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HK40020928B - Substituted 2-azabicycles and their use as orexin receptor modulators - Google Patents

Substituted 2-azabicycles and their use as orexin receptor modulators Download PDF

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HK40020928B
HK40020928B HK42020010838.9A HK42020010838A HK40020928B HK 40020928 B HK40020928 B HK 40020928B HK 42020010838 A HK42020010838 A HK 42020010838A HK 40020928 B HK40020928 B HK 40020928B
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azabicyclo
esi
compound
measured value
mixture
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HK42020010838.9A
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Chinese (zh)
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HK40020928A (en
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F. Gelin Christine
P. Lebold Terry
T. Shireman Brock
M. Ziff Jeannie
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Janssen Pharmaceutica Nv
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Substituted 2-azabicyclic compounds and their use as orexin receptor modulators
This application is a divisional application of patent applications having a filing date of 2014 12/3, an application number of 201480027437.2 (international application number of PCT/US 2014/024293), an invention name of "substituted 2-azabicyclo compounds and their use as orexin receptor modulators".
Cross Reference to Related Applications
This application claims the benefit of U.S. provisional application 61/780,378, filed on 3/13/2013, incorporated herein by reference in its entirety.
Technical Field
The present invention relates to substituted 2-azabicyclic compounds, pharmaceutical compositions comprising them, methods of preparing them, and methods of using them to modulate orexin receptors to treat disease states, disorders, and conditions mediated by orexin receptor activity.
Background
Orexin/hypothalamic secretin signaling is mediated by two receptors and two peptide agonists. The peptides (orexin a and orexin B) are cleavage products of the same gene (orexin). In the central nervous system, the proorexin-producing neurons are present only in the perifornix nucleus, the dorsal and lateral hypothalamus (Peyron et al, 1998, j. Neurosci.18, 9996-10015. Appetite-promoting cells within these regions project to many areas of the brain, extending rostrally to the olfactory bulb and caudally to the spinal cord (Van den Pol,1999, j.neurosci.19 3171-3182.
Orexin binds to two high affinity receptors known as the orexin 1 and orexin 2 receptors. Orexin 1 and orexin 2 receptors are G protein-coupled seven transmembrane receptors, sharing over 64% amino acid sequence identity with each other. Both receptors are approximately stimulatory and their common cellular response to orexin-induced receptor activation is an increase in intracellular calcium. The homology between species orthologous genes is high and there are no known pharmacological differences. Orexin A and orexin B are generally considered to be equivalent ligands for the orexin 2 receptor, but orexin B is considered to be a 5-fold to 100-fold weaker ligand for the orexin 1 receptor than orexin A (Sakurai et al, 1998, cell) 92573-585; ammoun et al, 2003, J.Pharmacol.Exp.Ther.305:507-514)。
Many regions of the brain are quite selective for orexin 1 or orexin 2 receptor expression (Marcus et al, 2001, j4356-25; trivedi et al, 1998, FEBS letters,438, 71-75). Orexin 1 receptor pair limbic system (The bed nuclei of terminal striation and amygdala), cingulate cortex, and norepinephrine neurons within the locus coeruleus are selective. In contrast, the orexin 2 receptor is almost unique in the histamine neurons in the nucleus of the tuberomamillary body (which play a critical role in arousal), the paraventricular nuclear neurons, and the parabrachial lateral nuclei. While in other brain regions such as the dorsal raphe, ventral tegmental area or prefrontal cortex, both receptors are co-expressed.
The widespread CNS distribution of orexin-producing cells, as well as of cells expressing orexin receptors, suggests that orexin is involved in many physiological functions, including feeding and metabolism, regulation of wakefulness and sleep, sympathetic activation, and stress response (de Lecea,2012, progress in Brain Research,198，15-24；Kukkonen，2013，Am J.Physiol.Cell Physiol.，304C2-C32). Orexin also plays a critical role in regulating incentives and rewards related to food intake and drug abuse (Mahler et al, 2012, progress in Brain Research, 198，79-121)。
Several lines of evidence indicate that the orexin system is an important regulator of consciousness. Rodents administered orexin in the lateral ventricles have a longer waking time (pip et al, 2000, j. Neurosci.12, 726-730. Orexin-mediated waking effects are associated with the projection of orexin neurons into histamine neurons in the tuberopapillary nucleus (Yamanaka et al, 2002, biochem. Biophysis. Res. Comm.).290:1237-1245). Rodents with a knockout of the orexin gene or with appetite-promoting neuronal death exhibit sleep/wake cycle changes similar to lethargy (Chemelli et al, 1999, cell 98, 437-451, hara et al, 2001, neuron30:345-354). A dog model with narcolepsy showed that it has a mutated or non-functional orexin 2 receptor (Lin et al, 1999, cell)98:365-376). Orexin signaling has further been clinically demonstrated to be the subject of sleep-promoting therapy by the observation of decreased orexin content and loss of appetite-promoting neurons in human narcolepsy patients (Mignot et al, 2001, am.j.hum.genet.68:686-699；Minot&Thorsby，2001，New England J.Med.344692) or, in rare cases, in combination with a mutation in the orexin 2 geneOff (Peyron et al, 2000, nature Med.6:991-997). Thus, disorders of the sleep-wake cycle are likely targets for orexin 2 receptor modulator activity. Examples of sleep-wake disorders that can be treated by agonists or other modulators that upregulate orexin 2 receptor-mediated processes include narcolepsy, jet lag (somnolence), and sleep disorders secondary to neurological disorders such as depression. Examples of disorders that may be treated by antagonists or other modulators that down-regulate orexin 2 receptor-mediated processes include insomnia, restless legs syndrome, jet lag (insomnia), and sleep disorders secondary to neurological disorders such as mania, schizophrenia, pain syndrome, and the like.
There is increasing evidence that orexin message transmission is clearly linked in the rewarding pathway related to drug dependence (Mahler et al, 2012, progress in Brain research,198, 79-121). Appetite-promoting neurons project to the ventral tegmental area and other brain areas involved in reward treatment. Orexin ligands mediate reward behaviors and antagonize these effects as selective orexin 1 receptor antagonists in various preclinical models of addiction, suggesting that these effects are mediated through orexin 1 receptors. Specifically, in addition to attenuating morphine withdrawal symptoms (Sharf et al, 2008, biol Psychiatry,64, 175-183) and nicotine self-management (Hollander et al, 2008, proc Natl Acad Sci USA, 105, 19480-19485), selective orexin 1 antagonists also attenuate morphine-regulated field preference and craving (Harris et al, 2005, nature,437, 556-5599, narita et al, 2006, J Neurosci.,26, 398-405, harris et al, 2007, behav Brain Res,183, 43-51), stress-induced cocaine craving, cocaine 2006-induced behavior and synaptic plasticity (Borglad et al, 2006, neuron,49, 589-601), and uptake and implication of ethanol and stress-induced craving (Lawrence et al, pharma Br, J, 148, 759-752). Another recent study also suggested the role of OX2R (Shoblock et al, 2011, psychopharmacology,215, 191-203).
The role of orexin in more complex emotional behaviors has also emerged gradually (Johnson et al, 2012, progress in Brain research,198, 133-161). Altered orexin content has been noted in patients with panic and post-traumatic stress disorders, associated with altered prevalence of anxiety behavior in narcolepsy patients (Johnson et al, 2010, nature medicine,16, 111-115, fortuyn et al, 2010, general Hospital psychotherapy, 32, 49-56, strawn et al, 2010, psychoneuroendocrinology,35, 1001-1007. Lactic acid perfusion or acute hypercapnia causes panic in humans and is used as an animal model of panic, activating orexin neurons in the hypothalamus around the fornix. This activation is associated with anxiety in social interaction capacity experiments or open field experiments. Blocking orexin message transmission with siRNA or selective orexin 1 receptor antagonists attenuates startle-like responses to lactate (Johnson et al, 2010, nature medicine,16, 111-115, johnson et al, 2012, neuropsychopharmacology,37, 1911, 1922).
The orexin content of cerebrospinal fluid (CSF) is lower in patients with a tendency to depression or suicide, and is inversely correlated with the severity of the disease (Brundin et al, 2007, european neuropsychopharmacology,17, 573-579, salomon et al, 2003, biol Psychiatry,54, 96-104. It has been reported that in forced swimming experiments in mice, a positive correlation between orexin 1 receptor mRNA in the amygdala and depressive behavior (Aredt, 2013, behavioral neuroscience,127, 86-94).
The orexin system also interacts with the brain dopamine system. The mouse intracerebroventricular injection of the orexin can improve the motor activity, the hair-conditioning behavior and the repetitive behavior; these behavioral effects can be reversed by administration of D2 dopamine receptor antagonists (Nakamura et al, 2000, brain res.873. Thus, orexin receptor modulators may be useful in the treatment of various neurological disorders; for example, stress disorders are treated with agonists or up-regulators, and Parkinson's disease, tourette's syndrome, anxiety, delusions and dementia are treated with antagonists or down-regulators.
Orexin and its receptors are found in both the internus and submucosal plexus of the enteric nervous system, where orexin has been shown to increase motility in vitro (Kirchgessner & Liu,1999, neuron 24 941-951) and stimulate gastric acid secretion in vitro (Takahashi et al, 1999, biochem. Biophysis. Res. Comm.254-623-627. The effect of orexin on the gut can be caused by vagal projections (van den Pol,1999, supra) because vagotomy or atropine blocks the effect of intracerebroventricular injections of orexin on gastric acid secretion (Takahashi et al, 1999, supra). Thus, orexin receptor antagonists or other down-regulators of orexin receptor-mediated systems are potential treatments for ulcers, irritable bowel syndrome, diarrhea, and gastroesophageal reflux.
Orexin-mediated regulation of appetite and metabolism may also affect body weight. Some of the effects of orexin on metabolism and appetite may be mediated in the gut, where orexin alters gastric motility and gastric acid secretion as previously described. Thus, orexin antagonists may be useful in the treatment of overweight or obesity, as well as conditions associated with overweight or obesity, such as insulin-resistant/type II diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, and osteoarthritis. Conversely, orexin agonists may be useful in the treatment of low weight and related conditions such as hypotension, bradycardia, menopause and related infertility, as well as eating disorders such as anorexia and binge eating.
Intraventricular administration of orexin has been shown to increase mean arterial blood pressure and heart rate in free-moving (awake) animals (Samson et al, 1999, brain res.831 248-253, shirasaka et al, 1999, am.j. Physiol.277, R1780-R1785), and similar results in carbamate anesthetized animals (Chen et al, 2000, am.j. Physiol.278R 692-R697. Orexin receptor agonists may be candidates for the treatment of hypotension, bradycardia and related heart failure, while orexin receptor antagonists may be useful in the treatment of hypertension, tachycardia and other arrhythmias, angina pectoris and acute heart failure.
As can be seen from the above discussion, the identification of orexin receptor modulators is highly advantageous for the development of therapeutic agents for the treatment of various disorders mediated through these receptor systems.
Disclosure of Invention
The present invention relates to compounds of formula I:
wherein X is N or CR 1 (ii) a Y is N or CR 2 ；R 1 Is H, alkoxy, halogen, triazolyl, thiazolyl, pyridazinyl, pyrimidinyl,Azolyl radical, iso-acylAzolyl group,Oxadiazolyl, pyridyl, phenyl or pyrazolyl, in which triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiazolyl, triazolyl, pyrimidinyl, triazolyl, thiazolyl or pyrazolyl,Azolyl radical, isoAzolyl group,(ii) oxadiazolyl, pyridinyl, phenyl or pyrazolyl is optionally substituted with up to two substituents selected from halogen and alkyl; r 2 Is H, alkyl, alkoxy or halogen; z is NH, N-CH 3 、N-CH 2 CH 3 、N-CH 2 -cyclopropyl, N-C (= O) CH 3 、N-CH 2 CH 2 OCH 3 Or O; r 3 Is H, alkyl, alkoxy, halogen, triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyridyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyridyl, phenyl or pyrazolyl, in which triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiazolyl, triazolyl, pyrimidinyl, triazolyl, thiazolyl or pyrazolyl,Azolyl radical, isoAzolyl group,(ii) oxadiazolyl, pyridinyl, phenyl or pyrazolyl is optionally substituted with up to two substituents selected from halogen and alkyl; r is 4 Is H or alkyl; or R 3 And R 4 Taken together with the atoms to which they are attached to form a 6-membered aromatic ring or a 5-or 6-membered heteroaromatic ring; r is 5 Is pyridyl, pyrazinyl, benzoOxazolyl, pyridazinyl, naphthyridinyl or pyrimidinyl, wherein the pyridyl, pyrazinyl, benzo(ii) oxazolyl, pyridazinyl, naphthyridinyl or pyrimidinyl optionally substituted with up to two groups selected from halo, alkoxy, hydroxymethyl and alkyl; and n is 1 or 2. Enantiomers and diastereomers, as well as pharmaceutically acceptable salts, of the compounds of formula I are also described.
Methods of preparing compounds of formula I are also described. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I. Methods of using the compounds of the invention are also within the scope of the invention.
Drawings
FIG. 1 depicts an Oak Ridge thermal ellipsoid plot program (ORTEP) shown at a 40% probability level in example 13 of an embodiment of the present invention.
Figure 2 depicts ORTEP shown at a 40% probability level for example 14, an embodiment of the present invention.
Detailed Description
The invention may be more completely understood by reference to the following description, including the following glossary and conclusive examples.
The term "alkyl" refers to a straight or branched alkyl group having 1 to 12 carbon atoms in the chain. In some embodiments, the alkyl group is C 1 -C 6 An alkyl group. In some embodiments, the alkyl group is C 1 -C 4 An alkyl group. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any of the foregoing examples in accordance with the ordinary skill in the art and the teachings provided herein. The alkyl groups of the present invention may be substituted, for example, with halogen atoms. One exemplary substituent is fluorine. Preferred substituted alkyl groups of the present invention include trihaloalkyl groups such as trifluoromethyl groups.
The alkyl groups of the present invention may also be referred to as "cycloalkyl" moieties. Cycloalkyl refers to a monocyclic non-aromatic hydrocarbon group having 3 to 7 carbon atoms. Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, 2-methylcyclopentyl, and the like.
The term "alkoxy" includes straight or branched chain alkyl groups having a terminal oxygen linking the alkyl group to the rest of the molecule. In some embodiments, the alkoxy group is C 1 -C 6 An alkoxy group. In some embodiments, the alkoxy group is C 1 -C 4 An alkoxy group. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and the like.
The term "aromatic ring" represents a monocyclic or bicyclic aromatic hydrocarbon ring structure. The aromatic ring may have 6 or 10 carbon atoms in the ring.
The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.
The term "heteroaromatic ring" represents a monocyclic or bicyclic aromatic ring structure comprising carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaromatic ring may contain a total of 5, 6, 9 or 10 ring atoms.
The term "isoOxazolyl "represents the following moiety:
the term "isoOxazolyl "represents the following moiety:
different from each otherThe azolyl moiety may be attached through any of the 3-, 4-, or 5-position carbon atoms. The invention is differentThe azolyl group may be optionally substituted, for example, with one or two alkyl groups, for example one or two methyl groups.
Term "Oxazolyl "represents the following moiety:
the azolyl moiety may be attached through any one of the carbon atoms.
Term "Oxadiazolyl "represents 1,2,3-Oxadiazole 1,2,4-Diazoles 1,2,5-Oxadiazoles or 1,3,4-Oxadiazole moiety:
the oxadiazolyl moiety may be attached through any one of the carbon or nitrogen atoms. Within the scope of the invention "The oxadiazolyl "group may be substituted with alkyl or halogen groups, preferably with methyl groups.
The term "pyridyl" represents the following moieties:
the pyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position carbon atoms.
The term "pyrimidinyl" represents the following moieties:
the pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms. Within the scope of the present invention, a "pyrimidinyl" group of the invention may be substituted by halogen, e.g. fluorine, or alkyl, e.g. methyl.
The term "pyrazinyl" represents the following moieties:
the pyrazinyl moiety may be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.
The term "pyridazinyl" represents the following moieties:
the pyridazinyl moiety may be attached through any of the 3-, 4-, 5-, or 6-position carbon atoms.
The term "pyrazolyl" represents the following moieties:
the pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position carbon atoms. The pyrazolyl group of the present invention can be optionally substituted, for example, with one or two substituted alkyl groups, such as one or two methyl groups.
The term "triazolyl" represents the 1,2,3-triazole or 1,2,4-triazole moiety:
the triazolyl moiety may be attached through any of their atoms.
The term "imidazolyl" represents the following moieties:
the imidazolyl moiety can be attached through any one of the 2-, 4-, or 5-position carbon atoms, or via the N-1 nitrogen atom. The imidazolyl groups of the present invention may be optionally substituted, for example, with one or two substituted alkyl groups, such as one or two methyl groups.
The term "thiazolyl" represents the following moiety:
the thiazolyl moiety may be attached through any carbon atom. The thiazolyl groups of the present invention may be optionally substituted, for example, with one or two substituted alkyl groups, such as one or two methyl groups.
The term "naphthyridinyl" represents the following moiety:
the naphthyridinyl moiety may be attached through any one carbon atom. The naphthyridinyl groups of the invention may optionally be substituted, for example, with one or two substituted alkyl groups such as one or two methyl groups or a halogen group.
The term "imidazothiazolyl" represents the following moiety:
the imidazothiazolyl moiety may be attached through any carbon atom. The imidazothiazolyl groups of the present invention may be optionally substituted, for example, with one or two substituted alkyl groups, such as one or two methyl groups.
"pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal or a state government of the united states or a corresponding agency in a country other than the united states, or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly humans.
"pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are pharmaceutically acceptable and possess the desired pharmaceutical activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt formed with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed by coordination of the acidic protons with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, and the like are included.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient, or vehicle with which the compound of the invention is administered. "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable or otherwise biologically suitable substance for administration to a subject, such as an inert substance, that is added to the pharmaceutical composition or that serves as a vehicle, carrier or diluent to facilitate and be compatible with administration of the agent. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
"subject" includes humans. The terms "human", "patient" and "subject" are used interchangeably herein.
In one embodiment, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or slowing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating a disease or disorder, either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.
In the method of treatment according to the invention, a therapeutically effective amount of an agent according to the invention is administered to a subject suffering from or diagnosed with such a disease, disorder or condition. By "therapeutically effective amount" is meant an amount or dose sufficient to produce the desired therapeutic or prophylactic benefit in a patient in need of such treatment for the specified disease, disorder or condition as a whole. An effective amount or dose of a compound of the invention can be determined by conventional methods, such as modeling, dose escalation studies, or clinical trials, and by consideration of conventional factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder or condition, the prior and ongoing therapy of the subject, the health and response of the subject to the drug, and the judgment of the attending physician. Examples of dosages are in the range of about 0.001 to about 200mg of compound per kg of subject body weight per day, preferably in the range of about 0.05 to 100 mg/kg/day, or in the range of about 1 to 35 mg/kg/day, in single dose units or in divided dose units (e.g., BID, TID, QID). Exemplary ranges for suitable dosages for a 70-kg human are from about 0.05 to about 7 g/day, or from about 0.2 to about 2.5 g/day.
The "compounds of the invention" and equivalent expressions are intended to cover the compounds of formula (I) as described herein, which expression includes pharmaceutically acceptable salts and solvates such as hydrates, where the context permits. Similarly, reference to intermediates, whether or not they are stated themselves, is intended to encompass their salts and solvates where the context permits.
