;
1-({(5S,7S)[6-(1-methylethyl)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile;
1-((7-(hydroxymethyl)(6-methoxymethylpyridinyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyloxo(4-(trifluoromethyl)pyridinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-(dimethylamino)pyrimidinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
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1-(((5S,7S)methyl(4-methylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(2-(2-hydroxypropanyl)pyrimidinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(4-methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(dimethylamino)pyrazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-{[(5S,7S)oxo(thieno[2,3-b]pyridinylmethyl)oxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile;
1-{[(trans)methyloxo(thieno[2,3-b]pyridinylmethyl)oxaazaspiro[4.5]dec
yl]methyl}-1H-benzimidazolecarbonitrile;
1-({(5S,7S)[(3-bromothieno[2,3-b]pyridinyl)methyl]oxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile; and
1-{[(5S,7S)(2-methyl{3-[1-(methyloxy)ethyl]-1,2,4-oxadiazolyl}propyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile;
1-(((5S,7S)((5-ethoxypyrazinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)((4-ethoxypyridinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)((5-ethoxypyridinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)((4-fluoropyridinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)((5-fluoropyridinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyl((4-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyl((6-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(2-methoxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
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1-(((5S,7S)(5-(2-(2-methoxyethoxy)propanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
2-((2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa
azaspiro[4.5]decanyl)pyrazinyl)propanyl)oxy)ethyl dimethylphosphinate;
1-(((5S,7S)(5'-fluoromethyl-[2,2'-bipyridin]yl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)methyl(4-methylmorpholinopyridinyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(2-hydroxypropanyl)pyridinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(5-(1-hydroxymethylpropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile;
1-(((5S,7S)(6-cyclopropylmethoxypyridinyl)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile;
or a pharmaceutically acceptable salt thereof.
Compound Preparation
The skilled artisan will appreciate that if a substituent described herein is not compatible
with the synthetic methods described herein, the substituent may be protected with a suitable
protecting group that is stable to the reaction conditions. The protecting group may be removed
at a suitable point in the reaction sequence to provide a desired intermediate or target
compound. Suitable protecting groups and the methods for protecting and de-protecting
different substituents using such suitable protecting groups are well known to those skilled in the
art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical
Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be
specifically selected to be reactive under the reaction conditions used. Under these
circumstances, the reaction conditions convert the selected substituent into another substituent
that is either useful as an intermediate compound or is a desired substituent in a target
compound.
The synthesis of the compounds of the general formula (I) and pharmaceutically
acceptable derivatives and salts thereof may be accomplished as outlined below in Schemes 1 -
8. In the following description, the groups are as defined above for compounds of formula (I)
unless otherwise indicated. Abbreviations are as defined in the Examples section. Starting
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materials are commercially available or are made from commercially available starting materials
using methods known to those skilled in the art.
Scheme 1
Ph Ph
O Ph
HBr, MeOH
I , Zinc, Diiodomethane,
HO OH
Et O
PPTS, Benzene
R Br
1. NMP Ph
Ph F
(R )
O HCOOH
NO Fe, CH(OMe) ,
O 1 R
HCOOH, MeOH N
1 K CO , MeCN
(R )
2. Hydrazine, MeOH 2 y (R )
Me SOI or Me SI
A-NH then CDI
or R1
+ R1
DMSO
(R )
2 y N
(R )
(R ) 2 y (R )
2 y 2 y
H (R )
As shown in Scheme 1, the compounds of Formula I can be prepared in a multi-step
sequence from 2-cyclohexenone or another substituted cyclohexenone such as 3-methyl
cyclohexenone. The cyclohexenone can be protected with (1R,2R)-1,2-diphenyl-1,2-
ethanediol in the presence of PPTS in solvent such as benzene under heating conditions to give
a dioxaspiro compound which can be treated with Zn/Cu in the presence of di-iodomethane to
give a cyclopropane compound. Opening of the cyclopropane with acids such as HBr in
solvents such as MeOH provides the bromomethyl intermediate. The bromomethyl intermediate
can be displaced by nucleophiles such as potassium phthalimide in the presence of solvents
such as NMP under heating conditions to give the phthalimide intermediate which can be
removed under standard conditions such as hydrazine in MeOH to give the methylamine
compound. The methylamine compound can undergo standard aromatic nucleophilic
substitution with appropriately substituted fluoro-nitrobenzene in the presence of bases such as
potassium carbonate. The nitro functional group in the resulting intermediate can be reduced
and cyclized in the presence of trimethyl orthoformate, formic acid and Fe under heating
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conditions in a solvent such as methanol to form the benzimidazole compound. Ketal
protection can be removed by heating the ketal in the presence of formic acid at high
temperature such as 70 C to form the ketone intermediate. Epoxide formation is accomplished
using either trimethylsulfoxonium iodide or trimethylsulfonium iodide in the presence of base
such as potassium t-butoxide or sodium hydride to provide a mixture of cis-/trans-epoxides.
Enantiopure trans epoxide can be obtained by separation of the cis and trans mixture by
separation techniques such as recrystallization or SFC. Two methods for converting the
epoxide into the compounds of Formula I are used. In the first method, the epoxide is treated
with an appropriately substituted amine (A-NH ) at elevated temperature in an alcohol solvent (i-
PrOH, MeOH, or EtOH) or DMF. The crude aminoalcohol is converted to the compound of
Formula I by treatment with either CDI or triphosgene/TEA. The second method involves
treating the epoxide with an appropriately substituted alkyl carbamate such as ethyl, isobutyl or
tert-butyl carbamate in solvents such as THF and/or NMP in the presence of bases such as
potassium tert-butoxide or n-BuLi under heating conditions to provide the compound of Formula
I in one step.
Scheme 2
CDI, 1,4-dioxane
1 OMe OMe
(R )
(R )
(R )
X-A O
CAN, MeCN
TFA, heat
(R ) N
(R )
As shown in Scheme 2, the trans epoxide intermediate can be opened with 1-[4-
(methyloxy)phenyl]methanamine to yield the aminoalcohol intermediate which can be cyclized in
the presence of CDI or triphosgene/Et N to give the spirocyclic carbamate. Deprotection of the
para-methoxybenzyl group using trifluoroacetic acid or CAN provides the unsubstituted
carbamate. Alternatively, the unsubstituted carbamate can be obtained in one-step from the
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trans epoxide intermediate using Boc-NH or NH CO Et in the presence of base such as n-BuLi
2 2 2
or LiOtBu. Unsubstitued carbamate can be functionalized with heterocyclic groups via a
copper-catalyzed N-arylation reaction with an appropriately substituted directed linked
heteroaryl halide (X-A = X-Het where X is halo) to give the compound of Formula I.
Alternatively, the unsubstituted carbamate can be alkylated with an appropriately substituted
alkyl halide or alkyl mesylate (X-A = X-(CH ) -Het where n is not 0, and X is halo or OMs) in the
presence of base such as NaH in solvent such as DMF to give the compound of Formula I.
Scheme 3
NH A
Cl Cl
EtOH or MeOH
TEA, THF R
(R )
2 y OR
(R )
CDI, Dioxane (R )
(R )
As shown in Scheme 3, the enantiopure trans epoxide can also be opened with
ammonia then cyclized under standard conditions to form the unsubstituted spirocyclic
carbamate. The unsubstituted carbamate can be alkylated with an appropriately substituted
alkyl halide or alkyl mesylate (XA = X-(CH ) -Het where n is not 0, and X is halo or OMs) in the
presence of NaH/DMF to give the compound of Formula I. Alternatively, the unsubstituted
carbamate can be functionalized with heterocyclic groups via a copper-catalyzed N-arylation
reaction with an appropriately substituted heteroaryl halide (X-A = X-Het where X is halo) to give
the compound of Formula I.
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Scheme 4
Alternatively, optically-pure compounds of Formula 1 can be prepared as shown in
Scheme 4. Michael addition of nitromethane into the cyclohexenone using a chiral thiourea
catalyst can provide an optically-enriched nitromethylcyclohexanone. The ketone can be
protected as the acetonide with ethylene glycol, and the nitro group can be reduced to the
primary amine using catalytic hydrogenation over palladium on carbon. The requisite
benzimidazole moiety can then be installed from the primary amine via S 2 addition of the
amine into a substituted 2-fluoronitrobenzene followed by reduction of the nitrobenzene to the
phenylenediamine. The diamine can be condensed with trimethyl orthoformate under acidic
conditions to form the substituted benzimidazole. The acetonide protecting group can then be
removed under acidic conditions to form a ketone. The ketone intermediate can be converted to
the compound of Formula I via the epoxide opening strategy as described in Schemes 1-3.
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Scheme 5
CO H
N 2 O O
O R'
X NH
R NH
(R )
(R )
As shown in Scheme 5, a carboxylic acid can be transformed to a 1,3,4-oxadiazole by
reacting the acid with an appropriately substituted hydrazine such as benzoyl hydrazine under
standard conditions such as triethylamine and 2-chloro-1,3-dimethylimidazolium chloride in
DCM to give the compound of Formula I.
Scheme 6
N R'
NaN , DMSO
(R )
(R )
As shown in Scheme 6, the spirocyclic carbamate with a terminal alkyne can be
transformed to a substituted 1,2,3-triazole under standard dipolar cycloaddition conditions such
as reaction of an aryl iodide and sodium azide in DMSO to provide the compound of Formula I.
Scheme 7
X-Het N
(R )
(R )
As shown in Scheme 7, the spirocyclic carbamate with a cyclic amine like pyrrolidine can
displace halo directly from X-Het where X is halo using cesium carbonate in NMP to form the
compound of Formula I.
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Scheme 8
(COCl) , Et N,
H , Rh/Al O 2 3 Me SOI, NaH
2 2 3 3
MeOH
DMSO
DMSO, DCM
OMe OMe
H N N
NaHMDS, THF
1. LAH, THF
2. NaBH , MeOH
DIEA, MsCl
NaN , DMSO
3 OBn
(R )
NaBH , NiCl ,
MeOH
K CO , Acetonitrile
(R )
1. CAN O
1. Fe, NH HCl, EtOH, H O
2. HBr
OBn OH
2. Trimethylorthoformate,
Formic Acid, H O
(R )
(R ) (R )
2 y 2 y
As shown in Scheme 8, an alternative racemic synthesis of compounds of Formula I can
be prepared in a multi-step sequence starting from methyl 3-hydroxybenzoate. Methyl 3-
hydroxybenzoate can be hydrogenated over rhodium on alumina in ethanol to provide an
appropriately substituted cyclohexanol. The cyclohexanol can be oxidized to the ketone using
ruthenium oxide and sodium perbromate. The ketone can be converted to the epoxide and,
subsequently, to the spirocyclic carbamate using conditions as described previously in Scheme
1. Incorporation of an R substituent can be introduced by alkylating a preformed ester enolate
with alkylating agents such as iodomethane or benzyloxymethyl chloride. The methyl ester can
be reduced with LiAlH and NaBH to provide alkyl alcohol. The resulting alcohol can be
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converted to the mesylate which can then be displaced with sodium azide to form the azide
compound. The azide can be reduced with sodium borohydride and nickel (II) chloride to
provide the methylamine. The methylamine compound can undergo standard aromatic
nucleophilic substitution with an appropriately substituted fluoronitrobenzene in the presence of
a base such as potassium carbonate. The nitro functional group in the resulting intermediate
can be reduced and cyclized in the presence of trimethyl orthoformate, formic acid and Fe under
heating conditions to form the benzimidazole compound. In the case of R = CH OBn, para-
methoxybenzyl group can be deprotected using standard conditions such as CAN to provide the
unsubstituted carbamate. In the case of R = Me, the para-methoxybenzyl group can also be
deprotected using TFA at elevated temperature. The benzyl group can be deprotected under
standard conditions such as HBr to provide primary alcohol in R . The resulting compound can
be further functionalized with heterocyclic groups via a copper-catalyzed N-arylation reaction
with an appropriately substituted directed linked heteroaryl halide (X-A = X-Het where X is halo)
to give the compound of Formula I.
Biological Activity
As stated above, the compounds according to Formula I are TRPV4 antagonists, and
are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal
edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis,
hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary
disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude
induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis,
sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of
function disorders, cardiovascular disease, renal dysfunction and osteoarthritis.
The biological activity of the compounds according to Formula I can be determined using
any suitable assay for determining the activity of a candidate compound as a TRPV4 antagonist,
as well as tissue and in vivo models.
The biological activity of the compounds of Formula (I) are demonstrated by the
following tests.
Ligand-gated assay:
TRP channel activation/opening results in an influx of divalent and monovalent cations
including calcium. The resulting changes in intracellular calcium were monitored using a
calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies). Dye loaded cells were
initially exposed to test compound to verify a lack of agonist activity. Cells were subsequently
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activated by addition of an agonist and inhibition of the agonist–induced activation was
recorded. Human embryonic kidney 293 cells stably expressing the macrophage scavenger
receptor class II (HEKMSR-II) and transduced with 1% BacMam (J.P. Condreay, S.M.
Witherspoon, W.C. Clay and T.A. Kost, Proc Natl Acad Sci 96 (1999), pp. 127–132) virus
expressing the human TRPV4 gene were plated at 15000 cells/well in a volume of 50 µL in a
384 well poly-D lysine coated plate. Cells were incubated for 24 hours at 37 degrees and 5%
CO . Media was then aspirated using a Tecan Plate-washer and replaced with 20 µL of dye
loading buffer: HBSS, 500 uM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye
loaded plates were then incubated in the dark at room temperature for 1-1.5 hours. 10 µL of
test compound diluted in HBSS (HBSS with 1.5 mM Calcium Chloride, 1.5 mM Magnesium
Chloride and 10 mM HEPES. pH 7.4),+ 0.01% Chaps was added to the plate, incubated for 10
min at room temperature in the dark and then 10 µL of agonist was added at a final
concentration equal to the agonist EC . Calcium release was measured using the FLIPRtetra
(MDS Analytical Technologies)or FLIPR384 (MDS Analytical Technologies).
All examples described herein possessed TRPV4 biological activity with IC s ranges
from 0.1 nM - 0.5 µM (see table below). IC between 0.1-10 nM (+++), >10-50 nM (++), >50-
500 nM (+).
Ex # IC Ex # IC Ex # IC Ex # IC Ex # IC Ex # IC
50 50 50 50 50 50
1 (++) 29 (++) 57 (+++) 85 (+++) 113 (++) 141 (++)
2 (+++) 30 (++) 58 (+) 86 (+) 114 (+++) 142 (++)
3 (+++) 31 (+++) 59 (+) 87 (++) 115 (+++) 143 (++)
4 (+++) 32 (+) 60 (+) 88 (+) 116 (++) 144 (+++)
(+++) 33 (++) 61 (+++) 89 (++) 117 (+) 145 (++)
6 (+++) 34 (+++) 62 (++) 90 (+++) 118 (+++) 146 (+++)
7 (+) 35 (++) 63 (++) 91 (+) 119 (+++) 147 (+++)
8 (+++) 36 (+) 64 (+++) 92 (++) 120 (+++) 148 (++)
9 (+++) 37 (++) 65 (++) 93 (+++) 121 (+++) 149 (+)
(+++) 38 (++) 66 (++) 94 (++) 122 (+++) 150 (+)
11 (++) 39 (+++) 67 (++) 95 (++) 123 (+++) 151 (+)
12 (+++) 40 (++) 68 (++) 96 (++) 124 (++) 152 (+++)
13 (+++) 41 (+++) 69 (+) 97 (++) 125 (+++) 153 (+++)
14 (+++) 42 (++) 70 (+++) 98 (+++) 126 (+++) 154 (+++)
(+++) 43 (++) 71 (+) 99 (+++) 127 (++) 155 (+++)
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16 (+++) 44 (+++) 72 (+) 100 (+++) 128 (+++) 156 (+++)
157 (+++)
17 (++) 45 (+++) 73 (+++) 101 (++) 129 (++)
158 (+++)
18 (++) 46 (+++) 74 (++) 102 (+++) 130 (+)
159 (+++)
19 (+++) 47 (+++) 75 (+++) 103 (+++) 131 (+)
160 (+++)
(+++) 48 (+++) 76 (+++) 104 (+) 132 (+++)
161 (+++)
21 (+) 49 (+++) 77 (+++) 105 (++) 133 (+++)
162 (+++)
22 (+++) 50 (+++) 78 (+++) 106 (++) 134 (+++)
23 (++) 51 (++) 79 (+++) 107 (+++) 135 (+) 163 (+++)
164 (++)
24 (+++) 52 (+) 80 (+++) 108 (+++) 136 (+)
165 (+++)
(+++) 53 (+++) 81 (+++) 109 (+) 137 (++)
166 (+++)
26 (+) 54 (+) 82 (+++) 110 (+++) 138 (+)
167 (+++)
27 (+++) 55 (+++) 83 (+++) 111 (++) 139 (+++)
168 (++)
28 (+++) 56 (++) 84 (+++) 112 (+++) 140 (+)
Hypotonicity assay (BHK cells):
BHK/AC9_DMEM/F12 conditioned (Baby Hamster Kidney) cells were transduced with
2% BacMam virus expressing the human TRPV4 gene and were plated at 10K cells per well in
a volume of 50 µL in 384 well poly-D-lysine coated plates. Cells were incubated for 18-24 hours
at 37 degrees and 5% CO The following day, the media was aspirated using a Tecan Plate-
washer and replaced with 20 µL of dye loading buffer: HBSS buffer (HBSS with 1.5 mM Calcium
Chloride, 1.5 mM Magnesium Chloride and 10 mM HEPES. pH 7.4), 2.5 mM Probenecid, 500
µM Brilliant Black, 2 µM Fluo-4. The dye loaded cells were incubated for 1-1.5 hours at room
temperature in the dark. 10 µL of test compound diluted in HBSS/H O (~1:2.3) + 0.01% Chaps
was added to the plate, incubated for 10 min at room temperature in the dark, and then 10 uL of
hypotonic buffer (H O + 1.5 mM CaCl + ~68 mM NaCl; 140 mOsm stock/260mOsm FAC) was
used to test the inhibition of the hypotonicity–induced activation. Reaction was measured on a
heated stage (37 degrees) using the FLIPRtetra. (pIC range 6.3 – 10.0)
Fluorescent Imaging Plate Reader (FLIPR) Assay
2+ 2+
The FLIPR assay detects changes in intracellular Ca (Ca ) ion concentrations
following stimulation of various biochemical pathways that can increase Ca levels. An
increase in Ca was quantified with the use of dye that becomes activated and subsequently
contained within cells, then selectively fluoresces when bound to Ca . A molecule known to
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selectively activate human TRPV4 channels, (N-((1S){[4-((2S){[(2,4-
dichlorophenyl)sulfonyl]amino}hydroxypropanoyl)piperazinyl]carbonyl}methylbutyl)
benzothiophenecarboxamide; GSK1016790A); (Thorneloe, et al., J Pharmacol Exp Ther,
326: 432, Aug 2008), was applied to cells to trigger TRPV4 channel-dependent influx of Ca
from the extracellular solution and prevention of the dye accumulation by a molecule was
considered as evidence of blockade of native TRPV4 channel activity.
Alveolar macrophages are critical mediators of Acute Lung Injury in multiple animal
models and mouse alveolar macrophages display functional changes that are triggered by a
prototypical TRPV4 activator (the phorbol ester 4αPDD) and absent in cells where the Trpv4
gene product has been deleted (Hamanaka, et al., 2010). In light of these findings, we obtained
primary alveolar macrophages from broncho-alveolar lavage (BAL) solutions obtained from
healthy human volunteers. BAL fluid was centrifuged and the resulting cell pellet was washed
phosphate-buffered saline (PBS) and resuspended. This solution was then centrifuged and the
cell pellet was resuspended in cell culture medium (DMEM with 10% fetal bovine serum
supplemented with 1000 units/L penicillin/1000 µg/L streptomycin). In humans and laboratory
animals, BAL cells consist largely of alveolar macrophages, although cell populations may be
further enriched for alveolar macrophages by adherence to plastic materials such as wells of 96-
well plates. We utilized this established principle to enrich for alveolar macrophages by plating
human alveolar macrophages at densities of ~40,000 cells/well in 96-well plates, followed by
washes with fresh medium after 30-60 minutes of incubation at 37 C in a 5% CO atmosphere
and again after 18-24h of incubation in the same conditions.
After 18 to 24 hours, media was aspirated and replaced with 100 ml load media
containing EMEM with Earl’s salts and L-Glutamine, 0.1% BSA (Millipore), 4 mM Fluo
acetoxymethyl ester fluorescent indicator dye (Fluo-4 AM, Invitrogen) and 2.5 mM probenecid.
Cells were then incubated for 1 hour at 37°C. After aspirating off the dye containing media, the
cells were washed 3 times with 100 mL of KRH assay buffer (120 mM NaCl, 4.6 mM KCl, 1.03
mM KH PO , 25 mM NaHCO , 1.0 mM CaCl , 1.1 mM MgCl , 11 mM Glucose, 20 mM HEPES,
2 4 3 2 2
0.1% gelatin, 2.5 mM probenecid, pH 7.4). To evaluate antagonist effects of a compound, 100
mL KRH assay buffer, containing 0.1% DMSO, 10 & 100 nM of the compound or the
precedented, non-selective TRPV channel blocker Ruthenium Red (10 µM), was added to the
wells and the plate warmed to 37°C for 15 minutes before being placed in FLIPR (Molecular
Devices, Sunnyvale, CA) where dye loaded cells are exposed to excitation light (488 nm) from a
6 watt Argon Laser. After the basal emission fluorescence measurements, the cellular response
to a concentration range of TRPV4 opener, GSK1016790A (0.3-1000 nM), was monitored in
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FLIPR for 10 minutes at 516 nm emission fluorescence intensity. A secondary response to
ionomycin (1 µM) was then recorded for all wells for 5 minutes. Peak emission from each well
after addition of each stimulant is then exported to an excel spreadsheet. Results from each
well were converted to % ionomycin. This data was then transferred to GraphPad Prism version
4.03 for plotting of response to each treatment condition. Shift of receptor EC50 response to
GSK1016790A in presence of compound compared to vehicle was utilized to determine
compound potency and type of receptor interaction using classical Schild analysis.
Patch clamp experiments
Patch clamp experiments can measure cationic currents moving through TRPV4-containing
channels in the plasma membrane of cells including human alveolar macrophages. In traditional
whole-cell patch-clamp recordings, cells are cultured in a manner such that multiple cells do not
directly contact one another to confound the capacitance value of an individual cell’s plasma
membrane. The membrane of a single cell is contacted by a glass electrode and the membrane
is ruptured, resulting in whole-cell configuration, which allows the investigator to fill the
cytoplasm of the cell with the contents of the electrode (intracellular) solution and also to evoke
membrane currents by manipulating the voltage of the cell membrane. Ionic gradients are
established based on the differences in the ions contained within the intracellular solution and
those contained within the extracellular solution, which is delivered over the cells via a gravity-
fed perfusion system. When applicable, agonists that provoke TRPV4-dependent currents
and/or blockers of TRPV4-containing channels can be added to the extracellular solution.
Human primary alveolar macrophages were plated on glass coverslips in growth
medium overnight at a low density in order to avoid direct contact between cells. Patch clamp
recordings were performed in whole-cell mode. Cells were perfused with standard extracellular
solution consisting of (in mM): mM): 140 NaCl, 5 NaCl, 2 MgCl .6 H O, 5 CsCl , 10 HEPES, and
2 2 2
D-Glucose, bubbled with 95% O /5% CO gas and adjusted to pH 7.4 with NaOH. The
internal solution used to fill the cell via the glass electrode consisted of (in mM: mM) 140 CsCl, 4
MgCl , 10 N-[2-hydroxyethyl] piperazine-N’-[2-ethanesulfonic acid] (HEPES), and 5 ethylene
glycol bis (β-aminoethyl ether)-N,N,N’,N’-tetraacetic acid (EGTA), adjusted to pH 7.2 with
CsOH. Voltage ramps from -80 to +80 mV over durations of 500 msec were applied and
sampled at 500 Hz, and the recordings were filtered at 10 kHz. Data were analyzed using
clampfit software and analyzed in Excel spreadsheets or Graphpad Prism 4.
Hypotonic solutions are often used as surrogates for application of mechanical force on
cells, as hypotonic extracellular solutions cause cell membranes to stretch. Since hypotonic
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solutions have been demonstrated to activate TRPV4 and produce TRPV4-dependent currents
in cells expressing TRPV4-containing ion channels (Alessandri-Haber, et al., Neuron, 39: 497,
Jul 2003), extracellular solution was replaced with a hypotonic extracellular solution consisting
of (in mM): 74 NaCl, 5 KCl, 1.2 KH PO , 1.3 MgCl , 2.4 CaCl , and 26 NaHCO , adjusted to pH
2 4 2 2 3
7.4 with NaOH in order to evoke TRPV4-dependent currents. Once the hypotonic solution had
evoked changes in currents (quantified at -80 and +80 mV), compound was added to the
hypotonic extracellular solution and the reduction in currents was quantified.
Methods of Use
The compounds of the invention are TRPV4 antagonists, and are useful in the treatment
or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal
edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone
related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive
pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema,
acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis/rhinitis,
asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders,
cardiovascular disease, renal dysfunction, osteoarthritis crohn's disease, colitis, diarrhea,
intestinal irregularity (hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel
syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance,
and flatulence. Accordingly, also described herein are methods of treating such conditions.
The methods of treatment described herein comprise administering a safe and effective
amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to
a patient in need thereof.
As used herein, "treat" in reference to a condition means: (1) to ameliorate or prevent
the condition or one or more of the biological manifestations of the condition, (2) to interfere with
(a) one or more points in the biological cascade that leads to or is responsible for the condition
or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more
of the symptoms or effects associated with the condition, or (4) to slow the progression of the
condition or one or more of the biological manifestations of the condition.
The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine,
"prevention" is understood to refer to the prophylactic administration of a drug to substantially
diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay
the onset of such condition or biological manifestation thereof.
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As used herein, "safe and effective amount" in reference to a compound of the invention
or other pharmaceutically-active agent means an amount of the compound sufficient to treat the
patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk
ratio) within the scope of sound medical judgment. A safe and effective amount of a compound
will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life
of the compound); the route of administration chosen; the condition being treated; the severity of
the condition being treated; the age, size, weight, and physical condition of the patient being
treated; the medical history of the patient to be treated; the duration of the treatment; the nature
of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be
routinely determined by the skilled artisan.
As used herein, "patient" refers to a human or other animal.
The compounds of the invention may be administered by any suitable route of
administration, including both systemic administration and topical administration. Systemic
administration includes oral administration, parenteral administration, transdermal
administration, rectal administration, and administration by inhalation. Parenteral administration
refers to routes of administration other than enteral, transdermal, or by inhalation, and is
typically by injection or infusion. Parenteral administration includes intravenous, intramuscular,
and subcutaneous injection or infusion. Inhalation refers to administration into the patient's
lungs whether inhaled through the mouth or through the nasal passages. Topical administration
includes application to the skin as well as intraocular, otic, intravaginal, and intranasal
administration.
The compounds of the invention may be administered once or according to a dosing
regimen wherein a number of doses are administered at varying intervals of time for a given
period of time. For example, doses may be administered one, two, three, or four times per day.
Doses may be administered until the desired therapeutic effect is achieved or indefinitely to
maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the
invention depend on the pharmacokinetic properties of that compound, such as absorption,
distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable
dosing regimens, including the duration such regimens are administered, for a compound of the
invention depend on the condition being treated, the severity of the condition being treated, the
age and physical condition of the patient being treated, the medical history of the patient to be
treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within
the knowledge and expertise of the skilled artisan. It will be further understood by such skilled
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artisans that suitable dosing regimens may require adjustment given an individual patient's
response to the dosing regimen or over time as individual patient needs change.
Typical daily dosages may vary depending upon the particular route of administration
chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per
dose. Preferred dosages are 1 – 500 mg once daily or BID per person.
Additionally, the compounds of the invention may be administered as prodrugs. As used
herein, a "prodrug" of a compound of the invention is a functional derivative of the compound
which, upon administration to a patient, eventually liberates the compound of the invention in
vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan
to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the
duration of action of the compound in vivo; (C) modify the transportation or distribution of the
compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or
overcome a side effect or other difficulty encountered with the compound. Typical functional
derivatives used to prepare prodrugs include modifications of the compound that are chemically
or enzymatically cleaved in vivo. Such modifications, which include the preparation of
phosphates, amides, ethers, esters, thioesters, carbonates, and carbamates, are well known to
those skilled in the art.