As used herein, the term "isotopic variant" refers to compounds that contain unnatural proportions of isotopes at one or more of the atoms that constitute such compounds. For example, an "isotopic variant" of a compound can be radiolabeled, i.e., contain one or more nonradioactive or radioactive isotopes, such as deuterium (ll) 2 H or D), carbon-13 ( 13 C) Nitrogen-15 ( 15 N), and the like. It is to be understood that in such isotopically substituted compounds, the following atoms, if present, can be varied such that, for example, any hydrogen can be 2 H/D, any carbon can be 13 C, or any nitrogen may be 15 N, and the presence and position of such atoms can be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, for example, where the resulting compounds are useful in drug and/or substrate tissue distribution studies. The radiolabeled compounds of the invention may be used in diagnostic methods such as Single Photon Emission Computed Tomography (SPECT). With radioactive isotopes of tritium 3 H and carbon-14 i.e 14 C are particularly useful because they are easily incorporated and have ready detection methods. In addition, positron emitting isotopes (e.g. for example) can be prepared 11 C、 18 F、 15 O and 13 n) substituted compounds, and the compounds are also useful in Positron Emission Tomography (PET) studies to examine the occupancy of substrate receptors.
All radioactive or non-radioactive isotopic variations of the compounds of the present invention are intended to be encompassed within the scope of the present invention. In one aspect, provided herein are deuterated analogs of compounds of formula I as described in the examples section. In one embodiment, the deuterated analog of the compound of formula I comprises a deuterogen attached to the 2-azabicyclo at one or more positions, e.g., the bridgehead carbon or the non-bridgehead carbon of the 2-azabicycloAnd preferably contains one or more deuterium atoms attached to the 2-azabicyclo non-bridgehead carbon. Within the scope of the embodiments described herein, compounds are also envisaged in which a single proton in the compound of formula I is replaced by deuterium, or 2 protons in the compound of formula I are replaced by deuterium, or more than 2 protons in the compound of formula I are replaced by deuterium. Deuteration of compounds of formula I may also be effected with one or more substituents present on the 2-azabicyclo ring (e.g., ring A, R) 1 、R 2 Or R 5 ) The above.
It is also understood that compounds having the same molecular formula but differing in the nature or order of their atomic bonding or in the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in their arrangement in atom space are referred to as "stereoisomers".
Stereoisomers that are not mirror images of each other are referred to as "diastereomers", while stereoisomers that are not overlapping mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, there may be a pair of mirror image isomers. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R-and S-order rules of Cahn and Prelog, or by the way the molecules rotate the plane of polarized light and are designated dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). The chiral compounds may exist as their individual enantiomers or as mixtures thereof. Mixtures containing the same ratio of enantiomers are referred to as "racemic mixtures".
"tautomer" refers to a compound that is structurally interchangeable with a particular compound, and that has a change in the position of hydrogen atoms and electrons. Thus, both structures can be in equilibrium via the movement of pi electrons and atoms (typically H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed by treatment with acids or bases.
The tautomeric form may be relevant to obtain the best chemical reactivity and biological activity of the compound of interest.
The compounds of the present invention may also exist as "optical isomers," i.e., configurational isomers, which arise when a different configuration of the rotation is hindered, which creates a rotational energy barrier that is overcome to switch from one configurational isomer to another.
The compounds of the invention may have one or more asymmetric centers; such compounds can thus be prepared as individual (R) -or (S) -stereoisomers or mixtures thereof.
Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures, either racemic or otherwise, thereof. Methods for determining stereochemistry and methods for separating stereoisomers are well known in the art.
The present invention relates to compounds of formula I:
wherein
X is N or CR 1
Y is N or CR 2
R 1 Is H, alkoxy, halogen, triazolyl, thiazolyl, pyridazinyl, pyrimidinyl,Azolyl radical, iso-acylAzole group,Oxadiazolyl, pyridyl, phenyl or pyrazolyl, in which triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiazolyl, triazolyl, pyrimidinyl, triazolyl, thiazolyl or pyrazolyl, Azolyl radical, isoAzolyl group,(ii) oxadiazolyl, pyridinyl, phenyl or pyrazolyl is optionally substituted with up to two substituents selected from halogen and alkyl;
R 2 is H, alkyl, alkoxy or halogen;
z is NH, N-CH 3 、N-CH 2 CH 3 、N-CH 2 -cyclopropyl, N-C (= O) CH 3 、N-CH 2 CH 2 OCH 3 Or O;
R 3 is H, alkyl, alkoxy, halogen, triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyridyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyridyl, phenyl or pyrazolyl, in which triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiazolyl, triazolyl, pyrimidinyl, triazolyl, thiazolyl or pyrazolyl,Azolyl radical, iso-acylAzolyl group,(ii) oxadiazolyl, pyridinyl, phenyl or pyrazolyl is optionally substituted with up to two substituents selected from halogen and alkyl;
R 4 is H or alkyl;
or R 3 And R 4 Taken together with the atoms to which they are attached to form a 6-membered aromatic ring or a 5-or 6-membered heteroaromatic ring;
R 5 is phenyl, pyridyl, pyrazinyl, benzoAzolyl, pyridazinyl, naphthyridinyl or pyrimidinyl, of which pyridyl, pyrazinyl, benzo(ii) oxazolyl, pyridazinyl, naphthyridinyl or pyrimidinyl optionally substituted with up to two groups selected from halo, alkoxy, hydroxymethyl and alkyl; and is provided with
n is 1 or 2.
In one aspect, the invention relates to compounds of formula I:
wherein
X is N or CR 1
Y is N or CR 2
R 1 Is H, alkoxy, halogen, triazolyl, pyrimidinyl,Azolyl radical, isoAzolyl group,Oxadiazolyl or pyrazolyl;
R 2 is H, alkyl, alkoxy or halogen;
z is NH or O;
R 3 is H, alkyl, alkoxy, halogen or triazolyl;
R 4 is H or alkyl;
or R 3 And R 4 Taken together with the atoms to which they are attached to form a 6-membered aromatic ring or a 5-or 6-membered heteroaromatic ring;
R 5 is pyridyl, pyrazinyl or pyrimidinyl, wherein pyridineOptionally substituted with halo or alkyl; and is provided with
n is 1 or 2.
Enantiomers and diastereomers of the compounds of formula I are also within the scope of the invention. Pharmaceutically acceptable salts of the compounds of formula I as well as pharmaceutically acceptable salts of enantiomers and diastereomers of the compounds of formula I are also within the scope of the invention. Isotopic variations of the compounds of formula I, such as deuterated compounds of formula I, are also within the scope of the invention.
In a preferred embodiment, Z is NH. In other embodiments, Z is O. In other preferred embodiments, Z is NH, N-CH 3 、N-CH 2 CH 3 、N-CH 2 -cyclopropyl, N-C (= O) CH 3 Or N-CH 2 CH 2 OCH 3 。
In a preferred embodiment, X is CR 1 And Y is CR 2 。
In other preferred embodiments, X is CR 1 And Y is N.
In other preferred embodiments, X is N and Y is CR 2 。
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is H. In other embodiments, R 1 Is alkoxy, e.g. C 1-6 Alkoxy, such as methoxy or ethoxy.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is a halogen, preferably F, cl or Br.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is triazolyl optionally substituted with up to two substituents selected from halogen and alkyl, preferably 1,2,3-triazolyl. In a preferred embodiment, 1,2,3-triazolyl is attached through the 2-position nitrogen atom. In other embodiments, 1,2,3-triazolyl is attached through the 1-position nitrogen atom.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is pyrimidinyl optionally substituted with up to two substituents selected from the group consisting of halogen and alkyl, which may be connected via any available atom.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is optionally substituted by up to two substituents(iii) an azole group, the substituents being selected from halogens and alkyl groups, which may be attached via any available atom.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is an optionally substituted hetero atom with up to two substituents(iii) an azole group, the substituents being selected from halogens and alkyl groups, which may be attached via any available atom.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is optionally substituted by up to two substituents(ii) an oxadiazolyl group, said substituent being selected from the group consisting of halogen and alkyl, which may be attached via any available atom. The above-mentionedThe oxadiazolyl group may be optionally substituted with alkyl groups such as methyl. In exemplary embodiments, substitutedThe diazole moiety is methyl-substituted 1,2,4-A diazolyl group.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And Y is N, R 1 Is pyridyl optionally substituted with up to two substituents selected from the group consisting of halogen and alkyl, which may be attached via any available atom. The pyridyl group may be optionally substituted with alkyl groups such as methyl or halogen.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is imidazolyl optionally substituted with up to two substituents selected from halogen and alkyl, which may be connected via any available atom. The imidazolyl group may be optionally substituted with alkyl groups such as methyl or halogen.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is phenyl optionally substituted with up to two substituents selected from halogen and alkyl, which may be connected via any available atom. The phenyl group may be optionally substituted with alkyl groups such as methyl or halogen.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is pyrazolyl optionally substituted with up to two substituents selected from the group consisting of halogen and alkyl, which may be connected via any available atom. Said pyrazolyl group optionally substituted by one or two C 1-6 Alkyl groups such as methyl.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is optionally at most twoThiazolyl substituted with a substituent selected from the group consisting of halogen and alkyl, which may be attached through any available atom.
In which X is CR 1 In those embodiments of (A), e.g. when X is CR 1 And Y is CR 2 Or X is CR 1 And when Y is N, R 1 Is a pyridazinyl group optionally substituted with up to two substituents selected from halo and alkyl, which may be attached via any available atom.
In which Y is CR 2 In a preferred embodiment, for example, X is CR 1 And Y is CR 2 Or X is N and Y is CR 2 ，R 2 Is H. In other embodiments, R 2 Is alkyl, e.g. C 1-6 Alkyl groups such as methyl.
In which Y is CR 2 In those embodiments of (A), e.g. X is CR 1 And Y is CR 2 Or X is N and Y is CR 2 ，R 2 Is an alkoxy radical such as C 1-6 Alkoxy groups such as methoxy or ethoxy.
In which Y is CR 2 In those embodiments of (A), e.g. X is CR 1 And Y is CR 2 Or X is N and Y is CR 2 ，R 2 Is a halogen, preferably one of F, cl or Br.
In a preferred embodiment, R 3 Is H. In other embodiments, R 3 Is alkyl, e.g. C 1-6 Alkyl groups such as methyl.
In other preferred embodiments, R 3 Is an alkoxy radical such as C 1-6 Alkoxy groups such as methoxy or ethoxy.
In other embodiments, R 3 Is a halogen, preferably F, cl or Br.
In other embodiments, R 3 Is triazolyl, preferably 1,2,3-triazolyl. In a preferred embodiment, the 1,2,3-triazolyl group is attached through the 2-position nitrogen atom. In other embodiments, 1,2,3-triazolyl is attached through the 1-position nitrogen atom.
In a preferred embodiment, R 4 Is H. In other embodiments, R 3 Is alkyl such as C 1-6 Alkyl groups such as methyl.
In an alternative embodiment, R 3 And R 4 Taken together with the atoms to which they are attached to form a 6-membered aromatic ring.
In other embodiments, R 3 And R 4 Taken together with the atoms to which they are attached to form a 5-membered heteroaromatic ring. Preferably, the 5-membered heteroaromatic ring contains one nitrogen atom.
In other embodiments, R 3 And R 4 Taken together with the atoms to which they are attached to form a 6-membered heteroaromatic ring. Preferably, the 6-membered heteroaromatic ring contains one nitrogen atom.
In some embodiments of the invention, R 5 Is a phenyl ring optionally substituted with one or two substituents independently selected from alkyl, cyano, alkoxy, and halogen, or selected from alkyl and halogen. In some embodiments of the invention, R 5 Is a heteroaromatic ring. In some such embodiments, R 5 Is heteroaryl optionally substituted with one or two substituents independently selected from alkyl, cyano, alkoxy, and halogen, or selected from alkyl and halogen. In a preferred embodiment, R 5 Is a pyridyl group, which may be attached through any available atom, optionally substituted with a halogen (preferably F, cl or Br) or an alkyl group. In some embodiments, the alkyl group is substituted with one or more halogen atoms. Preferred substituted alkyl groups are trihaloalkyl groups such as trifluoromethyl. Other substituted alkyl groups include difluoromethyl or monofluoromethyl. Preferably, R 5 Is pyridyl substituted at any available position by trifluoromethyl.
In a preferred embodiment, R 5 Is a pyrazinyl group, which may be attached through any available atom, optionally substituted with a halogen (preferably F, cl or Br) or an alkyl group. In some embodiments, the alkyl group is substituted with one or more halogen atoms. Preferred substituted alkyl groups are trihaloalkyl groups such as trifluoromethyl. Other substituted alkyl groups include difluoromethyl or monofluoromethyl. Preferably, R 5 Is pyrazinyl substituted at any available position with trifluoromethyl.
In a preferred embodiment, R 5 Is pyrimidinePyridyl, which may be attached through any available atom, optionally substituted with halogen (preferably F, cl or Br) or alkyl. In some embodiments, the alkyl group is substituted with one or more halogen atoms. Preferred substituted alkyl groups are trihaloalkyl groups such as trifluoromethyl. Other substituted alkyl groups include difluoromethyl or monofluoromethyl. Preferably, R 5 Is pyrimidinyl substituted by trifluoromethyl in any available position.
In other embodiments, R 5 Is benzeneAn azole group, which may be attached through any available atom, optionally substituted with a halogen (preferably F, cl or Br) or an alkyl group. In some embodiments, the alkyl group is substituted with one or more halogen atoms. A preferred substituted alkyl group is trifluoromethyl. Other substituted alkyl groups include difluoromethyl or monofluoromethyl. Preferably, R 5 Is benzo substituted in any available position by trifluoromethylOxazolyl, pyridazinyl or naphthyridinyl.
In other embodiments, R 5 Is a pyridazinyl group which may be attached through any available atom, optionally substituted with a halogen (preferably F, cl or Br) or an alkyl group. In some embodiments, the alkyl group is substituted with one or more halogen atoms. A preferred substituted alkyl group is trifluoromethyl. Other substituted alkyl groups include difluoromethyl or monofluoromethyl. Preferably, R 5 Is benzo substituted in any available position by trifluoromethylOxazolyl, pyridazinyl or naphthyridinyl.
In other embodiments, R 5 Is a naphthyridinyl group, which may be attached through any available atom, optionally substituted with a halogen (preferably F, cl or Br) or an alkyl group. In some embodiments, the alkyl group is substituted with one or more halogen atoms. A preferred substituted alkyl group is trifluoromethyl. Other substituted alkyl groups Groups include difluoromethyl or monofluoromethyl. Preferably, R 5 Is benzo substituted at any available position by trifluoromethylOxazolyl, pyridazinyl or naphthyridinyl.
In a preferred embodiment, n is 1. In other embodiments, n is 2.
In some embodiments of formula I, R 1 Is H and R 3 Preferably, R is as defined above for formula I 3 Is triazolyl,Azolyl, pyridyl, or pyrimidinyl. In other embodiments of formula I, R 3 Is H and R 1 Preferably, R is as defined in formula I above 1 Is a triazole group,Azolyl radical, isoAzole group,Oxadiazolyl, pyridinyl or pyrimidinyl.
In some embodiments of formula I, the groupIs a pyridyl group, preferably X is N, R 3 Is a ring selected from triazolyl, thiazolyl, pyridazinyl, pyrimidinyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyridinyl, phenyl or pyrazolyl; preferably triazolyl or pyridyl or pyrimidinyl; r 4 Is H or alkyl, preferably methyl; z is NH or O, preferably O; preferably NH, R 5 Is heteroaryl, preferably pyridyl or pyrazinyl. In some such embodiments, R 3 Is a ring in ortho position relative to the carbonyl group in formula I, and R 4 In ortho, meta or para position relative to the carbonyl group in formula I, preferably R 4 Located adjacent to R 3 Meta position of (b). In some such other embodiments, R 3 Is a ring in ortho position relative to the carbonyl group in formula I, and R 4 In ortho, meta or para position relative to the carbonyl group in formula I, preferably R 4 Located not adjacent to R 3 Meta position of (b). R is 3 And R 5 May be optionally substituted as described above.
In some embodiments of formula I, the groupIs a pyridyl group, preferably Y is N, R 1 Is a ring selected from triazolyl, thiazolyl, pyridazinyl, pyrimidinyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyridinyl, phenyl or pyrazolyl; preferably triazolyl or pyridyl or pyrimidinyl; r 4 Is H or alkyl, preferably methyl; z is NH or O, preferably O; preferably NH, R 5 Is heteroaryl, preferably pyridyl or pyrazinyl. In some such embodiments, R 1 Is a ring in ortho position relative to the carbonyl group in formula I, and R 4 In ortho, meta or para position relative to the carbonyl group in formula I, preferably R 4 Located adjacent to R 1 Meta position of (b). In some such other embodiments, R 1 Is a ring in ortho position relative to the carbonyl group in formula I, and R 4 In ortho, meta or para position relative to the carbonyl group in formula I, preferably R 4 Located not adjacent to R 1 Meta position of (b). R 1 And R 5 May be optionally substituted as described above.
In some embodiments of formula I, the groupIs a phenyl radical, R 3 Is a ring selected from triazolyl, thiazolyl, pyridazinyl, pyrimidinyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyridinyl, phenyl or pyrazolyl; preferably triazolyl or pyridyl or pyrimidinyl in the ortho position; r is 4 Is H or alkyl, preferably methyl; z is NH or O, preferably O; preferably NH, R 5 Is heteroaryl, preferably pyridyl or pyrazinyl. In some such embodiments, R 3 Is a ring in ortho position relative to the carbonyl group in formula I, and R 4 In ortho, meta or para position relative to the carbonyl group in formula I, preferably R 4 Located adjacent to R 3 Meta position of (b). In some such other embodiments, R 3 Is a ring in ortho position relative to the carbonyl group in formula I, and R 4 In ortho, meta or para position relative to the carbonyl group in formula I, preferably R 4 Is located not adjacent to R 3 Meta in (b). R is 3 And R 5 May be optionally substituted as described above.
Also provided herein are compounds of formula IA:
wherein
Ring a is a heteroaromatic ring selected from furyl, thiazolyl, imidazothiazolyl, and pyrazinyl;
R 1 Is H, alkoxy, halogen, triazolyl, thiazolyl, pyridazinyl, pyrimidinyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyridyl, phenyl or pyrazolyl, in which triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiazolyl, triazolyl, pyrimidinyl, triazolyl, thiazolyl or pyrazolyl,Azolyl radical, isoAzolyl group,(ii) oxadiazolyl, pyridinyl, phenyl or pyrazolyl is optionally substituted with up to two substituents selected from halogen and alkyl;
R 2 is H, alkyl, alkoxy or halogen;
z is NH, N-CH 3 、N-CH 2 CH 3 、N-CH 2 -cyclopropyl, N-C (= O) CH 3 、N-CH 2 CH 2 OCH 3 Or O;
R 3 is H, alkyl, alkoxy, halogen, triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyridyl,Azolyl radical, iso-acylAzolyl group,Oxadiazolyl, pyridyl, phenyl or pyrazolyl, in which triazolyl, thiazolyl, pyridazinyl, pyrimidinyl, triazolyl, thiazolyl, triazolyl, pyrimidinyl, triazolyl, thiazolyl or pyrazolyl,Azolyl radical, iso-acylAzolyl group,(ii) oxadiazolyl, pyridinyl, phenyl or pyrazolyl is optionally substituted with up to two substituents selected from halogen and alkyl;
R 4 is H or alkyl;
or R 3 And R 4 Taken together with the atoms to which they are attached to form a 6-membered aromatic ring or a 5-or 6-membered heteroaromatic ring;
R 5 is pyridyl, pyrazinyl, benzoAzolyl, pyridazinyl, naphthyridinyl or pyrimidinyl, of which pyridyl, pyrazinyl, benzo(ii) oxazolyl, pyridazinyl, naphthyridinyl or pyrimidinyl optionally substituted with up to two substituents selected from halo, alkoxy, hydroxymethyl and alkyl; and is
n is 1 or 2.
Enantiomers and diastereomers of compounds of formula IA are also within the scope of the invention. Pharmaceutically acceptable salts of the compounds of formula IA and pharmaceutically acceptable salts of enantiomers and diastereomers of the compounds of formula IA are also within the scope of the invention. Isotopic variations of the compounds of formula IA, such as deuterated compounds of formula IA, are also within the scope of the present invention.
In some embodiments, ring a is a furan ring. In some embodiments, ring a is a thiazole ring. In some embodiments, ring a is an imidazothiazole ring. In other embodiments, ring a is a pyrazine ring.
All of the above-mentioned formulae I with respect to the variable R 1 、R 2 、Z、R 3 、R 4 、R 5 The embodiments of and n also apply to formula IA and are expressly contemplated herein.
The present invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by orexin receptor activity. These methods are accomplished by administering a compound of the invention to a subject. In some embodiments, the compounds described herein are selective for orexin 1 receptor activity. In some embodiments, the compounds described herein are more selective for orexin 1 receptor activity than for orexin 2 receptor activity.
Diseases, disorders, and conditions mediated by orexin receptor activity include sleep-wake cycle disorders, insomnia, restless leg syndrome, jet lag, disturbed sleep, sleep disorders secondary to neurological disorders, mania, depression, bipolar disorder, schizophrenia, pain syndromes, fibromyalgia, neuropathic pain, stress, parkinson's disease, tourette's syndrome, anxiety, delusions, dementia, overweight, obesity or conditions associated with overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, cardiac arrhythmia, angina, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal esophagus, mood disorders, post-traumatic stress disorders, panic disorders, attention deficit disorders, cognitive deficits, or substance abuse.
The compounds of the invention are particularly useful for the treatment of mood disorders, post-traumatic stress disorders, panic disorders, attention deficit disorders, cognitive deficits or substance abuse.
In one aspect, the compounds of the invention are particularly suitable for the treatment of mood disorders. Non-limiting examples of mood disorders include anxiety-related mood disorders, depression, panic-related mood disorders, stress-related mood disorders, and the like. In another aspect, the compounds of the invention are suitable for the treatment of post-traumatic stress disorder, panic disorder, attention deficit disorder, cognitive deficit, or substance abuse (e.g., morphine abuse, cocaine abuse, alcohol abuse, etc.). It is to be understood that certain disorders such as depression and/or schizophrenia and/or substance abuse and/or cognitive impairment also have elements of anxiety and/or panic and/or stress associated therewith, and that combinations of treating such disorders and/or conditions are also within the scope of the embodiments shown herein. In some embodiments, it is advantageous that the compounds of the present invention treat mood disorders (e.g., anxiety), with less concomitant sedation and/or less impact on sleep (e.g., reduced arousal). In one embodiment, the compounds of the invention are particularly suitable for the treatment of anxious depression. In another embodiment, the compounds of the invention are particularly suitable for the treatment of panic, schizophrenia and substance abuse.
Sleep disorders include, but are not limited to: sleep-wake transition disorders, insomnia, restless leg syndrome, jet lag, disturbed sleep and sleep disorders secondary to neurological disorders (e.g., mania, depression, bipolar disorder, schizophrenia) and pain syndromes (e.g., fibromyalgia, neuropathic pain).
Metabolic disorders include, but are not limited to: overweight or obesity and overweight-or obesity-related disorders such as insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis.
Neurological disorders include, but are not limited to, parkinson's disease, alzheimer's disease, tourette's syndrome, stress, anxiety, delusions, and dementia.
In the method of treatment according to the invention, a therapeutically effective amount of an agent according to the invention is administered to a subject suffering from or diagnosed with such a disease, disorder or condition. By "therapeutically effective amount" is meant an amount or dose sufficient to produce the desired therapeutic or prophylactic benefit in a patient in need of such treatment for the specified disease, disorder or condition as a whole. An effective amount or dose of a compound of the invention can be determined by conventional methods, such as modeling, dose escalation studies or clinical trials, and by consideration of conventional factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder or condition, the prior and current therapy in the subject, the health and response of the subject to the drug, and the judgment of the attending physician. Examples of dosages are in the range of about 0.001 to about 200mg of compound per kg of subject body weight per day, preferably in the range of about 0.05 to 100 mg/kg/day, or in the range of about 1 to 35 mg/kg/day, in single dose units or in divided dose units (e.g., BID, TID, QID). Exemplary ranges for suitable dosages for a 70-kg human are from about 0.05 to about 7 g/day, or from about 0.2 to about 2.5 g/day.
Once the disease, disorder or condition of the patient is ameliorated, the dosage can be adjusted for prophylactic or maintenance treatment. For example, the dose or frequency of administration, or both, may be reduced, depending on the symptoms, to a level that maintains the desired therapeutic or prophylactic effect. Of course, if the symptoms have been reduced to an appropriate level, treatment may be discontinued. However, patients may require long-term intermittent treatment due to any recurrence of disease symptoms.
In addition, the compounds of the present invention may be used in combination with additional active ingredients for the treatment of the above-mentioned conditions. Additional active ingredients may be co-administered with the compounds of the present invention alone or included with such agents in pharmaceutical compositions according to the present invention. In an exemplary embodiment, the additional active ingredients are those active ingredients known or found to be effective in treating a condition, disorder or disease mediated by orexin activity, such as another orexin modulator or a compound active on another target associated with the particular condition, disorder or disease. The combinations may be used to increase efficacy (e.g., by including in the combination a compound that enhances the efficacy or effectiveness of an active agent according to the invention), to reduce one or more side effects, or to reduce the required dosage of an active agent according to the invention.
The compounds of the present invention are used alone or in combination with one or more additional active ingredients to formulate the pharmaceutical compositions of the present invention. The pharmaceutical composition of the present invention comprises: (a) An effective amount of at least one compound according to the invention; and (b) a pharmaceutically acceptable excipient.
Delivery forms of pharmaceutical compositions comprising one or more dosage units of an active agent can be prepared using suitable pharmaceutical excipients and compounding techniques known or available to those skilled in the art. The compositions may be administered in the methods of the invention by a suitable delivery route, such as by oral, parenteral, rectal, topical or ocular routes, or by inhalation.
The preparation can be in the form of tablet, capsule, sachet, sugar-coated pill, powder, granule, tablet, powder for reconstitution, liquid preparation or suppository. Preferably, the composition is formulated for intravenous infusion, topical administration, or oral administration.
For oral administration, the compounds of the invention may be provided in the form of tablets or capsules, or as solutions, emulsions or suspensions. To prepare oral compositions, the compounds can be formulated to give a dose of, for example, about 0.05 to about 100 mg/kg/day, or about 0.05 to about 35 mg/kg/day, or about 0.1 to about 10 mg/kg/day. For example, a total daily dose of about 5mg to 5g per day may be achieved by taking the drug once, twice, three times or four times a day.
Oral tablets may comprise a compound of the invention in admixture with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preserving agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are suitable disintegrants. Binders may include starch and gelatin. The lubricant (if present) may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glycerol monostearate or glycerol distearate to delay absorption in the gastrointestinal tract, or may be enteric coated.
Capsules for oral administration include hard and soft gelatin capsules. For the preparation of hard gelatin capsules, the compounds of the present invention may be mixed with solid, semi-solid or liquid diluents. Soft gelatin capsules may be prepared by mixing a compound of the invention with water, an oil (such as peanut oil or olive oil), liquid paraffin, a mixture of mono-and diglycerides of short chain fatty acids, polyethylene glycol 400 or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle immediately prior to use. Such liquid compositions may optionally comprise: pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous carriers such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (such as methyl or propyl paraben, or sorbic acid), wetting agents such as lecithin; and flavors or colors, if desired.
The active agents of the present invention may also be administered by non-oral routes. For example, the compositions may be formulated as suppositories for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in a parenterally acceptable oil. Suitable aqueous carriers include ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dosage form, e.g., ampoules or disposable injection devices, in multi-dose form, e.g., vials from which the appropriate dose may be drawn, or in solid form or preconcentrate form useful in the preparation of injectable preparations. An exemplary infusion dose may range from about 1 to 1000.Mu.g of compound per kg per minute, mixed with the pharmaceutical carrier for infusion over a period of minutes to days.
For topical administration, the compounds may be mixed together with a pharmaceutical carrier in a concentration ratio of about 0.1% to about 10%. Another way of administering the compounds of the present invention may be via transdermal delivery using a patch.
Alternatively, the compounds of the invention may be administered in the methods of the invention via inhalation by the intranasal route or the oral route (e.g., in a spray also containing a suitable carrier).
Exemplary compounds useful in the methods of the invention will now be described with reference to exemplary synthetic schemes, for their general preparation below and the specific examples that follow. The skilled artisan will recognize that to obtain the various compounds herein, the starting materials may be suitably selected such that, with or without protection as desired, the ultimately desired substituent will be carried throughout the reaction scheme to yield the desired product. Alternatively, it may be necessary or desirable to replace the ultimately desired substituent with a suitable group that can undergo the entire reaction scheme and be replaced, where appropriate, with the desired substituent. Unless otherwise indicated, the variables are as defined above for formula (I). The reaction may be carried out between the melting point of the solvent and the reflux temperature, and is preferably carried out between 0 ℃ and the reflux temperature of the solvent. The reaction may be heated using conventional heating or microwave heating. The reaction can also be carried out in a closed pressure vessel above the normal reflux temperature of the solvent.
Has a structureThe synthesis of exemplary intermediates of (a) is described in schemes 1-6 below and in the examples section below (intermediates a-1 to a-59).
Scheme 1
Intermediate compounds of formula (IIIa) and (IIIb) can be prepared as described in scheme 1 from commercially available or synthetically obtainable compounds of formula (A)Compound (I) wherein R is 3A 、R 4A is-H, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, or R 3A And R 4A Taken together with the atoms to which they are attached to form a 6-membered aromatic or 6-membered heteroaromatic ring, and X and Y are as defined above for formula (I). Compounds of the formulae (IIa) and (IIb) are prepared by reacting a compound of the formula (IIa) or (IIb) at K 2 CO 3 Obtained by reacting a compound of formula (a) with commercially available 1,2,3-triazole in DMF or dioxane at a temperature in the range of about 60 ℃ to about 100 ℃. The compounds of formula (IIIa) and (IIIb) are obtained by reacting compounds of formula (II) in the presence of a base such as NaOH in a solvent such as EtOH at a temperature in the range of about 80 ℃ to about 100 ℃. Those skilled in the art will recognize that 1,2,3-triazole can be defined as 2H- [1,2,3]Triazole and 1H- [1,2,3]Two tautomeric forms of triazole exist, explaining the formation of (IIIa) and (IIIb).
Scheme 2
As shown in scheme 2, commercially available or synthetically obtainable formula (IV) a-c ) To prepare intermediate compounds of formula (III). Compounds of formulae (Va) and (Vb) are prepared by reaction of compounds of formula (Va) with a base such as copper (I) iodide, cs 2 CO 3 And trans-N, N' -dimethyl-1,2-cyclohexanediamine, for example in DMF or dioxane, at a temperature in the range of from about 60 ℃ to about 120 ℃ in the presence of a solution of a compound of formulae (IVa), (IVb) and (IVc) (wherein Hal is-Br or-I; W is CO) 2 H、CO 2 Alkyl or CN, and R 3A And R 4A is-H, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, or R 3A And R 4A Taken together with the atoms to which they are attached to form a 6-membered aromatic or 6-membered heteroaromatic ring, and X and Y are as defined above in formula I) with commercially available 1,2,3-triazole. The compounds of formula (IVc) can be prepared by reaction of a base such as K 2 CO 3 In the presence of a solvent such as DMF, for example, by treatment with iodoalkane, the corresponding ester (Vb) is converted. Of the formula (III)The compounds are obtained by reacting compounds of formula (Va) and (Vb) in the presence of a base such as NaOH in a solvent such as EtOH at a temperature in the range of about 80 ℃ to about 100 ℃. Those skilled in the art will recognize that 1,2,3-triazole can be defined as 2H- [1,2,3]Triazole and 1H- [1,2,3]The two tautomeric forms of the triazole exist, so that the compounds of formulae (Va), (Vb) and (III) can also exist as N1 linked variants (structure not shown). It is to be understood that the heterocyclic rings in (Va) and (Vb) are not limited to triazole, and may be any other suitable heterocyclic ring.
Scheme 3
As shown in scheme 3, intermediate compounds of formula (IX) can be prepared from commercially available or synthetically available compounds of formula (VI), wherein R is 3A 、R 4A is-H, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, or R 3A And R 4A Taken together with the atoms to which they are attached to form a 6-membered aromatic or 6-membered heteroaromatic ring, and X and Y are as defined above for formula (I), G is SnBu 3 Or 4,4,5,5-tetramethyl-1, dioxaborolan and HAL is Cl or Br, preferably Br. A compound of formula (VIII) is prepared by reacting 1,1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride and a base such as Na 2 CO 3 Reacting a compound of formula (VI) with commercially available (VII) in the presence of a solvent such as 2-MeTHF or THF at a temperature in the range of about 60 deg.C to about 90 deg.C. The compounds of formula (IX) are prepared by reacting a compound of formula (IX) in the presence of a base such as NaOH, in a solvent such as MeOH, at a temperature in the range of from about 80 ℃ to about 100 ℃, or in an acid such as H 2 SO 4 In the presence of a solvent such as H 2 O, reacting a compound of formula (VIII) at a temperature in the range of about 80 ℃ to about 100 ℃. It is to be understood that the heterocycle in (VII) is not limited to pyrimidine, and may be any other suitable heterocycle.
Scheme 4
The intermediate compounds of formula (XIV) can be prepared from the commercially available compound (X) as shown in scheme 4. Compound (XI) is obtained by reacting compound (X) with commercially available acrolein in a solvent such as 1,4-dioxane at a temperature of about 200 ℃ in, for example, a microwave reactor. Compound (XII) can be obtained from compound (XI) by treatment with an acid such as HBr in a solvent such as toluene at a temperature of about 90 ℃. Compound (XIII) can be prepared by reaction in a solvent such as DMF at a temperature in the range of about 45 ℃ to about 65 ℃ with, for example, commercially available iodoethane and a base such as K 2 CO 3 Treating the compound (XII). Compound (XIV) is obtained by treating compound (XIII) with a base such as NaOH in a solvent such as MeOH at a temperature in the range of about 80 ℃ to about 100 ℃.
Scheme 5
As shown in scheme 5, intermediate compounds of formula (XVI) are prepared from commercially available or synthetically obtainable compounds of formula (XIV), wherein R 2B is-H, -C 1-4 Alkyl or-C 1-4 Alkoxy, or R 2B is-H, halogen, -C 1-4 Alkyl or-C 1-4 Alkoxy and HAL is halogen, preferably Cl or Br. The compound of formula (XV) is prepared by reaction over a catalyst such as Pd (dppf) Cl 2 And bases such as Na 2 CO 3 (VII) reacting a compound of formula (XIV) with commercially available (VII) in the presence of a solvent such as 2-MeTHF at a temperature in the range of about 75 ℃ to about 150 ℃. The compound of formula (XVI) is prepared by reacting a compound of formula (XV) in the presence of a base such as NaOH in a solvent such as MeOH at a temperature in the range of about 80 ℃ to about 100 ℃. It is to be understood that the heterocycle in (VII) is not limited to pyrimidine and may be any other suitable heterocycle.
Scheme 6
As shown in scheme 6, intermediate compounds of formula (XXI) can be prepared from commercially available or synthetically obtainable compounds of formula (XVII), wherein Hal is Br or I; and wherein R 3A And R 4A is-H, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, or R 3A And R 4A Taken together with the atoms to which they are attached to form a 6-membered aromatic or 6-membered heteroaromatic ring. Formula (XVIII) a ) The compound of (1) can be converted to the corresponding ester (XVIII) by treatment with, for example, thionyl chloride in a solvent such as MeOH b ). The compound of formula (XX) is prepared by reacting in a catalyst such as Pd (Ph) 3 P) 4 And bases such as Na 2 CO 3 In the presence of a solvent such as DME and H 2 O at a temperature in the range of about 100 ℃ to about 150 ℃ to form a mixture of formula (XVIII) b ) With a commercially available compound of formula XIX, wherein L is a heterocycle such as pyrazole, pyridyl orOxazole or any other heterocyclic ring described herein; g is SnBu 3 Or 4,4,5,5-tetramethyl-1, dioxaborolan, and R 1A And R 2A is-H, -C 1-4 Alkyl or-C 1-4 Alkoxy, or R 1A And R 2A is-H, halogen, -C 1-4 Alkyl or-C 1-4 An alkoxy group. The compound of formula (XXI) is obtained by reacting a compound of formula (XX) in the presence of a base such as NaOH in a solvent such as MeOH at a temperature in the range of about 80 ℃ to about 100 ℃.
Scheme 7
According to scheme 7, compound (XXV) (wherein n is 1 or 2) is prepared by reacting in an aqueous medium (wherein H is + HCl, acOH, etc.) in (XXII), (XXIII) (wherein H 2 PG of N-PG is H, benzyl (Bn), methylbenzyl, etc. -%, and (X) XIV) obtained as described in C.Chiu et al Synthetic Communications 1996, 26, 577-584 and S.Larsen et al J.Am.chem.Soc.1985, 107, 1768-1769. In a particularly preferred embodiment, the compound of formula (XXV), wherein n is 1, is obtained by reacting, for example, commercially available cyclopentadiene, (+) - α -methyl-benzylamine and formaldehyde in an aqueous medium with AcOH. Compounds of formula (XXVa) and (XXvb) in enantiomeric excess are obtained by chiral resolution (XXV) using a chiral acid such as commercially available L or D-dibenzoyltartaric acid and the like, followed by formation of the free base using a base such as aqueous NaOH and the like, as described in C.Chiu et al Synthetic Communications 1996, 26, 577-584. In a preferred embodiment, the compound of formula (XXV) is treated with, for example, D-dibenzoyltartaric acid and then with a base such as aqueous NaOH to obtain the compound of formula (XXVa) in enantiomeric excess. By sequential hydroboration/oxidation of an olefin to obtain a hydroxyl group; then, for example, an optional one-pot palladium-mediated hydrogenolysis and PG "exchange" (i.e., methylbenzyl to Boc); followed by the use of oxidizing agents such as IBX, SO 3 -pyridine, swern Condition [ (COCl) 2 、DMSO、Et 3 N]Etc. oxidation of the hydroxy group in a solvent such as EtOAc, DMSO, DCM, etc., at a temperature in the range of about-78 ℃ to room temperature (about 23 ℃) to obtain compound (XXVII) from (XXVa). In a preferred embodiment, a compound of formula (XXVa) wherein PG is methylbenzyl is reacted with, for example, BH 3 Treating then with H 2 O 2 And NaOH treatment to obtain hydroxyl groups, and for example, hydrogen gas (1 atm), pd/C and Boc 2 O, one-pot palladium mediated hydrogenolysis in EtOH at room temperature (23 ℃) to exchange the methylbenzyl group for the Boc group. The Boc protected intermediate is oxidized, e.g., with IBX, e.g., at EtOAc reflux, to afford the compound of formula (XXVII). Compound (XXVb) can also be subjected to the same set of transformations as compound (XXVa) to obtain the corresponding opposite enantiomer (structure not shown).