Compositions
The compounds of the invention will normally, but not necessarily, be formulated into
pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect
the invention is directed to pharmaceutical compositions comprising a compound of the
invention and one or more pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in
bulk form wherein a safe and effective amount of a compound of the invention can be extracted
and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical
compositions of the invention may be prepared and packaged in unit dosage form wherein each
physically discrete unit contains a safe and effective amount of a compound of the invention.
When prepared in unit dosage form, the pharmaceutical compositions of the invention typically
contain from 1 mg to 1000 mg.
The pharmaceutical compositions of the invention typically contain one compound of the
invention. However, in certain embodiments, the pharmaceutical compositions of the invention
contain more than one compound of the invention. For example, in certain embodiments the
pharmaceutical compositions of the invention contain two compounds of the invention. In
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addition, the pharmaceutical compositions of the invention may optionally further comprise one
or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically
acceptable material, composition or vehicle involved in giving form or consistency to the
pharmaceutical composition. Each excipient must be compatible with the other ingredients of
the pharmaceutical composition when commingled such that interactions which would
substantially reduce the efficacy of the compound of the invention when administered to a
patient and interactions which would result in pharmaceutical compositions that are not
pharmaceutically acceptable are avoided. In addition, each excipient must of course be of
sufficiently high purity to render it pharmaceutically-acceptable.
The compound of the invention and the pharmaceutically-acceptable excipient or
excipients will typically be formulated into a dosage form adapted for administration to the
patient by the desired route of administration. For example, dosage forms include those
adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders,
syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral
administration such as sterile solutions, suspensions, and powders for reconstitution; (3)
transdermal administration such as transdermal patches; (4) rectal administration such as
suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6)
topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and
gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular
dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be
chosen for a particular function that they may serve in the composition. For example, certain
pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the
production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be
chosen for their ability to facilitate the production of stable dosage forms. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying
or transporting of the compound or compounds of the invention once administered to the patient
from one organ, or portion of the body, to another organ, or portion of the body. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient
compliance.
Suitable pharmaceutically-acceptable excipients include the following types of
excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents,
coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers,
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sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents,
hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants,
preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate
that certain pharmaceutically-acceptable excipients may serve more than one function and may
serve alternative functions depending on how much of the excipient is present in the formulation
and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select
suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
In addition, there are a number of resources that are available to the skilled artisan which
describe pharmaceutically-acceptable excipients and may be useful in selecting suitable
pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical
Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower
Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American
Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and
methods known to those skilled in the art. Some of the methods commonly used in the art are
described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or
capsule comprising a safe and effective amount of a compound of the invention and a diluent or
filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch
(e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g.
microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid
dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch,
potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid,
tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline
cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable
disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and
sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant.
Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
The compounds may be administered alone or in conjunction with one or more other
therapeutic agents, said agents being selected from the group consisting of endothelin receptor
antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor
antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta
blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel
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modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, anti-
histamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective β-
adrenoceptor and α -adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin
inhibitors.
EXAMPLES
The following examples illustrate the invention. These examples are not intended to limit
the scope of the present invention, but rather to provide guidance to the skilled artisan to
prepare and use the compounds, compositions, and methods of the present invention. While
particular embodiments of the present invention are described, the skilled artisan will appreciate
that various changes and modifications can be made without departing from the spirit and scope
of the invention.
In the Examples:
Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J)
are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated
as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m
(multiplet), br (broad).
Flash column chromatography was performed on silica gel.
LCMS data was generated on an Agilent 1100 series system using a Sunfire C18, 5μm
column, 3 x 50 mm, kept at a constant 40 °C. A gradient elution of 10 – 100 % MeOH/water/0.1
% TFA over 2.5 min. was used for each sample with a 1.2 mL/min solvent flow rate.
The naming program used is ACD Name Pro 6.02 or Chem Draw.
The following abbreviations and terms had the indicated meanings throughout:
Abbreviation Meaning
aq Aqueous
Boc O di-tert-butyl dicarbonate
brine saturated aqueous NaCl
CAN ceric ammonium nitrate
CDI Carbonyldiimidazole
CH Cl or DCM methylene chloride
CH CN or MeCN Acetonitrile
CH I or MeI methyl iodide
(COCl) oxalyl chloride
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Cs CO cesium carbonate
CuCN copper cyanide
CuSO copper sulfate
d Day
DCA dichloroacetic acid
DMAP 4-dimethylaminopyridine
N,N-dimethylformamide
DMSO Dimethylsulfoxide
Equiv Equivalents
Et Ethyl
Et N or TEA Triethylamine
EtOH Ethanol
Et O diethyl ether
EtOAc ethyl acetate
h, hr Hour
(2-(7-Aza-1H-benzotriazoleyl)-1,1,3,3-tetramethyluronium
HATU
hexafluorophosphate)
HBr hydrobromic acid
HCl hydrochloric acid
HPLC high performance liquid chromatography
H SO sulfuric acid
i-PrOH or IPA Isopropanol
i-Pr NEt or DIEA N’,N’-diisopropylethylamine
K CO potassium carbonate
KNO potassium nitrate
KOtBu potassium tert-butoxide
LAH lithium aluminum hydride
LCMS liquid chromatography-mass spectroscopy
Me Methyl
MeOH or CH OH Methanol
MgSO magnesium sulfate
min Minute
MS mass spectrum
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MsCl methanesulfonyl chloride
MTBE methyl tert-butyl ether
μw Microwave
n-BuLi n-butyllithium
NaBH sodium borohydride
NaCl sodium chloride
Na CO sodium carbonate
NaH sodium hydride
NaHCO sodium bicarbonate
NaHMDS sodium hexamethyldisilazane
NaN sodium azide
NaOH sodium hydroxide
Na SO sodium sulfate
NCS N-chlorosuccinimide
NH Ammonia
NH Cl ammonium chloride
NH OH ammonium hydroxide
NiCl Nickel (II) chloride
NMP N-methyl pyrrolidone
Pd(PPh ) tetrakis (triphenylphosphine) palladium
Ph Phenyl
PPTS pyridinium p-toluenesulfonate
Rh/Al O rhodium on aluminum oxide
RT, rt room temperature
satd Saturated
SCX strong cation exchange
SFC supercritical fluid chromatography
SPE solid phase extraction
TFA trifluoroacetic acid
THF Tetrahydrofuran
t retention time
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INTERMEDIATE 1
1-{[(1S)methyloxocyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile
(2R,3R)Methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decene
(1R,2R)-1,2-diphenyl-1,2-ethanediol (150 g, 699 mmol) and 3-methylcyclohexen
one (77 g, 699 mmol) were suspended in benzene (1398 mL) and treated with PPTS (4.39 g,
17.48 mmol). The flask was fitted with a Dean-Stark trap filled with benzene and a condenser.
The reaction was heated to 115 °C for 3 days, and then the reaction was cooled to ambient
temperature and diluted with ether. The mixture was washed with saturated aq NaHCO . The
organic layer was dried over MgSO , filtered and concentrated to give a red/orange liquid (214
g, 100% yield). The liquid was used without further purification.
(1S,4'R,5'R,6R)Methyl-4',5'-diphenylspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxolane]
Zinc/copper couple was freshly prepared by quickly washing zinc dust with 1N HCl
(4x100 mL) in a flask and decanting the supernatant. The solid was then washed in the same
manner with distilled water (4x120 mL), 2 mol% CuSO solution (2x200 mL), distilled water
(4x120 mL), EtOH (4x120 mL) and Et O (5x100 mL). The Et O suspension of zinc/copper
couple was poured onto a funnel and dried by vacuum filtration. The resulting solid was added
to a 3 L flask and dried under vacuum at 50 C for 30 min, then cooled to RT. The flask was
fitted with an addition funnel and reflux condenser, then purged with nitrogen and kept under N
throughout the reaction. Next, 650 mL of Et O was added followed by I (0.886 g, 3.49 mmol),
and the solution was stirred and heated to reflux. Once at reflux, heating was stopped and
diiodomethane (150 mL, 1865 mmol) was slowly added making sure to not allow the reaction to
reflux out of control. (2R,3R)methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decene (214 g, 698
mmol in 600 mL Et O) was then added to the reaction mixture, followed by an additional 0.5 eq
of diiodomethane. The reaction was heated to reflux, and the reaction was monitored by LCMS.
After 1.5 h the reaction was cooled to RT and quenched with saturated aq Na CO (170 g in 800
mL water). The mixture was stirred for 30 min, then filtered through Celite©. The inorganics
were washed with Et O (2 L), then the combined organics were washed with saturated NH Cl (1
L), saturated NaHCO (1 L), brine (1 L), then dried over MgSO , filtered and concentrated to
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afford the crude product. Methanol (350 mL) was added to the residue and the suspension was
heated to 50 C. The resultant solution was cooled with stirring to RT to crystallize the product.
The slurry was stirred overnight at RT, then cooled to 0 C, and stirred for an additional 1 h. The
slurry was filtered, washed with a minimal amount of MeOH and dried under reduced pressure
to afford the desired product as a white solid (137 g, 61% yield).
(2R,3R,7S)(Bromomethyl)methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decane
(1S,4'R,5'R,6R)Methyl-4',5'-diphenylspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxolane]
(137 g, 428 mmol) was dissolved in MeOH (1993 mL) and treated with hydrobromic acid in
water (145 mL, 1283 mmol). The reaction was stirred at RT for 24 h, then concentrated to give a
yellow residue. To the residue was added hexane (1 L) and the solution was stirred for 5 min.
The hexane was decanted off leaving a yellow liquid behind. This process of adding hexane
followed by decanting was repeated. The final volume of yellow liquid was 100 mL. The
combined hexane washes were concentrated under reduced pressure to afford the desired
product as a light yellow oil (172 g, 100% yield). The oil was used without further purification.
{[(2R,3R,7S)Methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}amine
To a 1 L flask was added (2R,3R,7S)(bromomethyl)methyl-2,3-diphenyl-1,4-
dioxaspiro[4.5]decane (172 g, 428 mmol), potassium phthalimide (399 g, 2140 mmol), and NMP
(900 mL). The mixture was allowed to stir at 130 °C for 24 h, then 120 °C for 4 days. Next, the
mixture was cooled to RT and filtered. The solids were washed with Et O. The organics were
added to a separatory funnel and diluted with Et O and water. The ether was separated and
washed with saturated aq NaHCO , brine and then dried over Na SO , filtered and concentrated
3 2 4
under reduced pressure to afford the desired intermediate as a thick orange/yellow oil which
was used directly in the next reaction. To the oil was added methanol (2.25 L) followed by
hydrazine (40.3 mL, 1284 mmol). The solution was heated to reflux and the reaction was
monitored by LCMS. Following completion (2 h), the solution was then cooled to RT and filtered.
The filter cake was washed with MeOH, and the filtrate was then concentrated under reduced
pressure. To the residue was added THF and the mixture was stirred. The resulting white solids
were collected by filtration and the filtrate concentrated. A third crop was obtained by dissolving
the residue in hexane. The solution was stirred with heating, then cooled to RT and filtered.
Concentration of the hexane afforded the desired product as a light yellow oil (134.75 g, 93%
yield). MS (m/z) 338.2 (M+H ).
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3-({[(2R,3R,7S)Methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}amino)
nitrobenzonitrile
A solution of acetonitrile (2049 mL) in a 3 L flask was heated to 40 °C. Next, potassium
carbonate (198 g, 1434 mmol), 1-[(2R,3R,7S)methyl-2,3-diphenyl-1,4- dioxaspiro[4.5]dec
yl]methanamine (242 g, 717 mmol) and 3-fluoronitrobenzonitrile (119 g, 717 mmol) were
added slowly. The mixture was allowed to stir at 40 °C for 2 h, and then cooled to RT. Stirring
was continued at RT overnight. The next day, the slurry was filtered and the solids were washed
with acetonitrile (500 mL). The filtrate was concentrated to afford the crude product (while
keeping the temperature ~60 °C during concentration). To the thick dark residue was added
MeOH. The solution was heated to 60 °C on the rotovap and concentrated to a minimal volume.
To the residue was added ~500 mL of MeOH slowly with heating to avoid rapid crystallization,
and the solution was heated to reflux. Once at reflux, an additional 250 mL MeOH was slowly
added. The resulting slurry was allowed to stir at reflux for about 60 min, then heating was
stopped and the slurry was allowed to cool to RT and stirring was continued for 3 days. The
slurry was cooled to ~10 °C with an ice/water bath. Stirring was continued for ~2 h, and then the
slurry was filtered and washed with cold MeOH (100 mL). The solids were dried under reduced
pressure to give the desired product as a bright orange solid (245 g, 70.7% yield). This material
was used in the next step.
1-{[(2R,3R,7S)Methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile
A 5 L three neck flask was fitted with a mechanical stirrer and condenser. To the flask
was added 3-({[(2R,3R,7S)methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}amino)
nitrobenzonitrile (245.5 g, 508 mmol), MeOH (891 mL) and EtOAc (891 mL). Next, trimethyl
orthoformate (561 mL, 5077 mmol) and formic acid (195 mL, 5077 mmol) were added. The
resulting mixture was heated at 64 °C. Next, (2-3 eq) of formic acid, trimethylorthoformate and
iron were added every 15 min until the reaction was finished (3.5 h). Next, the mixture was
filtered to remove excess iron, and the iron was washed with EtOAc. The filtrate was
concentrated and the resulting thick purple residue (residue contained formic acid) was used
without further purification (235 g, 100% yield).
1-{[(1S)Methyloxocyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile
A mixture of 1-{[(2R,3R,7S)methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}-
1H-benzimidazolecarbonitrile (235 g, 508 mmol) in formic acid (1948 mL) was heated to 70
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°C for 18 h, then the solution was concentrated under reduced pressure, and diluted with sat.
NaHCO until it was basic. The resulting mixture was extracted with DCM (3x), and the
combined extracts were washed with brine and then concentrated under reduced pressure. To
the residue was added EtOAc (1 L) and then it was concentrated at 60 °C to a volume of
approximately 750 mL. The slurry was then allowed to cool. Once solids started to form, the
slurry was slowly diluted with 500 mL of hexanes and the temperature was raised to about 60
°C. An additional 500 mL of hexanes was slowly added and the temperature was raised to
reflux (about 68 °C). Once at reflux, heating was stopped, and the solution was allowed to cool
to RT and stir for 5 days. Then the slurry was filtered, the solids were washed with hexanes and
dried under reduced pressure to give 105.5 g of product (78% yield). The filtrate was
concentrated and loaded onto silica gel and purified on a 220 g column (like a plug of silica)
using vacuum to pull solvent through the column, and eluted with 500 mL of DCM, then 1 L of
50% EtOAc/DCM, then 1 L of 100% DCM, then 1 L each of 2.5%, 5%, 7.5%, and 10%
MeOH/DCM. Fractions were collected in 1 L portions. Fractions containing product were
concentrated to afford an additional 20.4 g (15% yield) of product. MS (m/z) 268.1 (M+H ).
INTERMEDIATE 2
1-{[(1S)Oxocyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile
(2R,3R)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decene
To a 2 L flask was added (1R,2R)-1,2-diphenyl-1,2-ethanediol (200 g, 924 mmol), 2-
cyclohexenone (101 g, 1017 mmol), benzene (1232 mL) and PPTS (11.61 g, 46.2 mmol).
The flask was fitted with a condenser and a dean-stark trap filled with benzene. The reaction
was heated to 115 C for 18 h (meanwhile trap contained 16.8 mL water indicating reaction
completion). The reaction was cooled to RT and diluted with ether. The mixture was washed
with saturated aq NaHCO . The organic layer was dried over MgSO , filtered and concentrated
to give an orange liquid. This was passed over a silica gel plug eluting with 100% hexane (500
mL), then 5% EtOAc/Hexane (2 L), then 10% EtOAc/Hexane (500 mL), then 25%
EtOAc/Hexane (500 mL). The product eluted in the first ~2.5 L of solvent. Removal of solvent
afforded a light yellow oil. To this residue was added ~275 mL of hexane and the solution was
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let stand and crystals started to rapidly form. After about 1 h at RT, the solution was cooled in
the freezer overnight. The next day, the hexane was decanted off, the solids washed with cold
hexane. The solids were dried under reduced pressure at 75 C, and 223.75 g of (2R,3R)-2,3-
diphenyl-1,4-dioxaspiro[4.5]decene was obtained. The hexane solution was concentrated
and purified by silica gel (ISCO, 330 g column, 100 mL/min, 0-10% EtOAc/Hexane over 40min).
Concentration of the pure fractions affforded (2R,3R)-2,3-diphenyl-1,4-dioxaspiro[4.5]decene
as an oil that solidified on sitting (30.47 g).
(1S,4'R,5'R,6R)-4',5'-Diphenylspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxolane]
The zinc/copper couple was freshly prepared by quickly washing zinc dust with 1N HCl
(4 x 100 mL), then washing with distilled water (4 x 120 mL), 2 mol% CuSO solution (2x200
mL), water (4 x 120 mL), EtOH (4 x 120 mL) and Et O (5 x 100 mL). The washings were done
in a flask with decanting of the liquid. The Et O washes were poured onto a funnel and dried by
vacuum filtration. The resulting solid was added to a 2 L flask and dried under vaccum at 115
C for 30 min, then cooled to RT. The flask was fitted with an addition funnel and reflux
condenser, then purged with nitrogen and kept under N throughout the reaction. Next, 400 mL
of Et O was added followed by I (0.551 g, 2.172 mmol), and the solution was stirred and
heated to reflux. Once at reflux, heating was stopped and diiodomethane (87 mL, 1086 mmol)
was slowly added making sure to not allow the reaction to reflux out of control. (2R,3R)-2,3-
diphenyl-1,4-dioxaspiro[4.5]decene (127 g, 434 mmol) was then added in 350 mL ether,
followed by an additional 0.5 eq of diiodomethane. The reaction was heated to reflux and the
reaction monitored by LCMS. After 1.5 h the reaction was cooled to RT and quenched with
saturated aq Na CO (230 g in 900 mL water). The mixture was stirred for 30 min, then filtered
through celite. The inorganics were washed with Et O (2 L), then the combined organics were
washed with saturated aq NH Cl (1 L), saturated aq NaHCO (1 L), brine (1 L). The organic
layers were dried over MgSO , filtered and concentrated to afford the crude product (176.45 g).
To the residue was added Et O (250 mL) and the suspension was heated to reflux, then allowed
to cool to RT to crystalize the product. The suspension was put in the freezer for 3 days, then
the ether decanted off. Drying of the solids gave (1S,4'R,5'R,6R)-4',5'-
diphenylspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxolane] (112.5 g, 85% yield). The material was
used as an intermediate without further purification.
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(2R,3R,7S)(Bromomethyl)-2,3-diphenyl-1,4-dioxaspiro[4.5]decane
The (4'R,5'R,6R)-4',5'-diphenylspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxolane] (112 g,
366 mmol) was dissolved in MeOH (1704 mL) and treated with hydrobromic acid in water (124
mL, 1097 mmol). The reaction was stirred at RT for 18 h and then concentrated. The residue
was dissolved in hexane, then the hexane was decanted off leaving a yellow oil behind (HBr
residue). The hexane was concentrated under reduced pressure to afford the (2R,3R,7S)
(bromomethyl)-2,3-diphenyl-1,4-dioxaspiro[4.5]decane as a light yellow oil (138.88 g, 98%
yield). The oil was used without further purification.
1-[(2R,3R,7S)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decyl]methanamine
To a 2 L flask was added (2R,3R,7S)(bromomethyl)-2,3-diphenyl-1,4-
dioxaspiro[4.5]decane (146 g, 377 mmol), potassium phthalimide (140 g, 754 mmol), and DMF
(750 mL). The mixture was allowed to stir at 80 C for 24 h, then cooled to RT. The mixture
was added to a separatory funnel and diluted with Et O and water. The ether was separated
and the water extracted again with Et O. The combined ether extracts were washed with
saturated aq NaHCO and brine. The Et O layers were dried over Na SO , filtered and
3 2 2 4
concentrated under reducde pressure to afford the desired intermediate as a pale yellow glassy
solid. To the residue was added MeOH (1875 mL) followed by hydrazine (35.5 mL, 1131
mmol). The solution was heated to reflux and the reaction monitored by LCMS. After 2 h, the
solution was cooled to RT, filtered and washed with MeOH. The filtrate was concentrated
under reduced pressure. To the residue was added THF and the mixture was stirred. The
resulting solid was filtered off and the THF concentrated. The residue was dissolved in hexane,
stirred with heating, then cooled to RT and filtered. Concentration of the hexane afforded the 1-
[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methanamine as a light yellow oil (116.28
g, 95% yield). The oil was used without further purification.
3-({[(2R,3R,7S)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}amino)nitrobenzonitrile
A mixture of 3-fluoronitrobenzonitrile (55.5 g, 334 mmol), 1-[(2R,3R,7S)-2,3-diphenyl-
1,4dioxaspiro[4.5]decyl]methanamine (103 g, 318 mmol) and potassium carbonate (88 g, 637
mmol) in acetonitrile (2654 mL) was stirred at RT for 5 days (~200 mL DCM was added to help
with solubility). The resulting solution was filtered and the solids washed with MeCN. The
resulting solution was concentrated to give the crude product that was dissolved in MeOH (500
mL) and allowed to crystallize with stirring. The slurry was allowed to stir at RT overnight,
filtered and the solids dried under reduced pressure to give 3-({[(2R,3R,7S)-2,3-diphenyl-1,4-
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dioxaspiro[4.5]decyl]methyl}amino)nitrobenzonitrile (131.41 g, 88% yield). The product
was used without further purification.
1-{[(2R,3R,7S)-2,3-Diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile
To a 3 L flask fitted with an overhead stirrer was added 3-({[(2R,3R,7S)-2,3-diphenyl-1,4-
dioxaspiro[4.5]decyl]methyl}amino)nitrobenzonitrile (131 g, 279 mmol), iron (156 g, 2790
mmol), MeOH (1 L), EtOAc (1 L), trimethyl orthoformate (0.308 L, 2790 mmol) and formic acid
(0.107 L, 2790 mmol). The mixture was heated to 64 °C. Every 15 min an additional 2-3 eq of
iron, formic acid and trimethyl orthoformate was added. After 3 h, the solution was cooled to RT
and filtered through Celite© and washed with EtOAc. The filtrate was concentrated to give 1-
{[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile
(125 g, 100% yield). MS (m/z) 450.2 (M+H ). The product was used without further
purification.
1-{[(1S)Oxocyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile
A mixture of 1-{[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile (125 g, 279 mmol) in formic acid (1.5 L) was heated to 70 °C
overnight. Then the formic acid was removed via concentration, and the mixture was diluted
with DCM and saturated aq NaHCO till basic. The mixture was extracted with DCM (3x). The
organic layers were dried over Na SO , filtered and concentrated and azeotroped with EtOAc.
EtOAc (250 mL) was then added and the mixture was stirred at RT which led to solids forming.
The slurry was stirred at RT for 15 min and then hexane (500 mL) was added slowly. The slurry
was allowed to stir for 3 days at RT and then filtered and washed with hexane. The solids were
dried under reduced pressure to give ~61 g product. The filtrate was concentrated and purified
via normal phase chromatography (Combiflash Rf, (2 x 330 g silica column), solid load, 100
mL/min, EtOAc/CH Cl 0-100% over 20min, then 0-10% MeOH/CH Cl over 10min, holding at
2 2 2 2
% MeOH/DCM untill all product had eluted from column) to afford the desired product as a
tan solid (~7 g). The material was dissolved in EtOAc (15 mL), and heated to reflux. Next,
hexane was added untill solids started to form. Heating was stopped and the solution was
allowed to cool to RT. Stirring was continued overnight at RT. FIltration of the slurry gave the
desired product as a light tan powder (3.5 g). MS (m/z) 254.1(M+H ).
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INTERMEDIATE 3
1-{[(3S,5S)Methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazolecarbonitrile
Route 1: To a 2 L flask was added DMSO (604 mL) and 1-{[(1S)methyl
oxocyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile (121 g, 453 mmol). The solution was
stirred and heated to ~35 °C to get all solids to go into solution. Next, trimethylsulfonium iodide
(112 g, 543 mmol) was added followed by potassium tert-butoxide (60.9 g, 543 mmol). The
mixture was allowed to stir and cool to RT. After 1 h, LCMS indicated the reaction was
complete. Next, the DMSO solution was added to a separatory funnel and diluted with 3 L
water and 1 L DCM. The DCM was separated, and the water was extracted with DCM (3 x 500
mL). The combined DCM extracts were washed with brine (2 L) then dried over Na SO , filtered
and concentrated. Half of the residue was purified by prep-SFC (total of 450-injections, 6 min
run each) using the following conditions: Column: GreenSep Silica (ES Industries), 25 cm x 21.2
mm, Co-solvent: MeOH, % Co-solvent: 25% Isocratic, Flow rate = 60 g/min, Temperature:
ambient. Following the purification of this material, the pressure on the SFC was too high to
continue purification. The remaining dark MeOH solution of material was concentrated (~70 g),
dissolved in DCM and purified by silica gel chromatography (ISCO): 8 x 220g column, 75
mL/min, 0-3.5% MeOH/DCM (0.1% TEA) over 15 min, then holding at 3.5% MeOH until product
eluted. Some early fractions contained pure cis product. These were concentrated and
combined with the cis product from the SFC purification. The late fractions, which were yellow,
were concentrated and re-purified on 3 x 220 g columns the same way as described above. In
this case, some late fractions were pure trans product, and these fractions were isolated and
combined with the trans product from the SFC. All mixed fractions were combined and
concentrated to give ~36 g of material. This was then purified on the SFC and resulted in no
pressure problems. Concentration of the appropriate fractions afforded 42.7 g (33.5% yield) of
trans epoxide (1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazole
carbonitrile) and 72.7 g (57% yield) of cis epoxide (1-{[(3R,5S)methyloxaspiro[2.5]oct
yl]methyl}-1H-benzimidazolecarbonitrile). MS (m/z) 282.2 (M+H ).
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Route 2: The cis epoxide can be converted to trans-epoxide using the two step procedure
described below.
HO HO
NC NC
NC NC
trans
cis trans
1-{[(1S,3S)Hydroxy(hydroxymethyl)methylcyclohexaneyl]methyl}-1H-benzimidazole
carbonitrile
To a 3 L flask was added 1-{[(3R,5S)methyloxaspiro[2.5]octyl]methyl}-1H-
benzimidazolecarbonitrile (94.7 g, 337 mmol). The material was azeotroped two times with
EtOAc to remove any trace amounts of MeOH from the SFC. Next, to the residue was added
DMF (731 mL) and water (731 mL). The solution was cooled to ~18 °C (with an ice water bath).
Next, a solution of TFA (51.9 mL, 673 mmol) in water (731 mL) added (pre-cooled to ~10 °C).
The entire solution was then cooled with an ice water bath to ~10 °C. The temperature was
held around 10 °C for about 2.5 h then allowed to warm to RT and stir overnight. The next day,
DCM (500 mL) was added, and the solution was made basic by slowly adding 6N NaOH. The
mixture was added to a separatory funnel, the DCM separated and the aqueous layer diluted
with 6N NaOH (300 mL), and then extracted with DCM (8 x 250 mL). The combined organic
extracts were concentrated under reduced pressure to remove as much DMF as possible. The
residue was dissolved in DCM (250 mL) and stirred at RT to crystallize the trans diol. After
stirring overnight, the solution was cooled to ~10 °C, and the solids were filtered off, washed
with DCM and dried under reduced pressure. This yielded 49.15 g of 1-{[(1S,3S)hydroxy
(hydroxymethyl)methylcyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile (trans diol) as
a white solid. The filtrate (~60 g material, a mixture of cis-diol, trans-diol, and elimination side
products) was concentrated, loaded onto silica gel and split into 3 equal portions and purified on
the ISCO RF (3 x 330 g column): 0-5% MeOH/DCM over 15min, hold at 5% for 10 min, then 5-
% over 10 min, then hold at 25%. The trans diol product was combined with the solids from
the crystallization and used without further purification. MS (m/z) 300.2 (M+H ).