A compound of formula (XXVIII) wherein Z is OH is prepared by reaction in a solvent such as THF, meOH, etc., with a reducing agent such as L-tri-sec-butyllithium borohydride, naBH at a temperature in the range of about-78 deg.C to room temperature (about 23 deg.C) 4 Iso-reduction ([ R ]]) Ketone in the compound of formula (XXVII). Alternatively, formula (XXVIII)Racemic forms of the compounds of (A) can be prepared by reduction of commercially available (R/S) -6-oxo-2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate, as described in r.nencka et al Tetrahedron 2012, 68, 1286-1298.
An alternative route to the compound of formula (XXVII) may be from commercially available (1S, 4R) -2-azabicyclo [2.2.1]Hept-5-en-3-one (XXVI). A compound of formula (XXV) is prepared by reacting a compound of formula (XXV) with a reducing agent such as LiAlH 4 Etc. and then protecting the free amine with a suitable protecting group. A compound of formula (XXVII) is prepared by sequential hydroboration/oxidation of an alkene to obtain a hydroxyl group; then using an oxidizing agent such as IBX, SO 3 -pyridine, swern Condition [ (COCl) 2 、DMSO、Et 3 N]Etc. oxidizing the hydroxy group in a solvent such as EtOAc, DMSO, DCM, etc., at a temperature in the range of about-78 ℃ to room temperature (about 23 ℃); and optionally one pot palladium mediated hydrogenolysis and PG "exchange" (i.e. Bn to Boc) from a compound of formula (XXV). In a preferred embodiment, a compound of formula (XXV), wherein PG is Bn, is subjected to the conditions described in j.of med.chem.1992, 35, 2184-2191 by f.carroll et al, followed by PG exchange (Bn for Boc) to obtain a compound of formula (XXVII), wherein PG is Boc.
A compound of formula (XXVIII) (wherein Z is NH) 2 ) By reacting a compound of the formula (XXVII) with an amine NH 2 -Q (wherein Q is OH or Bn) followed by reaction with a suitable reducing agent such as NaBH in a solvent such as MeOH or the like 4 (with or without metal salt additives such as NiCl 2 Etc.), raney Ni (H) 2 atm)、Zn(BH 4 ) 2 And the like by reducing the corresponding oxime or imine. In a particular embodiment, the reaction is carried out by reacting a compound of formula (XXVII) with an amine NH 2 -Q (wherein Q is OH) the oxime intermediate obtained from the reaction is obtained by reacting the compound of formula (XXVII) with a solution of commercially available hydroxylamine hydrochloride and triethylamine in EtOH at a temperature ranging from room temperature (about 23 ℃) to reflux. With NaBH 4 With NiCl 2 To obtain a compound of formula (XXVIII), wherein Z is NH 2 . Alternatively, the compound from formula (XXVII) is reacted with an amine NH 2 The imine intermediate of the reaction of-Q (where Q is Bn) is obtained by reaction of the formula (XXVI)I) With commercially available benzylamine. Reduction of the imine intermediate in situ with a reducing agent such as sodium triacetoxyborohydride and the like, followed by debenzylation, for example under palladium-mediated hydrogenolysis, affords compounds of formula (XXVIII) wherein Z is NH 2 。
Referring to scheme 7, synthetic compounds (where n is 2) are described in the examples section, e.g., intermediates C-1-C-11 and examples 248-283.
Scheme 8
According to scheme 8, compounds of formula (XXIX), wherein Z is O or NH, are prepared by reacting a compound of formula (XXVIII) with a compound R 5 S of-U N Ar reaction or metal-mediated cross-coupling reaction; wherein R is 5 -U is a halogen substituted heteroaryl compound suitably commercially available or synthetically obtainable, wherein R is 5 Is defined above in formula (I) and W is F, cl, br, I or OTf. Compounds of formula (XXIX) wherein Z is O are prepared by reaction of a base such as NaH, K 2 CO 3 Etc. in the presence of a solvent such as DMF at a temperature in the range of room temperature (about 23 ℃) to about 90 ℃, with a compound of formula (XXVIII) wherein Z is OH, and a compound R as described above 5 -W S N Ar is coupled to obtain. In a preferred embodiment, the base is NaH and the solvent is DMF. A compound of formula (XXIX) wherein Z is NH is prepared by reacting a compound of formula (XXVIII) wherein Z is NH in the presence of a palladium catalyst, a phosphine ligand such as BINAP or the like, a base such as NaOtBu or the like, in a solvent such as toluene, DME and DMF at a temperature in the range of room temperature (about 23 ℃) to about 100 ℃ 2 ) With a compound R as described above 5 W is obtained by metal-mediated cross-coupling. In a preferred embodiment, the palladium catalyst is Pd (OAc) 2 The ligand is BINAP, the base is NaOtBu, and the solvent is toluene. Alternatively, compounds of formula (XXIX) (wherein Z is NH) are prepared by reaction in a base such as NaH, K 2 CO 3 And the like, in a solvent such as DMF at a temperature in the range of from room temperature (about 23 ℃) to about 90 ℃Substance (wherein Z is NH) 2 ) With a compound R as described above 5 W is subjected to S N Ar is coupled to obtain. In a preferred embodiment, the base is K 2 CO 3 And the solvent is DMF. PG in the compound of formula (XXIX) (where PG is Boc, bn, methylbenzyl, etc.) is removed using methods known to those skilled in the art to obtain a compound of formula (XXX). In a preferred embodiment, where PG in the compound of formula (XXIX) is Boc and Z is O or NH, treatment with dioxane, e.g. HCl, provides a compound of formula (XXX).
A compound of formula (XXXI) is obtained from a compound of formula (XXX) by reacting a compound of formula (XXX) with a compound of formula (XXXII) under amide bond forming conditions. A compound of formula (XXXII) (wherein X, Y, R) 3 And R 4 As defined in formula (I) are commercially available, described or synthetically available suitably substituted aryl or heteroaryl carboxylic acids or carboxylates. Compounds of formula (XXX) as free bases or acid salts are prepared by reaction in a dehydrating agent such as HOBt/EDAC, CDI, HATU, HOAT, T 3 P; in the presence of a suitably selected base such as DIPEA, TEA; reaction with a compound of formula (XXXII) in an organic solvent or mixture thereof, such as toluene, meCN, etOAc, DMF, THF, DCM affords a compound of formula (XXXI). In particularly preferred embodiments, for example, the dehydrating agent HATU, the base DIPEA, and the solvent DMF are used; or a dehydrating agent T 3 P, alkali Et 3 N, and solvent mixture DCM/DMF to afford the compound of formula (XXXI). Alternatively, one skilled in the art may convert a compound of formula (XXXII) to the corresponding acid chloride or activated ester before the compound of formula (XXXII) forms an amide with a compound of formula (XXX).
Referring to scheme 8, synthetic compounds (where n is 2) are described in the examples section, e.g., intermediates C-1-C-11 and examples 248-283.
In one set of embodiments, provided herein are compounds of formula I in examples 1-84, having the structures and names as described in the examples section. In another set of embodiments, provided herein are compounds of formula I in examples 1-4, 7-92, 94-204, 206, 208-660, having the structure and name as described in the examples section below. In yet another embodiment, provided herein are compounds of formula I in examples 85-92, 94-204, 206, 208-660 having the structures and names as described in the examples section below. In one set of embodiments, provided herein are compounds of formula IA selected from examples 5, 6, 93, 205, and 207 having the structures and names as described in the examples section below. In one set of embodiments, provided herein are compounds of formula I or formula IA having the structures and names as set forth in table 2 below.
Examples of the invention
Abbreviations：
Chemical analysis：
In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed, unless otherwise indicated.
Unless otherwise indicated, the reaction mixture was magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where the solutions are "dry", they are usually in a desiccant such as Na 2 SO 4 Or MgSO (MgSO) 4 And (4) drying. In the case of "concentrating" the mixture, solution and extract, they are usually concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation were performed in a Biotage Initiator or CEM Discover instrument.
In the case of "purification by chromatography on silica gel" of the compound, a pre-packed cartridge is used, eluting with the indicated solvent, in silica gel (SiO) 2 ) Normal phase flash column chromatography was performed.
In the case of compound purification via "Shimadzu method X", the procedure used was:
in a column having Inertsil ODS-3 (3 μm, 30X 100mm, T =45 ℃ C.)) Shimadzu LC-8A series of HPLC on preparative reverse phase High Performance Liquid Chromatography (HPLC) with a mobile phase of 5% ACN in H 2 O (all with 0.05% TFA), 1 minute, then was graded to 5-99% ACN within 6 minutes, followed by 5 minutes under 99% ACN at a flow rate of 80mL/min.
Or alternatively
Preparative reverse phase High Performance Liquid Chromatography (HPLC) was performed on Shimadzu LC-8A series HPLC with XBridge C18 OBD column (5 μm,50 × 100 mm), mobile phase 5% acn in H2O (each with 0.05% tfa), held for 1 minute, then stepped up to 5-99% acn in 14 minutes, then held for 10 minutes at 99% acn, at a flow rate of 80mL/min.
In the case of compounds purified via "Agilent preparation method X", the method used was:
preparative reverse-phase High Performance Liquid Chromatography (HPLC) was performed on an Agilent 1100 series HPLC with an Xbridge C18 OBD column (5 μm, 30X 100 mM) with a mobile phase of 5% ACN in 20mM NH 4 OH, holding for 2 minutes, then staging to 5-99% ACN within 15 minutes, then holding for 5 minutes under 99% ACN at a flow rate of 40mL/min.
Or
Preparative reverse-phase High Performance Liquid Chromatography (HPLC) was performed on an Agilent 1100 series HPLC with an Xbridge C18 OBD column (5 μm, 50X 100 mM) with a mobile phase of 5% ACN in 20mM NH 4 OH, 2 minutes, then stepped up to 5-99% ACN within 15 minutes, followed by 5 minutes under 99% ACN at a flow rate of 80mL/min.
In the case of compounds purified via the "Gilson preparation method X", the procedure used was: preparative reverse phase High Performance Liquid Chromatography (HPLC) was performed on a Gilson HPLC with an Xbridge C18 column (5 μm, 100X 50 mM) with mobile phase 5-99% ACN in 20mM NH 4 OH, 10 minutes, then held at 99% ACN for 2 minutes at a flow rate of 80mL/min.
Unless otherwise indicated, mass Spectra (MS) were obtained in positive ion mode using electrospray ionization (ESI) on Agilent 1100 series MSD. The calculated mass corresponds to the exact mass.
In the case of amide bond coupling using an acid, the free acid or acid salt may be used interchangeably.
Nuclear Magnetic Resonance (NMR) spectra were obtained on a Bruker DRX-type spectrometer. Hereinafter, the following 1 The format of the H NMR data is: low field chemical shift (in ppm) with reference to tetramethylsilane (multiplicity, coupling constant J (in Hz), integral). The definition of multiplicity is as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. For compounds present as mixtures of optical isomers, ratios are shown such that the sum is 1, e.g. 0.80. Alternatively, only the major optical isomer shown may be recorded 1 H NMR data, or data may be recorded for one or more optical isomers, such that the sum is less than 1. It will be appreciated that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the solvent selected to perform the NMR spectrum and the concentration of the compound in solution.
Chemical names were generated using ChemDraw Ultra 12.0 (Cambridge soft corp., cambridge, MA) or ACD/Name version 10.01 (Advanced Chemistry).
The compounds identified as (R/S) are racemic compounds, wherein the relative stereochemistry is as shown.
Examples 63-65, 68-72, 75, 78-79, 81-82, 84, 164-165, 303-419, 421-660 are suitable for preparation using methods analogous to those described in the synthetic schemes and examples section.
Intermediates
Synthesis of 3-fluoro-2- (pyrimidin-2-yl) benzonitrile (intermediate in the Synthesis of intermediate A-2)
To a solution of 3-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzonitrile (4.98g, 19.1 mmol) and 2-bromopyrimidine (3.85g, 23mmol) in THF (96 mL) was added Na 2 CO 3 (6g, 57.4mmol), then water (43 mL) was added. The reaction mixture is treated with N 2 Degassing was carried out for 10 minutes. Adding PdCl 2 (dtbpf) (374mg, 0.57mmol) and the reaction mixture was stirred at 80 ℃ for 5h. The solution was cooled to room temperature and a mixture of EtOAc and water was added. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over MgSO4, filtered and evaporated. The title compound was precipitated by dissolving the residue in a minimal amount of EtOAc followed by addition of hexanes. The solid was filtered, washed with hexane and dried to obtain the title compound (2.46g, 64%). C 11 H 6 FN 3 Mass calculated MS (ESI) of 199.1; the measured value of m/z is 200.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d) Δ 9.02-8.91 (m, 2H), 7.65 (dt, J =7.7,1.0Hz, 1H), 7.60-7.52 (m, 1H), 7.51-7.43 (m, 1H), 7.41 (t, J =4.9Hz, 1H).
Intermediate A-19: 5-methyl-3- (2H-1,2,3-triazol-2-yl) picolinic acid.
Step A: 5-methyl-3- (2H-1,2,3-triazol-2-yl) picolinonitrile. To a solution of 3-bromo-5-methylpyridinecarboxylic acid (1.5g, 7.6 mmol) in DMF (19 mL) was added K 2 CO 3 (1.2g, 8.4 mmol) and 2H-1,2,3-triazole (440. Mu.L, 7.6 mmol). The mixture was heated at 100 ℃ for 16h, cooled to rt and extracted with EtOAc (2 ×). The combined organics were dried (Na) 2 SO 4 ) And concentrated. Purification via silica gel chromatography (5-60% etoac in hexanes) afforded the title compound (490 mg,35％) 1 h NMR (500 MHz, chloroform-d) 8.58-8.53 (m, 1H), 8.29-8.24 (m, 1H), 7.98 (s, 2H), 2.54 (s, 3H), and 5-methyl-3- (1H-1,2,3-triazol-1-yl) picolinenitrile (387mg, 27%).
And B: (5-methyl-3- (2H-1,2,3-triazol-2-yl) picolinic acid sodium salt). To a solution of the title compound of step A (489mg, 2.6 mmol) in EtOH (7 mL) was added 4N NaOH (660. Mu.L, 2.6 mmol). The mixture was heated at 100 ℃ for 24h. The reaction mixture was concentrated in vacuo to a white solid, which was used in the next step without further purification. C 9 H 8 N 4 O 2 The calculated mass MS (ESI) of (3) is 204.1; the measured value of m/z is 205.0[ m ] +H] + 。
Intermediate A-20: 6-methyl-3- (2H-1,2,3-triazol-2-yl) picolinic acid.
Step A: 6-methyl-3- (2H-1,2,3-triazol-2-yl) picolinonitrile. To a solution of 3-bromo-6-methyl picolinenitrile (2.2g, 11mmol) in DMF (28 mL) was added K 2 CO 3 (1.7 g, 12mmol) and 2H-1,2,3-triazole (650. Mu.L, 11 mmol). The mixture was heated at 100 ℃ for 36h, cooled to rt and extracted with EtOAc. The combined organics were dried (Na) 2 SO 4 ) And concentrated. Purification via silica gel chromatography (10-100% EtOAc in hexane) afforded the title compound (1g, 48%).
And B: 6-methyl-3- (2H-1,2,3-triazol-2-yl) picolinic acid. To a solution of the title compound of step A (730mg, 4mmol) in EtOH (10 mL) was added 4N NaOH (1mL, 4mmol). The mixture was heated at 100 ℃ for 24h. The reaction mixture was concentrated in vacuo to a white solid, which was used in the next step without further purification. C 9 H 8 N 4 O 2 The calculated mass MS (ESI) of (3) is 204.1; the measured value of m/z is 205.1[ m ] +H] + 。
Intermediate A-21: 3-ethoxyisoquinoline-4-carboxylic acid.
Step A: 3-Hydroxyisoquinoline-4-carboxylic acid ethyl ester. To a solution of ethyl 3-aminoisoquinoline-4-carboxylate (583mg, 2.70mmol) cooled to 0 ℃ in 6.8mL of 5N H 2 SO 4 To the suspension was added sodium nitrite (223mg, 3.24mmol, dissolved in 1mL of water). The reaction mixture was stirred at 0 ℃ for 2.5h, then 1N NaOH was added (aqueous solution) Until pH =7. The aqueous phase was extracted twice with DCM and the combined organic phases were washed over MgSO 4 The mixture was dried, filtered and evaporated to give the title compound of step a, which was used in the next step without further purification (583 mg, 99%). C 12 H 11 NO 3 Mass calculation of (ESI) of (2) is 217.1; the measured value of m/z is 218.1[ m ] +H] + 。
And B, step B: 3-ethoxyisoquinoline-4-carboxylic acid ethyl ester. To a solution of the title compound of step A (583mg, 2.68mmol) in THF (13 mL) was added triphenylphosphine (1.06g, 4.03mmol), ethanol (0.24mL, 4.03mmol) and DIAD (0.79mL, 4.03mmol). The reaction mixture was stirred at room temperature for 16h, then the solvent was evaporated. The crude product was purified by silica gel chromatography (0-30% etoac in hexanes) to give the title compound of step B (498mg, 76%). C 14 H 15 NO 3 Mass calculated MS (ESI) of 245.1; the measured value of m/z is 246.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) delta 8.97 (s, 1H), 7.91-7.82 (m, 2H), 7.65-7.60 (m, 1H), 7.42-7.36 (m, 1H), 4.59-4.48 (m, 4H), 1.48-1.39 (m, 6H).
And C: 3-ethoxyisoquinoline-4-carboxylic acid. To the title compound of step B (492mg, 2mmol) in MeOH (15 mL) was added 2M NaOH (aqueous solution) (2.5 mL). The reaction mixture was stirred at 60 ℃ for 16h, then 4M NaOH was added (aqueous solution) (2 mL), and the mixture was stirred at 70 ℃ for 4h. MeOH was evaporated, and the aqueous phase was cooled to 0 deg.C and 6N HCl added (aqueous solution) And (4) acidifying. The solid was filtered, washed with cold water, and dried to obtain the title compound (285mg, 65%). C 12 H 11 NO 3 MS (ESI) mass calculation of (A)A value of 217.1; the measured value of m/z is 218.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d6)δ13.36(s,1H),9.15(s,1H),8.13-8.06(m,1H),7.82-7.70(m,2H),7.54-7.47(m,1H),4.50(q,J＝7.0Hz,2H),1.35(t,J＝7.0Hz,3H)。
Intermediate A-24: 2-methoxy-6- (pyrimidin-2-yl) benzoic acid.
Step A: 2-methoxy-6- (pyrimidin-2-yl) benzoic acid methyl ester. In a microwave vial, methyl 2-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzoate (CAS 1146214-77-8) (500mg, 1.71mmol) and 2-bromopyrimidine (344mg, 2.05mmol) were dissolved in THF (8.5 mL). Then Na is added 2 CO 3 (544mg, 5.14mmol), followed by addition of water (4 mL), and reaction mixture was treated with N 2 Degassing for 10 minutes. Then PdCl is added 2 (dtbpf) (CAS 95408-45-0) (45mg, 0.069mmol) and the reaction mixture was heated at 80 ℃ for 4h. The mixture was cooled to room temperature, and water and EtOAc were added. The reaction mixture was extracted with EtOAc (3 ×). The combined organic layers were dried over Na 2 SO 4 Filtered and concentrated. The crude product was purified via silica gel chromatography (0-70% etoac in hexanes) to afford the title compound (265mg, 63%). C 13 H 12 N 2 O 3 Mass calculated MS (ESI) of 244.1; the measured value of m/z is 245.1[ deg. ] M + H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.78 (d, J =4.9hz, 2h), 7.99 (dd, J =7.9,0.9hz, 1h), 7.49 (t, J =8.1hz, 1h), 7.19 (t, J =4.8hz, 1h), 7.09 (dd, J =8.3,0.9hz, 1h), 3.90 (s, 3H), 3.89 (s, 3H).