1-{[(3S,5S)Methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazolecarbonitrile
To a 1 L flask was added 1-{[(1S,3S)hydroxy(hydroxymethyl)
methylcyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile (21.2 g, 70.8 mmol) and DCM
PU64638
(698 mL) and the temperature was lowered to 5 °C. Next DMAP (6.49 g, 53.1 mmol), tosyl-Cl
(20.25 g, 106 mmol) and triethylamine (20.23 mL, 145 mmol) were added. The solution was
allowed to stir and warm to RT. Stirring was continued for 18 h and then the solution was added
to a separatory funnel and diluted with saturated aq NaHCO (1 L). The DCM was separated,
and washed sequentially with saturated aq NH Cl, then saturated aq NaHCO . The DCM was
then passed over a phase separator to remove leftover water, concentrated, and taken directly
onto the next step. To the yellow residue was added methanol (698 mL) followed by K CO
(10.77 g, 78 mmol). The mixture was stirred at RT for 3 h. Following completion, the solution
was filtered, and the solids were washed with MeOH. The mixture was then diluted with DCM
(500 mL) and saturated aq NaHCO (1 L). The solution was added to a 3 L separatory funnel,
and the aqueous layer extracted three times with DCM. The combined DCM extracts were
washed with brine and then dried over Na SO , filtered and concentrated. The crude solid was
azeotroped with EtOAc two times to give a yellow residue. The residue was dried under
reduced pressure to give 1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-
benzimidazolecarbonitrile as a yellow solid (19.9 g, 95% yield). MS (m/z) 282.2 (M+H ).
INTERMEDIATE 4
1-[(3S,5S)Oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile
A solution of trimethylsulfoxonium iodide (63.1 g, 287 mmol) in DMSO (500 mL) was
added sodium hydride (11.46 g, 287 mmol) in portions under nitrogen. The resulting mixture
was stirred at RT for 1 h. To the mixture was added a solution of 1-{[(1S)
oxocyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile (60.5 g, 239 mmol) in DMSO (500
mL) dropwise under nitrogen. The resulting light brown solution was stirred at RT for 1 h. LCMS
indicated the mixture was 9:1 trans/cis. Next, the DMSO solution was poured into 2 L water,
and then extracted with DCM (3x). The combined DCM extracts were washed with water (2 L)
and brine (2 L), and the organic layers were dried over Na SO , filtered and concentrated to
give 68 g of a tan solid. To the residue was added 500 mL of EtOAc. The mixture was heated
to reflux with stirring. Once all solids were in solution, the EtOAc was allowed to evaporate off
untill the amount of EtOAc was 320 mL, then the heating was stopped and the solution was
PU64638
allowed to cool to RT with stirring. Stirring was continued overnight at RT, then cooled to 5 C
and let stir for 3 h. The slurry was then filtered, washed with minimal amount of cold EtOAc,
followed by hexane. The resulting tan solid was dried under reduced pressure to give 1-
[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile (46g of a 95:5 trans:cis
mixture). The filtrate was concentrated to give 1-[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-
benzimidazolecarbonitrile (22 g, 61:39 trans:cis mixture) and the process repeated. The
products were used in subsequent steps as an intermediate. MS (m/z) 268 (M+H ).
INTERMEDIATE 5
3-{(5S,7S)[(6-Cyano-1H-benzimidazolyl)methyl]oxooxaazaspiro[4.5]dec
yl}-2,2-dimethylpropanoic acid
3-[({3-[(6-Cyano-1H-benzimidazolyl)methyl]hydroxycyclohexaneyl}methyl)amino]-2,2-
dimethylpropanoate
A solution of 1-[(5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile
(1.064 g, 3.98 mmol) and methyl 3-amino-2,2-dimethylpropanoate (0.679 g, 5.17 mmol) in
isopropanol (13.27 mL) was stirred at 100 C for 1 day. Reaction was concentrated and purified
via silica gel chromatography (ISCO, 120 g silica gel column. Solvent A was DCM and solvent
B was 0.1M NH in MeOH; 0-10% B over 15 min; 10% B over 6 min) to give methyl 3-[({3-[(6-
cyano-1H-benzimidazolyl)methyl]hydroxycyclohexaneyl}methyl)amino]-2,2-
dimethylpropanoate as a sticky solid (1.05 g, 66.1% yield). MS (m/z) 399.2 (M+H ).
Methyl 3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxaazaspiro[4.5]dec
yl}-2,2-dimethylpropanoate
A solution of methyl 3-[({3-[(6-cyano-1H-benzimidazolyl)methyl]
hydroxycyclohexaneyl}methyl)amino]-2,2-dimethylpropanoate (1.048 g, 2.63 mmol) and CDI
(0.853 g, 5.26 mmol) in 1,4-dioxane (15 mL) was stirred at 100 C for 1 day. The reaction was
then concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel column;
solvent A = DCM; solvent B = MeOH (0.1M NH ); 0-5% B over 15 min; then 5% B over 5 min) to
PU64638
give methyl 3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxa
azaspiro[4.5]decyl}-2,2-dimethylpropanoate as a beige solid (1.06 g, 95% yield). MS (m/z)
425.2 (M+H ).
3-{(5S,7S)[(6-Cyano-1H-benzimidazolyl)methyl]oxooxaazaspiro[4.5]decyl}-2,2-
dimethylpropanoic acid
A suspension of methyl 3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxo
oxaazaspiro[4.5]decyl}-2,2-dimethylpropanoate (1.06 g, 2.505 mmol) and potassium
trimethylsilanolate (0.482 g, 3.76 mmol) in THF (12.5 mL) was stirred at RT overnight. LCMS
showed the reaction was not complete. Additional potassium trimethylsilanolate (0.482 g, 3.76
mmol) was then added, and the reaction was stirred for one additional day. The reaction mixture
was then concentrated to a light yellow solid. The solid was washed with a mixture of DCM and
Et O and dried under vacuum to give 3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]
oxooxaazaspiro[4.5]decyl}-2,2-dimethylpropanoic acid as a light yellow solid. This
product was used in the next step without any further purification. MS (m/z) 411.2 (M+H ).
INTERMEDIATE 6
1-({(5S,7S)[(3-Methylpyrrolidinyl)methyl]oxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile
1,1-Dimethylethyl 3-{[({(1S,3S)[(6-cyano-1H-benzimidazolyl)methyl]
hydroxycyclohexaneyl}methyl)amino]methyl}methylpyrrolidinecarboxylate
A solution of 1,1-dimethylethyl 3-(aminomethyl)methylpyrrolidinecarboxylate (0.677
g, 3.16 mmol) and 1-[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile
(0.844 g, 3.16 mmol) in isopropanol (5 mL) was heated at 102 C overnight. The reaction
mixture was concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel
column. Solvent A : DCM; B: MeOH; 0-10% B: 15 min; 10% B: 10 min) to give 1,1-dimethylethyl
3-{[({(1S,3S)[(6-cyano-1H-benzimidazolyl)methyl]
PU64638
hydroxycyclohexaneyl}methyl)amino]methyl}methylpyrrolidinecarboxylate (950 mg, 62.4%
yield).
1,1-Dimethylethyl 3-({(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxa
azaspiro[4.5]decyl}methyl)methylpyrrolidinecarboxylate
1,1-Dimethylethyl3-{[({(1S,3S)[(6-cyano-1H-benzimidazolyl)methyl]
hydroxycyclohexaneyl}methyl)amino]methyl}methylpyrrolidinecarboxylate was treated with
CDI (1.537 g, 9.48 mmol) in 1,4-dioxane (5.00 mL) at 103 C overnight. The reaction mixture
was concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel column.
Solvent A : DCM; B: MeOH; 0-5% B: 10 min; 5%B: 10 min) to give 1,1-dimethylethyl 3-
({(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxaazaspiro[4.5]dec
yl}methyl)methylpyrrolidinecarboxylate as a white foam (752 mg, 46.9% yield). MS (m/z)
508.3 (M+H ).
1-({(5S,7S)[(3-Methylpyrrolidinyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1,1-Dimethylethyl 3-({(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxa
azaspiro[4.5]decyl}methyl)methylpyrrolidinecarboxylate (747 mg, 1.472 mmol) was
treated with hydrochloric acid (4M in dioxane) (4 mL, 16.00 mmol) overnight. The rxn was
concentrated to 1-({(5S,7S)[(3-methylpyrrolidinyl)methyl]oxooxaazaspiro[4.5]dec-
7-yl}methyl)-1H-benzimidazolecarbonitrile as a crispy foam. MS (m/z) 408.2 (M+H ). The
product was used without further purification.
INTERMEDIATE 7
1-{[(5S,7S)Methyloxo(2-propynyl)oxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
To a 20 mL microwave tube was added 1-{[(3S,5S)methyloxaspiro[2.5]oct
yl]methyl}-1H-benzimidazolecarbonitrile (840 mg, 2.99 mmol) and propargyl amine (822 mg,
PU64638
14.93 mmol) in MeOH (5 mL). The tube was sealed and heated at 100 C for 2 h on a hotplate.
The reaction mixture was then evaporated down directly to a crispy foam, codistilled 2x with
DCM, and left on highvac for 3 h to remove any residual MeOH and the volatile amine. The
yellow residue was then treated with CDI (2.42 g, 14.93 mmol) and 1,4-dioxane (5 mL) was
added. The reaction mixture was stirred and heated at 100 ºC for 2 h, then left at RT overnight.
LCMS then indicated the reaction was not complete. The reaction mixture was then heated at
120 ºC for 6 h. The mixture (dark orange oil) was loaded onto florisil and purified using silica gel
chromatography (ISCO): 0.5-5% MeOH/DCM (30 min), 5% (10 min), 120 g silica. The desired
product eluted at 18 min. The product was dried under vacuum at RT overnight to yield 1-
{[(5S,7S)methyloxo(2-propynyl)oxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile as an yellow oil (109 mg, 5% yield). MS (m/z) 363 (M+H ).
INTERMEDIATE 8
1-{[(5S,7S)Methyloxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile
Route 1:
1-(((5S,7S)(4-methoxybenzyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile may be prepared using procedures analogous to
Example 4 using 4-methoxybenzylamine as an amine to react with 1-{[(3S,5S)methyl
oxaspiro[2.5]octyl]methyl}-1H-benzimidazolecarbonitrile.
Alternatively, 1-(((5S,7S)(4-methoxybenzyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile may also be prepared
using procedures analogous to Example 12 using methyl iodide as an alkylating agent instead
of benzyl chloromethyl ether in reaction with the enolate of 3-{[4-(methyloxy)phenyl]methyl}
oxooxaazaspiro[4.5]decanecarboxylate (see Scheme 8). The modification to Scheme 8
required to prepare enantiomerically pure material is at the intermediate trans-(3-(4-
methoxybenzyl)methyloxooxaazaspiro[4.5]decanyl)methyl methanesulfonate
stage. This racemic mixture (10 g) was separated into the enantiomers using SFC chiral
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chromatography (Chiralpak AS-H, Co-solvent: EtOH (35% Isocratic), 4 mL/min, 8 min/per
injection, Column Temp. = 40.1 °C, Front Pressure = 133 bar, Back Pressure = 100 bar). Peak
2 gave the desired enantiomer, ((5S,7S)(4-methoxybenzyl)methyloxooxa
azaspiro[4.5]decanyl)methyl methanesulfonate (4.25 g, 42.5%), as a white solid.
A yellow solution of 1-(((5S,7S)(4-methoxybenzyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (2.012 g, 4.53 mmol) in
TFA (20.12 ml) was heated at 70 ºC. The reaction mixture turned dark brown overnight.
Additional TFA (5 mL) was then added to the reaction mixture. After 21 h, additional TFA (5
mL) was added. After 23 h, reaction was completed as indicated by LCMS. The reaction
mixture was then cooled to RT and concentrated. 2N NaOH (40 mL) and DCM (50 mL) were
added to the mixture (aqueous layer was pH 13). The layers were separated and the aqueous
layer was extracted with DCM (2 X 25 mL). Combined organic layers were dried over Na SO ,
filtered, and concentrated. The compound was loaded onto florisil and purified using silica gel
chromatography (ISCO): 1-5% MeOH/DCM (30 min), 5% (15 min), 40 g silica. Product began
eluting at 22 minutues. The product was dried under high vacuum at 40 ºC overnight to yield 1-
{[(5S,7S)methyloxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile
as a yellow solid (729 mg, 47.2% yield). MS (m/z) 325 (M+H ).
Route 2:
A mixture of ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.259 g, 2.310 mmol) in
NMP (8.89 mL) was heated at 100 ºC for 15 min. 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (0.500 g, 1.777 mmol) was then added. The
reaction mixture was stirred overnight (stopped heating at some point because of storm power
outage). The reaction mixture was heated at 100 ºC and stirred for an additional 6 h. Additional
ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.065 g, 0.578 mmol) were added and stirred
for 16 h. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.130 g, 1.156 mmol)
were then added and heated at 110 ºC for 16 h. The reaction mixture was heated at 130 ºC for
2 days. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.065 g, 0.578 mmol)
were added and mixture stirred for additional 3 h. The reaction mixture was heated at 110 ºC
for an additional 3 days, followed by the addition of 2N NaOH (30 mL) and EtOAc (75 mL). The
layers were then separated and the organic layer washed with water (3 x 50 mL). The organic
layer was dried over Na SO , filtered, and concentrated. The compound was loaded onto florisil
and purified using silica gel chromatography (ISCO): 1-3.5% MeOH/DCM (18 min), 3.5% (7
min), 25 g silica. Product eluted at 13 min. The product was dried under high vacuum at 40 ºC
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overnight. 1-{[(5S,7S)methyloxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole-
6-carbonitrile was obtained as a white solid (336 mg, 55.4% yield). MS (m/z) 325 (M+H ).
INTERMEDIATE 9
1-{[(5S,7S)Methyloxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile
A suspension of 1-[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazole
carbonitrile (760 mg, 2.84 mmol) in MeOH (8 mL) was treated with 7M ammonia in MeOH
(1.429 mL, 10.00 mmol) in a 20 mL microwave vial. The vial was sealed and heated in a
microwave at 100 °C for 3 h. The reaction mixture was cooled to RT and blown down to
dryness with nitrogen for 24 h to give crude 1-{[(1S,3S)(aminomethyl)
hydroxycyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile which was used without further
purification. A solution of 1-{[(1S,3S)(aminomethyl)hydroxycyclohexaneyl]methyl}-1H-
benzimidazolecarbonitrile (808 mg, 2.84 mmol) in THF (24 mL) was sealed under nitrogen in
three 20 mL microwave vials and heated with microwave at 160 °C for 3 h. The combined
reaction mixture was then concentrated to dryness and 50 mL of water was added. The solid
was then filtered and washed with 2 x 10 mL of water. The solid was air-dried under house
vacuum overnight. The compound was purified under normal phase flash column
chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%) to give 1-
{[(5S,7S)oxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile as an
off-white solid (856 mg, 97 % yield). The aromatic region of the NMR spectra showed that the
product contained less than 8% of the cis-diastereomer. MS (m/z) 311.1 (M+H ).
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INTERMEDIATE 10
1-((3S,5S)Oxaspiro[2.5]octanylmethyl)fluoro-1H-benzo[d]imidazole
carbonitrile
1-Bromo-2,5-difluoronitrobenzene
To a stirred solution of 2-bromo-1,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of
concentrated H SO was added KNO by portions at 0 C. After this addition, the mixture was
2 4 3
allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold
water and extracted with DCM. The combined organic layers were washed with brine, dried over
Na SO and concentrated to give 1-bromo-2,5-difluoronitro-benzene (95 g, 78.1% yield) as a
yellow solid. H NMR (400 MHz, CDCl ) δ 7.91-7.87 (dd, 1H), 7.52-7.57 (dd, 1H).
2,5-Difluoronitrobenzonitrile
A mixture of 1-bromo-2,5-difluoronitro-benzene (95 g, 399 mmol) and CuCN (71.8 g,
798 mmol) in NMP (700 mL) was set to a pre-heated 160 C oil-base and stirred at 160 C
under N over 450 min. The mixture was cooled to RT, charged with Na SO (300 g) and MTBE
2 2 4
(1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was
charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The
combined organic layers were washed with water and brine, dried over Na SO and
concentrated. The material was recrystallized from EtOH/water (2/1) to yield 2,5-Difluoro
nitro-benzonitrile (50 g, 68% yield) as a pale brown solid. H NMR (400 MHz, CDCl ) δ 7.96-
7.95 (dd, 1H), 7.67-7.64 (dd, 1H).
1-((3S,5S)oxaspiro[2.5]octanylmethyl)fluoro-1H-benzo[d]imidazolecarbonitrile
1-((3S,5S)oxaspiro[2.5]octanylmethyl)fluoro-1H-benzo[d]imidazolecarbonitrile
may be prepared using procedures analogous to those described for Intermediate 4. MS (m/z)
286 (M+H ).
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INTERMEDIATE 11
4-Chloro[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile
4-Aminochlorofluorobenzonitrile
A solution of 4-aminofluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185
mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed ~17% of
starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for
1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH
(100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts
were dried over Na SO and concentrated to a pink solid. The NMR spectrum showed some of
the succinimate side product still remained. The crude product was washed with H O and air
dried to give the desired product as a beige solid. This product was used in the next step
without any futher purification. MS (m/z) 171.1 (M+H ).
3-Chlorofluoronitrobenzonitrile
Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to
60 C. A solution of 4-aminochlorofluorobenzonitrile (29.02 g, 170 mmol) in acetic acid
(500 mL) was added dropwise and the reaction was stirred at 60 C for 16 h. The LCMS the
indicated the reaction showed ~50% conversion. Additional sodium perborate tetrahydrate (14.4
g) was added and the reaction stirred at 70 C for 2 h. Then additional sodium perborate
tetrahydrate (70 g) was added and the reaction was stirred at 80 C for 5 h, followed by RT for 2
days. The reaction was then poured into ice water and extracted with EtOAc (3x). The
combined organic extracts were washed with H O (2x), brine, dried over MgSO and
concentrated. When most of the acetic acid was evaporated, water was added to the residue.
The orange precipitate was collected by filtration, washed with H O and air dried to give the
crude product as an orange solid. NMR showed the product contaminated with ~10% of
starting material. This product was used without any further purification.
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4-Chloro[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile
4-Chloro[(3S,5S)oxaspiro[2.5]octylmethyl]-1H-benzimidazolecarbonitrile may
be prepared using procedures analogous to those described for Intermediate 4. MS (m/z) 302.1
(M+H ).
INTERMEDIATE 12
1-{[(5S,7R)(Hydroxymethyl)oxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
Methyl 3-hydroxycyclohexanecarboxylate
Methyl 3-hydroxycyclohexanecarboxylate (70.0 g, 460 mmol) and rhodium on alumina
(7.5 g, 460 mmol) were added to a nitrogen purged 2 L Parr flask. Ethanol (300 mL) was
carefully added and the flask was then shaken under hydrogen pressure (55 psi) on the Parr
hydrogenator for 18 h. The Parr flask was carefully purged with N . The reaction mixture was
filtered through a plug of Celite©, and the eluent was evaporated to provide the crude title
compound which was used without further purification. H NMR (400 MHz, CDCl ) δ 3.66 (s,
3H), 2.64-2.74 (m, 2H), 1.97-2.05 (m, 2H), 1.64-1.83 (m, 3H), 1.46-1.54 (m, 2H), 1.22-1.30 (m,
1H).
Methyl 3-oxocyclohexanecarboxylate
Ruthenium (IV) oxide hydrate (1.47 g, 11.1 mmol) and sodium bromate (100 g, 664
mmol) were combined in diethyl ether (600 mL) and water (300 mL). The resulting black
mixture was stirred for 10 min and then cooled in an ice bath. Methyl 3-
hydroxycyclohexanecarboxylate (35 g, 221 mmol) was dissolved in ether (to bring total volume
to 100 mL) and was added dropwise to the ice cold reaction mixture. The temperature was not
allowed to go above 30 °C. The reaction mixture was stirred for 1 h with the reaction
temperature at ~15 °C. Isopropanol was carefully added to the reaction mixture at a rate
necessary to keep the reaction temperature at ~27 °C. The layers were separated and the
organic layers were washed with ether. The combined organics were washed with saturated
aqueous NaHCO solution and brine. The organics were then dried over MgSO , filtered, and
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concentrated to provide methyl 3-oxocyclohexanecarboxylate (34.5 g, 100 % yield) which was
used without further purification. H NMR (400 MHz, CDCl ) δ 3.68 (s, 3H), 2.79 (m, 1H), 2.52
(d, J = 7.78 Hz, 2H), 2.23 - 2.42 (m, 2H), 1.98 - 2.15 (m, 2H), 1.82 (d, J = 10.29 Hz, 1H), 1.61 -
1.77 (m, 1H).
Methyl 1-oxaspiro[2.5]octanecarboxylate
To a solution of trimethylsulfoxonium iodide (53.3 g, 242 mmol) in dry DMSO (300 mL)
under N , was added sodium hydride (9.69 g, 242 mmol) portionwise over 30 min. This light
yellow mixture was stirred at RT for 1 h. The reaction mixture was then cooled in an ice bath
and treated with methyl 3-oxocyclohexanecarboxylate (29.0 g, 186 mmol) dropwise while
maintaining a temperature at or below 27 °C. The resulting reaction mixture was allowed to
warm slowly to RT and stir overnight. The reaction was diluted with water and extracted with
DCM. The combined organics were washed with water, dried over MgSO , filtered, and
concentrated to provide methyl 1-oxaspiro[2.5]octanecarboxylate (31.8 g, 85 % yield) which
was used without further purification. H NMR (400 MHz, CDCl ) δ 3.66 (s, 3H), 2.71 (m, 1H),
2.65 (d, J = 1.76 Hz, 2H), 2.00 (dd J = 11.8, 13.6 Hz, 2H), 1.74 - 1.85 (m, 2H), 1.60 - 1.74 (m,
1H), 1.40 - 1.56 (m, 2H), 1.17 - 1.32 (m, 1H).
Methyl 3-{[4-(methyloxy)phenyl]methyl}oxooxaazaspiro[4.5]decanecarboxylate
To methyl 1-oxaspiro[2.5]octanecarboxylate (5 g, 29.4 mmol) (about 6:1 trans:cis)
dissolved in MeOH (8.39 mL) was added 4-methoxybenzylamine (4.03 g, 29.4 mmol). This
reaction mixture was heated at 110 ºC behind a blast shield for 18 h. The reaction was then
cooled to RT and concentrated. The compound was loaded onto florisil and purified using silica
gel chromatography (ISCO): 0-10% MeOH/DCM (35 min), 10% (20 min), 120 g silica. The
product began eluting at 41 minutes and pure fractions were concentrated to yield an orange oil
(5.693 g). The oil was dissolved in 1,4-dioxane (50.4 mL), and CDI (9.53 g, 58.8 mmol) was
added. The reaction mixture was heated at 110 ºC for 16 h. The reaction was then
concentrated to an orange solid and EtOAc (150 mL) and 1N HCl (100 mL) were added. The
layers were separated and the organic layer was washed with 1N HCl (50 mL). The organic
layer was then dried over Na SO , filtered, and concentrated. The compound was loaded onto
florisil and purified using silica gel chromatography (ISCO): 5-35% ethyl acetate/hexanes (30
min), 80 g silica to obtain methyl 3-{[4-(methyloxy)phenyl]methyl}oxooxa
azaspiro[4.5]decanecarboxylate as a light yellow solid (5.05 g, 49% yield). MS (m/z) 334.0
(M+H ).
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Methyl 3-{[4-(methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxa
azaspiro[4.5]decanecarboxylate
To a solution of methyl 3-{[4-(methyloxy)phenyl]methyl}oxooxa
azaspiro[4.5]decanecarboxylate (5.05 g, 15.15 mmol) in THF (38.7 mL) under nitrogen at
-78 ºC was added sodium bis(trimethylsilyl)amide, (1M in THF, 45.4 mL, 45.4 mmol) over 30
minutes. The reaction mixture was stirred at -78 ºC for 1 h. Benzyl chloromethyl ether (7.12 g,
45.4 mmol) was then added. After 1 h, the reaction was quenched slowly with water (5 mL).
Saturated aq NaCl (100 mL) was then added and the mixture was extracted with EtOAc (2 x
125 mL). The combined organic layers were dried over Na SO , filtered, and concentrated. The
compound was then loaded onto florisil and purified using silica gel chromatography (ISCO): 10-
% ethyl acetate/hexanes (30 min), 25% (5 min.), 25-45% (15 min), 45% (5 min), 120 g silica.
The product eluted at 45 minutes. Methyl 3-{[4-(methyloxy)phenyl]methyl}oxo
{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decanecarboxylate was obtainted as a light
yellow oil (4.62 g, 64% yield) and NMR and LCMS were 95% clean for trans product. MS (m/z)
454.0 (M+H ).
7-(Hydroxymethyl){[4-(methyloxy)phenyl]methyl}{[(phenylmethyl)oxy]methyl}oxa
azaspiro[4.5]decanone
To a solution of methyl 3-{[4-(methyloxy)phenyl]methyl}oxo
{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decanecarboxylate (6.523 g, 14.38 mmol)
in THF (27.9 mL) under nitrogen at -78 ºC was added lithium aluminium hydride (1M in THF,
71.9 mL, 71.9 mmol) over 10 minutes and stirred for 2 days. The reaction was then quenched
slowly with water (5 mL), followed by the addition of 2N HCl (200 mL). The reaction mixture was
then extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over Na SO ,
filtered, and concentrated. To the solution in THF (27.9 mL) was added lithium borohydride (2N
in THF, 10.79 mL, 21.57 mmol) and the mixture was stirred for 30 minutes, then heated at 50
ºC. The additional lithium borohydride (2N in THF, 3.6 mL, 7.19 mmol) was added. The reaction
mixture was then cooled to RT and quenched slowly with 2N HCl (100 mL). The mixture was
then extracted with EtOAc (2 x 100 mL) and the combined organic layers were dried over
Na SO , filtered, and concentrated. The mixture was then loaded onto florisil and purified using
silica gel chromatography (ISCO): 10-80% ethyl acetate/hexanes (30 min), 80% (5 min), 80 g
silica. The product eluted at 26 minutes to yield 7-(Hydroxymethyl){[4-
PU64638
(methyloxy)phenyl]methyl}{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decanone as
a colorless oil (5.2 g, 81% yield). MS (m/z) 426.1 (M+H ).
(3-{[4-(Methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]dec-
7-yl)methyl methanesulfonate
To a solution of 7-((benzyloxy)methyl)(hydroxymethyl)(4-methoxybenzyl)oxa
azaspiro[4.5]decanone (5.26 g, 12.36 mmol) in DCM (56 mL) at RT was added DIEA (4.32
mL, 24.7 mmol) and methanesulfonyl chloride (1.25 mL, 16.1 mmol). After 1 h, 2N HCl (100
mL) was added to the reaction. The layers were separated, and the aqueous layer was washed
with DCM (100 mL). The combined organics were dried over sodium sulfate, filtered, and
concentrated. The crude product was purified on a 80 g silica gel column (10-70%
EtOAc/hexanes, 30 min gradient; 70% EtOAc/hexanes, 5 min; 60 mL/min elution; 254 nm
detection) to afford (3-{[4-(Methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxa-
3-azaspiro[4.5]decyl)methyl methanesulfonate (5.71 g, 87% yield). MS (m/z) 504.2 (M+H ).
7-(Azidomethyl){[4-(methyloxy)phenyl]methyl}{[(phenylmethyl)oxy]methyl}oxa
azaspiro[4.5]decanone
To a light orange solution of (7-((benzyloxy)methyl)(4-methoxybenzyl)oxooxa
azaspiro[4.5]decanyl)methyl methanesulfonate (5.71 g, 11.3 mmol) in DMSO (45.4 mL) was
added sodium azide (2.21 g, 34.0 mmol). The reaction was heated at 120 ºC behind a blast
shield. After 4 days the reaction was cooled to RT and diluted with 1:1 EtOAc:Et O (150 mL).
This mixture was washed with water (3 x 100 mL), and the resulting organic layer was dried
over magnesium sulphate, filtered, and concentrated to provide 7-(azidomethyl){[4-
(methyloxy)phenyl]methyl}{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decanone
(4.78 g, 89% crude yield) which was used without further purification. MS (m/z) 451.0 (M+H ).
7-(Aminomethyl){[4-(methyloxy)phenyl]methyl}{[(phenylmethyl)oxy]methyl}oxa
azaspiro[4.5]decanone
To an orange solution of 7-(azidomethyl)((benzyloxy)methyl)(4-methoxybenzyl)
oxaazaspiro[4.5]decanone (4.78 g, 10.6 mmol) in MeOH (141 mL) was added nickel (II)
chloride hexahydrate (2.52 g, 10.6 mmol). The reaction mixture was cooled to 0 °C, and with
quick stirring, sodium borohydride (0.802 g, 21.2 mmol) was added in 4 portions. The reaction
turned from green to black with significant gas evolution. After 1 h, the reaction mixture was
filtered through a pad of Celite©. The filtrate was concentrated and treated with 1N NaOH (100
PU64638
mL) and EtOAc (300 mL). A green suspension formed which was filtered through celite. The
layers were separated, and the aqueous layer was washed with EtOAc (50 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and concentrated to the crude title
compound (4.27 g, 90% crude yield) as an orange oil which was used without further
purification. MS (m/z) 425.1 (M+H ).