And B: 2-methoxy-6- (pyrimidin-2-yl) benzoic acid. To a solution of the title compound of step A (265mg, 1.09mmol) in THF (4 mL) was added 2M NaOH (2 mL). The mixture was heated at 50 ℃ for 72h. The reaction mixture was cooled to room temperature,and concentrated in vacuo to remove THF. Then 1M HCl was added (aqueous solution) And the aqueous phase was extracted with 10 dcm/2,2,2-trifluoroethanol (3 ×). The combined organic layers were washed with Na 2 SO 4 Dried, filtered and concentrated to give intermediate a-24, which was used in the next step without further purification. C 12 H 10 N 2 O 3 Mass calculated MS (ESI) of 230.1; the measured value of m/z is 231.1[ m ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ12.63(s,1H),8.86(d,J＝4.9Hz,2H),7.77(dd,J＝7.9,1.0Hz,1H),7.51(t,J＝8.1Hz,1H),7.45(t,J＝4.9Hz,1H),7.25(dd,J＝8.4,1.0Hz,1H),3.83(s,3H)。
Intermediate A-25: 7-ethoxyquinoline-8-carboxylic acid.
Step A: 7-methoxyquinoline-8-carboxylic acid. In a separate batch (1 g), a solution of a mixture of 2-amino-6-methoxybenzoic acid (11g, 66mmol) and acrolein (4.8mL, 72mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor at 200 ℃ for 20 minutes. After combining the reactions, the mixture was concentrated and purified by silica gel chromatography (0-10% meoh in DCM) to obtain the title compound (2.8g, 20%). C 11 H 19 NO 3 The mass calculation value of MS (ESI) of (1) was 203.1; the measured value of m/z is 204.0[ m ] +H] + 。
And B: 7-hydroxyquinoline-8-carboxylic acid. A solution of the title compound of step A (2.9g, 14.1mmol) in HBr (14 mL) was heated at 90 deg.C for 1h. The mixture was then concentrated with PhCH 3 Washed and used in the next step without further purification.
And C: 7-ethoxyquinoline-8-carboxylic acid ethyl ester. To the title compound of step B (800mg, 3.9mmol) and K 2 CO 3 To a solution of (1.4g, 10.4 mmol) in DMF (15 mL) was added ethyl iodide (560mL, 6.9mmol). After stirring overnight at room temperature, the reaction was concentrated and purified via silica gel chromatography (0-30% etoac in hexanes) to obtain the title compound. C 14 H 15 NO 3 Mass calculated MS (ESI) of (1) of 245.1; the measured value of m/z is 246.0[ M ] +H] + 。
Step D: 7-ethoxyquinoline-8-carboxylic acid. To the title compound of step C (1.3g, 5.4 mmol) in THF (22 mL) and H 2 To a solution of O (11 mL), liOH hydrate (675mg, 16.5mmol) and MeOH were added. The mixture was heated at 67 ℃ for 12h. Additional LiOH hydrate (675mg, 16.5mmol) was added and heating continued at 70 ℃ for 1 day. Additional LiOH hydrate (1.4g, 33mmol) was added and heating continued at 75 ℃ for 1 day. The reaction was cooled to room temperature and 1N HCl was used (aqueous solution) Acidified to pH =3 and concentrated. Purification via preparative HPLC gave the title compound (1g, 84%). C 12 H 11 NO 3 Mass calculated as 217.1 for MS (ESI); the measured value of m/z is 218.0[ m ] +H] + 。
Intermediate A-27: 3-methyl-2-, (Oxazol-2-yl) benzoic acid.
Step A: 3-methyl-2-, (Oxazol-2-yl) benzoic acid ethyl ester. In a microwave vial, ethyl 2-iodo-3-methylbenzoate (627mg, 2.16mmol) and 2- (tributylstannyl)Oxazole (0.54mL, 0.07mmol) was dissolved in DME (2.59 mL). The solution is treated with N 2 Degassed for 5 min, then added CuI (21mg, 0.11mmol) and Pd (PPh) 3 ) 4 (125mg, 0.11mmol). Will react with N 2 Purged and heated at 150 ℃ for 1h. The reaction was cooled to room temperature, filtered through a pad of celite, and purified via silica gel chromatography (0-40% etoac in hexanes) to obtain the title compound of step a (333mg, 67%)。C 13 H 13 NO 3 The calculated mass MS (ESI) of (a) was 231.1; the measured value of m/z is 232.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) δ 7.89-7.82 (m, 1H), 7.79 (d, J =0.8hz, 1h), 7.48-7.43 (m, 2H), 7.30 (d, J =0.9hz, 1h), 4.17 (q, J =7.1hz, 2h), 2.27 (s, 3H), 1.18 (t, J =7.1hz, 3h).
And B: 3-methyl-2-, (Oxazol-2-yl) benzoic acid. To the title compound of step A (166mg, 0.72mmol) was added MeOH (7.2 mL) and 1M NaOH (aqueous solution) (7.2 mL). MeOH was evaporated, then 1M HCl was added (aqueous solution) . DCM was added to the solution and the aqueous phase was extracted with DCM (3 ×). The combined organic layers were over MgSO 4 Dried above, filtered and evaporated to obtain the title compound (145 mg). C 11 H 9 NO 3 The mass calculation value of MS (ESI) of (1) was 203.1; the measured value of m/z is 204.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.20(s,1H),7.79-7.68(m,1H),7.65-7.49(m,2H),7.35(s,1H),4.34(s,1H),2.20(s,3H)。
Intermediate A-30: 2-methoxy-6- (1H-pyrazol-5-yl) benzoic acid.
Step A: 2-methoxy-6- (1H-pyrazol-5-yl) benzoic acid ethyl ester. In a microwave vial, ethyl 2-bromo-6-methoxybenzoate (500mg, 1.54mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -1H-pyrazole (330mg, 1.70mmol) were dissolved in DME (10 mL) and water (2 mL). Then Na is added 2 CO 3 (259mg, 3.09mmol), followed by addition of Pd (PPh) 3 ) 4 (89mg, 0.077 mmol) and the reaction mixture is stirred with N 2 Degassing for 10 minutes. The reaction mixture was then heated to 100 ℃ in a microwave ovenHeating for 1h. The mixture was cooled to room temperature, filtered through celite, and washed with EtOAc and DCM. The crude product solution was concentrated in vacuo and directly purified (10-80% etoac in hexanes) via silica gel chromatography to afford the title compound (125mg, 33%). C 13 H 14 N 2 O 3 Calculated mass MS (ESI) of 246.3; the measured value of m/z is 247.1[ m ] +H ] + 。 1 H NMR (400 MHz, chloroform-d) δ 7.63 (d, J =2.2hz, 1h), 7.44-7.37 (m, 1H), 7.24 (d, J =8.1hz, 1h), 6.94 (dd, J =8.3,0.9hz, 1h), 6.53 (d, J =2.3hz, 1h), 4.29 (q, J =7.2hz, 2h), 3.88 (s, 3H), 1.25-1.16 (m, 3H).
And B: 2-methoxy-6- (1H-pyrazol-5-yl) benzoic acid. Preparation was analogous to intermediate a-24, step B, to obtain the title compound. C 11 H 10 N 2 O 3 The mass calculated value of MS (ESI) of (5) is 218.1; the measured value of m/z is 219.1[ m ] +H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ12.85(br.s,1H),7.71(d,J＝2.2Hz,1H),7.39(t,J＝8.0Hz,1H),7.35-7.28(m,1H),7.04(dd,J＝8.3,1.0Hz,1H),6.51(d,J＝2.3Hz,1H),3.80(s,3H)。
Intermediate A-31:2- (1,4-dimethyl-1H-pyrazol-5-yl) benzoic acid.
Step A: methyl 2- (1,4-dimethyl-1H-pyrazol-5-yl) benzoate. Preparation was analogous to intermediate a-30, step a, to obtain the title compound. C 13 H 14 N 2 O 2 Mass calculated MS (ESI) of 230.1; the measured value of m/z is 231.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.04 (dd, J =7.8,1.5hz, 1h), 7.61 (td, J =7.5,1.5hz, 1h), 7.53 (td, J =7.7,1.4hz, 1h), 7.35 (s, 1H), 7.28 (dd, J =7.6,1.4hz, 1h), 3.71 (s, 3H), 3.58 (s, 3H), 1.84 (s, 3H).
And B, step B:2- (1,4-dimethyl-1H-pyrazol-5-yl) benzoic acid. To a solution of the title compound of step A (680 mg, 2.95mmol) in MeOH (15 mL) was added 4M LiOH (4 mL). The mixture was heated at 50 ℃ overnight. MeOH was removed and HCl was added until pHAnd (2). A white solid precipitated from the reaction mixture and the precipitate was filtered, washed with EtOAc and collected to give intermediate a-31, which was used in the next step without further purification. C 12 H 12 N 2 O 2 Mass calculated MS (ESI) of 216.1; the measured value of m/z is 217.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),7.95(dd,J＝7.8,1.5Hz,1H),7.67(td,J＝7.5,1.5Hz,1H),7.59(td,J＝7.6,1.4Hz,1H),7.33(dd,J＝7.6,1.4Hz,1H),7.25(s,1H),3.48(s,3H),1.77(s,3H)。
Intermediate A-33: 3-fluoro-2- (1H-1,2,3-triazol-1-yl) benzoic acid.
To a mixture of dioxane (33.8 mL) and H 2 To 3-fluoro-2-iodobenzoic acid (4.5 g,16.9 mmol) in O (0.09 mL) was added Cs 2 CO 3 (11.02g, 33.8mmol), cuI (161mg, 0.85mmol), 2H-1,2,3-triazole (1.96mL, 33.8mmol), and trans-N, N-dimethyl-1,2-cyclohexanediamine (0.53mL, 3.38mmol). The mixture was then heated at 100 ℃ overnight, cooled to room temperature and washed with H 2 O diluted and extracted with EtOAc. The aqueous layer was then acidified and extracted with EtOAc. The combined organics were dried and concentrated. A solid precipitated from the concentrate to afford intermediate A-33 (285mg, 8%). C 9 H 6 FN 3 O 2 Mass calculated as 207.0 for MS (ESI); the measured value of m/z is 208.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ6.81-6.77(m,1H),6.46-6.40(m,2H),6.30-6.23(m,1H),6.18-6.12(m,1H)。
Intermediate A-34:2- (5-fluoropyrimidin-2-yl) benzoic acid.
Step A: 5-fluoro-2-iodopyrimidine. To a solution of 2-chloro-5-fluoropyrimidine (4 mL, 32mmol) in propionitrile (33 mL) were added chlorotrimethylsilane (12mL, 97mmol) and sodium iodide (15g, 97mmol), and the reaction mixture was heated at 150 ℃ for 1h. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed. The residue was taken up in EtOAc and saturated NaHCO 3 In solution. The organic layer was over MgSO 4 Dried, filtered and evaporated. Purification via silica gel chromatography (0-20% etoac in hexanes) afforded the title compound (2.82g, 39%).
And B:2- (5-fluoropyrimidin-2-yl) benzonitrile. In a microwave vial, 2-cyanophenylboronic acid (500mg, 3.40mmol) is dissolved in THF (15 mL) and the reaction mixture is treated with N 2 And (4) degassing. Then, the title compound of step A (915mg, 4.08mmol), na were added 2 CO 3 (1.08g, 10.2mmol), water (5 mL) and PdCl 2 (dtbpf) (CAS 95408-45-0) (89mg, 0.14mmol) and the reaction mixture was stirred at room temperature for 1h, then heated via microwave for 2h at 75 ℃. The mixture was cooled to room temperature and water and EtOAc were added. The reaction mixture was extracted with EtOAc. The combined organic layers were over MgSO 4 Dried, filtered and concentrated. The crude product was purified by silica gel chromatography (0-30% etoac in hexanes) to afford the title compound (280mg, 41%). C 11 H 6 FN 3 Mass calculated MS (ESI) of 199.1; the measured value of m/z is 200.0[ m ] +H] + 。
And C:2- (5-fluoropyrimidin-2-yl) benzoic acid. The title compound of step B (1.24g, 6.22mmol) in H 2 SO 4 (6 mL) and water (6 mL) were stirred at 80 ℃ for 1h. The reaction mixture was then cooled to 0 ℃, and the aqueous phase was extracted with DCM (2 ×). A20M NaOH (11 mL) solution was added to the aqueous layer until pH 3-4. The aqueous layer was extracted again with EtOAc and DCM. The combined organic layers were over MgSO 4 Dried, filtered and concentrated to obtain the title compound (672mg, 50%). C 11 H 7 FN 2 O 2 The mass calculated value of MS (ESI) of (5) is 218.1; m/z is found to be219.1[M+H] + 。
Intermediate A-35: 3-fluoro-2- (5-fluoropyrimidin-2-yl) benzoic acid.
Preparation analogous to intermediate A-34, 2-cyanophenylboronic acid was replaced with (2-cyano-6-fluorophenyl) boronic acid (CAS 656235-44-8). C 11 H 6 F 2 N 2 O 2 Mass calculated MS (ESI) of 236.0; measured value of m/z is 237.1[ 2 ], [ M ] +H] + 。
Intermediate A-36:2- (5-fluoropyrimidin-2-yl) -3-methylbenzoic acid.
Step A:2- (5-Fluoropyrimidin-2-yl) -3-methylbenzoic acid methyl ester. A solution of methyl 3-methyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzoate (CAS 887234-98-2) (3g, 111mmol) in THF (30 mL) was treated with N 2 And (4) degassing. Then 2-chloro-5-fluoropyrimidine (1.6mL, 13.04mmol) and Na were added 2 CO 3 (3.45g, 32.6 mmol), water (10 mL) and Pd (dppf) Cl 2 (354mg, 0.434mmol) and the reaction mixture was stirred at 100 ℃ overnight. The mixture was cooled to room temperature, and water and EtOAc were added. The reaction mixture was extracted with EtOAc. The combined organic layers were over MgSO 4 Dried, filtered and concentrated. The crude product was purified by silica gel chromatography (0-40% etoac in hexanes) to give the title compound (1.07g, 40%).
And B, step B:2- (5-fluoropyrimidin-2-yl) -3-methylbenzoic acid. To a solution of the title compound of step A (1.46g, 5.93mmol) in MeOH (20 mL) was added 1M NaOH (12 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the crude product was diluted with water until pH =10. The aqueous layer was extracted with EtOAc. Aqueous layer with 12M HCl (aqueous solution) Further acidified until pH =2 and extracted with EtOAc. The combined organic layers were over MgSO 4 Upper dryingFiltered and concentrated to obtain the title compound (1.19g, 83%). C 12 H 9 FN 2 O 2 The mass calculation value of MS (ESI) of (2) is 232.1; the measured value of m/z is 233.1[ m ] +H] + 。
Intermediate A-46: 5-methyl-2- (pyrimidin-2-yl) nicotinic acid.
Step A: 5-methyl-2- (pyrimidin-2-yl) nicotinic acid methyl ester. To a solution containing methyl 2-chloro-5-methylnicotinate (CAS 65169-43-9) (745mg, 4.01mmol), cuI (38mg, 0.2mmol), liCl (1699 mg, 4.01mmol), and Pd (PPh) 3 ) 4 (31mg, 0.2mmol) in toluene (15 mL) was added 2- (tributylstannyl) pyrimidine (1.5mL, 4.4 mmol) in a sealed tube and the reaction mixture was heated at 120 ℃ overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were over MgSO 4 Dried, filtered and evaporated. Purification via silica gel chromatography (0-50% etoac in hexanes) afforded the title compound (494mg, 52%). C 12 H 11 N 3 O 2 Mass calculation of (ESI) of (2) is 229.1; the m/z is found to be 229.99.
And B: 5-methyl-2- (pyrimidin-2-yl) nicotinic acid. To a solution of the title compound of step A (466 mg, 2.03mmol) in MeOH (10 mL) was added 10M NaOH (1 mL) and the reaction mixture was stirred at room temperature for 2h. The solvent was removed and the crude product was diluted with water and acidified with 6M aqueous HCl until pH =3. The aqueous layer was saturated with solid NaCl and 20% of iPrOH in CHCl 3 Solution extraction (3 ×). The combined organic layers were over MgSO 4 Drying, filtering andconcentration gave the title compound (432mg, 99%). C 11 H 9 N 3 O 2 The calculated mass MS (ESI) of (1) was 215.1; the measured value of m/z is 216.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ8.90(br.s,2H),8.64(br.s,1H),8.17(s,1H),7.55(br.s,1H),2.51(s,3H)。
Intermediate A-47: lithium 5-methyl-3- (pyrimidin-2-yl) picolinate.
Step A: 5-methyl-3- (pyrimidin-2-yl) picolinic acid methyl ester. Preparation analogous to intermediate a-46, step a, methyl 2-chloro-5-methylnicotinate was replaced with methyl 3-bromo-5-methylpyridinecarboxylate. C 12 H 11 N 3 O 2 Mass calculated as 229.1 for MS (ESI); the measured value of m/z is 230.0[ m ] +H] + 。
And B: lithium 5-methyl-3- (pyrimidin-2-yl) picolinate. To a solution of the title compound of step A (592mg, 2.58mmol) in THF (5 mL) was added 4M LiOH (0.8 mL) and water (1.5 mL), and the reaction mixture was stirred at room temperature for 2.5h. The solvent was removed and the crude reaction mixture was placed under vacuum overnight to give the title compound (591 mg), which was used in the next step without further purification. C 11 H 9 N 3 O 2 Calculated mass MS (ESI) of 215.1; the measured value of m/z is 216.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ8.83(d,J＝4.9Hz,2H),8.39(br.s,1H),8.23-8.18(m,1H),7.38(t,J＝4.9Hz,1H),2.44(s,3H)。
Intermediate A-48Oxazol-2-yl) benzoic acid.
Step A: 2-bromo-N- (2,2-dimethoxyethyl) -6-fluorobenzamides. To a solution of 2-bromo-6-fluorobenzoic acid (2g, 9.1mmol) in DMF (27 mL) were added HBTU (5.20g, 13.7mmol) and DIPEA (4.7mL, 27mmol), and the reaction mixture was stirred for 10 minutes. 2,2-dimethoxyethylamine (1.3 mL,11.9 mmol) was then added and the reaction mixture was stirred at room temperature for 12h. The reaction mixture was diluted with EtOAc and saturated NaHCO 3 And (4) washing with an aqueous solution. The combined organic layers were over MgSO 4 Dried, filtered and concentrated. Purify via silica gel chromatography (0-25% EtOAc in hexane) to obtain the title compound (2.3g, 82%).