3-{[(3-{[4-(Methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxa
azaspiro[4.5]decyl)methyl]amino}nitrobenzonitrile
To a light yellow solution of 7-(aminomethyl)((benzyloxy)methyl)(4-methoxybenzyl)-
1-oxaazaspiro[4.5]decanone (4.27 g, 10.1 mmol) in acetonitrile (67.1 mL) was added
potassium carbonate (2.78 g, 20.1 mmol) and 3-fluoronitrobenzonitrile (2.51 g, 15.1 mmol)
and the reaction was stirred at RT. After stirring 15 h, the reaction was filtered through a frit.
The collected inorganics were washed with DCM/EtOAc. The filtrate was concentrated onto
florisil and purified on a 80 g silica gel column (20-55% EtOAc/hexanes, 30 min gradient; 55%
EtOAc/hexanes, 5 min.; 60 mL/min elution; 254 nm detection) to provide 3-{[(3-{[4-
(methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]dec
yl)methyl]amino}nitrobenzonitrile (5.02 g, 83% yield) as a reddish-orange oil. MS (m/z) 571.0
(M+H ).
1-[(3-{[4-(Methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile
To an orange suspension of 3-((7-((benzyloxy)methyl)(4-methoxybenzyl)oxo
oxaazaspiro[4.5]decanyl)methyl)amino)nitrobenzonitrile (5.02 g, 8.80 mmol) in MeOH
(74.9 mL) was added iron (4.91 g, 88.0 mmol), trimethyl orthoformate (9.72 mL, 88.0 mmol),
and formic acid (3.37 mL, 88 mmol). The reaction was stirred at 65 ºC for 17 h and found to
have 90% conversion to product by LCMS. Additional iron (0.98 g, 17.6 mmol) and trimethyl
orthoformate (1.94 mL, 17.6 mmol) were added to the reaction. After 2 h, the reaction was
cooled to RT and diluted with EtOAc (50 mL) and DCM (50 mL). The mixture was filtered
through Celite© and concentrated. The crude material was suspended in 2N NaOH (75 mL)
and extracted into EtOAc (2 x 100 mL). The combined organics were dried over sodium sulfate,
filtered, and concentrated onto florisil for purification on a 80 g silica gel column (25-100 %
EtOAc/hexanes, 25 min gradient; 100% EtOAc, 10 min; 60 mL/min elution; 254 nm detection)
yielding 1-[(3-{[4-(methyloxy)phenyl]methyl}oxo{[(phenylmethyl)oxy]methyl}oxa
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azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile (3.51 g, 70.3 % yield) as a yellow
foam. MS (m/z) 551.1 (M+H ).
1-[(2-Oxo{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
To a colorless solution of 1-[(3-{[4-(methyloxy)phenyl]methyl}oxo
{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decyl)methyl]-1H-benzimidazole
carbonitrile (1.55 g, 2.81 mmol) in acetonitrile (28.1 mL) was added ceric ammonium nitrate
(3.09 g, 5.63 mmol) and the mixture was stirred at room temperature. The reaction was then
heated to 60 ºC and stirred for 22 h. The reaction was then cooled to RT and the orange
suspension was filtered using Buchner vacuum filtration. The solid was rinsed with MeCN (3 x
mL) and the filtrate concentrated to yield a glassy orange oil. Ethyl acetate (75 mL) and 2 N
NaOH (50 mL) were then added. The mixture was filtered using Buchner vacuum filtration. The
filtrate layers were separated and the aqueous layer was washed with EtOAc (50 mL). The
combined organic layers were dried over Na SO , filtered, and concentrated. The concentrated
organic layer was loaded onto florisil and purified using silica gel chromatography (ISCO): 1-4%
methanol/dichloromethane (25 min), 40 g silica. The product eluted at 11 minutes to yield 1-[(2-
oxo{[(phenylmethyl)oxy]methyl}oxaazaspiro[4.5]decyl)methyl]-1H-benzimidazole
carbonitrile as a orange foam (653 mg, 51% yield). MS (m/z) 431.0 (M+H ).
1-{[(5S,7R)(Hydroxymethyl)oxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole-
6-carbonitrile
To a light orange suspension of 1-((7-((benzyloxy)methyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (0.120 g, 0.279 mmol) in
1,4-dioxane (2.157 mL) was added concentrated hydrobromic acid (0.631 mL, 5.57 mmol). The
reaction mixture was heated at 70 ºC for 17 h. The reaction was then cooled to RT. Next, 6N
NaOH was added till the pH was adjusted to 13 and then the mixture extracted with EtOAc (2 x
mL). The combined organic layers were dried over Na SO , filtered, and concentrated. The
compound was loaded onto florisil and purified using silica gel chromatography: 1-5%
methanol/dichloromethane (25 min), 4 g silica. The product eluted early from 2-10 mintues.
Next, the compound was loaded onto florisil and purified using silica gel chromatography: 1-
% methanol/dichloromethane (30 min), 12 g silica. The product did not elute cleanly but did
yield 1-{[(5S,7R)(hydroxymethyl)oxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile (70% pure, 62 mg, 46% yield). MS (m/z) 341.0 (M+H ).
PU64638
EXAMPLE 1
1-({(5S,7S)[3-(1,1-Dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile
Bis(1,1-dimethylethyl) [3-(1,1-dimethylethyl)isoxazolyl]imidodicarbonate
-Aminotert-butylisoxazole (50 g, 357 mmol) and Boc O (174 mL, 749 mmol) were
dissolved in dichloromethane (DCM) (300 mL) in a 500 mL round bottom flask. TEA (54.7 mL,
392 mmol) and DMAP (0.436 g, 3.57 mmol) were added and the mixture stirred overnight. After
18 h stirring, additional Boc O (5 g, 35.7 mmol) was added and the reaction stirred overnight.
Additional Boc O (2 g, 14.3 mmol) was added and the reaction was stirred for 5 h. The reaction
mixture was poured into water (300 mL) and the layers separated. The organic layer was
washed three times with water, dried over MgSO , filtered and concentrated under reduced
pressure. The residue was dissolved and evaporated three times with toluene and the residue
dried under high vacuum to obtain bis(1,1-dimethylethyl) [3-(1,1-dimethylethyl)
isoxazolyl]imidodicarbonate as a solid (116.6 g, 96% yield). MS (m/z) 341.2 (M+H ).
1-({(5S,7S)[3-(1,1-Dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile
To a 250 mL flask was added potassium tert-butoxide (7.18 g, 64.0 mmol), bis(1,1-
dimethylethyl) [3-(1,1-dimethylethyl)isoxazolyl]imidodicarbonate (21.78 g, 64.0 mmol) and 1-
{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazolecarbonitrile (15 g, 53.3
mmol) followed by NMP (142 mL). The reaction was stirred at 115 C for 19 h and then cooled
to RT, diluted with DCM and saturated aq NaHCO . The organic layer was separated, and the
aqueous layer was extracted 2 more times with DCM. The combined DCM extracts were
combined, washed with water, then brine, and dried over Na SO , filtered and concentrated to
afford the crude residue which contained NMP. To the residue was added about 150 mL of
ACN, then water was slowly added until the solution became cloudy. To the cloudy solution
was added a small crystalline seed, and the volume of the solution was slowly increased by
adding 1 L of water. The solution was stirrred at RT for about 2 h and then filtered. The solids
were added to a 1 L flask follwed by 400 mL of IPA. The solution was heated to reflux, then
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cooled to RT, and water was added until a volume of ~900 mL. The solution was stirred for ~30
min, then the solids were filtered off. The filtrate was added to a separatory funnel and
extracted with DCM to remove any remaining organics. The resulting tan solids were added to
a 500 mL flask and slurried in 200 mL of IPA overnight. The next day, the slurry was filtered
and concentrated. The filtrate was concentrated to give 2.5 g of residue that was purified by
silica gel chromatography (ISCO) (Column 1): 120 g column, 0-10% MeOH/DCM over 30 min.
The solid (12 g) was purified via ISCO (Column 2): 330 g column, 0-10% MeOH/DCM over 60
min. The mother liquor residue from the 2nd crystallization was purified via ISCO (Column 3)
using a 330 g column using the same conditions as above. All fractions containing desired
product were concentrated to give brown solid that contained impurities. Impure fractions from
column 1 and 2 were combined and repurified on a 120 g column (Column 4). Impure fractions
were purified on another 120 g column (Column 5). All fractions containing product from column
and 3 were combined and purified by SFC. All isolated pure fractions from columns 1, 2 and 4
were combined and concentrated. To the residue was added ~250 mL of IPA, and the mixture
was heated to 80 C and then slowly cooled to RT. The product formed white crystals. The
solution stirred at RT for 1 h, then cooled to 5 C with an ice/water bath. The mixture was stirred
at 5 C for 1 h, then the solid was filtered off, washed with IPA and dried under reduced
pressure to give the desired product as an off white solid (11 g). The filtrate was concentrated
to give a brown residue. All fractions containing desired product from columns 5 and 3 were
combined along with the filtrate and purified by SFC. Concentration of the MeOH from the SFC
gave the product as an off white residue. This residue was disolved in IPA and added to the 11
g of solids collected above. The material was slurried in IPA for ~2 h, then filtered, and the
solids were washed with IPA. The solids were then dried under reduced pressure to give 1-
({(5S,7S)[3-(1,1-dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile as a white solid (14.58 g, 60.5% yield). H NMR
(400 MHz, CDCl3) δ 8.25 (br. s., 1H), 7.92 (d, J = 8.28 Hz, 1H), 7.76 (s, 1H), 7.59 (dd, J = 1.25,
8.28 Hz, 1H), 6.17 (s, 1H), 4.04 (s, 2H), 3.83 (q, 2H), 2.09 (br. s., 1H), 1.93 (d, J = 14.05 Hz,
1H), 1.70 - 1.80 (m, 1H), 1.64 (d, J = 12.80 Hz, 1H), 1.57 (d, J = 14.05 Hz, 1H), 1.36 - 1.49 (m,
3H), 1.32 (s, 9H), 1.28 (s, 3H). MS (m/z) 448.2 (M+H ).
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EXAMPLE 2
1-(((5S,7S)(3-(2-Cyanopropanyl)isoxazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
1,1-Dimethylethyl [3-(1-cyanomethylethyl)isoxazolyl]carbamate
2-(5-Aminoisoxazolyl)methylpropanenitrile (1.5 g, 9.92 mmol) and Boc O (2.304
mL, 9.92 mmol) were dissolved in DCM (25 mL). Triethylamine (1.383 mL, 9.92 mmol) and
DMAP (0.012 g, 0.099 mmol) were added and the mixture stirred at RT for 16 h. The mixture
was then concentrated, chased with DCM and concentrated. The product (2.4 g) was used
without further purification. MS (m/z) 252.2 (M+H ).
1-(((5S,7S)(3-(2-Cyanopropanyl)isoxazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazolecarbonitrile
(100 mg, 0.355 mmol) and potassium tert-butoxide (51.8 mg, 0.462 mmol) were added to a 20
mL microwave vial with nitrogen purging. 1,1-Dimethylethyl [3-(1-cyanomethylethyl)
isoxazolyl]carbamate (357 mg, 1.422 mmol) dissolved in NMP (3 mL) was then added. The vial
was capped and heated to 125 °C for 16 h. The reaction mixture was purified by RP Gilson
HPLC; 10-90% MeCN/H O, 0.1% TFA to yield 10.9 mg of product. The reaction was repeated
using similar procedures as above using 150 mg of 1-{[(3S,5S)methyloxaspiro[2.5]oct
yl]methyl}-1H-benzimidazolecarbonitrile and 3 equivalents of 1,1-dimethylethyl [3-(1-cyano
methylethyl)isoxazolyl]carbamate. The reaction was heated for 3 h. The mixture was filtered
and purified by RP Gilson HPLC; 10-90% MeCN/H O, 0.1% TFA 30 x 150 mm Waters Sunfire,
40 mL/min, 14 min. Fractions were concentrated and the TFA salt of 1-(((5S,7S)(3-(2-
cyanopropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile was isolated (55 mg, 25.7% yield). H NMR (400 MHz, CDCl )
δ 10.60 (br. s., 1H), 9.14 (s, 1H), 8.07 (d, J = 8.53 Hz, 1H), 8.01 (s, 1H), 7.78 (dd, J = 1.25, 8.53
Hz, 1H), 6.29 (s, 1H), 4.25 (d, 2H), 3.92 (s, 2H), 2.08 - 2.17 (m, 1H), 1.98 - 2.05 (m, 1H), 1.87 -
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1.98 (m, 1H), 1.75 - 1.85 (m, 2H), 1.73 (s, 6H), 1.60 - 1.68 (m, 1H), 1.53 - 1.61 (m, 1H), 1.42 -
1.53 (m, 1H), 1.28 (s, 3H). MS (m/z) 459.3 (M+H ).
EXAMPLE 3
1-({(5S,7S)[5-(1,1-Dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile
1,1-Dimethylethyl [5-(1,1-dimethylethyl)isoxazolyl]carbamate
-(1,1-Dimethylethyl)isoxazolamine (500 mg, 3.57 mmol), Boc O (0.828 mL, 3.57
mmol), DMAP (4.36 mg, 0.036 mmol) and TEA (0.497 mL, 3.57 mmol) were dissolved in DCM
(8 mL) in a 50 mL round bottom flask. The mixture was stirred over night. The mixture was
evaporated, and crude 1,1-dimethylethyl [5-(1,1-dimethylethyl)isoxazolyl]carbamate used
without purification. MS (m/z) 241.2 (M+H ).
1-({(5S,7S)[5-(1,1-Dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile
1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazolecarbonitrile
(150 mg, 0.533 mmol), 1,1-dimethylethyl [5-(1,1-dimethylethyl)isoxazolyl]carbamate (320 mg,
1.333 mmol) and potassium tert-butoxide (78 mg, 0.693 mmol) were added to a 10 mL
microwave vial while nitrogen purging. Then, NMP (3 mL) was added and the vial was capped
and heated to 125 °C for 16 h. The reaction was filtered and purified to give 42 mg (13.3%) of
1-({(5S,7S)[5-(1,1-dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile. H NMR (400 MHz, MeOH-d ) δ 8.43 (br. s., 1H),
8.19 (s, 1H), 7.82 (d, J = 8.28 Hz, 1H), 7.58 (d, J = 8.28 Hz, 1H), 6.56 (s, 1H), 4.19 (s, 2H), 3.66
- 3.79 (m, 2H), 2.04 (d, J = 5.77 Hz, 1H), 1.95 (d, J = 14.05 Hz, 1H), 1.78 - 1.90 (m, 1H), 1.65 -
1.78 (m, 2H), 1.40 - 1.63 (m, 3H), 1.32 (s, 9H), 1.18 (s, 3H). MS (m/z) 448.3 (M+H ).
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EXAMPLE 4
1-{[(5S,7S)Methyloxo(2-pyridinylmethyl)oxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
A 5 mL microsome vial was charged with 1-{[(3S,5S)methyloxaspiro[2.5]oct
yl]methyl}-1H-benzimidazolecarbonitrile (100 mg, 0.355 mmol), (2-pyridinylmethyl)amine
(38.4 mg, 0.355 mmol) and MeOH (4 mL). The tube was sealed and heated to 120 °C for 18 h.
The reaction was then cooled, concentrated and azetroped with DCM (3x). The crude
aminoalcohol was dissolved in 1,4-dioxane (4.00 mL) and CDI (288 mg, 1.777 mmol) was
added, and the reaction were heated to 120 C in sealed tubes for 24 h. Dioxane was then
removed and the product was isolated by waters HPLC (10-30% MeCN/H O for B and 10-50%
MeCN/H O for A, 16 min, 0.1% TFA, Sunfire column) to afford TFA salt of 1-{[(5S,7S)methyl-
2-oxo(2-pyridinylmethyl)oxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile (37 mg, 15.37% yield) as a yellow solid. H NMR (400 MHz, CDCl ) δ 8.83 (d, J =
.52 Hz, 1H), 8.80 (s, 1H), 8.22 - 8.29 (td, J = 7.8, 1.6 Hz, 1H), 8.04 (d, J = 8.53 Hz, 1H), 7.89
(s, 1H), 7.82 (d, J = 7.78 Hz, 1H), 7.73 - 7.80 (m, 1H), 7.71 (dd, J = 1.25, 8.53 Hz, 1H), 4.84 (d,
J = 15.8 Hz, 1H), 4.72 (d, J = 15.8 Hz, 1H), 4.10 (s, 2H), 3.42 (s, 2H), 2.04 (d, J = 15.31 Hz,
1H), 1.81 - 1.99 (m, 2H), 1.66 - 1.77 (m, 1H), 1.59 (d, J = 12.80 Hz, 1H), 1.46 (d, J = 14.05 Hz,
1H), 1.28 - 1.43 (m, 2H), 1.19 (s, 3H). MS (m/z) 416.0 (M+H ).
EXAMPLE 5
1-({(5S,7S)[2-Methyl(5-phenyl-1,3,4-oxadiazolyl)propyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile
To a solution of 3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxa
azaspiro[4.5]decyl}-2,2-dimethylpropanoic acid (150 mg, 0.334 mmol) in DCM (4 mL) was
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added benzoyl hydrazine (45.4 mg, 0.334 mmol) and 2-chloro-1,3-dimethylimidazolium chloride
(113 mg, 0.667 mmol). After stirring for 15 min at RT, TEA (0.233 mL, 1.668 mmol) was added
over a period of 2 min, and the reaction mixture was stirred for 18 h at RT. Next, NaHCO was
added and the reaction was extracted with DCM. The organic layer was dried over Na SO and
concentrated. The residue was purified via HPLC (Waters, Sunfire C-18 column, OBD, 20-60%
MeCN in water (0.1% TFA), 16 min, with at-column dilution, flow rate=45 mL/min). Fractions
containing desired product were concentrated to give TFA salt of 1-({(5S,7S)[2-methyl(5-
phenyl-1,3,4-oxadiazolyl)propyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile as a white solid (21 mg, 10% yield). H NMR (400 MHz, CDCl ) δ
9.03 (s, 1H), 8.00 - 8.12 (m, 3H), 7.94 (s, 1H), 7.78 (dd, J = 1.25, 8.53 Hz, 1H), 7.49 - 7.64 (m,
3H), 4.22 (ddd, 2H), 3.60 - 3.70 (m, 1H), 3.47 - 3.57 (m, 1H), 3.09 - 3.21 (m, 2H), 2.41 (m, 1H),
1.93 – 2.01 (m, 2H), 1.60 - 1.76 (m, 3H), 1.53 (d, J = 6.78 Hz, 6H), 1.13 - 1.40 (m, 2H), 1.03 (m,
1H). MS (m/z) 511.3 (M+H ).
EXAMPLE 6
1-({(5S,7S)[2-(3-Ethyl-1,2,4-oxadiazolyl)methylpropyl]oxooxaazaspiro[4.5]dec-
7-yl}methyl)-1H-benzimidazolecarbonitrile
3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxaazaspiro[4.5]dec
yl}-2,2-dimethylpropanoic acid (200 mg, 0.381 mmol), HATU (217 mg, 0.572 mmol) and DIEA
(0.200 mL, 1.144 mmol) in DCM (4 mL) were stirred for 30 min at RT. N'-
hydroxypropanimidamide (50.4 mg, 0.572 mmol) was added and the reaction mixture were
stirred at RT for 18 h. The reaction mixture was then extracted with DCM. The organic layers
was dried over Na SO and filtered, and the filtrate was concentrated. The residues were
disolved in 1,4-dioxane (4 mL) and heated at 108 C for 16 h. Reaction mixture was
concentrated and purified via HPLC (Waters, Sunfire C-18 colummn, OBD, 20-60% MeCN in
water (0.1% TFA), 16 min, with at-column dilution, flow rate 45 mL/min). Fractions containing
desired products were concentrated to give TFA salt of 1-({(5S,7S)[2-(3-ethyl-1,2,4-
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oxadiazolyl)methylpropyl]oxooxaazaspiro[4.5]decyl}methyl)-1H-benzimidazole-
6-carbonitrile as a white solid (108 mg, 48.1% yield). MS (m/z) 463.3 (M+H ).
EXAMPLE 7
1-[((5S,7S){[3-Methyl(2-pyrimidinyl)pyrrolidinyl]methyl}oxooxaazaspiro[4.5]dec-
7-yl)methyl]-1H-benzimidazolecarbonitrile
A suspension of 1-({(5S,7S)[(3-methylpyrrolidinyl)methyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile (0.1 g, 0.208 mmol), 2-
chloropyrimidine (0.026 g, 0.229 mmol), and cesium carbonate (0.203 g, 0.624 mmol) in NMP
(1 mL) was subjected to microwave reactor for 1 h at 120 C. DIEA (0.5 mL) was then added,
and the reaction mixture was microwaved for 30 min at 120 C. Next, the reaction mixture was
extracted with DCM and concentrated. The residue was purified via HPLC to give TFA salt of 1-
[((5S,7S){[3-methyl(2-pyrimidinyl)pyrrolidinyl]methyl}oxooxaazaspiro[4.5]dec
yl)methyl]-1H-benzimidazolecarbonitrile as a brown solid (55.6 mg, 44.5%). MS (m/z) 486.3
(M+H ).
EXAMPLE 8
1-({(5S,7S)Methyloxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec-
7-yl}methyl)-1H-benzimidazolecarbonitrile
To a yellow solution of 1-{[(5S,7S)methyloxo(2-propynyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile (0.105 g, 0.232 mmol) in DMSO
(2.086 mL) in a vial was added iodobenzene (0.047 g, 0.232 mmol), sodium azide (0.015 g,
0.232 mmol), D,L-proline (5.34 mg, 0.046 mmol), sodium carbonate (4.91 mg, 0.046 mmol),
sodium L-ascorbate (4.59 mg, 0.023 mmol), copper(II) sulfate pentahydrate (5.79 mg, 0.023
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mmol), and water (0.232 mL). The vial was capped and heated thermally at 65 ºC. After 2 h,
the reaction mixture was dark brown solution. Next, the reaction mixture was cooled to RT and
1 mL of DMSO was added and then the mixture was filtered using Buchner funnel filtration. The
filtrate was purified using Gilson prep HPLC: 30-40% CH CN/H O, 0.1% TFA, 30 X 150 mm
Sunfire C18, 25 mL/min, 15 min to yield the TFA salt of 1-({(5S,7S)methyloxo[(1-phenyl-
1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H-benzimidazole
carbonitrile was obtained as an orange foam (15.8 mg, 10.9% yield). H NMR (400 MHz,
DMSO-d ) δ 8.78 (s, 1H), 8.57 (br. s., 1H), 8.41 (br. s., 1H), 7.88 - 7.96 (m, 2H), 7.84 (d, J =
7.78 Hz, 1H), 7.57 - 7.66 (m, 3H), 7.44 - 7.55 (m, 1H), 4.49 (m, 2H), 4.13 (s, 2H), 3.29 (dd, J =
8.0, 16.0 Hz, 2H), 1.85 (m, 1H), 1.73 (m, 1H), 1.50 - 1.67 (m, 3H), 1.25 - 1.47 (m, 3H), 1.02 (s,
3H). MS (m/z) 482 (M+H ).
EXAMPLE 9
1-{[(5S,7S)Oxo({1-[5-(trifluoromethyl)pyridinyl]-1H-1,2,3-triazolyl}methyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile
1-{[(5S,7S)Oxo(2-propynyl)oxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile
To a solution of 5-(trifluoromethyl)pyridinamine (0.150 g, 0.925 mmol) in EtOAc (3
mL) at 0 ºC was added concentrated HCl (0.5 mL). The reaction mixture was stirred for 10 min,
then a solution of sodium nitrite (0.192 g, 2.78 mmol, 3 eq; dissolved in 1 mL of water) was
added over 2 min. The reaction mixture was then stirred for 30 min. A solution of sodium azide
(0.180 g, 2.78 mmol) (3 eq; dissolved in 1 mL of water) was then added over 5 min. After 1 h, a
solution of 10% Na CO was added to the mixture to make the solution a pH 9-10. The mixture
was then extracted with EtOAc (2 x 10 mL). Organic layers were dried over MgSO , filtered, and
concentrated in vacuo. The product was placed in high vacuum for 30 min. 1-{[(5S,7S)oxo
(2-propynyl)oxaazaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile was
obtained as a low viscosity dark orange oil (100 mg, 57% yield).
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1-{[(5S,7S)Oxo({1-[5-(trifluoromethyl)pyridinyl]-1H-1,2,3-triazolyl}methyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile
To a light orange solution of 1-{[(5S,7S)oxo(2-propynyl)oxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile (0.100 g, 0.287 mmol) (93:7
trans:cis) in tert-butanol (1.435 mL) and water (1.435 mL) in a vial was added 3-azido
(trifluoromethyl)pyridine (0.054 g, 0.287 mmol), sodium L-ascorbate (0.011 g, 0.057 mmol),
copper(II) sulfate pentahydrate (0.014 g, 0.057 mmol), and water (1.435 mL). After 18 h, 1 mL
of MeOH was added and the mixture was vacuum filtered using a small Buchner funnel. The
filtrate was filtered through Acrodisc CR 25 mm syringe filter with 0.2 um PTFE membrane and
purified by Gilson prep HPLC: 25-45% CH CN/H O, 0.1% TFA, 30 X 150 mm Sunfire C18, 25
mL/min, 15 min to yield the TFA salt of 1-{[(5S,7S)oxo({1-[5-(trifluoromethyl)pyridinyl]-
1H-1,2,3-triazolyl}methyl)oxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole
carbonitrile as an orange foam (18.1 mg, 9.2% yield). MS (m/z) 537 (M+H ).
EXAMPLE 10
1-({(5S,7S)[4-Chloro(1,1-dimethylethyl)isoxazolyl]methyloxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile
To a vial was added 1-({(5S,7S)[3-(1,1-dimethylethyl)isoxazolyl]methyloxo
oxaazaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile (85 mg, 0.190 mmol) and
chloroform (950 µL) at RT, followed by NCS (25.4 mg, 0.190 mmol). The reaction mixture was
stirred at RT followed by 65 C for 5 h. Ater 22 h reaction at 65 C the crude mixture was
purified by reverse phase HPLC (30-80% MeCN/H O, 0.1% TFA modifier, 30 x 150 mm Sunfire
18 column), and TFA salt of 1-({(5S,7S)[4-chloro(1,1-dimethylethyl)isoxazolyl]methyl-
2-oxooxaazaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile was obtained
(62.4 mg, 54% yield). MS (m/z) 482.2 (M+H ).
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EXAMPLE 11
1-({(5S,7S)Methyloxo[5-(trifluoromethyl)pyridinyl]oxaazaspiro[4.5]dec
yl}methyl)-1H-benzimidazolecarbonitrile
A 5 mL microwave vial was charged with 1-{[(3S,5S)methyloxaspiro[2.5]oct
yl]methyl}-1H-benzimidazolecarbonitrile (150 mg, 0.533 mmol), ethyl [5-(trifluoromethyl)
pyridinyl]carbamate (137 mg, 0.586 mmol), KOtBu (90 mg, 0.800 mmol), and NMP (4 mL). The
reaction mixture was was heated to 100 °C for 3 h. The reaction mixture was partitioned
between water and DCM, and the layers were separated. The aqeous layer was extracted with
DCM (2x), and the combined organic extracts were washed with brine, eluted through a phase
separator and concentrated to afford an oil. The oil was purified by MDAP HPLC (TFA 0.1 %,
16 min, 30-70% MeCN/H O, Sunfire column) to afford TFA salt of 1-({(5S,7S)methyloxo
[5-(trifluoromethyl)pyridinyl]oxaazaspiro[4.5]decyl}methyl)-1H-benzimidazole
carbonitrile as a white solid (75 mg, 22.9% yield). H NMR (400 MHz, CDCl ) δ 9.17 (br. s., 1H),
8.57 (s, 1H), 8.35 (d, J = 9.03 Hz, 1H), 8.09 (d, J = 8.53 Hz, 1H), 7.89 - 7.95 (m, 2H), 7.78 (dd, J
= 1.13, 8.41 Hz, 1H), 4.22 (s, 2H), 3.92 - 4.05 (m, 2H), 2.15 (m, 1H), 1.97 (d, J = 13.55 Hz, 2H),
1.79 (m, 1H), 1.64 - 1.69 (m, 2H), 1.38 - 1.56 (m, 2H), 1.31 (s, 3H). MS (m/z) 470 (M+H ).
EXAMPLE 12
'1-({(5S,7S)[6-(Ethyloxy)pyridinyl]methyloxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
1-{[(1S,3S)({[6-(Ethyloxy)pyridinyl]amino}methyl)hydroxy
methylcyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile
A 5 mL microwave vial was charged with 1-{[(3S,5S)methyloxaspiro[2.5]oct
yl]methyl}-1H-benzimidazolecarbonitrile (150 mg, 0.533 mmol),6-(ethyloxy)pyridinamine
(221 mg, 1.599 mmol) and MeOH (4 mL). The reaction mixture was stirred and heated to 120
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°C for 24 h. The reaction mixture was concentrated down to afford an oil. The oil was purified
by silica gel (40 g) loading and initially elluting in DCM through to 6% MeOH/DCM over 18
column volumes to afford 1-{[(1S,3S)({[6-(ethyloxy)pyridinyl]amino}methyl)hydroxy
methylcyclohexaneyl]methyl}-1H-benzimidazolecarbonitrile as an colorless oil. MS (m/z) 420
(M+H ).
1-({(5S,7S)[6-(Ethyloxy)pyridinyl]methyloxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
A 5 mL microwave vial was charged with 1-{[(1S,3S)({[6-(ethyloxy)
pyridinyl]amino}methyl)hydroxymethylcyclohexaneyl]methyl}-1H-benzimidazole
carbonitrile (78 mg, 0.186 mmol), DCA (151 mg, 0.930 mmol) and 1,4-dioxane (4 mL) to give a
yellow solution. Reaction mixture was stirred and heated at 120 °C for 24 h and then the
reaction mixture was concentrated to afford an oil. The oil was purified by MDAP HPLC (TFA
0.1%, 16 min, 10-50% MeCN/H O, Sunfire column) to afford TFA salt of 1-({(5S,7S)[6-
(ethyloxy)pyridinyl]methyloxooxaazaspiro[4.5]decyl}methyl)-1H-benzimidazole-
6-carbonitrile as a cream solid (31 mg, 28.3% yield). H NMR (400 MHz, CDCl ) δ 9.48 (br. s.,
1H), 8.64 (dd, J = 1.76, 9.29 Hz, 1H), 8.17 (d, J = 2.01 Hz, 1H), 8.13 (d, J = 8.53 Hz, 1H), 7.98
(s, 1H), 7.79 (d, J = 8.78 Hz, 1H), 6.98 (d, J = 9.29 Hz, 1H), 4.43 (q, J = 6.86 Hz, 2H), 4.29 (dd,
J = 12.0, 20.0 Hz, 2H), 3.93 (d, J = 8.0 Hz, 1H), 3.76 (d, J = 8.0 Hz, 1H), 2.13 (d, J = 5.27 Hz,
1H), 1.94 – 2.04 (m, 2H), 1.75 – 1.87 (m, 2H), 1.67 (m, 1H), 1.56 (dd, J = 4.0, 16.0 Hz, 1H),
1.48 (t, J = 7.03 Hz, 3H), 1.41 (dd, J = 4.0, 12.0 Hz, 1H), 1.29 (s, 3H). MS (m/z) 446 (M+H ).
EXAMPLE 13
1-(((5S,7S)(6-Methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
Route 1:
Tert-butyl (6-methoxypyridinyl)carbamate
To a 500 mL flask was added THF (206 mL), 6-methoxypyridinamine (25 g, 191
mmol) and Boc O (48.9 mL, 210 mmol). The dark solution was heated to reflux for 18 h, then
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cooled to RT and concentrated. The residue was purified via silica gel chromatography on the
ISCO-RF: liquid load, 330 g column, 0-10% EtOAc/Hexane over 30 min. Concentration of
fractions containing product afforded tert-butyl (6-methoxypyridinyl)carbamate as a slightly
yellow oil. This was used without further purification.
1-(((5S,7S)(6-Methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
To a 4 mL vial was added NMP (1997 µL), tert-butyl (6-methoxypyridinyl)carbamate
(448 mg, 1.997 mmol) and potassium tert-butoxide (213 mg, 1.898 mmol) at RT. After stirring
for ~1 min at RT, 1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazole
carbonitrile (281 mg, 0.999 mmol) was added. The solution was then heated to 55 C and
stirred for 17 h. The resulting solution was cooled to RT, diluted with 2 mL of MeCN, then
purified on HPLC: 20-60% MeCN/Water over 14 min, Sunfire C-18 column, 0.1% TFA.
Fractions containing product were added to a separatory funnel, diluted with DCM and saturated
NaHCO . DCM layer was separated, passed over a phase separator and concentrated to give
1-(((5S,7S)(6-methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile (145 mg, 34% yield). H NMR (400 MHz, CDCl ) δ 8.08
(dd, J = 4, 12 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J = 4 Hz, 1H), 7.76 (s, 1H), 7.58 (dd, J = 4 Hz, 1H),
6.80 (d, J = 12 Hz, 1H), 4.02 (s, 2H), 3.94 (s, 3H), 3.66 (q, J = 8 Hz, 2H), 2.14-2.18 (m, 1H),
1.94-2.00 (m, 2H), 1.66-1.77 (m, 2H), 1.51 (d, J = 16 Hz, 1H), 1.36-1.44 (m, 2H), 1.33 (s, 3H).
MS (m/z) 432.2 (M+H ).
Alternatively, 1-(((5S,7S)(6-methoxypyridinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile can be obtained using
similar procedures as described above except using 1.0 eq KOtBu and 1.25 eq Boc amine, and
heat the reaction mixture at 80 C for 6 h.
Route 2:
1-(((5S,7S)(6-Methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
To a solution of tert-butyl (6-methoxypyridinyl)carbamate (5.98 g, 26.7 mmol) in
tetrahydrofuran (THF) (20 mL) at -78 °C under N was added n-BuLi (2.5M in hexanes) (10.66
mL, 26.7 mmol). The mixture was allowed to warm up to RT and stirred for 20 min, to the
mixture was added 1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazole
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carbonitrile (6.0 g, 21.33 mmol) followed by N-methylpyrrolidone (NMP) (20.00 mL). The
mixture was heated at 75 ºC for 2 days and then cooled to RT. The reaction mixture was
diluted with EtOAc/H O and extracted with 3x EtOAc, The organic layers were washed with 2x
brine, dried over Na SO filtered and concentrated. To the residue was added 250 mL of i-
2 4,
PrOH, heated to reflux for 2 hours, and then cooled to RT for 2 days. The solid was filtered and
air dried to afford 1-(((5S,7S)(6-methoxypyridinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a white solid (7.43 g,
79% yield).
EXAMPLE 14
1-(((5S,7S)(5-Ethoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
Route 1:
1,1-Dimethylethyl (5-chloropyrazinyl)carbamate
To a 500 mL flask was added THF (83 mL), 5-chloropyrazinamine (10 g, 77 mmol)
and Boc O (19.71 mL, 85 mmol). The dark solution was heated to reflux for 48 h, then cooled to
RT, concentrated, and the residue purified via silica gel chromatography on the ISCO RF (liquid
load, 330 g column, 0-10% EtOAc/Hexane over 30 min). Concentration of fractions containing
product afforded 1,1-dimethylethyl (5-chloropyrazinyl)carbamate as a slightly yellow oil. This
was used without further purification. Approximately 5 g of starting material was recovered. The
rest of the material was a mixture of products.
Ethyl (5-ethoxypyrazinyl)carbamate
The mixed products from 1,1-dimethylethyl (5-chloropyrazinyl)carbamate were
combined and refluxed in 24% sodium ethoxide for 5 days, then cooled to RT, neutralized with
HCl, and the product extracted out with DCM. The DCM was washed with saturated NaHCO ,
then concentrated to afford a black residue. Addition of EtOAc afforded solids that were filtered
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off, washed with EtOAc to give ethyl (5-ethoxypyrazinyl)carbamate as a brown solid (3.5 g,
42.9%).
1-(((5S,7S)(5-Ethoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
To a 10 mL flask was added NMP (7.11 mL), ethyl (5-ethoxypyrazinyl)carbamate
(0.863 g, 4.09 mmol) and potassium tert-butoxide (0.399 g, 3.55 mmol) at RT. After stirring for
~5 min at RT, 1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-1H-benzimidazole
carbonitrile (1 g, 3.55 mmol) was added. The solution was then heated to 70 C (oil bath) and
stirred for 7 h. At 7 h, the temperature was taken to 80 C, then at 8 h, it was taken to 90 C.
The mixture was allowed to stir at 90 C for 16 h. The resulting solution was cooled to RT and
added dropwise to a 50 mL solution of IPA/Water (1:1) that contained a small crystalline seed.
The mixture was allowed to stir at RT overnight. The next day, the slurry was filtered, and the
solids slurried in MeCN overnight. The next day, the solids were filtered off, dried under
reduced pressure to give 1-(((5S,7S)(5-ethoxypyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a very light yellow solid
(968 mg, 61% yield). H NMR (400 MHz, DMSO-d ) δ 8.80 (d, J = 1.25 Hz, 1H), 8.48 (s, 1H),
8.38 (s, 1H), 8.10 (d, J = 1.51 Hz, 1H), 7.83 (d, J = 8.53 Hz, 1H), 7.59 (dd, J = 1.25, 8.28 Hz,
1H), 4.32 (q, J = 7.03 Hz, 2H), 4.16 (s, 2H), 3.80 - 3.88 (m, 2H), 1.98 (d, J = 13.80 Hz, 1H), 1.88
(d, J = 14.31 Hz, 1H), 1.64 - 1.73 (m, 3H), 1.49 - 1.53 (m, 2H), 1.34 - 1.38 (m, 2H), 1.32 - 1.38
(t, J = 8.0 Hz, 2H), 1.07 (s, 3H). MS (m/z) 447.2 (M+H ).
Route 2:
1-(((5S,7S)(5-Ethoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
A suspension of ethyl (5-ethoxypyrazinyl)carbamate (2.102 g, 9.95 mmol) in THF (7
mL) was cooled to -78 C and 2.5N n-butyllithium in hexanes (3.84 mL, 9.60 mmol) was added
dropwise over 2 minutes. The resulting mixture was stirred for 15 minutes and then allowed to
warm to RT. 1-(((3S,5S)methyloxaspiro[2.5]octanyl)methyl)-1H-benzo[d]imidazole
carbonitrile (2 g, 7.11 mmol) was added as the solid followed by NMP (7.00 mL). The resultant
was heated to 75 C at which point it became a solution. The reaction contained a vent and no
condenser to allow the removal of THF and hexanes in order to increase the reaction rate. The
reaction mixture was stirred for two days. The reaction was cooled and diluted with 20 mL of
IPA and was poured into 40 mL of stirred water. Additional water was added until a solid
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precipated from solution (an oil also formed). The oily mixture was stirred overnight. Ethyl
acetate was added to dissolve the product and the resultant liquors were separated. The
aqueous layer was extracted twice with EtOAc and the combined organics washed with water
(2x), brine, dried over sodium sulfate and concentrated to afford a brown solid 3.2 g. The solid
was crystalized from hot MeCN (40 mL) to afford 1-(((5S,7S)(5-ethoxypyrazinyl)methyl-
2-oxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (1.1 g,
2.340 mmol, 32.9% yield) as a light brown solid.
EXAMPLE 15
1-(((5S,7S)(6-Methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
Route 1:
Ethyl [4-methyl(methyloxy)pyridinyl]carbamate
To a 100 mL flask was added 4-methyl(methyloxy)pyridinamine (850 mg, 6.15
mmol), pyridine (10 mL) and then ethyl chloroformate (0.650 mL, 6.77 mmol) portionwise. The
reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was then concentrated and
partitioned between ammonium chloride and DCM, and the aqueous layer was extracted with
DCM (2x). The combined organics layers were washed with brine (1x), eluted through a phase
separator then concentrated to afford ethyl [4-methyl(methyloxy)pyridinyl]carbamate
(1.223 g, 90 % yield).
1-(((5S,7S)(6-Methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
A mixture of ethyl (6-methoxymethylpyridinyl)carbamate (0.593 g, 2.82 mmol) and
potassium tert-butoxide (0.275 g, 2.452 mmol) in NMP (4.90 mL) was stirred at RT for 5 min
before 1-(((3S,5S)methyloxaspiro[2.5]octanyl)methyl)-1H-benzo[d]imidazole
carbonitrile (0.69 g, 2.452 mmol) was added. The reaction mixture was stirred at 55 C for 16 h,
then at 70 C for 2.5 h and then at 85 C for 16 h. Saturated aq NaHCO was added and the
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mixture was extracted with EtOAc. The organic layer was concentrated and purified via HPLC
(Waters, Sunfire C-18 colummn, OBD, 20-60% MeCN in water (0.1%TFA), 16 min, with at-
column dilution, flow rate 45 mL/min). Fractions contained desired products were free based
with NaHCO , extracted with DCM, dried over Na SO and concentrated. The resulted foam
3 2 4
was crystallized by stirring with a solution of 1/3 DCM/isopropanol (4 mL total) in an uncapped
vial overnight. The resulted cloudy mix was concentrated to ~2 mL volume and then stirred for
1 h. The resulted light pink solids were collected by filtration and dried on high vacumn for 2 h
to yield 1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile. H NMR (400 MHz,
CDCl ) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 8.53 Hz, 1H), 7.78 (s, 1H), 7.59 (dd, J = 1.25,
8.28 Hz, 1H), 6.66 (s, 1H), 4.04 (s, 2H), 3.93 (s, 3H), 3.52 - 3.58 (m, 2H), 2.25 (s, 4H), 2.01 (d, J
= 13.80 Hz, 2H), 1.63 - 1.77 (m, 2H), 1.60 (s, 1H), 1.50 (d, J = 13.80 Hz, 1H), 1.37 - 1.42 (m,
4H). MS (m/z) 446.2 (M+H ).
Route 2:
1-(((5S,7S)(6-Methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a 3 neck, 250 mL round bottom flask under N equipped with thermometer and septa,
was added tert-butyl (6-methoxymethylpyridinyl)carbamate (1.059 g, 4.44 mmol) and THF
(3.55 mL). This mixture was stirred and brought to -78 °C while n-butyllithium (1.777 mL, 4.44
mmol) was added slowly via small additions keeping the reaction temperature below -70 C. The
light brown solution was allowed to stir 10 min at this temperature, then the ice bath was
removed and when temperature reached 5 °C, 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (1 g, 3.55 mmol) followed by NMP (3.55 mL) was
added. This new light brown mixture was heated using an oil bath to internal temperature of
75°C for 16 h. To a 50 mL, 3 neck flask equipped with N was added tert-butyl (6-methoxy
methylpyridinyl)carbamate (350 mg, 1.5 mmol) in THF (1 mL), at -78 C and 2.5M n-
butyllithium (0.6 mL) while keeping the reaction temperature below -70 C. Upon completion of
addition, the mixture was allowed to warm to 5 C and was added to original reaction via
syringe. This was heated to 75 C using an oil bath and monitored. Ethyl acetate (15 mL) and
H O (10 mL) were added, and the mixture was sonicated until all residue dissolved. The layers
were separated, and the water layer was extracted with EtOAc (2x). The organic layers were
combined and washed with water, dried over MgSO and then concentrated to give a light
brown film. This was dissolved in 27 mL of IPA, transfered to a 100 mL round bottom flask and
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brought to reflux for 2 h, then allowed to cool and stir at room temp for 20 h. The solid was then
filtered, washed with IPA (2 x 5 mL) and dried on house vacuum to yield 1.2 g off-white solid.
The solid was taken up in IPA (30 mL) and 3 mL DCM (for solubility) and refluxed for 2 h. The
mixture was allowed to cool to RT and stir for 3 days. The solid was filtered and washed with
IPA to yield 1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (784 mg, 47% yield).
EXAMPLE 16
1-(((5S,7S)(1-Ethylmethyl-1H-pyrazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
A solution of 1-ethylmethyl-1H-pyrazolamine, 2 hydrochloride (0.5 g, 2.52 mmol),
Boc O (0.703 ml, 3.03 mmol), TEA (1.055 mL, 7.57 mmol) and DMAP (10 mg, 0.082 mmol) in
DCM (18.74 mL) was stirred at RT for 16 h. The mixture was then extracted with DCM, dried
over Na SO and filtered. The filtrate was concentrated and purified via silica gel
chromatography (ISCO, 40 g column; 0-5% MeOH/DCM) to give tert-butyl (1-ethylmethyl-1H-
pyrazolyl)carbamate as brown oil (300 mg, 52.8% yield). To a solution of tert-butyl (1-ethyl-
-methyl-1H-pyrazolyl)carbamate (0.162 g, 0.719 mmol) in THF (1 mL) at -78 °C under N
was added n-BuLi (2.5M in hexane) (0.27 ml, 0.675 mmol) dropwise. The mixture was allowed
to warm up to RT and stirred for 20 min. 1-{[(3S,5S)methyloxaspiro[2.5]octyl]methyl}-
1H-benzimidazolecarbonitrile (0.15 g, 0.533 mmol) was then added followed by NMP (0.5
mL). The solution was then heated at 70 C for 16 h. Water was then added to the reaction
mixture and extracted with EtOAc. The organic layer was concentrated and purified via HPLC
to give 1-(((5S,7S)(1-ethylmethyl-1H-pyrazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a white solid (89.6 mg,
38.9% yield). H NMR (400 MHz, DMSO-d ) δ 8.47 (s, 1H), 8.38 (s, 1H), 7.83 (d, J = 8.28 Hz,
1H), 7.59 (dd, J = 1.51, 8.28 Hz, 1H), 7.41 (s, 1H), 4.16 (br. s., 2H), 4.03 (q, J = 7.03 Hz, 2H),
3.54 (s, 2H), 2.14 (s, 3H), 1.95 (d, J = 14.0 Hz, 1H), 1.86 (d, J = 14.31 Hz, 1H), 1.61 (d, J =
13.55 Hz, 3H), 1.31 - 1.51 (m, 3H), 1.28 (t, 3H), 1.06 (s, 3H). MS (m/z) 433.3 (M+H ).
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EXAMPLE 17
1-(((7S)(5-Methoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
Methyl (5-methoxypyrazinyl)carbamate
A 20 mL microwave vial was charged with ethyl (5-chloropyrazinyl)carbamate (500
mg, 2.480 mmol) and 22% sodium methoxide in MeOH (10 mL). The tube was sealed and
heated to 100 C for 6 h. The reaction mixture was then concentrated, diluted between DCM
and 2N HCl. The layers were separated and the aqueous layer was extracted with DCM (2x).
The combined organic layers were washed with 2N HCl, brine, eluted through a phase
separator and concentrated to afford methyl (5-methoxypyrazinyl)carbamate as a brown oil
(100 mg, 22.01% yield). MS (m/z) 184 (M+H ).
1-(((7S)(5-Methoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
A 5 mL microwave vial was charged with 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (125 mg, 0.444 mmol), methyl (5-
methoxypyrazinyl)carbamate (106 mg, 0.578 mmol), potassium tert-butoxide (54.8 mg, 0.489
mmol) and DMF (3 mL). The tube was sealed and heated to 70 °C for 16 h. The reaction
mixture was loaded onto a 10 g SCX column and eluted with 3 volumes of MeOH followed by 3
volumes of 2N ammonia in MeOH. The fractions were combined and concentrated. Crude
product was purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1% TFA, 16 min,
50 mL/min, Sunfire column) to afford TFA salt of 1-(((5S,7S)(5-methoxypyrazinyl)
methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a
yellow solid (30 mg, 11.74% yield). H NMR (400 MHz, CDCl ) δ 11.81 (br. s., 1H), 8.90 - 9.00
(m, 2H), 8.07 (d, J = 8.53 Hz, 1H), 7.89 - 7.98 (m, 2H), 7.76 (d, J = 8.53 Hz, 1H), 4.17 (s, 2H),
3.97 (s, 3H), 3.91 (d, J = 12.0 Hz, 1H), 3.83 (d, J = 8.0 Hz, 1H), 2.17 (br.s., 1H), 1.99 (d, J =
13.8 Hz, 2H), 1.77 (m, 1H), 1.64 (d, J = 12.55 Hz, 1H), 1.56 (d, J = 13.80 Hz, 1H), 1.35 - 1.52
(m, 2H), 1.31 (s, 3H). MS (m/z) 433 (M+H ).
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EXAMPLE 18
1-(((5S,7S)(6-Chloropyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
A 5 mL microwave vial was charged with 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (200 mg, 0.711 mmol), tert-butyl (6-chloropyridin-
3-yl)carbamate (195 mg, 0.853 mmol), potassium tert-butoxide (96 mg, 0.853 mmol) and DMF.
The tube was sealed and heated to 70 C for 16 h. The reaction mixture was loaded onto a 10
g SCX SPE and eluted with 3 volumes of MeOH followed by 3 volumes of 2N ammonia in
MeOH. The ammonia fractions were combined and concentrated and the crude product then
purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1%TFA, 16 min, 50 mL/min,
Sunfire column) to afford the TFA salt of 1-(((5S,7S)(6-chloropyridinyl)methyloxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a cream solid (55
mg, 12.67 % yield). MS (m/z) 435.9 (M+H ).
EXAMPLE 19
1-(((5S,7S)(6-(Dimethylamino)pyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
A 5 mL microwave vial was charged with a solution of 1-(((5S,7S)(6-chloropyridin
yl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
(50 mg, 0.115 mmol) in 2N dimethylamine in MeOH (4 mL, 8.00 mmol). The tube was sealed
and heated for 24 h at 120 C. The reaction mixture was then concentrated, dissolved in MeOH
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and purified by Waters reverse phase HPLC (10% to 40% MeCN, 0.1% TFA, 16 min, 50
mL/min, Sunfire column) to afford the TFA salt of 1-(((5S,7S)(6-(dimethylamino)pyridinyl)-
7-methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as
a cream solid (5 mg, 7.4% yield). MS (m/z) 445 (M+H ).
EXAMPLE 20
Tert-butyl (2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa
azaspiro[4.5]decanyl)isoxazolyl)methylpropyl) carbonate
Tert-butyl (2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa
azaspiro[4.5]decanyl)isoxazolyl)methylpropyl) carbonate
To a 2 mL nitrogen purged microwave vial was added 1-(((3S,5S)methyl
oxaspiro[2.5]octanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (100 mg, 0.355 mmol),
potassium tert-butoxide (51.8 mg, 0.462 mmol), bis(1,1-dimethylethyl) {3-[2-({[(1,1-
dimethylethyl)oxy]carbonyl}oxy)-1,1-dimethylethyl]isoxazolyl}imidodicarbonate (325 mg,
0.355 mmol) and NMP (1.5 mL). This mixture was heated to 120 C for 2 h. The mixture was
then heated for an additional 5 h. The mixture was then filtered through paper, and the paper
washed with MeOH (2 mL), then concentrated. The mixture was purified on reverse phase
Gilson HPLC: 30 mm x 150 mm Waters Sunfire column, neutral conditions 10 - 100%
MeCN/H O, 14 min, 40 mL/min to give tert-butyl (2-(5-((5S,7S)((6-cyano-1H-
benzo[d]imidazolyl)methyl)methyloxooxaazaspiro[4.5]decanyl)isoxazolyl)
methylpropyl) carbonate as a clear light brown film (33 mg, 14.8% yield). MS (m/z) 564.3
(M+H ).
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EXAMPLE 21
1-(((5S,7S)(3-(1-Hydroxymethylpropanyl)isoxazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a 2 mL microwave vial was added tert-butyl (2-(5-((5S,7S)((6-cyano-1H-
benzo[d]imidazolyl)methyl)methyloxooxaazaspiro[4.5]decanyl)isoxazolyl)
methylpropyl) carbonate (30 mg, 0.053 mmol), K CO (5.15 µg, 0.037 µmol), water (0.500 mL)
and MeOH (0.5 mL). The vial was capped and heated to 110 °C for 3 h. The mixture was then
filtered through paper, and the paper washed with MeOH (2 mL), then concentrated. This
mixture was purified on reverse phase Gilson HPLC: 30 mm x 150 mm Waters Sunfire column,
neutral conditions 10 - 100% MeCN/H O, 14 min, 40 mL/min to give 1-(((5S,7S)(3-(1-
hydroxymethylpropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile as a white solid (6.2 mg, 24% yield). MS (m/z)
464.3 (M+H ).
EXAMPLE 22
1-(((5S,7S)(4,6-Dimethoxypyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
1-(((1S,3S)(((4,6-Dimethoxypyridinyl)amino)methyl)hydroxy
methylcyclohexaneyl)methyl)-1H-benzo[d]imidazolecarbonitrile
A mixture of 1-(((3S,5S)methyloxaspiro[2.5]octanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile (100 mg, 0.355 mmol) and 4,6-bis(methyloxy)pyridinamine
(110 mg, 0.711 mmol) in isopropanol (10 mL) was heated to reflux overnight. The reaction
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mixture was cooled to RT, and solvent was removed. The residue was redissolved in DCM and
hexane was added. The solvent was removed, and the residue was purified via silica gel
chromatography (ISCO, 40 g Silica, 40 mL/min, 0%-10% MeOH/CH Cl ). Fractions with product
were collected and concentrated to afford 1-(((1S,3S)(((4,6-dimethoxypyridin
yl)amino)methyl)hydroxymethylcyclohexaneyl)methyl)-1H-benzo[d]imidazolecarbonitrile
(100 mg, 64.6% yield). MS (m/z) 436 (M+H ).
1-(((5S,7S)(4,6-Dimethoxypyridinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
A mixture of 1-(((1S,3S)(((4,6-dimethoxypyridinyl)amino)methyl)hydroxy
methylcyclohexaneyl)methyl)-1H-benzo[d]imidazolecarbonitrile (100 mg, 0.230 mmol) and
CDI (372 mg, 2.296 mmol) in 1,4-dioxane (10 mL) was heated to reflux for 16 h. The reaction
mixture was evaporated and diluted with DCM and saturated aq NaHCO and extracted with
DCM (3x). The organic layers were washed brine (2x), dried over Na SO , filtered and
concentrated. The residue was purified via reverse phase HPLC to afford the TFA salt of 1-
(((5S,7S)(4,6-dimethoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile (19.7 mg, 14.9% yield). H NMR (400 MHz, DMSO-d ) δ
8.63 (s, 1H), 8.45 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.53 Hz, 1H), 7.64 (d, J = 8.53 Hz, 1H), 6.51
(s, 1H), 4.19 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.50 (s, 2H), 1.99 (d, J = 12.0 Hz, 1H), 1.86 (d, J
= 14.31 Hz, 1H), 1.58 - 1.73 (m, 3H), 1.42 - 1.52 (m, 2H), 1.28 - 1.41 (m, 1H), 1.07 (s, 3H). MS
(m/z) 462.3 (M+H ).
EXAMPLE 23
1-(((5S,7S)(6-Ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
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Tert-butyl (6-ethoxymethylpyridinyl)carbamate
A solution of 6-ethoxymethylpyridinamine (2.2 g, 14.46 mmol) and di-tert-butyl
dicarbonate (3.47 g, 15.90 mmol) in THF (30 mL) was heated slowly to reflux for 3 h. After
cooling to RT, the reaction mixture was concentrated, and the residue purified via silica gel
chromatography ISCO (80 g Silica, 60 mL/min, 0%-20% Hexanes/EA). Fractions containing
products were collected and concentrated to afford tert-butyl (6-ethoxymethylpyridin
yl)carbamate (3 g, 82% yield).
1-(((5S,7S)(6-Ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazolecarbonitrile
A solution of potassium tert-butoxide (63.0 mg, 0.561 mmol), 1-((3S,5S)
oxaspiro[2.5]octanylmethyl)-1H-benzo[d]imidazolecarbonitrile (100 mg, 0.374 mmol), tert-
butyl (6-ethoxymethylpyridinyl)carbamate (236 mg, 0.935 mmol) in NMP (1 mL) was
stirred and heated at 80 °C for 8 h. The reaction mixture was cooled to RT, and diluted with
acetonitrile. The crude product was purified via reverse phase HPLC to afford the TFA salt of 1-
(((5S,7S)(6-ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile (45.4 mg, 19.5% yield). H NMR (400 MHz, DMSO-d ) δ 8.70
(d, J = 7.03 Hz, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.87 (d, J = 8.28 Hz, 1H), 7.65 (d, J = 8.28 Hz,
1H), 6.73 (s, 1H), 4.18 - 4.37 (m, 6H), 2.17 - 2.32 (m, 1H), 2.11 (s, 3H), 2.04 (d, J = 8.0 Hz, 1H),
1.97 (d, J = 12.0 Hz, 1H), 1.67 (br. s., 1H), 1.34 - 1.62 (m, 4H), 1.29 (t, J = 7.03 Hz, 3H), 1.08
(m, 1H). MS (m/z) 446.3 (M+H ).