And B:2- (2-bromo-6-fluorophenyl)And (3) azole. To P 2 O 5 Methanesulfonic acid (52mL, 801mmol) was added (6.4g, 22.6 mmol) and the reaction mixture was stirred at room temperature for 1h. The title compound of step A (2.3g, 7.54mmol) was then added to the reaction mixture and the mixture was heated at 140 ℃ for 2h. DCM was added and the mixture was poured slowly into saturated NaHCO on ice 3 In aqueous solution. The mixture was extracted with DCM. The combined organic layers were over MgSO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-10% EtOAc in hexane) afforded the title compound (1.5g, 82%). C 9 H 5 MS (ESI) mass calculation for BrFNO 240.95; the measured value of m/z is 242.0[ m ] +H] + 。
And C: 3-fluoro-2-, (Oxazol-2-yl) benzoic acid methyl ester. The title compound from step B (2.18g, 8.99mmol), pd (OAc) 2 (40mg, 0.18mmol), 1,1' -bis (diphenylphosphino) ferrocene (199mg, 0.36mmol), and Et 3 A solution of N (3.7mL, 27mmol) in 1MeOH/1,4-dioxane (36 mL) was dissolved with N 2 Degassing for 15 minutes. The mixture was then stirred at 95 ℃ under carbon monoxide atmosphere overnight. The reaction mixture was diluted with EtOAc and with NaHCO 3 And (4) washing the solution. The organic layer was separated over MgSO 4 Drying, filtering, and concentrating. Purification by silica gel chromatography (0-12% etoac in hexane) afforded the title compound (1.7g, 83%). C 11 H 8 FNO 3 The mass calculation value of MS (ESI) of (1) is 221.1; measured value of m/z is 222.0[ m ] +H] + 。
Step D: 3-fluoro-2-, (Oxazol-2-yl) benzoic acid. To a solution of the title compound of step C (1.65g, 7.46mmol) in MeOH (22 mL) was added 2M NaOH (7.5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1M aqueous HCl and the solvent was evaporated in vacuo. The mixture was diluted with water and extracted with DCM. The combined organic layers were over MgSO 4 Dried above, filtered and concentrated to obtain the title compound (905mg, 58%). C 10 H 6 FNO 3 Mass calculated as 207.0 for MS (ESI); the measured value of m/z is 208.0[ M ] +H] + 。MP＝182℃。
Intermediate A-49: 5-fluoro-2-, (Oxazol-2-yl) benzoic acid.
Step A: 5-fluoro-2-, (Oxazol-2-yl) benzoic acid methyl ester. To a mixture of methyl 2-bromo-5-fluorobenzoate (1.1g, 4.8mmol) and 2- (tri-n-butylstannyl)To a solution of oxazole (1.3 mL,6.2 mmol) in toluene (14 mL) was added Pd (PPh) 3 ) 4 (550mg, 0.476mmol) and the reaction mixture is heated via microwave for 30 minutes at 150 ℃. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were over MgSO 4 Drying, filtering andand concentrated. Purification via silica gel chromatography (0-40% etoac in hexane, followed by second column purification, 0-10% etoac in hexane) afforded the title compound (553 mg, 52%). C 11 H 6 FNO 3 The mass calculation value of MS (ESI) of (1) is 221.1; the measured value of m/z is 222.1[ m ] +H] + 。
And B: 5-fluoro-2-, (Oxazol-2-yl) benzoic acid. Preparation the title compound was obtained in analogy to intermediate 48, step D (858mg, 99%). C 10 H 6 FNO 3 Mass calculated as 207.0 for MS (ESI); measured value of m/z is 208.1[ 2 ], [ M ] +H] + 。
Intermediate A-50: 2-fluoro-6-, (Oxazol-2-yl) benzoic acid.
Preparation was analogous to intermediate 48, substituting 2-bromo-6-fluorobenzoic acid with 2-bromo-3-fluorobenzoic acid. C 10 H 6 FNO 3 Mass calculated as 207.0 for MS (ESI); the measured value of m/z is 208.0[ M ] +H] + 。
Intermediate A-51: 4-fluoro-2- (3-methyl-1,2,4-Oxadiazol-5-yl) benzoic acid.
Step A:5- (2-bromo-5-fluorophenyl) -3-methyl-1,2,4-Diazole. To a solution of bromo-5-fluorobenzoyl chloride (2.17g, 9.13mmol) in THF (18 mL) was added DIPEA (1.7mL, 10mmol). Acetamide oxime (676mg, 9.13mmol) was then added dropwise and the reaction mixture was stirred at 70 ℃ for 16h. The reaction mixture was diluted with EtOAc and saturated NaHCO 3 And (4) washing the solution. The combined organic layers were over MgSO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-20% etoac in hexanes) afforded the title compound (2.35g, 57%). C 9 H 6 BrFN 2 MS (ESI) mass calculated for O is 255.96; measured value of m/z is 257.0[ m ] +H] + 。
And B: 4-fluoro-2- (3-methyl-1,2,4-Oxadiazol-5-yl) benzoic acid. Preparation the title compound was obtained in analogy to intermediate 48 steps C and D. C 10 H 7 FN 2 O 3 Mass calculated as 222.0 for MS (ESI); the measured value of m/z is 223.0[ M ] +H] + 。
Enantiomerically pure pathway a (2-azabicyclo [2.2.1] heptan-6-ol):
intermediate B-1: (1S, 4R) -2- ((R) -1-phenylethyl) -2-azabicyclo [2.2.1] hept-5-ene.
Intermediate B-1 was prepared according to C.Chiu et al [ Synthetic Communications 1996, 26, 577-584](-) - α -methyl-benzylamine is replaced by (+) - α -methyl-benzylamine and L-dibenzoyltartaric acid is replaced by D-dibenzoyltartaric acid. C 14 H 17 MS (ESI) mass calculation for N was 199.1; the measured value of m/z is 200.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d) δ 7.36-7.25 (m, 4H), 7.23-7.17 (m, 1H), 6.35-6.30 (m, 1H), 6.11 (dd, J =5.7,2.0hz, 1h), 4.16-4.12 (m, 1H), 3.05 (q, J =6.5hz, 1h), 2.89 (dd, J =8.9,3.1hz, 1h), 2.85-2.81 (m, 1H), 1.65-1.59 (m, 1H), 1.48-1.43 (m, 1H), 1.37-1.31 (m, 4H).
Intermediate B-2: (1S,4R,6S) -2- ((R) -1-phenylethyl) -2-azabicyclo [2.2.1] heptan-6-ol.
Intermediate B-2 was synthesized on an analogous substrate according to F.Carroll et al [ J.Med.chem.1992, 35, 2184-2191]. 1M BH at 0 ℃ via addition funnel 3 -THF solution (1M BH) 3 A THF solution of 359.3mL of 359.3mmol of intermediate B-1 (35.8 g,179.6 mmol) was added dropwise to a stirred THF (359 mL) solution of intermediate B-1. BH 3 After the addition of-THF was complete, the reaction mixture was stirred at 0 ℃ for 2h. Then with THF-H 2 O solution quenching excess BH 3 . The 3M NaOH (132 mL) solution was heated and then H was added dropwise 2 O 2 (30% w/w H 2 O solution, 140 mL) and the reaction mixture was brought to 40 ℃ and stirred for 1.5h. The two-phase mixture was then cooled to room temperature and K was added in one portion 2 CO 3 (17g) In that respect The resulting mixture was concentrated under reduced pressure to remove THF and was again dissolved in DCM. Crude reaction mixture with H 2 O wash and extract the aqueous phase with DCM (3 ×). The combined organics were then washed with brine, over Na 2 SO 4 Drying, filtering and concentrating to obtain a clear oil which is further purified (5-10% meoh (having 10%2m NH) by silica gel chromatography 3 ) DCM solution) to obtain intermediate B-2 (20.2g, 93.0mmol, 52%) as a clear oil. C 14 H 19 MS (ESI) mass calculation of NO 217.2; the measured value of m/z is 218.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) δ 7.34-7.27 (m, 4H), 7.24-7.19 (m, 1H), 4.03 (d, J =6.9hz, 1h), 3.46 (q, J =6.5hz, 1h), 3.01 (s, 1H), 2.56-2.48 (m, 1H), 2.42-2.33 (m, 1H), 2.25 (dd, J =8.8,1.3hz, 1h), 1.82 (ddd, J =13.1,6.9,2.2hz, 1h), 1.53-1.43 (m, 2H), 1.33-1.28 (m, 1H), 1.27 (d, J =6.5hz, 3h).
Intermediate B-3: (1S,4R,6S) -6-hydroxy-2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
To intermediatesBoc was added to a solution of B-2 (500mg, 2.3 mmol) in EtOH (11.5 mL) 2 O (603mg, 2.76mmol) and 10 wt% Pd/C wet Degussa (490mg, 0.46mmol). Reaction mixture is kept at room temperature in H 2 Stirring for 22h under atmosphere (balloon). The reaction mixture was then filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated to a clear oil to give the title compound in quantitative yield, which was used without further purification. C 11 H 19 NO 3 Mass calculation of (5) MS (ESI) of 213.1; the measured value of m/z is 158.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers) δ 4.08-3.99 (m, 1H), 3.99-3.92 (m, 1H), 3.18-3.09 (m, 1H), 2.80 (dd, J =28.1,9.2hz, 1h), 2.18-1.37 (m, 14H).
Intermediate B-4: (1S,4R) -6-oxo-2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
To a solution of intermediate B-3 (7g, 33mmol) in EtOAc (219 mL) was added IBX (24.5g, 39.4 mmol) and the heterogeneous reaction mixture was stirred at 80 ℃ overnight. Upon completion, the reaction mixture was then filtered through celite, washed with EtOAc, and concentrated to a white solid. The crude reaction mixture was redissolved in EtOAc and was digested with 5% Na 2 CO 3 The aqueous solution was washed once. The aqueous layer was extracted again with EtOAc (2 ×), and the combined organics were washed with brine, na 2 SO 4 Dried, filtered and concentrated to obtain intermediate B-4 (6.12g, 28.9mmol, 88%) as a light yellow solid, which was used in the next step without further purification. C 11 H 17 NO 3 Mass calculated MS (ESI) of 211.1; the measured value of m/z is 156.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d) δ 4.32-4.04 (m, 1H), 3.45 (ddd, J =9.6,3.1,1.8hz, 1h), 3.25-3.04 (m, 1H), 2.89-2.77 (m, 1H), 2.21 (ddd, J =18.0,4.6,1.8hz, 1h), 2.04-1.96 (m, 1H), 1.95-1.82 (m, 1H), 1.75-1.66 (m, 1H), 1.45 (s, 9H).
Intermediate B-5: (1S,4R,6R) -6-hydroxy-2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
A solution of 1M L-tri-sec-butyllithium borohydride (1M in THF, 19.8mL,19.8 mmol) was added to a solution of intermediate B-4 (1.67g, 7.91mmol) in dry THF (40 mL) at-78 deg.C and the reaction mixture was stirred at this temperature for 3h. The reaction mixture was then brought to 0 ℃ and 3M NaOH (8.4 mL) solution was added, followed by H 2 O 2 Solution (30% w/w H 2 O solution, 4.3 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2h. The biphasic mixture was then concentrated in vacuo to remove THF, and the aqueous layer was extracted with DCM (3 ×). The combined organics were washed with brine, washed with Na 2 SO 4 Dried, filtered and concentrated to an oil which was further purified by silica gel chromatography (10-90% etoac in hexanes) to afford intermediate B-2 as a white solid (1.1lg, 5.44mmol, 67%). C 11 H 19 NO 3 Mass calculation of (5) MS (ESI) of 213.1; the measured value of m/z is 158.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as mixture of optical isomers) δ 4.38-4.10 (m, 2H), 3.36 (br.s, 1H), 3.09 (dd, J =9.6,1.4hz, 1h), 2.54-1.38 (m, 14H), 1.16-1.00 (m, 1H).
Intermediate B-5 can also be prepared from commercially available (1S,4R) -2-azabicyclo [2.2.1] hept-5-en-3-one. The method comprises the following steps:
enantiomerically pure pathway B (2-azabicyclo [2.2.1] heptan-6-ol):
intermediate B-6: (1S,4R,6S) -2-benzyl-2-azabicyclo [2.2.1] heptan-6-ol.
To a mixture containing commercially available (1S,4R) -2-azabicyclo [2.2.1] at 0 deg.C]To a round-bottomed flask containing a solution of hept-5-en-3-one (2.0 g,18.3 mmol) in THF (100 mL) was added LiAlH 4 Solution (1M in THF)Liquid, 40.3ml,40.3 mmol), and the reaction mixture is refluxed overnight. The reaction mixture was then cooled to 0 ℃ and H was carefully added dropwise 2 It was quenched with O (15 mL). Mixing diatomite and solid Na 2 CO 3 Was added to the slurry and the reaction mixture was stirred vigorously at room temperature for 3h. The slurry was then filtered and the solid was washed with THF. Benzyl bromide (2.4mL, 20.2mmol) and Na 2 CO 3 Aqueous solution (3.2 g of 30mL H 2 O solution) was added to the filtrate, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated to give crude (1S, 4R) -2-benzyl-2-azabicyclo [ 2.2.1) as a yellow oil]Hept-5-ene, which was directly hydroborated according to the method of F.Carroll et al [ J.Med.chem.1992, 35, 2184-2191]. The crude alcohol is purified via silica gel chromatography (0-15% MeOH (having 5% NH) 4 OH) in DCM) to obtain intermediate B-6 (2.66g, 13.1mmol, 71% in 3 steps) as a clear oil. C 13 H 17 MS (ESI) mass calculated for NO 203.1; the measured value of m/z is 204.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) Δ 7.39-7.28 (m, 4H), 7.26-7.21 (m, 1H), 4.18-4.09 (m, 1H), 3.76-3.66 (m, 2H), 3.06 (br.s, 1H), 2.51 (dt, J =9.0,3.0Hz, 1H), 2.44-2.35 (m, 2H), 1.90-1.81 (m, 1H), 1.68-1.53 (m, 2H), 1.38-1.30 (m, 1H).
Intermediate B-7: (1S,4R,6R) -2-benzyl-2-azabicyclo [2.2.1] heptan-6-ol.
Intermediate B-7 was prepared from intermediate B-6 according to F.Carroll et al [ J.Med.chem.1992, 35, 2184-2191]。C 13 H 17 MS (ESI) mass calculated for NO 203.1; the measured value of m/z is 204.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) δ 7.37-7.22 (m, 5H), 4.56 (s, 1H), 4.05-3.94 (m, 1H), 3.80 (d, J =13.0hz, 1h), 3.62 (d, J =12.9hz, 1h), 3.20-3.11 (m, 1H), 2.77 (d, J =9.2hz, 1h), 2.45-2.34 (m, 2H), 1.88-1.79 (m, 1H), 1.76-1.64(m,1H),1.30(d,J＝10.4Hz,1H),0.99(dt,J＝13.3,2.9Hz,1H)。
Intermediate B-5: (1S,4R,6R) -6-hydroxy-2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
To a solution of intermediate B-7 (3.41g, 16.8 mmol) in EtOH (168 mL) was added Boc 2 O (5.49g, 25.2mmol) and 20 wt% Pd (OH) 2 C (2.36g, 3.36mmol). Reaction mixture was heated at room temperature to H 2 Stir overnight under atmosphere (balloon). The reaction mixture was then filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated to a clear oil which was further purified by silica gel chromatography (10-60% etoac in hexanes) to afford intermediate B-5 as a white solid (3.1g, 1.5mmol, 87%). [ alpha ] to] D 20 -11.2(c 0.0065，MeOH)。C 11 H 19 NO 3 Mass calculation of (5) MS (ESI) of 213.1; the measured value of m/z is 158.1[ m ] +2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers) δ 4.39-4.12 (m, 2H), 3.35 (br.s, 1H), 3.08 (dd, J =9.4,1.4hz, 1h), 2.56-1.39 (m, 14H), 1.15-0.99 (m, 1H).
Racemic pathway (2-azabicyclo [2.2.1] heptan-6-ol):
intermediate B-8: (R/S) -6-hydroxy-2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
Intermediate B-8 according to the method of R.Nencka et al, from commercially available (R/S) -6-oxo-2-azabicyclo [2.2.1]]Heptan-2-carboxylic acid tert-butyl ester to obtain Tetrahedron 2012,68,1286-1298 ]。C 11 H 19 NO 3 Mass calculation of (5) MS (ESI) of 213.1; the measured value of m/z is 158.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d) delta 4.39-4.08 (m, 2H), 3.36 (br.s, 1H), 3.10 (dd, J =9.6,1.4Hz, 1H), 2.56-1.41 (m, 14H), 1.17-1.01(m,1H)。
Enantiomerically pure pathway (2-azabicyclo [2.2.1] hept-6-amine):
intermediate B-9: (1S, 4R) -6- (hydroxyimino) -2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
To a round bottom flask containing intermediate B-4 (1.0g, 4.7mmol) dissolved in EtOH (20 mL) was added NEt 3 (2.0mL, 14.4mmol) and hydroxylamine hydrochloride (789mg, 2.40mmol), and the reaction mixture was brought to reflux. After completion, the reaction mixture was concentrated with H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were then washed with H 2 O, brine, washing with MgSO 4 Dried, filtered and concentrated to give intermediate B-9 (1.018 g) as an off-white solid, which was used without further purification. C 11 H 18 N 2 O 3 The calculated mass MS (ESI) of (5) is 226.1; the measured value of m/z is 171.1[ m ] +2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d) delta 7.71 and 7.41 (2s, 1H), 4.62 and 4.48 (2s, 1H), 3.40-3.33 (m, 1H), 3.15-2.96 (m, 1H), 2.79-2.70 (m, 1H), 2.54-2.43 (m, 1H), 2.29-2.19 (m, 1H), 1.87-1.64 (m, 1H), 1.61-1.53 (m, 1H), 1.45 (s, 9H).
Intermediate B-10: (1S,4S,6R) -6-amino-2-azabicyclo [2.2.1] hepta-2-carboxylic acid tert-butyl ester.
Mixing NiCl 2 A solution of a mixture of (1.15g, 8.84mmol) and intermediate B-9 (1.0g, 4.4mmol) in MeOH (30 mL) was cooled to-35 deg.C and the NaBH was cooled over 30 minutes 4 (3.34g, 88.4 mmol) was added to the reaction mixture in portions. NaBH 4 After the addition was complete, the reaction mixture was stirred for an additional 25 minutes and then allowed to warm to room temperature. After 30 minutes at room temperature, the reaction mixture is washed with H 2 O quench and concentrate under reduced pressure to a dark brown residue, which is redissolvedIn a mixture of DCM and 15% aqueous naoh solution, and the aqueous layer was extracted with DCM (3 ×). The combined organics were washed with MgSO 4 Dried, filtered and concentrated to give intermediate B-10 (209 mg). Then 5N NH 4 The OH solution was added to the aqueous layer with DCM, naCl and celite and after stirring for several minutes the mixture was filtered to remove solids. The filtrate was then transferred to a separatory funnel, the layers separated and the aqueous layer extracted with DCM (2 ×). The combined organics were washed with MgSO 4 Dried, filtered and concentrated to give additional intermediate B-10 (582 mg), which was combined with the above fractions to give intermediate B-10 (791 mg) as a brown oil, which was used without further purification. C 11 H 20 N 2 O 2 Mass calculated MS (ESI) of 212.2; the measured value of m/z is 213.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) delta 4.13-3.92 (m, 1H), 3.41-3.27 (m, 2H), 2.99 (dd, J =24.3,9.6Hz, 1H), 2.51-2.39 (m, 1H), 2.16-2.05 (m, 1H), 1.68-1.57 (m, 1H), 1.47 (s, 10H), 1.22-1.07 (m, 2H), 0.85-0.74 (m, 1H).
Pathway A (2-azabicyclo [2.2.1] heptan-6-ol and 2-azabicyclo [2.2.2] oct-6-amine):
intermediate C-1: (R/S) -2-benzyl-2-azabicyclo [2.2.2] oct-5-ene.
Intermediate C-1 was prepared according to the method of S.Larsen et al [ J.Am.chem.Soc.1985, 107, 1768-1769]. To benzylamine (3.92g, 27.3 mmol) in H 2 To a solution of O (5 mL) was added aqueous formaldehyde (2.03mL, 27.3mmol,37 wt% H 2 O solution). After 2 minutes 1,3-cyclohexadiene (2ml, 21mmol) was added and the reaction mixture was heated at 55 ℃ for 4 days. The reaction mixture was cooled to room temperature and washed with H 2 Diluted with O and Et 2 O extraction (2X). The organic layer was discarded and the aqueous layer was basified with solid KOH and further with Et 2 O extraction (2X). The organic layer was washed with brine, over MgSO 4 Dried, filtered and concentrated. Concentrating the pill with silica gelSpectral purification (100-100% DCM-MeOH (having 10-percent of 2M NH) 3 ) DCM solution) to obtain intermediate C-1 as a brown oil, containing minor impurities. Intermediate C-1 was used without further purification. C 14 H 17 The calculated mass MS (ESI) for N was 199.1; the measured value of m/z is 200.1[ m ] +H] + 。
Intermediate C-2: (R/S) -2-benzyl-2-azabicyclo [2.2.2] oct-6-ol.
Intermediate C-2 was synthesized on an analogous substrate according to F.Carroll et al [ J.Med.chem.1992, 35, 2184-2191]. 1M BH at 0 DEG C 3 -THF solution (1M BH) 3 THF solution of THF, 1.11L, 1.11mol) was added dropwise via addition funnel to a stirred solution of intermediate C-1 (37g, 186mmol) in THF (250 mL). BH 3 After the addition of-THF was complete, the reaction mixture was stirred at 0 ℃ for 3h. Then excess BH is added 3 With THF-H 2 And quenching the O solution. 4M NaOH (100 mL) solution was added followed by dropwise addition of H 2 O 2 (30% w/w of H 2 O solution, 100 mL) and the reaction mixture was raised to 40 ℃ and stirred overnight. The two-phase mixture is then cooled to room temperature and K is added in portions 2 CO 3 . The resulting mixture was concentrated under reduced pressure to remove THF. Solid NaCl was added to the remaining aqueous layer, and the crude mixture was extracted with EtOAc (3 ×). The combined organics were then washed with brine, over Na 2 SO 4 Drying, filtering and concentrating to obtain a yellow-orange oil which was further purified via silica gel chromatography (0-100% etoac in hexane, then 10% meoh (having 10%2m NH% 3 ) To obtain intermediate C-2 (20.7g, 95.3mmol, 51%) as a yellow oil containing minor impurities. Intermediate C-2 was used without further purification. C 14 H 19 MS (ESI) mass calculated for NO 217.2; the measured value of m/z is 218.2[ m ] +H] + 。
Intermediate C-3: (R/S) -6-hydroxy-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
To a solution of intermediate C-2 (20.7g, 95.3mmol) in EtOH (477 mL) was added Boc 2 O (27.1g, 124mmol) and 10 wt% Pd/C wet Degussa (5g, 4.77mmol). Reaction mixture was taken at room temperature in H 2 Stirring for 48h under an atmosphere (balloon). Analysis of the crude reaction mixture showed that the majority of the mixture was deprotected amine 2-azabicyclo [2.2.2]]Octan-6-ol. Additional equivalents of Boc were added 2 O (27.1g, 124mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated to a yellow oil to obtain intermediate C-3, which was used without further purification. C 12 H 21 NO 3 The calculated mass MS (ESI) of (1) is 227.2; the measured value of m/z is 172.2[ m ] +2H-tBu] + 。
Intermediate C-4A: (R/S) -6-oxo-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
To a solution of intermediate C-3 (21.6g, 95.0 mmol) in EtOAc (380 mL) was added IBX (31.9g, 114mmol) and the heterogeneous reaction mixture was stirred at 80 ℃ overnight. After completion, the reaction mixture was then filtered through celite, washed with EtOAc and concentrated. The crude reaction mixture was redissolved in EtOAc and was digested with 5% Na 2 CO 3 The aqueous solution was washed once. The aqueous layer was further extracted with EtOAc (2 ×), and the combined organics were washed with brine, over Na 2 SO 4 Dried, filtered and concentrated to a brown residue. The concentrate was further purified by silica gel chromatography (0-35% etoac in hexanes) to afford intermediate C-4A as a yellow solid. C 12 H 19 NO 3 The mass calculation of MS (ESI) of (3) was 225.1; the measured value of m/z is 170.1[ m ] +2H-tBu] + . Analytical type HPLC using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 2 minutes and then 2 minutes at 100% acn, at a flow rate of 2.5mL/min (temperature =45 ℃). R at 280nm t =1.91 minutes.
Intermediate C-4B: (1S, 4R) -6-oxo-2-azabicyclo [2.2.2] octa-2-carboxylic acid tert-butyl ester.
20% iPrOH by using a Chiralpak IC column (5 μm, 250X 20 mm) 2 The mobile phase, and a flow rate of 80mL/min (temperature =35 ℃), to perform chiral SFC purification of intermediate C-4A to obtain the title compound in the form of a single enantiomer. Elution was monitored by absorbance at 250 nm. Using a Chiralpak IC column (5 μm, 150X 4.6 mm), 20% iPrOH + (0.3% iPrNH% 2 )：80％CO 2 Mobile phase, and 3mL/min flow, for 7 minutes (temperature =35 ℃), enantiomeric purity was confirmed by analytical SFC. Elution was monitored by absorbance at 250 nm. Enantiomeric purity 100%, it eluted as a peak (1.56 minutes retention time). C 12 H 19 NO 3 The mass calculation of MS (ESI) of (3) was 225.1; measured value of m/z is 170.1[ 2M + ] 2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers) Δ 4.42-4.15 (m, 1H), 3.62-3.34 (m, 2H), 2.49-2.32 (m, 3H), 2.21-2.06 (m, 1H), 1.97-1.85 (m, 1H), 1.79-1.68 (m, 1H), 1.66-1.56 (m, 1H), 1.45 (s, 9H).
Intermediate C-4C: (1R, 4S) -6-oxo-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
By using Chiralpak IC columns (5 μm, 250X 20 mm), 20% iPrOH 2 Mobile phase, and a flow rate of 80mL/min (temperature =35 ℃), chiral SFC purification of intermediate C-4A was carried out to obtain the title compound in the form of a single enantiomer. Elution is according to 250nmAnd (4) monitoring the absorbance. Using a Chiralpak IC column (5 μm, 150X 4.6 mm), 20% iPrOH + (0.3% iPrNH% 2 )：80％CO 2 Mobile phase, and 3mL/min flow, for 7 minutes (temperature =35 ℃), enantiomeric purity being confirmed by analytical SFC. Elution was monitored by absorbance at 250 nm. Enantiomeric purity 100%, it eluted as a peak (2.18 minutes retention time). C 12 H 19 NO 3 The mass calculation of MS (ESI) of (3) was 225.1; the measured value of m/z is 170.1[ m ] +2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers) Δ 4.41-4.13 (m, 1H), 3.57-3.31 (m, 2H), 2.46-2.31 (m, 3H), 2.22-2.08 (m, 1H), 1.96-1.86 (m, 1H), 1.83-1.68 (m, 1H), 1.67-1.56 (m, 1H), 1.45 (s, 9H).
Intermediate C-5A: (R/S) -6-hydroxy-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
1M L-tri-sec-butyllithium borohydride solution (1M in THF, 1.7mL, 1.7mmol) was added to a solution of intermediate C-4A (150mg, 0.666 mmol) in dry THF (3 mL) at-78 deg.C and the reaction mixture was stirred at this temperature for 3h. The reaction mixture was then brought to 0 ℃ and a solution of 3M NaOH (0.71 mL) was added, followed by H 2 O 2 (30% w/w of H 2 O solution, 0.37 mL) solution. The resulting mixture was allowed to warm to room temperature and stirred for 2h. The biphasic mixture was then concentrated in vacuo to remove THF, and the aqueous layer was extracted with DCM (3 ×). The combined organics were washed with brine, washed with Na 2 SO 4 Dried, filtered and concentrated to an oil which was further purified by silica gel chromatography (10-100% etoac in hexanes) to afford intermediate C-5A as a white solid (114mg, 0.502mmol, 75%). C 12 H 21 NO 3 The calculated mass MS (ESI) of (1) is 227.2; the measured value of m/z is 172.2[ m ] +2H-tBu] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ3.97-3.86(m,2H),3.38-3.20(m,2H),2.09-2.00(m,1H),1.96-1.87(m,1H),1.87-1.79(m,1H),1.62-1.48(m,3H),1.46(d,J＝4.9Hz,9H),1.43-1.37(m,1H)。
Intermediate C-5B: (1S,4R,6R) -6-hydroxy-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
Intermediate C-5B was prepared analogously to intermediate C-5A by replacing the enantiomerically pure intermediate C-4B with the racemic intermediate C-4A. C 12 H 21 NO 3 The calculated mass MS (ESI) of (1) is 227.2; the measured value of m/z is 172.1[ m ] +2H-tBu] + 。
Intermediate C-6A: (R/S) -6- (hydroxyimino) -2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
To a flask containing intermediate C-4A (324mg, 1.44mmol) dissolved in EtOH (5 mL) was added NEt 3 (1mL, 7.2mmol) and hydroxylamine hydrochloride (300mg, 4.32mmol), and the reaction mixture was heated at 70 ℃ overnight. After completion, the reaction mixture was cooled to room temperature, concentrated, and taken up with H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were then washed with MgSO 4 Dried, filtered and concentrated to give intermediate C-6A (351 mg) as a pale purple solid, which was used without further purification. C 12 H 20 N 2 O 3 The calculated mass MS (ESI) of (3) was 240.2; the measured value of m/z is 184.1[ m ] +2H-tBu] + 。
Intermediate C-6B: (1S, 4R) -6- (hydroxyimino) -2-azabicyclo [2.2.2] octan-2-carboxylic acid tert-butyl ester.
Intermediate C-6B was prepared analogously to intermediate C-6A by replacing the enantiomerically pure intermediate C-4B with the racemic intermediate C-4A. C 12 H 20 N 2 O 3 The calculated mass MS (ESI) of (3) was 240.2; the measured value of m/z is 241.2[ m ] +H] + 。
Intermediate C-7A: (R/S) -6-amino-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
Mixing NiCl 2 A solution of a mixture of (373mg, 2.88mmol) and intermediate C-6A (346 mg) in MeOH (12 mL) was cooled to-35 deg.C and the NaBH 4 (1.09g, 28.8mmol) was added in portions to the reaction mixture. NaBH 4 After the addition was complete, the reaction mixture was allowed to warm to room temperature. After 2H at room temperature, the reaction mixture was washed with H 2 And quenching by O. Celite was added and the crude reaction mixture was stirred for 30 minutes. The crude reaction mixture was filtered and the filtrate was concentrated under reduced pressure to a dark brown residue, which was again dissolved in a mixture of DCM and 15% aqueous naoh. The aqueous layer was extracted with DCM (3 ×). The combined organics were filtered through celite, mgSO 4 Dried, filtered and concentrated to give intermediate C-7A (308 mg) as a brown oil, which was used without further purification. C 12 H 22 N 2 O 2 Calculated mass MS (ESI) of 226.2; the measured value of m/z is 227.2[ m ] +H] + 。
Intermediate C-7B: (1S,4R,6R) -6-amino-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
Intermediate C-7B was prepared similarly to intermediate C-7A, substituting racemic intermediate C-6A for enantiomerically pure intermediate C-6B. C 12 H 22 N 2 O 2 Calculated mass MS (ESI) of 226.2; the measured value of m/z is 227.2[ m ] +H] + 。
Alternative pathway (2-azabicyclo [2.2.1] heptan-6-ol):
intermediate C-8: (R/S) -2- ((R) -1-phenylethyl) -2-azabicyclo [2.2.2] oct-5-ene.
Intermediate C-8 was prepared on a similar substrate according to C.Chiu et al [ Synthetic Communications 1996, 26, 577-584 ]. To H 2 To a solution of O (5.4 mL) and 12M HCl (5 mL) was added (+) - α -methyl-benzylamine (6.95mL, 54.6 mmol), and the reaction mixture was stirred at room temperature for 5 minutes. Aqueous formaldehyde (4.06mL, 54.6mmol,37 wt% H) was then added 2 O solution) and 1,3-cyclohexadiene (4 ml, 42mmol), and the reaction mixture was heated at 55 ℃ for 4 days. The reaction mixture was cooled to room temperature and washed with H 2 O dilution and crude reaction mixture was treated with Et 2 O extract (2 ×). Basified the aqueous phase with KOH and Et 2 O extraction (2X), saturation with solid NaCl, and Et 2 And extracting the O once more. The combined organics were washed with Na 2 SO 4 Dried, filtered and concentrated to obtain an orange oil which was further purified via silica gel chromatography (0-10% meoh (with 10%2m NH) 3 ) DCM) to obtain intermediate C-8 as a yellow-orange oil (about 3. Intermediate C-8 proceeded as a mixture of diastereomers. C 15 H 19 MS (ESI) mass calculation of N was 213.2; the measured value of m/z is 214.2[ m ] +H] + 。
Intermediate C-9: (R/S) -2- ((R) -1-phenylethyl) -2-azabicyclo [2.2.2] oct-6-ol.
Intermediate C-9 was synthesized according to F.Carroll et al on an analogous substrate [ J.Med.chem.1992, 35, 2184-2191]. 1M BH at 0 DEG C 3 -THF solution (1M BH) 3 -THF solution of THF, 68mL, 68mmol) was added dropwise via addition funnel to a stirred solution of intermediate C-8 (2.88g, 13.5 mmol) in THF (42 mL). BH 3 After the addition of-THF was complete, the reaction mixture was stirred at 0 ℃ for 2h. Then excess B is addedH 3 With THF-H 2 And quenching the O solution. 4M NaOH (8 mL) solution was added followed by dropwise addition of H 2 O 2 (30% w/w of H 2 O solution, 8 mL) and the reaction mixture was raised to 40 ℃ and stirred for 2h. The two-phase mixture was then cooled to room temperature and K was added in one portion 2 CO 3 . The resulting mixture was concentrated under reduced pressure to remove THF and was again dissolved in DCM. Crude reaction mixture with H 2 O wash and extract the aqueous phase with DCM (3 ×). The combined organics were then washed with brine, na 2 SO 4 Drying, filtering and concentrating, and further purifying the concentrate via silica gel chromatography (0-10% meoh (having 10%2m NH) 3 ) To yield intermediate C-9 (1.35g, 5.84mmol, 43%) as an orange brown foam. C 15 H 21 MS (ESI) mass calculated for NO 231.2; measured value of m/z is 232.2[ m ] +H] + 。
Intermediate C-10: (R/S) -6-hydroxy-2-azabicyclo [2.2.2] oct-2-carboxylic acid tert-butyl ester.
Intermediate C-10 was prepared analogously to intermediate C-3 by substituting racemic intermediate C-2 for intermediate C-9.C 12 H 21 NO 3 The calculated mass MS (ESI) of (1) is 227.2; the measured value of m/z is 172.2[ m ] +2H-tBu] + . Intermediate C-10 can be transferred to intermediate C-4A, which can be obtained as a single enantiomer (intermediate C-4B or C-4C) via chiral SFC purification as described above.
Intermediate C-11: (R/S) -2-benzyl-6-hydroxy-2-azabicyclo [2.2.2] oct-3-one.
Intermediate C-11 was synthesized according to the procedure in US 3674793. Reacting 7-oxabicyclo [4.1.0 ]]A mixture of methyl hepta-3-carboxylate (268.0 g, 1.72mol) and benzylamine (170.0 g, 1.58mol) in ethanol (1.3L) was heatedReflux for 20h, and the reaction mixture was evaporated. The oil residue was stirred at 200 ℃ for 2h to evaporate off low-boiling by-products. The resulting oil was cooled to room temperature, diluted with a solution of sodium hydroxide (51.0 g, 1.27mol) in methanol (1.0L), and heated to reflux for 10 minutes. The reaction mixture was cooled to room temperature and diluted with a mixture of brine (1.5L) and water (750 mL). The aqueous layer was extracted with dichloromethane (3 ×), and the combined organic layers were extracted with MgSO 4 Dried, filtered and concentrated. The oil residue was triturated with diisopropyl ether (400 mL) to give intermediate C-11 as a white solid (190.0 g,0.82mol, 48%). C 14 H 17 NO 2 Mass calculated MS (ESI) of 231.1; the measured value of m/z is 232.1[ m ] +H ] + 。 1 H NMR(300MHz,DMSO-d 6 )δ7.43-7.12(m,5H),4.99(d,J＝3.3Hz,1H),4.48(d,J＝14.7Hz,1H),4.39(d,J＝14.7Hz,1H),3.76-3.61(m,1H),3.31-3.23(m,1H),2.38-2.24(m,1H),2.15-1.91(m,2H),1.79-1.51(m,2H),1.45-1.16(m,2H)。
Intermediate C-2: 2-benzyl-2-azabicyclo [2.2.2] oct-6-ol.
To a suspension of lithium aluminum hydride (54.4g, 1.43mol) in THF (180 mL) at 0 ℃ under argon, a solution of intermediate C-11 (170.0 g,716.4 mmol) was added dropwise as a solution in THF (720 mL). The reaction mixture was allowed to warm to room temperature, then carefully heated to 60 ℃ and stirred for 2h. The resulting suspension was cooled to 0 ℃ and diluted with ether (540 mL). To this suspension was added sodium sulfate decahydrate (450 g) in small portions. The mixture was stirred at room temperature for 16h. The suspension was filtered and the filtrate was evaporated. The residue was triturated with hexane (100 mL) to give intermediate C-2 (130.2g, 0.60mol, 84%) as a white solid. C 14 H 19 MS (ESI) mass calculated for NO 217.2; measured value of m/z is 218.3[ m ] +H] + 。 1 H NMR(300MHz,DMSO-d 6 )δ7.41-7.25(m,4H),7.25-7.10(m,1H),4.50(d,J＝3.6Hz,1H),3.97-3.86(m,1H),3.71(d,J＝14.7Hz,1H),3.66(d,J＝14.4Hz,1H),2.61(d,J＝9.3Hz,1H),2.48-2.32(m,2H),1.94(t,J＝111Hz, 1H), 1.82-1.66 (m, 2H), 1.66-1.56 (m, 1H), 1.52-1.37 (m, 2H), 1.32-1.15 (m, 1H). Intermediate C-2 can be transferred to intermediate C-4A which can be obtained in a single enantiomeric form (intermediate C-4B or C-4C) via chiral SFC purification as described above.