EXAMPLE 24
1-(((5S,7S)(6-Ethoxymethylpyridazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
6-Chloromethylpyridazinamine
A 100 mL flask was charged with 4-bromochloropyridazinamine (1 g, 4.80 mmol),
dimethylzinc (9.59 mL, 9.59 mmol), Pd(PPh ) (0.277 g, 0.240 mmol) and DMF (10 mL). The
PU64638
reaction mixture was stirred at RT. Then the reaction mixture was quenched with MeOH and
concentrated. The crude product was loaded onto a 10 g SCX SPE, and 3 volumes of MeOH
followed by 3 volumes of 2N ammonia in MeOH were added. The fractions were combined and
concentrated to afford 6-chloromethylpyridazinamine (693 mg, 80% yield).
Ethyl (6-chloromethylpyridazinyl)carbamate
A 100 mL flask was charged with 6-chloromethylpyridazinamine (700 mg, 4.88
mmol) and pyridine (20 mL) then ethyl chloroformate (0.421 mL, 4.39 mmol) was added
portionwise. The reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was then
concentrated and partitionned between ammonium chloride and DCM. The aqueous layer was
extracted with DCM (2x). The organic layers were combined and washed with brine (1x), eluted
through a phase separator and concentrated to afford ethyl (6-chloromethylpyridazin
yl)carbamate (549 mg, 49.6% yield).
Ethyl (6-ethoxymethylpyridazinyl)carbamate
A 20 mL microwavable vial was charged with ethyl (6-chloromethylpyridazin
yl)carbamate (550 mg, 2.55 mmol) and sodium ethoxide (3.11 mL, 17.85 mmol), then stirred
and heated at 110 °C for 12 h. The reaction mixture was then concentrated and partitioned
between ammonium chloride and DCM. The layers were separated and the aqueous layers
were washed with DCM (2x). The combined organic layers were washed with water, brine, and
eluted through a phase separator. The organic layers were concentrated to afford ethyl (6-
ethoxymethylpyridazinyl)carbamate (398 mg, 65.8% yield).
1-(((5S,7S)(6-Ethoxymethylpyridazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
A 5 mL microwave vial was charged with 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (200 mg, 0.711 mmol), ethyl (6-ethoxy
methylpyridazinyl)carbamate (208 mg, 0.924 mmol), KOtBu (104 mg, 0.924 mmol) and NMP
(4 mL). The reaction mixture was stirred and heated to 80 °C for 20 h. Then the reaction
mixture was loaded onto a 10 g SCX SPE, and eluted with 3 volumes of MeOH followed by 3
volumes of 2N ammonia in MeOH. The fractions were combined and concentrated and purified
by MDAP HPLC (TFA 0.1%, 16 min, 20-60% MeCN/Water, Sunfire column) to afford TFA salt of
1-(((5S,7S)(6-ethoxymethylpyridazinyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile as an oil (20 mg, 4.65% yield). H NMR (400
PU64638
MHz, CDCl ) δ 8.65 (s, 1H), 8.04 (d, J = 8.53 Hz, 1H), 7.88 (s, 1H), 7.71 (d, J = 8.53 Hz, 1H),
6.88 (s, 1H), 6.56 (br. s., 1H), 4.53 (d, J = 7.03 Hz, 2H), 4.13 (s, 2H), 4.05 (d, J = 9.54 Hz, 1H),
3.94 (d, J = 9.29 Hz, 1H), 2.35 (s, 3H), 2.27 (d, J = 16.0 Hz, 1H), 2.05 (d, J = 14.05 Hz, 1H),
1.97 (m, 1H), 1.78 (m, 1H), 1.52 - 1.69 (m, 2H), 1.35 – 1.51 (m, 1H), 1.44 (t, J = 7.03 Hz, 3H),
1.31 (s, 3H). MS (m/z) 461 (M+H ).
EXAMPLE 25
1-(((5S,7S)Methyloxo(2-(trifluoromethyl)pyrimidinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
O N F
O N N
A 5 mL microwave vial was charged with 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (160 mg, 0.570 mmol), tert-butyl (2-
(trifluoromethyl)pyrimidinyl)carbamate (300 mg, 1.140 mmol), KOtBu (121 mg, 1.083 mmol),
and NMP (4 mL). The reaction mixture was stirred and heated to 80 °C for 20 h then 2 h at 100
C. The reaction mixture was then loaded onto a 10 g SCX SPE and eluted with 3 volumes of
MeOH followed by 3 volumes of 2N ammonia in MeOH. The fractions were combined and
concentrated and purified by MDAP HPLC (TFA 0.1%, 16 min, 30-70% MeCN/Water, Sunfire
column) to afford TFA salt of 1-(((5S,7S)methyloxo(2-(trifluoromethyl)pyrimidinyl)
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a white solid (77
mg, 11% yield). H NMR (400 MHz, CDCl ) δ 9.12 (s, 2H), 8.46 (s, 1H), 8.01 (d, J = 8.28 Hz,
1H), 7.83 (s, 1H), 7.68 (dd, J = 1.25, 8.53 Hz, 1H), 4.10 (s, 2H), 3.78 (dd, J = 8.78, 14.05 Hz,
2H), 2.18 (d, J = 13.05 Hz, 1H), 1.92 – 2.06 (m, 2H), 1.82 (m, 1H), 1.70 (d, J = 12.3 Hz, 1H),
1.58 (d, J = 14.05 Hz, 1H), 1.37 - 1.54 (m, 2H), 1.34 (s, 3H). MS (m/z) 471 (M+H ).
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EXAMPLE 26
1-(((5S,7S)Methyloxo(3-(trifluoromethyl)pyridinyl)oxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a light yellow suspension of 1-(((5S,7S)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile (0.050 g, 0.154 mmol) in 1,4-dioxane (2.052
mL) was added copper(I) iodide (2.94 mg, 0.015 mmol), potassium phosphate tribasic (0.065 g,
0.308 mmol), trans-1,2-diaminocyclohexane (3.71 µL, 0.031 mmol), and 2-bromo
(trifluoromethyl)pyridine (0.042 g, 0.185 mmol). The reaction mixture was heated at 100 ºC for
h. Additional 2-bromo(trifluoromethyl)pyridine (0.042 g, 0.185 mmol), copper(I) iodide
(2.94 mg, 0.015 mmol), and trans-1,2-diaminocyclohexane (3.71 µL, 0.031 mmol) was added to
the reaction mixture. The mixture was stirred for an additional 49 h. Additional 2-bromo
(trifluoromethyl)pyridine (0.6 eq, 0.021 g, 0.093 mmol), copper(I) iodide (2.94 mg, 0.015 mmol),
and trans-1,2-diaminocyclohexane (3.71 µL, 0.031 mmol) was added. The reaction was stirred
for 18 h and then cooled to RT and MeCN (3 mL) was added and the mixture was vacuum
filtered using a Hirsch funnel. The filtrate was filtered through Acrodisc CR 25 mm syringe filter
with 0.2 um PTFE membrane. The mixture was then purified by Waters prep HPLC: 20-60%
CH CN/H O, 0.1% TFA, 30 X 150 mm Sunfire C18, 25 mL/min, 15 min. The product eluted at
12 mintues yielding the TFA salt of 1-(((5S,7S)methyloxo(3-(trifluoromethyl)pyridinyl)-
1-oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as an orange foam
(53 mg, 56% yield). MS (m/z) 470 (M+H ).
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EXAMPLE 27
1-({(5S,7S)[(5-Chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
A solution of 1-{[(5S,7S)oxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole-
6-carbonitrile (350 mg, 1.128 mmol) in DMF (20 mL) was treated with sodium hydride (45.1 mg,
1.128 mmol) in one portion under nitrogen at RT. After 20 min of stirring, 3-(bromomethyl)
chlorobenzothiophene (324 mg, 1.241 mmol) was added in one portion into the pale brown
suspension. The resulting mixture was stirred at RT under nitrogen for 5 h. The reaction
mixture was quenched with water (1 mL) and the resulting solution was poured into a 50 mL
saturated aq NH Cl solution. The precipitation was filtered, washed with distilled water (2x 20
mL) and air-dried under house vacuum. The product was purified through reverse phase HPLC
(Waters, Sunfire 30 x 100 C-18 prep column, CH CN/Water w/ 0.1% TFA 30-80% over 14 min)
to yield the TFA salt of 1-({(5S,7S)[(5-chlorobenzothienyl)methyl]oxooxa
azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile as a white solid (253 mg, 36.3%
yield). MS (m/z) 491.1 (M+H ).
EXAMPLE 28
1-{[(5S,7S)(2-{3-[1-(Ethyloxy)ethyl]-1,2,4-oxadiazolyl}methylpropyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile
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1-[((5S,7S){2-[3-(1-Hydroxyethyl)-1,2,4-oxadiazolyl]methylpropyl}oxooxa
azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile
A suspension of 3-{(5S,7S)[(6-cyano-1H-benzimidazolyl)methyl]oxooxa
azaspiro[4.5]decyl}-2,2-dimethylpropanoic acid (1.2 g, 2.67 mmol), DIEA (1.399 mL, 8.01
mmol), HATU (1.522 g, 4.00 mmol), and 2,N-dihydroxy-propionamidedine (0.417 g, 4.00 mmol)
in DCM (10 mL) was stirred at RT for 18 h. The reaction mixture was extracted with DCM (2x),
dried over Na SO and concentrated. The residue was taken up in 1,4-dioxane (3 mL) and
stirred at 105 C for 16 h. The reaction mixture was concentrated and purified via silica gel
column chromatography (ISCO, 80 g silica gel column. Solvent A = DCM; B = MeOH; 0-5% B:
min; 5% B: 10 min; 5-15% B: 10 min) to yield 1-[((5S,7S){2-[3-(1-hydroxyethyl)-1,2,4-
oxadiazolyl]methylpropyl}oxooxaazaspiro[4.5]decyl)methyl]-1H-benzimidazole-
6-carbonitrile as a white crispy foam (0.4 g, 31.3% yield).
1-{[(5S,7S)(2-{3-[1-(Ethyloxy)ethyl]-1,2,4-oxadiazolyl}methylpropyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile
A solution of 1-[((5S,7S){2-[3-(1-hydroxyethyl)-1,2,4-oxadiazolyl]methylpropyl}
oxooxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile (0.07 g, 0.146 mmol)
in DMF (0.704 mL) was cooled to 0 C and sodium hydride (7.61 mg, 0.190 mmol) was added.
The reaction mixture was stirred for 30 min. Iodoethane (0.015 ml, 0.190 mmol) was then
added, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was heated to
40 C for 3 h. The mixture was quenched with saturated aq NH Cl and extracted with EtOAc.
The organic layer was concentrated, and the residue was purified via HPLC to yield the TFA salt
of 1-{[(5S,7S)(2-{3-[1-(ethyloxy)ethyl]-1,2,4-oxadiazolyl}methylpropyl)oxooxa
azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile as a white solid. MS (m/z) 507.3
(M+H ).
The following compounds were prepared using procedures analogous to those
described in Example 1, 2, 3 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
PU64638
Ex Name Structure
(m/z)
1-{[(5S,7S)methyl(5-methyl
pyridinyl)oxooxa
29 416
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-({(5S,7S)methyl[3-(1-
methylethyl)isoxazolyl]oxo
434.2
oxaazaspiro[4.5]decyl}methyl)- N
1H-benzimidazolecarbonitrile
1-({(5S,7S)methyl[3-(2-
methylpropyl)isoxazolyl]oxo
31 448.3
oxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
1-{[(5S,7S)(1-tert-butyl-1H-pyrazol-
4-yl)methyloxooxa
32 447.3
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile N
1-{[(5S,7S)(3-ethylisoxazolyl) O
methyloxooxa
33 420.3
azaspiro[4.5]decyl]methyl}-1H- N
benzimidazolecarbonitrile
1-{[(5S,7S)(3-cyclopropyl
isoxazolyl)methyloxooxa
34 432
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
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1-{[(5S,7S)methyloxo(3- O
phenylisoxazolyl)oxa
468.2
azaspiro[4.5]decyl]methyl}-1H- N
benzimidazolecarbonitrile
1-({(5S,7S)[3-(1,1-dimethylethyl)
methyl-1H-pyrazolyl]methyl
36 oxooxaazaspiro[4.5]dec 461.3
yl}methyl)-1H-benzimidazole
carbonitrile
1-({(5S,7S)methyloxo[3-
(trifluoromethyl)isoxazolyl]oxa
37 460
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-({(5S,7S)[3-(1-
cyanocyclopropyl)isoxazolyl]
38 methyloxooxa 457.1
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-(((5S,7S)(3-(2-fluoropropan
yl)isoxazolyl)methyloxo
39 oxaazaspiro[4.5]decan 452.2
yl)methyl)-1H-benzo[d]imidazole N
carbonitrile
1-(((5S,7S)(3-cyclobutylisoxazol
yl)methyloxooxa
40 446.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
PU64638
1-(((5S,7S)(3-(tert-butyl)
methylisoxazolyl)methyloxo-
41 1-oxaazaspiro[4.5]decan 462
yl)methyl)-1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(4-(tert-butyl)oxazol
yl)methyloxooxa
42 448.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
1-(((5S,7S)(1-(tert-butyl)-1H-
pyrazolyl)methyloxooxa
43 447.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
1-(((5S,7S)(3-(tert-butyl)
fluoroisoxazolyl)methyloxo
44 oxaazaspiro[4.5]decan 466.2
yl)methyl)-1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(3-(1,1-
difluoroethyl)isoxazolyl)methyl-
45 2-oxooxaazaspiro[4.5]decan 456.2
yl)methyl)-1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(3-(tert-butyl) O
methylisoxazolyl)oxooxa
46 448.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
1-(((5S,7S)(3-(tert-butyl)
fluoroisoxazolyl)oxooxa
47 452.2
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile N
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1-(((5S,7S)(6-(tert-butyl)pyridazin- O
3-yl)methyloxooxa
48 459.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
1-(((5S,7S)(5-(tert-butyl)pyrimidin-
2-yl)methyloxooxa
49 459.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile N
1-(((5S,7S)(2-(tert-butyl)-2H-1,2,3-
triazolyl)methyloxooxa
50 448.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile N
1-(((5S,7S)methyl(3-(1-methyl- O
1H-pyrazolyl)isoxazolyl)oxo-
51 1-oxaazaspiro[4.5]decan 472.2
yl)methyl)-1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(1-(tert-butyl)-1H-1,2,3-
triazolyl)methyloxooxa
52 448.3
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
1-(((5S,7S)(5-(tert-butyl)pyrazin N
yl)methyloxooxa
53 459.2
azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
PU64638
1-(((5S,7S)methyloxo(5-
(trifluoromethyl)pyrimidinyl)oxa-
54 471.2
3-azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
1-(((5S,7S)(6-(2-methoxypropan
yl)pyridinyl)methyloxooxa-
55 474.2
3-azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile N
1-(((5S,7S)methyloxo(3-
(propenyl)isoxazolyl)oxa-
56 432.2
3-azaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile
EXAMPLE 57
1-(((5S,7S)(3,4-Dimethylisoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
1-(((5S,7S)(3,4-Dimethylisoxazolyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a microwave vial was added (bis-N,N-(tert-butoxycarbonyl)amino-3,4-
dimethylisoxazole (175 mg, 0.561 mmol) and 1-(((3S,5S)methyloxaspiro[2.5]octan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (105 mg, 0.374 mmol) in NMP (1870 µL). To this
solution was added potassium tert-butoxide (50.4 mg, 0.449 mmol), and the vial was capped
and heated at 80 ºC for 16 h. The reaction was then diluted with 10% Na CO , extracted with
DCM (3x), washed with brine, dried and evaporated to a dark oil. This oil was purified by
PU64638
reverse phase HPLC purification (20-60% MeCN/Water w/ 0.1% TFA, 30 mm x 150 mm Sunfire
column) to yield 1-(((5S,7S)(3,4-dimethylisoxazolyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (29.5 mg, 14.6% yield). H
NMR (500 MHz, DMSO-d ) δ 8.53 (s, 1H), 8.39 (s, 1H), 7.84 (d, J = 8.30 Hz, 1H), 7.61 (d, J =
8.55 Hz, 1H), 4.17 (s, 2H), 3.70 – 3.80 (m, 2H), 2.16 (s, 3H), 2.00 (d, J = 12.0 Hz, 1H), 1.92 (d,
J = 14.16 Hz, 1H), 1.86 (s, 3H), 1.68 (d, J = 14.40 Hz, 1H), 1.59 – 1.68 (m, 2H), 1.41 - 1.54 (m,
2H), 1.34 (m, 1H), 1.05 (s, 3H). MS (m/z) 420.2 (M+H ).
The following compound was prepared using procedures analogous to those described
in Example 57 using appropriate substituted starting materials. As is appreciated by those
skilled in the art, this analogous example may involve variations in general reaction conditions.
Ex Name Structure
(m/z)
1-(((5S,7S)(3,4-dimethylisoxazol
yl)oxooxaazaspiro[4.5]decan-
58 406.2
7-yl)methyl)-1H-benzo[d]imidazole
carbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 4 using appropriate substituted starting materials. As is appreciated
by those skilled in the art, these analogous examples may involve variations in general
reaction conditions.
Ex Name Structure
(m/z)
1-({3-[(5-chlorobenzothien
yl)methyl]oxooxa
59 490.1
azaspiro[4.5]decyl}methyl)-1H-
indolecarbonitrile
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1-({3-[(5-chlorobenzothien N
yl)methyl]oxooxa
60 azaspiro[4.5]decyl}methyl) 559.1
(trifluoromethyl)-1H-benzimidazole
carbonitrile F
O Cl
1-({3-[(5-chlorobenzothien
yl)methyl]oxooxa
61 491.1
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-{[3-(1-benzothienylmethyl)
oxooxaazaspiro[4.5]dec
62 457.2
yl]methyl}-1H-benzimidazole
carbonitrile
1-({(5S,7S)oxo[(2-phenyl-1,3-
thiazolyl)methyl]oxa
63 484.2
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-({(5S,7S)oxo[(6-phenyl
pyridinyl)methyl]oxa
64 478.3
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-[((5S,7S){2-methyl[3-
(tetrahydro-2H-pyranyl)-1,2,4- N
65 oxadiazolyl]propyl}oxooxa 519.3
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
PU64638
1-({(5S,7S)oxo[(4-phenyl-1,3- S
thiazolyl)methyl]oxa
66 483.9
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-[((5S,7S){[3-(4-chlorophenyl)
isoxazolyl]methyl}oxooxa
67 501.9
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-({(5S,7S)oxo[(3-phenyl
isoxazolyl)methyl]oxa
68 468
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-({(5S,7S)[(1-methylphenyl-1H-
pyrazolyl)methyl]oxooxa
69 481
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-{[(5S,7S)({4-[3-methyl
(methyloxy)phenyl]-1,3-thiazol
70 yl}methyl)oxooxa 528
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-({(5S,7S)oxo[(3-phenyl-1H-
1,2,4-triazolyl)methyl]oxa
71 468
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
1-({(5S,7S)oxo[(5-phenyl
pyridinyl)methyl]oxa
72 azaspiro[4.5]decyl}methyl)-1H- 478.2
benzimidazolecarbonitrile
trifluoroacetate
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4-chloro({(5S,7S)[2-methyl(3-
phenyl-1,2,4-oxadiazolyl)propyl]
73 oxooxaazaspiro[4.5]dec 545.2
yl}methyl)-1H-benzimidazole
carbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 6 using appropriately substituted starting materials. As is appreciated
by those skilled in the art, these analogous examples may involve variations in general
reaction conditions.
Ex Name Structure
(m/z)
1-({(5S,7S)[2-methyl(3-methyl-
1,2,4-oxadiazolyl)propyl]oxo
74 449.2
oxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
1-({(5S,7S)[2-methyl(3-phenyl-
1,2,4-oxadiazolyl)propyl]oxo O
75 511.3
oxaazaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
PU64638
1-[((5S,7S){2-methyl[3-(1-
methylethyl)-1,2,4-oxadiazol N
76 yl]propyl}oxooxa 477.2
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-({(5S,7S)[2-(3-cyclopentyl-1,2,4-
oxadiazolyl)methylpropyl]oxo-
77 1-oxaazaspiro[4.5]dec 503.3
yl}methyl)-1H-benzimidazole
carbonitrile
1-[((5S,7S){2-methyl[3-(5-
pyrimidinyl)-1,2,4-oxadiazol
78 yl]propyl}oxooxa 513.3
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-[((5S,7S){2-[3-(1,1-
dimethylethyl)-1,2,4-oxadiazolyl] N
79 methylpropyl}oxooxa 491.3
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-[((5S,7S){2-methyl[3-
(trifluoromethyl)-1,2,4-oxadiazol F
80 yl]propyl}oxooxa 503.2
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
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1-{[(5S,7S)(2-methyl{3-
[(methyloxy)methyl]-1,2,4-oxadiazol-
81 5-yl}propyl)oxooxa 479.3
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-[((5S,7S){2-methyl[3-(2-
methylpropyl)-1,2,4-oxadiazol
82 yl]propyl}oxooxa 491.3
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-({(5S,7S)[2-methyl(3-{[(1-
methylethyl)oxy]methyl}-1,2,4-
83 oxadiazolyl)propyl]oxooxa 507.3
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile N
4-chloro[((5S,7S)oxo{[4-(3-
phenyl-1,2,4-oxadiazol
84 yl)tetrahydro-2H-pyranyl]methyl} 587.2
oxaazaspiro[4.5]decyl)methyl]-
1H-benzimidazolecarbonitrile
4-chloro[((5S,7S){[4-(3-
cyclopentyl-1,2,4-oxadiazol
yl)tetrahydro-2H-pyranyl]methyl}
85 579.3
oxooxaazaspiro[4.5]dec
yl)methyl]-1H-benzimidazole
carbonitrile
PU64638
The following compound was prepared using procedures analogous to those
described in Example 7 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, this analogous example may involve variations in
general reaction conditions.
Ex Name Structure
(m/z)
1-[((5S,7S)oxo{[1-(2-pyridinyl)-
3-pyrrolidinyl]methyl}oxa
86 azaspiro[4.5]decyl)methyl]-1H- 471.3
benzimidazolecarbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 8 using appropriately substituted starting materials. As is appreciated
by those skilled in the art, these analogous examples may involve variations in general
reaction conditions.
Ex Name Structure
(m/z)
1-({(5S,7S)oxo[(1-phenyl-
1H-1,2,3-triazolyl)methyl]
87 oxaazaspiro[4.5]dec 468
yl}methyl)-1H-benzimidazole
carbonitrile
1-[((5S,7S){[1-(4-cyanophenyl)-
1H-1,2,3-triazolyl]methyl}
88 oxooxaazaspiro[4.5]dec 493
yl)methyl]-1H-benzimidazole
carbonitrile
1-[((5S,7S){[1-(4-chlorophenyl)-
1H-1,2,3-triazolyl]methyl}
89 oxooxaazaspiro[4.5]dec 502
yl)methyl]-1H-benzimidazole
carbonitrile
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1-[((5S,7S){[1-(3-chlorophenyl)-
1H-1,2,3-triazolyl]methyl}
90 oxooxaazaspiro[4.5]dec 502
yl)methyl]-1H-benzimidazole
carbonitrile
1-[((5S,7S){[1-(4-
methylphenyl)-1H-1,2,3-triazol
91 yl]methyl}oxooxa 482
azaspiro[4.5]decyl)methyl]-1H- N
benzimidazolecarbonitrile
1-[((5S,7S){[1-(3-cyanophenyl)-
1H-1,2,3-triazolyl]methyl}
92 oxooxaazaspiro[4.5]dec 493
yl)methyl]-1H-benzimidazole
carbonitrile
1-{[(5S,7S)oxo({1-[3-
(trifluoromethyl)phenyl]-1H-1,2,3-
93 triazolyl}methyl)oxa 536
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-[((5S,7S){[1-(3-fluorophenyl)-
1H-1,2,3-triazolyl]methyl}
94 oxooxaazaspiro[4.5]dec 486
yl)methyl]-1H-benzimidazole
carbonitrile
1-{[(5S,7S)({1-[3- O
(methyloxy)phenyl]-1H-1,2,3-
95 triazolyl}methyl)oxooxa 498
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-[((5S,7S){[1-(3-
methylphenyl)-1H-1,2,3-triazol
96 yl]methyl}oxooxa 482
azaspiro[4.5]decyl)methyl]-1H- N
benzimidazolecarbonitrile
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1-({(5S,7S)[(1-cyclohexaneyl- O
1H-1,2,3-triazolyl)methyl]
97 oxooxaazaspiro[4.5]dec 474
yl}methyl)-1H-benzimidazole
carbonitrile
1-{[(5S,7S)({1-[4-cyano
(trifluoromethyl)phenyl]-1H-1,2,3-
98 triazolyl}methyl)oxooxa 561
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile N
1-[((5S,7S){[1-(3-chloro
cyanophenyl)-1H-1,2,3-triazol N
99 yl]methyl}oxooxa 527
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-{[(5S,7S)oxo({1-[2-
(trifluoromethyl)pyridinyl]-1H-
100 1,2,3-triazolyl}methyl)oxa 537
azaspiro[4.5]decyl]methyl}-1H- N
benzimidazolecarbonitrile
1-[((5S,7S){[1-(3,5-
difluorophenyl)-1H-1,2,3-triazol
101 yl]methyl}oxooxa 504
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-{[(5S,7S)oxo({1-[4-
(trifluoromethyl)phenyl]-1H-1,2,3-
102 triazolyl}methyl)oxa 536
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-[((5S,7S){[1-(3-cyano
fluorophenyl)-1H-1,2,3-triazol
103 yl]methyl}oxooxa 511
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
PU64638
1-[((5S,7S)methyl{[1-(1-
methylethyl)-1H-1,2,3-triazol
104 yl]methyl}oxooxa 448
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
1-({(5R,7S)methyloxo[(1-
phenyl-1H-1,2,3-triazol
105 yl)methyl]oxa 482
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
The following compound was prepared using procedures analogous to those
described in Example 9 using appropriately substituted starting materials. As is appreciated
by those skilled in the art, this analogous example may involve variations in general reaction
conditions.
Ex Name Structure
(m/z)
1-[((5S,7S){[1-(5-chloro
pyridinyl)-1H-1,2,3-triazol
yl]methyl}oxooxa
106 503
azaspiro[4.5]decyl)methyl]-1H-
benzimidazolecarbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 10 using appropriately substituted starting materials. NCS was used
PU64638
for chlorination while NBS was used for bromination. As is appreciated by those skilled in
the art, these analogous examples may involve variations in general reaction conditions.
Ex Name Structure
(m/z)
1-(((5S,7S)(4-chloro(2-
cyanopropanyl)isoxazolyl) O
methyloxooxa
107 492.9
azaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazole
carbonitrile
1-({(5S,7S)[4-bromo(1,1-
dimethylethyl)isoxazolyl]
108 methyloxooxa 526
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 11 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
Ex Name Structure
(m/z)
1-({(5S,7S)methyl[2-
(methyloxy)pyridinyl]oxo
109 oxaazaspiro[4.5]dec 432
yl}methyl)-1H-benzimidazole
carbonitrile
PU64638
1-({(5S,7S)[2,6-bis(methyloxy)-
3-pyridinyl]methyloxooxa-
110 462
3-azaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
1-({(5S,7S)[4-methyl O
(methyloxy)pyridinyl]oxo
111 oxaazaspiro[4.5]dec 432
yl}methyl)-1H-benzimidazole
carbonitrile
1-(((7S)(3,5-dichloropyridin
yl)methyloxooxa Cl
112 azaspiro[4.5]decanyl)methyl)- 469.9
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(2-ethoxypyrimidin- N
-yl)methyloxooxa
113 azaspiro[4.5]decanyl)methyl)- 447
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(5-chloro
fluoropyridinyl)methyloxo-
114 1-oxaazaspiro[4.5]decan 454
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)methyloxo(5-
O N N
(trifluoromethyl)pyrazinyl)
115 oxaazaspiro[4.5]decan 471
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
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1-(((5S,7S)(2-(tert- N
butyl)pyrimidinyl)oxooxa-
116 3-azaspiro[4.5]decanyl)methyl)- 445.3
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)methyl(5- N
methylpyrazinyl)oxooxa
117 azaspiro[4.5]decanyl)methyl)- 417
1H-benzo[d]imidazole N
carbonitrile
1-(((5S,7S)(6-ethoxy
methylpyridinyl)methyl
118 oxooxaazaspiro[4.5]decan 460.3
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
Chiral
1-(((5S,7S)(6-chloro
methylpyridinyl)methyl
119 oxooxaazaspiro[4.5]decan 450.2
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile N
1-(((5S,7S)(6-chloro
methylpyridinyl)oxooxa O
120 azaspiro[4.5]decanyl)methyl)- 436.2
1H-benzo[d]imidazole N
carbonitrile
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1-(((5S,7S)(5-chloro
methylpyridinyl)methyl
121 oxooxaazaspiro[4.5]decan 450
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(6-chloro O
methoxypyridinyl)methyl O
122 oxooxaazaspiro[4.5]decan 466.2
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(6-chloro
methoxypyridinyl)oxooxa-
123 3-azaspiro[4.5]decanyl)methyl)- 452.2
1H-benzo[d]imidazole N
carbonitrile
1-(((5S,7S)(4-methyl N
(trifluoromethyl)pyrimidinyl)
124 oxooxaazaspiro[4.5]decan 471.1
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(6-ethoxy N
methylpyridinyl)oxooxa
125 azaspiro[4.5]decanyl)methyl) 464.2
fluoro-1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(2-methoxy
methylpyridinyl)methyl
126 oxooxaazaspiro[4.5]decan 446.2
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
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1-(((5S,7S)(3-methoxy
methylpyridinyl)methyl
127 oxooxaazaspiro[4.5]decan 446
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(3-chloro
methylpyridinyl)methyl
128 oxooxaazaspiro[4.5]decan 450.2
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(3-ethylpyridinyl)-
7-methyloxooxa
129 azaspiro[4.5]decanyl)methyl)- 430
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(3,5-
dimethylpyrazinyl)methyl
130 oxooxaazaspiro[4.5]decan 431
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(3-methyl N
(trifluoromethyl)pyrazinyl)
131 oxooxaazaspiro[4.5]decan 471.2
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
PU64638
1-(((5S,7S)(6-methoxy
methylpyridinyl)methyl
132 oxooxaazaspiro[4.5]decan 446
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 15 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
Ex Name Structure
(m/z)
1-(((5S,7S)(6-(2-cyanopropan-
2-yl)pyridinyl)methyloxo- O
133 1-oxaazaspiro[4.5]decan 469.3
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
1-(((5S,7S)(2-(tert- O
butyl)pyrimidinyl)methyl O
134 oxooxaazaspiro[4.5]decan 459.3
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 17 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
PU64638
Ex Name Structure
(m/z)
1-({(5S,7S)methyl[5-
(methyloxy)pyridinyl]oxo
135 oxaazaspiro[4.5]dec 432
yl}methyl)-1H-benzimidazole
carbonitrile
1-({(5S,7S)[6-(ethyloxy)
pyridazinyl]methyloxooxa-
136 447
3-azaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
1-{[(5S,7S)(3-chloro
pyridinyl)methyloxooxa
137 436
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
1-({(5S,7S)methyl[3-
(methyloxy)pyridinyl]oxo
138 oxaazaspiro[4.5]dec 432
yl}methyl)-1H-benzimidazole
carbonitrile N
1-({(5S,7S)methyloxo[6-
(trifluoromethyl)pyridinyl]oxa-
139 470
3-azaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
PU64638
1-(((5S,7S)methyl(6-
methylpyridinyl)oxooxa
140 azaspiro[4.5]decanyl)methyl)- 416.2
1H-benzo[d]imidazole
carbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 22 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
Ex Name Structure
(m/z)
1-({(5S,7S)[4,6-bis(methyloxy)-
3-pyridinyl]oxooxa
141 448.2
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile N
1-({(5S,7S)[6-(1-methylethyl) N
pyridinyl]oxooxa
142 430.3
azaspiro[4.5]decyl}methyl)-1H-
benzimidazolecarbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 26 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
PU64638
Ex Name Structure
(m/z)
1-((7-(hydroxymethyl)(6-
methoxymethylpyridinyl)
143 oxooxaazaspiro[4.5]decan 462
yl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile N
1-(((5S,7S)methyloxo(4-
(trifluoromethyl)pyridinyl)oxa-
144 3-azaspiro[4.5]decanyl)methyl)- 470
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(2- N
(dimethylamino)pyrimidinyl)
methyloxooxa
145 446
azaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)methyl(4-
methylpyridinyl)oxooxa
146 azaspiro[4.5]decanyl)methyl)- 416
1H-benzo[d]imidazole
carbonitrile
EXAMPLE 147
1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
PU64638
Route 1:
2-(5-bromopyrazinyl)propanol
To a solution of methyl 5-bromopyrazinecarboxylate (0.250 g, 1.152 mmol) in
Tetrahydrofuran (THF) (6.53 ml) at 0 ºC under nitrogen was added methylmagnesium bromide,
3 M in diethyl ether (1.152 ml, 3.46 mmol) slowly. After 1 hour at 0 ºC, 2N HCl (15 mL) was
added slowly. The mixture was extracted with ethyl acetate (2 X 15 mL). The combined organic
extracts were dried (Na SO ), filtered, and concentrated. The residue was purified using silica
gel chromatography (ISCO): 10-30% ethyl acetate/hexanes (20 min), 12 gram silica gel column.
Obtained 2-(5-bromopyrazinyl)propanol as an orange oil (71 mg, 24%). MS (m/z) 216.9
(M+).
1-(((5S,7S)(5-(2-Hydroxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a light yellow solution of 1-(((5S,7S)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (0.050 g, 0.154 mmol) in 1,4-dioxane (2.052 mL)
was added copper(I) iodide (2.94 mg, 0.015 mmol), potassium phosphate tribasic (0.065 g,
0.308 mmol), trans-1,2-diaminocyclohexane (3.71 µL, 0.031 mmol), and 2-(5-bromopyrazin
yl)propanol (0.040 g, 0.185 mmol). The reaction mixture was heated at 100 ºC for 15 h.
Then, additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane
(3.71 µL, 0.031 mmol) were added and stirred for an additional hour at 100 ºC. Additional
copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 µL, 0.031
mmol) were then added and stirred for an additional 3 h at 100 ºC. The reaction was then
cooled to RT and CH CN (5 mL) was added and the mixture vacuum filtered using a Hirsch
funnel. The solid was rinsed with CH CN (3 x 2 mL) and the filtrate was loaded onto florisil and
purified using silica gel chromatography (ISCO): 0.5-2% MeOH/DCM (30 min), 12 g silica gel
column. The product eluted at 19 minutes to obtain 1-(((5S,7S)(5-(2-hydroxypropan
yl)pyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazole-
6-carbonitrile as an orange foam (43 mg, 38% yield). H NMR (400 MHz, DMSO-d ) δ 9.18 (s,
1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J = 8.28 Hz, 1H), 7.58 (d, J = 8.28 Hz, 1H),
.41 (s, 1H), 4.16 (br. s., 2H), 3.77 - 3.96 (m, 2H), 1.98 (d, J = 7.03 Hz, 1H), 1.82 - 1.93 (m, 1H),
1.72 (d, J = 14.56 Hz, 2H), 1.58 – 1.67 (m, 2H), 1.28 – 1.57 (m, 8H), 1.06 (s, 3H). MS (m/z)
461.0 (M+H ).
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Route 2:
2-(5-chloropyrazinyl)propanol
A well-stirring solution of methyl 5-chloropyrazinecarboxylate (23.5 g, 136 mmol) in
Tetrahydrofuran (THF) (172 ml) under nitrogen was cooled to -10 ºC and became a thick tan
suspension. Added methylmagnesium bromide, 3M in diethyl ether (100 ml, 300 mmol) slowly
making sure the temperature did not rise above 0 ºC. After 1 hour, the reaction now at 0 ºC was
quenched with saturated NH Cl (100 mL) slowly, followed by EtOAc (100 mL), and the dark
mixture was stirred overnight. The mixture was diluted with 400 mL water and 100 mL EtOAc,
and the layers were separated. The aqueous layer was extracted with EtOAc (2 X 300 mL). The
combined EtOAc extracts were dried over MgSO , filtered, and concentrated to give a dark
residue, which was divided into two batches. Each batch was loaded (with 10%
CH Cl /cyclohexane) onto a pre-equilibrated (with hexanes) 330 g silica cartridge and purified
using normal phase chromatography (ISCO): 0-25% ethyl acetate/hexanes (30 min), 25% (15
min). Product began eluting at 33 minutes. Product fractions were concentrated to afford 2-(5-
chloropyrazinyl)propanol (6.232 g, 25%) as a low viscosity orange oil. MS (m/z) 173.1
(M+H ).
1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
Two identical reactions were set up: To a 1 L flask containing 2-(5-chloropyrazin
yl)propanol (18.29 g, 106 mmol) was added reagents in the following order: first potassium
phosphate tribasic (36.0 g, 170 mmol), followed by 1-(((5S,7S)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (27.5 g, 85 mmol). Next
1,4-dioxane (424 mL) was added followed by N1,N2-dimethylethane-1,2-diamine (7.47 g, 85
mmol). To the resulting white slurry was added copper(I) iodide (8.07 g, 42.4 mmol). The slurry
was put under nitrogen and heated to 100 °C (Reaction 1 = 44 h, Reaction 2 = 68 h). After
completion, the mixture was cooled to RT, diluted with DCM and water and 7N NH in MeOH
and allowed to stir for 10 min. The layers were separated and the aqueous layer was extracted
with DCM (2x). The combined DCM extracts were diluted with 7N NH in MeOH (300 mL) (to
remove residual copper ions), and then washed with water (2 x 500 mL), and dried over
Na SO , filtered, and concentrated. Each residue was purified on the ISCO: 4 x 330g silica, 0-
% MeOH/DCM over 10 CV. Fractions containing product were concentrated, dissolved in
DCM, and washed one final time with water/7N NH in MeOH to remove any leftover copper.
PU64638
The resulting layers were separated, the aqueous layer extracted with DCM (2x), and the
combined DCM extracts were dried over Na SO , filtered, and concentrated. The residue was
then azeotroped with MeCN (300 mL) and then diluted to a volume of ~650 mL. The solution
was heated to 70 °C (all solids went into solution affording a yellow solution), then allowed to
cool to RT with stirring and crystals started to form. After stirring at RT for ~2 h, the slurry was
diluted with 2 L water. Stirring was continued overnight before the slurry was filtered and the
solids dried under reduced pressure to 1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)
methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (71.3
g, 91%) as a white solid. MS (m/z) 461.2 (M+H ) H NMR (400 MHz, DMSO-d ) δ 9.18 (s, 1H),
8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J = 8.28 Hz, 1H), 7.58 (d, J = 8.28 Hz, 1H), 5.41
(s, 1H), 4.16 (br. s., 2H), 3.77 - 3.96 (m, 2H), 1.98 (d, J = 7.03 Hz, 1H), 1.82 - 1.93 (m, 1H), 1.72
(d, J = 14.56 Hz, 2H), 1.58 – 1.67 (m, 2H), 1.28 – 1.57 (m, 8H), 1.06 (s, 3H). MS (m/z) 461.0
(M+H ).
The following compounds were prepared using procedures analogous to those
described in Example 26 using appropriately substituted starting materials. As is appreciated by
those skilled in the art, these analogous examples may involve variations in general reaction
conditions.
1-(((5S,7S)(2-(2-
hydroxypropanyl)pyrimidin
yl)methyloxooxa
148 461
azaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(4-methoxypyridin
yl)methyloxooxa
149 azaspiro[4.5]decanyl)methyl)- 432
1H-benzo[d]imidazole
carbonitrile N
PU64638
1-(((5S,7S)(5-
(dimethylamino)pyrazinyl)
methyloxooxa
150 446
azaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazole
carbonitrile
The following compounds were prepared using procedures analogous to those
described in Example 27 using appropriately substituted starting materials. As is
appreciated by those skilled in the art, these analogous examples may involve variations in
general reaction conditions.
Ex Name Structure
(m/z)
1-{[(5S,7S)oxo(thieno[2,3- N
b]pyridinylmethyl)oxa
151 458.2
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile N
1-{[(trans)methyloxo
(thieno[2,3-b]pyridinylmethyl)
152 oxaazaspiro[4.5]dec 472.2
yl]methyl}-1H-benzimidazole N
carbonitrile
1-({(5S,7S)[(3-bromothieno[2,3-
b]pyridinyl)methyl]oxooxa-
153 536.1
3-azaspiro[4.5]decyl}methyl)-
1H-benzimidazolecarbonitrile
following compound was prepared using procedures analogous to those described in
Example 28 using appropriately substituted starting materials. As is appreciated by those
skilled in the art, these analogous examples may involve variations in general reaction
conditions.
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Ex Name Structure
(m/z)
1-{[(5S,7S)(2-methyl{3-[1- N N
(methyloxy)ethyl]-1,2,4-oxadiazol-
154 5-yl}propyl)oxooxa 493.2
azaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile
EXAMPLE 155
1-(((5S,7S)((5-ethoxypyrazinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
2-(bromomethyl)ethoxypyrazine
A mixture of 2-ethoxymethylpyrazine (0.86 g, 6.22 mmol), NBS (1.440 g, 8.09 mmol),
and diphenylperoxyanhydride (0.151 g, 0.622 mmol) in carbon tetrachloride (20 mL) was heated
to 80 °C overnight. Cooled to RT, diluted with saturated NaHCO , and extracted with ethyl
acetate (3x). The combined organic extracts were washed with saturated NaCl (2x), dried over
Na SO , filtered, and concentrated. The residue was purified via ISCO (40 g silica, 40 mL/min,
0-30% EtOAc/Hexanes over 25 min) to afford 2-(bromomethyl)ethoxypyrazine (430 mg,
32%). MS (m/z) 217.0 (M+).
1-(((5S,7S)((5-ethoxypyrazinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a solution of 1-{[(5S,7S)methyloxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile (150 mg, 0.462 mmol) in N,N-Dimethylformamide (DMF) (2 mL)
was added 60% sodium hydride in mineral oil (24.04 mg, 0.601 mmol) and stirred for 30
minutes. To the mixture was added 2-(bromomethyl)ethoxypyrazine (120 mg, 0.555 mmol)
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and stirred overnight. The reaction was diluted with saturated NH Cl and extracted with ethyl
acetate (3x). The combined organic extracts were washed with saturated NaCl (2x), dried over
Na SO , filtered, and concentrated. The residue was purified via silica gel ISCO
chromatography (40 g silica gel, 40 mL/min, 0-10% MeOH/CH Cl over 25 min) to afford 1-
(((5S,7S)((5-ethoxypyrazinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile (125 mg, 56%). H NMR (400 MHz, DMSO-d ) δ
8.45 (s, 1H), 8.35 (d, J = 0.75 Hz, 1H), 8.21 (d, J = 1.25 Hz, 1H), 8.13 (d, J = 1.51 Hz, 1H), 7.83
(d, J = 8.28 Hz, 1H), 7.59 (dd, J = 8.28, 1.51 Hz, 1H), 4.31 - 4.41 (m, 4H), 4.12 (s, 2H), 3.21 (dd,
J = 23.09, 9.03 Hz, 2H), 1.81 (d, J = 13.30 Hz, 1H), 1.49 - 1.74 (m, 4H), 1.22 - 1.46 (m, 6H),
1.02 (s, 3H). MS (m/z) 461.2 (M+H ).
The following compounds were prepared using procedures analogous to those
described in Example 155 using appropriately substituted starting materials. As is appreciated
by those skilled in the art, these analogous examples may involve variations in general reaction
conditions.
Ex Name Structure
(m/z)
1-(((5S,7S)((4-ethoxypyridin
yl)methyl)methyloxooxa-
156 3-azaspiro[4.5]decanyl)methyl)- 460.2
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)((5-ethoxypyridin
yl)methyl)methyloxooxa-
3-azaspiro[4.5]decanyl)methyl)-
157 460.2
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)((4-fluoropyridin
yl)methyl)methyloxooxa-
3-azaspiro[4.5]decanyl)methyl)-
158 434.2
1H-benzo[d]imidazole
carbonitrile
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1-(((5S,7S)((5-fluoropyridin
yl)methyl)methyloxooxa-
3-azaspiro[4.5]decanyl)methyl)-
159 434.2
1H-benzo[d]imidazole
carbonitrile
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EXAMPLE 160
1-(((5S,7S)methyl((4-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
4-bromo(bromomethyl)pyridine
A mixture of 4-bromomethylpyridine (2.0 g, 11.63 mmol), NBS (2.69 g, 15.11 mmol),
and diphenylperoxyanhydride (0.282 g, 1.163 mmol) in carbon tetrachloride (50 mL) was heated
to 100 °C overnight. Cooled to RT, diluted with saturated NaHCO , and extracted with ethyl
acetate (3x). The combined organic extracts were washed with saturated NaCl (2x), dried over
Na SO , filtered, and concentrated. The residue was purified via silica gel chromatography
(ISCO, 120 g silica, 60 mL/min, 0-80% EtOAc/Hexanes over 45 min) to afford 4-bromo
(bromomethyl)pyridine (1.05 g, 36%). MS (m/z) 251.9.
1-(((5S,7S)((4-bromopyridinyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a solution of 1-{[(5S,7S)methyloxooxaazaspiro[4.5]decyl]methyl}-1H-
benzimidazolecarbonitrile (1.0 g, 3.08 mmol) in N,N-Dimethylformamide (DMF) (7 mL) was
added 60% sodium hydride in mineral oil (0.160 g, 4.01 mmol) and stirred for 30 minutes. To the
mixture was added 4-bromo(bromomethyl)pyridine (0.928 g, 3.70 mmol) and stirred
overnight. The reaction was diluted with saturated NH Cl and extracted with ethyl acetate (3x).
The combined organic extracts were washed with saturated NaCl (2x), dried over Na SO ,
filtered, and concentrated. The residue was purified via silica gel chromatography (ISCO, 120 g
silica, 60 mL/min, 0-10% MeOH/CH Cl over 45 min) to afford 1-(((5S,7S)((4-bromopyridin
yl)methyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazole
carbonitrile (1.41 g, 93%). MS (m/z) 494.1 (M+).
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1-(((5S,7S)methyl((4-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a microwave vial was added 1-(((5S,7S)((4-bromopyridinyl)methyl)methyl
oxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (100 mg,
0.202 mmol), sodium carbonate (64.3 mg, 0.607 mmol), 1-methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2yl)-1H-pyrazole (63.1 mg, 0.303 mmol), and PdCl (dppf) (14.80 mg, 0.020 mmol)
in 1,4-Dioxane (3.0 mL) and Water (1.000 mL). The mixture was subjected to the microwave at
120 °C for 20 minutes. The mixture was diluted with saturated NaHCO and extracted with DCM
(3x). The combined DCM extracts were passed through a phase separator and concentrated.
The residue was purified via reverse HPLC (Waters Sunfire 30 x 150 mm Acetonitrile:Water
TFA 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO resin SPE to yield
1-(((5S,7S)methyl((4-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (99 mg, 94%). H NMR
(400 MHz, DMSO-d ) δ 8.50 - 8.61 (m, 3H), 8.38 (s, 1H), 8.22 (s, 1H), 7.85 (d, J = 8.28 Hz, 1H),
7.73 - 7.82 (m, 2H), 7.61 (dd, J = 8.28, 1.25 Hz, 1H), 4.53 (dd, J = 21.83, 16.31 Hz, 2H), 4.07 -
4.20 (m, 2H), 3.93 (s, 3H), 3.28 (dd, J = 19.07, 8.78 Hz, 2H), 1.97 (d, J = 13.30 Hz, 1H), 1.79 (d,
J = 14.56 Hz, 1H), 1.52 - 1.73 (m, 3H), 1.25 - 1.49 (m, 3H), 1.05 (s, 3H). MS (m/z) 496.3
(M+H ).
The following compounds were prepared using procedures analogous to those
described in Example 160 using appropriately substituted starting materials. As is appreciated
by those skilled in the art, these analogous examples may involve variations in general reaction
conditions.
Ex Name Structure
(m/z)
1-(((5S,7S)methyl((6-(1-
methyl-1H-pyrazolyl)pyridin
yl)methyl)oxooxa
161 496.3
azaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazole
carbonitrile
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EXAMPLE 162
1-(((5S,7S)(5-(2-methoxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a solution of 1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)methyloxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (75 mg, 0.163 mmol)
in N,N-Dimethylformamide (DMF) (1 mL) was added sodium hydride (9.77 mg, 0.244 mmol) at
RT. After 10 minutes, MeI (0.020 mL, 0.326 mmol) was added. The mixture stirred for an hour
and was purified by reverse phase HPLC (Waters Sunfire 30 x 150mm Acetonitrile:Water 0.1%
TFA 30-70%, 50 mL/min, 15 min). The product was free based with PL-HCO resin SPE to yield
1-(((5S,7S)(5-(2-methoxypropanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a white powder (45 mg,
58%). H NMR (400 MHz, DMSO-d ) δ 9.25 (d, J = 1.51 Hz, 1H), 8.47 - 8.53 (m, 2H), 8.39 (d,
J = 1.00 Hz, 1H), 7.84 (d, J = 8.78 Hz, 1H), 7.60 (dd, J = 8.53, 1.51 Hz, 1H), 4.17 (s, 2H), 3.88
(dd, J = 23.09, 10.29 Hz, 2H), 3.09 (s, 3H), 2.00 (d, J = 14.05 Hz, 1H), 1.89 (d, J = 14.56 Hz,
1H), 1.59 - 1.78 (m, 3H), 1.30 - 1.56 (m, 9H), 1.08 (s, 3H). MS (m/z) 443.2 (M-OMe).
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EXAMPLE 163
1-(((5S,7S)(5-(2-(2-methoxyethoxy)propanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
1-(((5S,7S)(5-(2-(2-hydroxyethoxy)propanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a solution of 1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)methyloxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (500 mg, 1.086
mmol, example 147) in ethylene glycol (4.93 mL) was added concentrated H SO (0.5 mL, 9.38
mmol) at RT and heated at 60 °C overnight. The reaction mixture was cooled to RT, diluted with
water, and extracted 5x DCM. The combined DCM layers were washed with brine,
concentrated, and purified by reverse phase HPLC (Waters Sunfire 30 x 150 mm column,
acetonitrile:water 0.1% TFA long 20-60%, 50 mL/min, 15 min). The product was free based with
PL-HCO resin SPE to yield 1-(((5S,7S)(5-(2-(2-hydroxyethoxy)propanyl)pyrazinyl)
methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a
white solid (121 mg, 21%). MS (m/z) 505.3 (M+H ).
1-(((5S,7S)(5-(2-(2-methoxyethoxy)propanyl)pyrazinyl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a solution of 1-(((5S,7S)(5-(2-(2-hydroxyethoxy)propanyl)pyrazinyl)methyl-
2-oxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (40 mg,
0.079 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was added sodium hydride (4.76 mg,
0.119 mmol) at RT. After 10 minutes, MeI (0.020 mL, 0.317 mmol) was added and stirred for an
hour. To the mixture was added 0.5 mL MeOH and 2 drops 5% AcOH to buffer to pH 10, then
filtered and purified by reverse phase HPLC (Waters Sunfire 30x150mm Acetonitrile:Water
0.1% TFA 50-100%, 50 mL/min, 15 min). The product was free based with PL-HCO resin SPE
to yield 1-(((5S,7S)(5-(2-(2-methoxyethoxy)propanyl)pyrazinyl)methyloxooxa
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azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile as a white solid (16.5 mg,
39%). H NMR (400 MHz, DMSO-d ) δ 9.23 (d, J = 1.51 Hz, 1H), 8.57 (d, J = 1.51 Hz, 1H), 8.50
(s, 1H), 8.39 (d, J = 0.75 Hz, 1H), 7.84 (d, J = 8.53 Hz, 1H), 7.60 (dd, J = 8.41, 1.38 Hz, 1H),
4.12 - 4.23 (m, 2H), 3.88 (dd, J = 23.09, 10.29 Hz, 2H), 3.43 - 3.48 (m, 2H), 3.34 - 3.39 (m, 2H),
3.26 (s, 3H), 2.00 (d, J = 13.30 Hz, 1H), 1.89 (d, J = 14.31 Hz, 1H), 1.58 - 1.77 (m, 3H), 1.43 -
1.56 (m, 8H), 1.30 - 1.41 (m, 1H), 1.07 (s, 3H). MS (m/z) 519.3 (M+H ).
EXAMPLE 164
2-((2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa
azaspiro[4.5]decanyl)pyrazinyl)propanyl)oxy)ethyl dimethylphosphinate
To a solution of 1-(((5S,7S)(5-(2-(2-hydroxyethoxy)propanyl)pyrazinyl)methyl-
2-oxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (60 mg,
0.119 mmol) in dichloromethane (DCM) (1127 µl) was added DIEA (62.3 µl, 0.357 mmol) and
dimethylphosphinic chloride (40.1 mg, 0.357 mmol) at RT. The mixture was stirred for 2 hours,
concentrated and reconstituted in DMSO/MeOH and filtered. The solution was purified by
reverse phase HPLC (Waters Sunfire 30 x 150 mm Acetonitrile:Water TFA 30-70%, 50 mL/min,
min.). The product was free based with PL-HCO resin SPE to yield 2-((2-(5-((5S,7S)((6-
cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxaazaspiro[4.5]decan
yl)pyrazinyl)propanyl)oxy)ethyl dimethylphosphinate as a white solid (5.8 mg, 8%). H
NMR (400 MHz, DMSO-d ) δ 9.24 (d, J = 1.51 Hz, 1H), 8.60 (d, J = 1.26 Hz, 1H), 8.48 (s, 1H),
8.38 (s, 1H), 7.83 (d, J = 8.53 Hz, 1H), 4.12 - 4.21 (m, 2H), 3.94 - 4.03 (m, 2H), 3.88 (dd, J =
23.09, 10.04 Hz, 2H), 3.42 (t, J = 4.77 Hz, 2H), 2.00 (d, J = 13.30 Hz, 1H), 1.88 (d, J = 14.05
Hz, 1H), 1.59 - 1.78 (m, 3H), 1.30 - 1.56 (m, 15H), 1.07 (s, 3H). MS (m/z) 581.3 (M+H ).
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EXAMPLE 165
1-(((5S,7S)(5'-fluoromethyl-[2,2'-bipyridin]yl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
1-(((5S,7S)methyl(4-methyloxo-1,6-dihydropyridinyl)oxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
To a suspension of 1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (5000 mg, 11.22
mmol) and sodium iodide (5047 mg, 33.7 mmol) in Acetonitrile (42.900 mL) was added TMSCl
(4.30 mL, 33.7 mmol). The reaction was stirred at room temperature overnight. More sodium
iodide (5047 mg, 33.7 mmol) and TMSCl (4.30 mL, 33.7 mmol) were added and stirred
overnight at room temperature. The reaction mixture was concentrated to remove MeCN, and
the residue was partitioned between saturated aqueous sodium metabisulfite (30 mL) and 10%
MeOH/DCM (50 mL). The layers were separated, and the aqueous layer was extracted with 2 x
DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated.
The material was purified by ISCO Rf chromatography (220 g column, silica load): 0-20%
MeOH/DCM (20 min), 20% MeOH/DCM (20 min). Obtained 1-(((5S,7S)methyl(4-methyl
oxo-1,6-dihydropyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H-
benzo[d]imidazolecarbonitrile as a white foam (3.35 g, 69%). MS (m/z) 432.2 (M+H ).
-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa
azaspiro[4.5]decanyl)methylpyridinyl trifluoromethanesulfonate
To a solution of 1-(((5S,7S)methyl(4-methyloxo-1,6-dihydropyridinyl)oxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (2.25 g, 5.21 mmol)
and pyridine (4.22 ml, 52.1 mmol) in Dichloromethane (DCM) (38.9 ml) cooled to 0 °C under
nitrogen was added triflic anhydride (2.202 ml, 13.04 mmol). After 1 hour, the reaction mixture
was diluted with water and extracted with 3 x DCM. The combined organic extracts were
PU64638
washed with 0.5 M HCl, dried over sodium sulfate, filtered, and concentrated. The material was
purified by ISCO Rf chromatography (220 g silica): 0-10% MeOH/DCM (20 min), 10%
MeOH/DCM (20 min). Obtained 5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)
methyloxooxaazaspiro[4.5]decanyl)methylpyridinyl trifluoromethanesulfonate as
a yellow foam (2.79 g, 95%). MS (m/z) 564.1 (M+H ).
1-(((5S,7S)(5'-fluoromethyl-[2,2'-bipyridin]yl)methyloxooxa
azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile
A mixture of 5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxo
oxaazaspiro[4.5]decanyl)methylpyridinyl trifluoromethanesulfonate (120 mg, 0.213
mmol) and Pd(PPh ) (12.30 mg, 10.65 µmol) in Tetrahydrofuran (THF) (4 mL) was treated with
(5-fluoropyridinyl)zinc(II) bromide (0.5M in THF) (4.26 mL, 2.129 mmol) under nitrogen and
stirred at room temperature overnight. The reaction was concentrated and purified by normal
phase chromatography (ISCO Rf, 80 g silica, 0-5% MeOH/DCM). Obtained desired product
containing 10% triphenylphosphine oxide, which was dissolved in 1 mL of MeOH and
recrystallized to afford 1-(((5S,7S)(5'-fluoromethyl-[2,2'-bipyridin]yl)methyloxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (50.5 mg, 44%). H
NMR (400 MHz, DMSO-d ) δ 8.69 (d, J = 2.76 Hz, 1H), 8.63 (s, 1H), 8.50 (s, 1H), 8.39 - 8.46
(m, 2H), 8.27 (s, 1H), 7.82 - 7.92 (m, 2H), 7.61 (dd, J = 8.28, 1.51 Hz, 1H), 4.15 - 4.24 (m, 2H),
3.78 (dd, J = 13.80, 8.78 Hz, 2H), 2.33 (s, 3H), 2.10 (d, J = 13.55 Hz, 1H), 1.97 (d, J = 14.31 Hz,
1H), 1.59 - 1.80 (m, 3H), 1.44 - 1.56 (m, 2H), 1.32 - 1.43 (m, 1H), 1.10 (s, 3H). MS (m/z) 511.2
(M+H ).
EXAMPLE 166
1-(((5S,7S)methyl(4-methylmorpholinopyridinyl)oxooxaazaspiro[4.5]decan
yl)methyl)-1H-benzo[d]imidazolecarbonitrile
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A mixture of 5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxo
oxaazaspiro[4.5]decanyl)methylpyridinyl trifluoromethanesulfonate (100 mg, 0.177
mmol) and morpholine (0.077 mL, 0.887 mmol) in Dimethyl Sulfoxide (DMSO) (1.5 mL) was
heated in the microwave for 35 minutes at 100 °C. The solution was purified by reverse phase
HPLC (Waters Sunfire 30 x 150 mm Acetonitrile:Water 0.1% TFA 10-50%, 50 mL/min, 15 min)
to afford the bis-TFA salt of 1-(((5S,7S)methyl(4-methylmorpholinopyridinyl)oxo
oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile (60 mg, 46%). H
NMR (400 MHz, DMSO-d ) δ 8.65 (s, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.88 (d, J = 8.28 Hz, 1H),
7.65 (dd, J = 8.28, 1.25 Hz, 1H), 6.94 (s, 1H), 4.15 - 4.25 (m, 2H), 3.67 - 3.74 (m, 4H), 3.59 (s,
2H), 3.45 - 3.52 (m, 4H), 2.17 (s, 3H), 2.04 (d, J = 13.55 Hz, 1H), 1.92 (d, J = 14.56 Hz, 1H),
1.58 - 1.77 (m, 3H), 1.30 - 1.52 (m, 3H), 1.08 (s, 3H). MS (m/z) 501.3 (M+H ).
The following compounds were prepared using procedures analogous to those
described in Example 26 using appropriately substituted starting materials. As is appreciated by
those skilled in the art, these analogous examples may involve variations in general reaction
conditions.
1-(((5S,7S)(5-(2-
hydroxypropanyl)pyridinyl)
methyloxooxa
167 460
azaspiro[4.5]decanyl)methyl)-
1H-benzo[d]imidazole
carbonitrile
1-(((5S,7S)(5-(1-hydroxy
methylpropanyl)pyrazinyl)
methyloxooxa
azaspiro[4.5]decanyl)methyl)-
168 475
1H-benzo[d]imidazole
carbonitrile
PU64638
EXAMPLE 169
1-(((5S,7S)(6-cyclopropylmethoxypyridinyl)methyloxooxaazaspiro[4.5]decan-
7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile
2-cyclopropylmethoxynitropyridine
A mixture of 2-chloromethoxynitropyridine (1.6 g, 8.48 mmol), cyclopropylboronic
acid (1.458 g, 16.97 mmol), PdCl (dppf)-CH Cl adduct (1.386 g, 1.697 mmol), cesium
2 2 2
carbonate (8.29 g, 25.5 mmol), and 1,4-Dioxane (15 mL) were heated using the microwave at
140 ºC for 10 minutes. The reaction mixture was purified by normal phase chromatography
(ISCO, 120 g silica, 0-3% methanol/DCM) to afford 2-cyclopropylmethoxynitropyridine as a
red solid (492 mg, 28%). MS (m/z) 195.0 (M+H ).
6-cyclopropylmethoxypyridinamine
To a mixture of 2-cyclopropylmethoxynitropyridine (805 mg, 4.15 mmol), nickel(II)
chloride, 6 H O (2956 mg, 12.44 mmol), and methanol (25 mL), cooled to 0 ºC, was added
sodium borohydride (941 mg, 24.87 mmol) portion wise over 1 minute. After 5 minutes, the
reaction was diluted with DCM (50 mL), saturated sodium bicarbonate (50 mL), and water (50
mL), and filtered through Celite©. The layers of the filtrate were separated and the aqueous
layer was further extracted with DCM (50 mL). The combined organic extracts were washed
with water (50 mL), brine (50 mL), eluted through a phase separator, and concentrated to afford
6-cyclopropylmethoxypyridinamine (448 mg, 63%) as a yellow oil. MS (m/z) 165.1 (M+H ).
tert-butyl (6-cyclopropylmethoxypyridinyl)carbamate
A solution of 6-cyclopropylmethoxypyridinamine (448 mg, 2.73 mmol), di-tert-butyl
dicarbonate (655 mg, 3.00 mmol), and tetrahydrofuran (THF) (20 mL) was stirred at 60 ºC
overnight. The reaction was diluted with DCM (50 mL) and water (50 mL), and the layers were
separated. The aqueous layer was further extracted with DCM (25 mL), and the combined
organic extracts were washed with water (50 ml), brine (50 mL), eluted through a phase
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separator, and concentrated. The resultant oil was purified by normal phase chromatography
(ISCO, 120 g silica, 0-4% methanol/DCM) to afford tert-butyl (6-cyclopropylmethoxypyridin
yl)carbamate (500 mg, 66%) as a red solid. MS (m/z) 265.1 (M+H ).
PU64638
Claims (17)
1. A compound of Formula (I): (R ) R 2 y 3 Wherein: R is hydrogen, C alkyl, CH OH, CH -O-CH , CH OCH Ph, CH CN, CN, halo or C(O)OCH ; 1 1-3 2 2 3 2 2 2 3 R is independently hydrogen, CN, CF , halo, SO C alkyl, C alkyl or CΞCH; 2 3 2 1-3 1-3 R is hydrogen, C alkyl, CF or OH; 3 1-2 3 R is hydrogen, halo or C alkyl; 4 1-3 X is CR or N; A is (CH ) – Het; or A is (CH ) -(CR R )-(CH ) -Het; 2 n a b 2 m R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more a 1-3 1-3 halos; R is C alkyl; b 1-3 or R and R together with the carbon atom they are attached form a C cycloalkyl group; or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with nitrogen to form a pyrrolidinyl or piperidinyl group; PU64638 Het is: S O O , , , N N N N N N N N , N , , , , , S S ; wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl, CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl, 2 2 3 3-6 2 n 1-3 2 n 2 n pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, CH(OH)-C alkyl, C(CH ) – R , C(O)N(CH ) , 3 1-3 1-5 3 2 5 3 p N(C alkyl) , NH , C(O)NH , oxetane, oxetane-CH , tetrahydrofuryl, tetrahydropyranyl, 1-3 p 2 2 3 morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl or CF ; 3 1-3 3 and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by CN or 1-5 3-6 R is CN, O-C alkyl, (CH ) – OH, (CH ) – O – C(O) - O – C alkyl, or O-(CH ) -O –R ; 5 1-4 2 m 2 p 1-5 2 p 6 R is C alkyl or P(O) (CH ) ; 6 1-4 2 3 2 n is independently 0, 1 or 2; m is independently 0, 1 or 2; p is independently 1 or 2; and y is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. PU64638
2. A compound of Formula (I): (R ) R Wherein: R is hydrogen, C alkyl, CH OH, CH -O-CH , CH OCH Ph, CH CN, CN, halo or C(O)OCH ; 1 1-3 2 2 3 2 2 2 3 R is independently hydrogen, CN, CF , halo, SO C alkyl, C alkyl or CΞCH; 2 3 2 1-3 1-3 R is hydrogen, C alkyl, CF or OH; 3 1-2 3 R is hydrogen, halo or C alkyl; 4 1-3 X is CR or N; A is (CH ) – Het; or A is (CH ) -(CR R )-(CH ) -Het; 2 n a b 2 m R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more a 1-3 1-3 halos; R is C alkyl; b 1-3 or R and R together with the carbon atom they are attached form a C cycloalkyl group; a b 3-6 or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with nitrogen to form a pyrrolidinyl or piperidinyl group; Het is PU64638 N N N S O O , , , N N N N N N N N N , N , , , , , S N or Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl, CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl, 2 2 3 3-6 2 n 1-3 2 n 2 n pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN, 3 1-3 3 2 3 2 3 3 2 C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH , 3 2 2 3 2 2 1-5 3 p 1-3 p 2 2 oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl or CF ; 3 1-3 3 and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by 1-5 3-6 CN or OH; n is independently 0, 1 or 2; m is independently 0, 1 or 2; p is independently 1 or 2; y is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
3. A compound of claim 2 wherein: R is hydrogen, C alkyl or CH OH; 1 1-3 2 R is CN; R is hydrogen; X is N; A is (CH ) – Het; or A is (CH ) -(CR R )-(CH ) -Het; 2 n a b 2 m R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more a 1-3 1-3 halos; PU64638 R is C alkyl; b 1-3 or R and R together with the carbon atom they are attached to form a C cycloalkyl group; a b 3-6 or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with nitrogen to form a pyrrolidinyl or piperidinyl group; Het is S O O , , , N N N N N N N N N N , N , , , , , S S ; S N or Wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl, CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl, 2 2 3 3-6 2 n 1-3 2 n 2 n pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN, 3 1-3 3 2 3 2 3 3 2 C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH , 3 2 2 3 2 2 1-5 3 p 1-3 p 2 2 oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl or CF ; 3 1-3 3 and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by 1-5 3-6 CN or OH; n is independently 0 or 1; m is independently 0 or 1; p is independently 1 or 2; and y is 1 or 2; or a pharmaceutically acceptable salt thereof.
4. A compound of claim 2 wherein: PU64638 R is hydrogen, C alkyl or CH OH; 1 1-3 2 R is CN; R is hydrogen; X is N; A is (CH ) – Het; or A is (CH ) -(CR R )-(CH ) -Het; 2 n a b 2 m R is hydrogen or C alkyl, wherein the C alkyl may be further substituted with one or more a 1-3 1-3 halos; R is C alkyl; b 1-3 or R and R together with the carbon atom they are attached to form a C cycloalkyl group; a b 3-6 or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C cycloalkyl group formed by R and R may be replaced 3-6 a b with nitrogen to form a pyrrolidinyl or piperidinyl group; Het is S O O , , , , N N N N N N N S N N N , N , wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl, CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl, 2 2 3 3-6 2 n 1-3 2 n 2 n pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN, 3 1-3 3 2 3 2 3 3 2 C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH , 3 2 2 3 2 2 1-5 3 p 1-3 p 2 2 oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl, or CF ; 3 1-3 3 and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by 1-5 3-6 CN or OH; n is independently 0 or 1; m is independently 0 or 1; p is independently 1 or 2; and PU64638 y is 1 or 2; or a pharmaceutically acceptable salt thereof.
5. A compound of claim 2 wherein: R is hydrogen, C alkyl or CH OH; 1 1-3 2 R is CN; R is hydrogen; X is N; A is (CH ) – Het; Het is N N N O , , , or ; , N N wherein Het may be substituted by one, two or three substituents chosen from: halo, C alkyl, CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl, 2 2 3 3-6 2 n 1-3 2 n 2 n pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN, 3 1-3 3 2 3 2 3 3 2 C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH , 3 2 2 3 2 2 1-5 3 p 1-3 p 2 2 oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl, or CF ; 3 1-3 3 and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by 1-5 3-6 CN or OH; n is independently 0 or 1; p is independently 1 or 2; and y is 1 or 2; or a pharmaceutically acceptable salt thereof.
6. A compound of claim 2 wherein: R is hydrogen, C alkyl or CH OH; 1 1-3 2 PU64638 R is CN; R is hydrogen; X is N; A is (CH ) – Het; Het is N N N , or ; Wherein Het may be substituted by one, two or three substituents chosen from: Halo, C alkyl, CN, CH F, CHF , CF , C cycloalkyl, (CH ) -O-C alkyl, (CH ) -phenyl, (CH ) -pyridyl, 2 2 3 3-6 2 n 1-3 2 n 2 n pyrimidinyl, pyrazinyl, CH(CH )–O-C alkyl, C(CH ) -OH, C(CH ) -O-CH , C(CH ) -CN, 3 1-3 3 2 3 2 3 3 2 C(CH ) -CH OH, C(CH ) -CH -O-C(O)-O-C alkyl, C(O)N(CH ) , N(C alkyl) , NH , C(O)NH , 3 2 2 3 2 2 1-5 3 p 1-3 p 2 2 oxetane, oxetane-CH , tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH , C alkyl, or CF ; 3 1-3 3 and the C alkyl and C cycloalkyl substituent on the Het may be further substituted by 1-5 3-6 CN or OH; n is 0; p is independently 1 or 2; and y is 1 or 2; or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 chosen from: 1-({(5S,7S)[3-(1,1-dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-(((5S,7S)(3-(2-cyanopropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan- 7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-({(5S,7S)[5-(1,1-dimethylethyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; PU64638 1-{[(5S,7S)methyloxo(2-pyridinylmethyl)oxaazaspiro[4.5]decyl]methyl}-1H- benzimidazolecarbonitrile; 1-({(5S,7S)[2-methyl(5-phenyl-1,3,4-oxadiazolyl)propyl]oxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[2-(3-ethyl-1,2,4-oxadiazolyl)methylpropyl]oxooxaazaspiro[4.5]dec- 7-yl}methyl)-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[3-methyl(2-pyrimidinyl)pyrrolidinyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5S,7S)methyloxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec- 7-yl}methyl)-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)oxo({1-[5-(trifluoromethyl)pyridinyl]-1H-1,2,3-triazolyl}methyl)oxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[4-chloro(1,1-dimethylethyl)isoxazolyl]methyloxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)methyloxo[5-(trifluoromethyl)pyridinyl]oxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[6-(ethyloxy)pyridinyl]methyloxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-(((5S,7S)(6-methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-ethoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(1-ethylmethyl-1H-pyrazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((7S)(5-methoxypyrazinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-chloropyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-(dimethylamino)pyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; tert-butyl (2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa azaspiro[4.5]decanyl)isoxazolyl)methylpropyl) carbonate; PU64638 1-(((5S,7S)(3-(1-hydroxymethylpropanyl)isoxazolyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(4,6-dimethoxypyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-ethoxymethylpyridazinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyloxo(2-(trifluoromethyl)pyrimidinyl)oxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyloxo(3-(trifluoromethyl)pyridinyl)oxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-({(5S,7S)[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-{[(5S,7S)(2-{3-[1-(ethyloxy)ethyl]-1,2,4-oxadiazolyl}methylpropyl)oxooxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)methyl(5-methylpyridinyl)oxooxaazaspiro[4.5]decyl]methyl}-1H- benzimidazolecarbonitrile; 1-({(5S,7S)methyl[3-(1-methylethyl)isoxazolyl]oxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)methyl[3-(2-methylpropyl)isoxazolyl]oxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)(1-tert-butyl-1H-pyrazolyl)methyloxooxaazaspiro[4.5]dec yl]methyl}-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)(3-ethylisoxazolyl)methyloxooxaazaspiro[4.5]decyl]methyl}-1H- benzimidazolecarbonitrile; 1-{[(5S,7S)(3-cyclopropylisoxazolyl)methyloxooxaazaspiro[4.5]decyl]methyl}- 1H-benzimidazolecarbonitrile; 1-{[(5S,7S)methyloxo(3-phenylisoxazolyl)oxaazaspiro[4.5]decyl]methyl}-1H- benzimidazolecarbonitrile; 1-({(5S,7S)[3-(1,1-dimethylethyl)methyl-1H-pyrazolyl]methyloxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)methyloxo[3-(trifluoromethyl)isoxazolyl]oxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; PU64638 1-({(5S,7S)[3-(1-cyanocyclopropyl)isoxazolyl]methyloxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-(((5S,7S)(3-(2-fluoropropanyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan- 7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-cyclobutylisoxazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-(tert-butyl)methylisoxazolyl)methyloxooxaazaspiro[4.5]decan- 7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(4-(tert-butyl)oxazolyl)methyloxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(1-(tert-butyl)-1H-pyrazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-(tert-butyl)fluoroisoxazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-(1,1-difluoroethyl)isoxazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-(tert-butyl)methylisoxazolyl)oxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-(tert-butyl)fluoroisoxazolyl)oxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-(tert-butyl)pyridazinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(tert-butyl)pyrimidinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-(tert-butyl)-2H-1,2,3-triazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyl(3-(1-methyl-1H-pyrazolyl)isoxazolyl)oxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(1-(tert-butyl)-1H-1,2,3-triazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(tert-butyl)pyrazinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyloxo(5-(trifluoromethyl)pyrimidinyl)oxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; PU64638 1-(((5S,7S)(6-(2-methoxypropanyl)pyridinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyloxo(3-(propenyl)isoxazolyl)oxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3,4-dimethylisoxazolyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3,4-dimethylisoxazolyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-({3-[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-1H- indolecarbonitrile; 1-({3-[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl) (trifluoromethyl)-1H-benzimidazolecarbonitrile; 1-({3-[(5-chlorobenzothienyl)methyl]oxooxaazaspiro[4.5]decyl}methyl)-1H- benzimidazolecarbonitrile; 1-{[3-(1-benzothienylmethyl)oxooxaazaspiro[4.5]decyl]methyl}-1H-benzimidazole- 6-carbonitrile; 1-({(5S,7S)oxo[(2-phenyl-1,3-thiazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-({(5S,7S)oxo[(6-phenylpyridinyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H- benzimidazolecarbonitrile; 1-[((5S,7S){2-methyl[3-(tetrahydro-2H-pyranyl)-1,2,4-oxadiazolyl]propyl}oxo oxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5S,7S)oxo[(4-phenyl-1,3-thiazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-[((5S,7S){[3-(4-chlorophenyl)isoxazolyl]methyl}oxooxaazaspiro[4.5]dec yl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5S,7S)oxo[(3-phenylisoxazolyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H- benzimidazolecarbonitrile; 1-({(5S,7S)[(1-methylphenyl-1H-pyrazolyl)methyl]oxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)({4-[3-methyl(methyloxy)phenyl]-1,3-thiazolyl}methyl)oxooxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-({(5S,7S)oxo[(3-phenyl-1H-1,2,4-triazolyl)methyl]oxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; PU64638 1-({(5S,7S)oxo[(5-phenylpyridinyl)methyl]oxaazaspiro[4.5]decyl}methyl)-1H- benzimidazolecarbonitrile trifluoroacetate; 4-chloro({(5S,7S)[2-methyl(3-phenyl-1,2,4-oxadiazolyl)propyl]oxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[2-methyl(3-methyl-1,2,4-oxadiazolyl)propyl]oxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[2-methyl(3-phenyl-1,2,4-oxadiazolyl)propyl]oxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-[((5S,7S){2-methyl[3-(1-methylethyl)-1,2,4-oxadiazolyl]propyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[2-(3-cyclopentyl-1,2,4-oxadiazolyl)methylpropyl]oxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-[((5S,7S){2-methyl[3-(5-pyrimidinyl)-1,2,4-oxadiazolyl]propyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S){2-[3-(1,1-dimethylethyl)-1,2,4-oxadiazolyl]methylpropyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S){2-methyl[3-(trifluoromethyl)-1,2,4-oxadiazolyl]propyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)(2-methyl{3-[(methyloxy)methyl]-1,2,4-oxadiazolyl}propyl)oxooxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-[((5S,7S){2-methyl[3-(2-methylpropyl)-1,2,4-oxadiazolyl]propyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[2-methyl(3-{[(1-methylethyl)oxy]methyl}-1,2,4-oxadiazolyl)propyl]oxo oxaazaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 4-chloro[((5S,7S)oxo{[4-(3-phenyl-1,2,4-oxadiazolyl)tetrahydro-2H-pyran yl]methyl}oxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 4-chloro[((5S,7S){[4-(3-cyclopentyl-1,2,4-oxadiazolyl)tetrahydro-2H-pyranyl]methyl}- 2-oxooxaazaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S)oxo{[1-(2-pyridinyl)pyrrolidinyl]methyl}oxaazaspiro[4.5]decyl)methyl]- 1H-benzimidazolecarbonitrile; 1-({(5S,7S)oxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(4-cyanophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; PU64638 1-[((5S,7S){[1-(4-chlorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3-chlorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(4-methylphenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3-cyanophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)oxo({1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazolyl}methyl)oxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3-fluorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)({1-[3-(methyloxy)phenyl]-1H-1,2,3-triazolyl}methyl)oxooxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3-methylphenyl)-1H-1,2,3-triazolyl]methyl}oxooxaazaspiro[4.5]dec- 7-yl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[(1-cyclohexaneyl-1H-1,2,3-triazolyl)methyl]oxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)({1-[4-cyano(trifluoromethyl)phenyl]-1H-1,2,3-triazolyl}methyl)oxooxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3-chlorocyanophenyl)-1H-1,2,3-triazolyl]methyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)oxo({1-[2-(trifluoromethyl)pyridinyl]-1H-1,2,3-triazolyl}methyl)oxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3,5-difluorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-{[(5S,7S)oxo({1-[4-(trifluoromethyl)phenyl]-1H-1,2,3-triazolyl}methyl)oxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-[((5S,7S){[1-(3-cyanofluorophenyl)-1H-1,2,3-triazolyl]methyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-[((5S,7S)methyl{[1-(1-methylethyl)-1H-1,2,3-triazolyl]methyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-({(5R,7S)methyloxo[(1-phenyl-1H-1,2,3-triazolyl)methyl]oxaazaspiro[4.5]dec- 7-yl}methyl)-1H-benzimidazolecarbonitrile; PU64638 1-[((5S,7S){[1-(5-chloropyridinyl)-1H-1,2,3-triazolyl]methyl}oxooxa azaspiro[4.5]decyl)methyl]-1H-benzimidazolecarbonitrile; 1-(((5S,7S)(4-chloro(2-cyanopropanyl)isoxazolyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-({(5S,7S)[4-bromo(1,1-dimethylethyl)isoxazolyl]methyloxooxa azaspiro[4.5]decyl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)methyl[2-(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-({(5S,7S)[2,6-bis(methyloxy)pyridinyl]methyloxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[4-methyl(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-(((7S)(3,5-dichloropyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-ethoxypyrimidinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-chlorofluoropyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyloxo(5-(trifluoromethyl)pyrazinyl)oxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-(tert-butyl)pyrimidinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyl(5-methylpyrazinyl)oxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-ethoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-chloromethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-chloromethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-chloromethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-chloromethoxypyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; PU64638 1-(((5S,7S)(6-chloromethoxypyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(4-methyl(trifluoromethyl)pyrimidinyl)oxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-ethoxymethylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl) fluoro-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-chloromethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-ethylpyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3,5-dimethylpyrazinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(3-methyl(trifluoromethyl)pyrazinyl)oxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-methoxymethylpyridinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-(2-cyanopropanyl)pyridinyl)methyloxooxaazaspiro[4.5]decan- 7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-(tert-butyl)pyrimidinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-({(5S,7S)methyl[5-(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-({(5S,7S)[6-(ethyloxy)pyridazinyl]methyloxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-{[(5S,7S)(3-chloropyridinyl)methyloxooxaazaspiro[4.5]decyl]methyl}-1H- benzimidazolecarbonitrile; 1-({(5S,7S)methyl[3-(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)- 1H-benzimidazolecarbonitrile; 1-({(5S,7S)methyloxo[6-(trifluoromethyl)pyridinyl]oxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; PU64638 1-(((7S)methyl(6-methylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-({(5S,7S)[4,6-bis(methyloxy)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-1H- benzimidazolecarbonitrile; 1-({(5S,7S)[6-(1-methylethyl)pyridinyl]oxooxaazaspiro[4.5]decyl}methyl)-1H- benzimidazolecarbonitrile; 1-((7-(hydroxymethyl)(6-methoxymethylpyridinyl)oxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyloxo(4-(trifluoromethyl)pyridinyl)oxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-(dimethylamino)pyrimidinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyl(4-methylpyridinyl)oxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(2-(2-hydroxypropanyl)pyrimidinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(4-methoxypyridinyl)methyloxooxaazaspiro[4.5]decanyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(dimethylamino)pyrazinyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-{[(5S,7S)oxo(thieno[2,3-b]pyridinylmethyl)oxaazaspiro[4.5]decyl]methyl}-1H- benzimidazolecarbonitrile; 1-{[(trans)methyloxo(thieno[2,3-b]pyridinylmethyl)oxaazaspiro[4.5]dec yl]methyl}-1H-benzimidazolecarbonitrile; 1-({(5S,7S)[(3-bromothieno[2,3-b]pyridinyl)methyl]oxooxaazaspiro[4.5]dec yl}methyl)-1H-benzimidazolecarbonitrile; and 1-{[(5S,7S)(2-methyl{3-[1-(methyloxy)ethyl]-1,2,4-oxadiazolyl}propyl)oxooxa azaspiro[4.5]decyl]methyl}-1H-benzimidazolecarbonitrile; 1-(((5S,7S)((5-ethoxypyrazinyl)methyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)((4-ethoxypyridinyl)methyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; PU64638 1-(((5S,7S)((5-ethoxypyridinyl)methyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)((4-fluoropyridinyl)methyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)((5-fluoropyridinyl)methyl)methyloxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyl((4-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyl((6-(1-methyl-1H-pyrazolyl)pyridinyl)methyl)oxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(2-methoxypropanyl)pyrazinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(2-(2-methoxyethoxy)propanyl)pyrazinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 2-((2-(5-((5S,7S)((6-cyano-1H-benzo[d]imidazolyl)methyl)methyloxooxa azaspiro[4.5]decanyl)pyrazinyl)propanyl)oxy)ethyl dimethylphosphinate; 1-(((5S,7S)(5'-fluoromethyl-[2,2'-bipyridin]yl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)methyl(4-methylmorpholinopyridinyl)oxooxaazaspiro[4.5]decan yl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(2-hydroxypropanyl)pyridinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(5-(1-hydroxymethylpropanyl)pyrazinyl)methyloxooxa azaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; 1-(((5S,7S)(6-cyclopropylmethoxypyridinyl)methyloxooxaazaspiro[4.5]decan- 7-yl)methyl)-1H-benzo[d]imidazolecarbonitrile; or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 which is 1-(((5S,7S)(5-Ethoxypyrazinyl)methyloxo oxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; or a pharmaceutically acceptable salt thereof. PU64638
9. A compound of claim 1 which is 1-(((5S,7S)(5-(2-hydroxypropanyl)pyrazinyl) methyloxooxaazaspiro[4.5]decanyl)methyl)-1H-benzo[d]imidazolecarbonitrile; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of claims 1–9 and a pharmaceutically acceptable carrier or excipient.
11. The use of a compound of any one of claims 1 to 9 in the preparation of a medicament for treating a disorder selected from atherosclerosis, disorders related to intestinal edema, post- surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis crohn's disease, colitis, diarrhea, intestinal irregularity (hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence .
12. A use according to claim 11 wherein the medicament is formulated for oral administration.
13. A use according to claim 11 wherein the compound is formulated for intravenous administration.
14. A use according to claim 11 wherein the compound is formulated for administration by inhalation.
15. A use according to claim 11 wherein the disease is congestive heart failure.
16. A use according to claim 11 wherein the disease is acute lung injury.
17. A pharmaceutical composition according to claim 10 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
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US201161498110P | 2011-06-17 | 2011-06-17 | |
US61/498,110 | 2011-06-17 | ||
PCT/US2012/042622 WO2013012500A1 (en) | 2011-06-17 | 2012-06-15 | Trpv4 antagonists |
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NZ618221A NZ618221A (en) | 2015-02-27 |
NZ618221B2 true NZ618221B2 (en) | 2015-05-28 |
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