Example 1: (R/S) - (2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (R/S) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1 ]Tert-butyl hepta-2-carboxylate. To intermediate B-8 (100mg, 0.469mmol) dissolved in DMF (3 mL) was added NaH (28mg, 0.70mmol,60% dispersion in mineral oil). After 5 minutes, 2-chloro-5- (trifluoromethyl) pyrazine (0.087ml, 0.70mmol) was then added and the mixture was heated to 90 ℃. After heating at 90 ℃ for 3.5h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with O. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, washing with MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-20% EtOAc in hexane) afforded the title compound (151mg, 0.420mmol, 90%). C 16 H 20 F 3 N 3 O 3 Calculated mass MS (ESI) of 359.1; the measured value of m/z is 304.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers) Δ 8.46-8.41 (m, 1H), 8.27-8.24 and 8.16-8.12 (2m, 1H), 5.45-5.30 (m, 1H), 4.63-4.48 (m, 1H), 3.48-3.33 (m, 1H), 3.28-3.13 (m, 1H), 2.67-2.54 (m, 1H), 2.32-2.19 (m, 1H), 1.85-1.04 (m, 12H).
And B: (R/S) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (151mg, 0.42mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (6 mL). After 3.25h, the reaction was concentrated to obtain the title compound of step B, which was allowed to stand without further purification The application is. C 11 H 12 F 3 N 3 Calculated mass MS (ESI) for O is 259.1; the measured value of m/z is 260.1[ m ] +H] + 。
Step C: (R/S) - (2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (43 mg) and intermediate A-1 (24mg, 0.13mmol) in DMF (1.5 mL) was added DIPEA (0.4mL, 2.32mmol) and HATU (48mg, 0.13mmol). After completion of the reaction, purification was performed by Agilent preparation X to obtain the title compound (9 mg). C 20 H 17 F 3 N 6 O 2 Mass calculated MS (ESI) of (1) of 430.1; the measured value of m/z is 431.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.80: J =7.5hz, 1h), 4.97 (dt, J =10.2,3.3hz, 1h), 4.03-3.96 (m, 1H), 3.62 (dt, J =11.0,3.2hz, 1h), 3.44 (dd, J =10.9,1.5hz, 1h), 2.68-2.63 (m, 1H), 2.27-2.18 (m, 1H), 1.48 (dt, J =13.6,3.6hz, 1h), 1.40 (d, J =10.6hz, 1h), 1.33-1.25 (m, 1H).
Example 2: (R/S) - (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 1, intermediate A-1 was replaced with intermediate A-20. C 20 H 18 F 3 N 7 O 2 The mass calculation of MS (ESI) of (1) was 445.1; the measured value of m/z is 446.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.78m,4H),1.60-1.48(m,3H)。
Example 3: (R/S) - (3-ethoxyisoquinolin-4-yl) ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 1, intermediate A-1 was replaced with intermediate A-21. C 23 H 21 F 3 N 4 O 3 Mass calculated as 458.2 for MS (ESI); the measured value of m/z is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers) δ 8.72 (d, J =0.8hz, 1h), 7.77-7.72 (m, 1H), 7.71-7.68 (m, 1H), 7.64-7.58 (m, 2H), 7.52-7.47 (m, 1H), 7.30 (ddd, J =8.1,6.8,1.1hz, 1h), 4.87 (dt, J =10.2,3.4hz, 1h), 4.68-4.39 (m, 3H), 3.87 (dt, J =11.1,3.2hz, 1h), 3.56 (dd, J =11.1,1.6hz, 1h), 2.83-2.77 (m, 1H), 2.35-2.26 (m, 1H), 2.01-1.95 (m, 1H), 1.84-1.75 (m, 1H), 1.56-1.38 (m, 4H).
Example 4: (R/S) -5-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 1, intermediate A-1 was replaced with intermediate A-19. C 20 H 18 F 3 N 7 O 2 The mass calculation of MS (ESI) of (1) was 445.1; the measured value of m/z is 446.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 5: (R/S) - (5- (4-fluorophenyl) -2-methylthiazol-4-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (R/S) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-8 (200mg, 0.94mmol) dissolved in DMF (5 mL) was added NaH (56mg, 1.41mmol,60% dispersion in mineral oil). After 5 min, 2-chloro-5- (trifluoromethyl) pyridine (340mg, 1.87mmol) was then added and the mixture was heated to 80 ℃. After heating at 80 ℃ for 5.75h, the mixture was cooled to room temperature and quenched with saturated NH 4 Quenching with Cl solution and H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-30% EtOAc in hexane) afforded the title compound (300mg, 0.84mmol, 89%). C 17 H 21 F 3 N 2 O 3 Mass calculated as 358.2 for MS (ESI); the measured value of m/z is 359.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d) delta 8.47-8.37 (m, 1H), 7.84-7.69 (m, 1H), 6.87-6.68 (m, 1H), 5.45-5.29 (m, 1H), 4.63-4.52 (m, 1H), 3.47-3.34 (m, 1H), 3.26-3.11 (m, 1H), 2.66-2.52 (m, 1H), 2.31-2.16 (m, 1H), 1.80-1.09 (a series of m, 12H).
And B: (R/S) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (300mg, 0.84mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (5 mL). After 7h, the reaction was concentrated to obtain the title compound of step B (243 mg), which was used without further purification. C 12 H 13 F 3 N 2 MS (ESI) mass calculated for O was 258.1; measured value of m/z is 259.1[ deg. ] M + H] + 。
And C: (R/S) - (5- (4-fluorophenyl) -2-methylthiazol-4-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. Go to step To a solution of the title compound of step B (30 mg) and intermediate A-14 (24mg, 0.10 mmol) in DMF (1 mL) were added DIPEA (0.1mL, 0.58mmol) and HATU (38mg, 0.10 mmol). Upon completion, the reaction was diluted with H2O and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were washed with H2O, brine, dried over MgSO4, filtered and concentrated. Purification of the concentrate was performed using Agilent preparative method X to obtain the title compound (40.3 mg). C 23 H 19 F4N 3 O 2 MS (ESI) mass calculation value of S is 477.1m/z found value of 478.1[ deg. ] M + H]+.1H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.85.
Example 6: (R/S) - (6-methylimidazo [2,1-b ] thiazol-5-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, intermediate A-14 was replaced with intermediate A-17. C 19 H 17 F 3 N 4 O 2 MS (ESI) mass calculation of S422.1; measured value of m/z is 423.1[ m ] +H ] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.08 (br.s, 1H), 7.54-7.37 (m, 2H), 6.68 (d, J =4.5hz, 1h), 6.53-6.41 (m, 1H), 5.22-5.08 (m, 1H), 4.98-4.85 (m, 1H), 3.87-3.65 (m, 1H), 3.57-3.46 (m, 1H), 2.77-2.71 (m, 1H), 2.39 (s, 3H), 2.36-2.24 (m, 1H), 2.04-1.95 (m, 1H), 1.85 (d, J =10.5hz, 1h), 1.49 (dt, J =13.6,3.5hz, 1h).
Example 7: (R/S) - (2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate A-1.C 21 H 18 F 3 N 5 O 2 Mass calculation of MS (ESI) of 429.2; the measured value of m/z is 430.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, reporting major optical isomers) δ 8.02-7.99 (m, 1H), 7.87-7.74 (m, 4H), 7.35-7.29 (m, 1H), 7.03 (dd, J =7.7,1.5hz, 1h), 6.84-6.78 (m, 2H), 5.00 (dt, J =10.1,3.3hz, 1h), 4.07-4.03 (m, 1H), 3.61 (dt, J =11.0,3.2hz, 1h), 3.40 (dd, J =10.9,1.5hz, 1h), 2.65-2.60 (m, 1H), 2.25-2.16 (m, 1H), 1.45-1.37 (m, 2H), 1.33-1.25 (m, 1H).
Example 8: (R/S) - (3-ethoxyisoquinolin-4-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was similar to example 5, using intermediate a-21, and additional purification using Shimadzu preparation method X. C 24 H 22 F 3 N 3 O 3 Mass calculation of MS (ESI) of 457.2; the measured value of m/z is 458.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d) delta 8.71 (s, 1H), 7.81-7.76 (m, 1H), 7.71-7.68 (m, 1H), 7.61 (d, J =8.2Hz, 1H), 7.46 (ddd, J =8.4,6.8,1.3Hz, 1H), 7.29-7.23 (embedded m, 1H), 7.10 (dd, J =8.7,2.5Hz, 1H), 6.11 (d, J =8.6Hz, 1H), 4.91 (dt, J =10.3,3.4Hz, 1H), 4.68-4.66 (m, 1H), 4.65-4.58 (m, 1H), 4.49-4.40 (m, 1H), 3.86 (dt, J =11.2,3.2hz, 1H), 3.58 (dd, J =11.1,1.7hz, 1H), 2.84-2.76 (m, 1H), 2.36-2.24 (m, 1H), 1.99-1.94 (m, 1H), 1.80 (d, J =10.4hz, 1H), 1.50 (dt, J =13.7,3.8hz, 1H), 1.44 (t, J =7.1hz, 3h).
Example 9: (R/S) - (5-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate A-19.C 21 H 19 F 3 N 6 O 2 Mass calculated as 444.2 for MS (ESI); the measured value of m/z is 445.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.93.
Example 10: (R/S) - (7-ethoxyquinolin-8-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-25.C 24 H 22 F 3 N 3 O 3 Mass calculation of MS (ESI) of 457.2; measured value of m/z is 458.2[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.49 min (main optical isomer).
Example 11: (R/S) - (3-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate A-2.C 23 H 18 F 4 N 4 O 2 Mass calculated value of MS (ESI) of 458.1; the measured value of m/z is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.82, 0.18), reporting the major optical isomer) δ 8.86 (d, J =4.9hz, 2h), 8.14-8.10 (m, 1H), 7.79 (dd, J =8.8,2.6hz, 1h), 7.30-7.26 (m, 1H), 7.10-7.03 (m, 1H), 6.95-6.81 (m, 3H), 5.06 (dt, J =10.2,3.4hz, 1h), 4.27-4.23 (m, 1H), 3.34-3.30 (m, 2H), 2.57-2.51 (m, 1H), 2.25-2.14 (m, 1H), 1.46-1.40 (m, 1H), 1.36 (J =13.6,3.6, 6, 6h), 1.94-0.87H, 1H), 1.36 (m, 1H).
Example 12: (R/S) - (4-methoxy-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
To the title compound of example 5, step B (20 mg) and intermediate A-15 (15mg, 0.066 mmol) was added DCM (0.8 mL) and DIPEA (0.05mL, 0.29mmol). Then dropwise adding T 3 P (0.11mL, 0.18mmol,50% DMF solution), and the mixture was heated to 45 ℃. After completion, the reaction was quenched with saturated NaHCO 3 The solution was quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were washed with saturated NaHCO 3 The solution, washed with brine, over MgSO 4 Dried, filtered, and concentrated. Purification of the concentrate was performed using Agilent preparation X to obtain the title compound (9.3 mg). C 24 H 21 F 3 N 4 O 3 Mass calculated MS (ESI) of 470.2; the measured value of m/z is 471.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.82.
Example 13: (R/S) -4-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-5.C 22 H 20 F 3 N 5 O 3 Mass calculated as 459.1 for MS (ESI); the measured value of m/z is 460.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
The ORTEP of example 13 is shown in figure 1.
Example 14: (R/S) - (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate A-10.C 21 H 17 F 4 N 5 O 2 Mass calculation of (ESI) of (2) is 447.1; the measured value of m/z is 448.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.85, 0.15), reporting the major optical isomer) δ 8.09-8.05 (m, 1H), 7.85-7.78 (m, 4H), 7.00 (ddd, J =9.0,7.6,2.9hz, 1H), 6.82 (d, J =8.7hz, 1h), 6.78 (dd, J =8.1,2.9hz, 1h), 5.02 (dt, J =10.2,3.3hz, 1h), 4.06-4.01 (m, 1H), 3.59 (dt, J =10.9,3.2hz, 1h), 3.40 (dd, J =10.9,1.5hz, 1h), 2.66-2.60 (m, 1H), 2.28-2.17 (m, 1H), 1.47 (m, 1H), 1.27H, 1H).
The ORTEP of example 14 is shown in figure 2.
Example 15: (R/S) -2-methoxy-6- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-13.C 22 H 20 F 3 N 5 O 3 Mass calculation of (ESI) of (2) is 459.2; measured value of m/z is 460.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, reporting major optical isomers) δ 8.00-7.95 (m, 1H), 7.82 (s, 2H), 7.73 (d, J =10.6hz, 1h), 7.46 (dd, J =8.2,0.9hz, 1h), 7.28-7.21 (m, 1H), 6.75-6.71 (m, 1H), 6.42 (dd, J =8.4,0.9hz, 1h), 4.82 (dt, J =10.2,3.4hz, 1h), 4.18-4.12 (m, 1H), 3.63-3.58 (m, 1H), 3.57 (s, 3H), 3.37 (dd, J =11.0,1.5hz, 1h), 2.58-2.52 (m, 1H), 2.19-2.09 (m, 1H), 1.74-1.66 (m, 1H), 1.45-1.37 (m, 1H), 1.32-1.23 (m, 1H).
Example 16: (R/S) - (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-16.C 21 H 17 F 4 N 5 O 2 Mass calculated as 447.1 for MS (ESI); measured value of m/z is 448.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.86.
Example 17: (R/S) - (3-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-22.C 22 H 20 F 3 N 5 O 2 MS (ESI) mass calculation value of (443.2 m/z found 444.2[ 2 ], [ M + H ]] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.85, 0.15), reporting the major optical isomer) δ 8.15-8.11 (m, 1H), 7.86-7.77 (m, 3H), 7.24-7.19 (m, 1H), 6.99-6.82 (m, 3H), 5.09 (dt, J =10.1,3.3hz, 1h), 4.25-4.19 (m, 1H), 3.31-3.23 (m, 2H), 2.57-2.50 (m, 1H), 2.27-2.11 (m, 4H), 1.53-1.47 (m, 1H), 1.37-1.28 (m, 1H), 1.27-1.21 (m, 1H).
Example 18: (R/S) - (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate A-11.C 21 H 17 F 4 N 5 O 2 Mass calculated as 447.1 for MS (ESI); the measured value of m/z is 448.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers) δ 8.04-8.02 (m, 1H), 7.85-7.72 (m, 4H), 7.32-7.26 (m, 1H), 6.92-6.88 (m, 1H), 6.61 (td, J =8.4,1.0hz, 1h), 5.00-4.94 (m, 1H), 4.03-4.00 (m, 1H), 3.65 (dt, J =11.0,3.2, 1h), 3.44 (dd, J =10.9,1.5hz, 1h), 2.68-2.60 (m, 1H), 2.28-2.17 (m, 1H), 1.46-1.37 (m, 2H), 1.31-1.25 (m, 1H).
Example 19: (R/S) - (5-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate A-7.C 23 H 18 F 4 N 4 O 2 The mass calculation value of MS (ESI) is 458.1m/z and the measured value is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 20: (R/S) - (4-fluoro-2- (pyrimidin-2-yl) phenyl) (-6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-23.C 23 H 18 F 4 N 4 O 2 MS (ESI) mass calculation value of 458.1m/z found value of 459.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.84.
Example 21: (R/S) - (2- (4H-1,2,4-triazol-4-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 5, using intermediate a-9.C 21 H 18 F 3 N 5 O 2 Calculated value of MS (ESI) by mass is 429.1m/z found 430.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.84.
Example 22: (R/S) - (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 5, using intermediate a-20.C 21 H 19 F 3 N 6 O 2 Mass calculated as 444.2 for MS (ESI); measured value of m/z is 445.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.82.
Example 23: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1R, 4S, 6S) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Using a Chiralpak IC column (5um 250X 21 mm), 20% EtOH 2 The mobile phase, and a flow rate of 40mL/min (temperature =40 ℃), the chiral SFC purification of example 22 was carried out to obtain the title compound in the form of a single enantiomer, the absolute configuration of which was confirmed by example 25. Elution was monitored by absorbance at 270 nm. 20% EtOH using a Chiralpak IC column (5um 250X 4.6 mm) 2 Mobile phase, and 2mL/min flow, for 45 minutes (temperature =40 ℃), enantiomeric purity was confirmed by analytical SFC. Elution was monitored by absorbance at 270 nm. (enantiomeric purity)>98%) which eluted as two peaks, initially the minor peak, followed by the second major peak (due to optical isomers), 6.77 minutes and 23.40 minutes retention time. C 21 H 19 F 3 N 6 O 2 Mass calculated as 444.2 for MS (ESI); the measured value of m/z is 445.2[ m ] +H] + 。 1 H NMR data is consistent with example 22.
Example 24: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Using a Chiralpak IC column (5um 250X 21 mm), 20% EtOH 2 The mobile phase, and a flow rate of 40mL/min (temperature =40 ℃), the chiral SFC purification of example 22 was carried out to obtain the title compound in the form of a single enantiomer, the absolute configuration of which was confirmed by example 25. Elution was monitored by absorbance at 270 nm. 20% EtOH using a Chiralpak IC column (5um 250X 4.6 mm) 2 Mobile phase, and 2mL/min flow, for 45 minutes (temperature =40 ℃), enantiomeric purity was confirmed by analytical SFC. Elution was monitored by absorbance at 270 nm. (enantiomeric purity)>98%) which eluted as two peaks, initially the minor peak, followed by the second major peak (due to optical isomers), 7.75 minutes and 11.79 minutes retention time). C 21 H 19 F 3 N 6 O 2 Mass calculation of (ESI) of (2) is 444.2; the m/z was found to be 445.2[M+H] + 。 1 H NMR data is consistent with example 22.
Example 25: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hepta-2-carboxylic acid tert-butyl ester. To intermediate B-5 (422mg, 1.98mmol) dissolved in DMF (8 mL) was added NaH (119mg, 2.97mmol,60% dispersion in mineral oil). After 5 min, 2-chloro-5- (trifluoromethyl) pyridine (718mg, 3.96mmol) was then added and the mixture was heated to 80 ℃. After heating at 80 ℃ for 4.75h, the mixture was cooled to room temperature and quenched with saturated NH 4 Quenching with Cl solution and H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-25% EtOAc in hexane) afforded the title compound (622mg, 1.74mmol, 88%). C 17 H 21 F 3 N 2 O 3 Mass calculated as 358.2 for MS (ESI); the measured value of m/z is 359.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.75.
And B: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (622mg, 1.74mmol) in EtOAc (1 mL) was added a 4M solution of HCl in dioxane (10 mL). After 2h, the reaction was concentrated to obtain the title compound of step B (507 mg), which wasIt was used without further purification. C 12 H 13 F 3 N 2 MS (ESI) mass calculated for O was 258.1; measured value of m/z is 259.1[ deg. ] M + H] + 。
And C: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone
To a solution of the title compound of step B (100 mg) and intermediate A-20 (84mg, 0.37mmol) in DMF (4 mL) was added DIPEA (0.3 mL, 1.74mmol) and HATU (142mg, 0.37mmol). After completion, H is used for the reaction 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (112 mg). 20% EtOH using a Chiralpak IC column (5um 250X 4.6 mm) 2 Mobile phase, and 2mL/min flow, for 45 minutes (temperature =40 ℃), enantiomeric purity was confirmed by analytical SFC. Elution was monitored by absorbance at 270 nm. (100% single enantiomer) which eluted as two peaks, initially the minor peak, followed by the second major peak (due to optical isomers), 7.69 minutes and 11.90 minutes retention time). C 21 H 19 F 3 N 6 O 2 Mass calculated as 444.2 for MS (ESI); the measured value of m/z is 445.2[ m ] +H] + 。 1 H NMR data is consistent with example 22.
Example 26: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-23. C 23 H 18 F 4 N 4 O 2 The mass calculation value of MS (ESI) is 458.1m/z, and the measured value is 459.1[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers(0.85, 0.15), the major optical isomers reported) δ 8.80 (d, J =4.8hz, 2h), 8.13-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.84-7.78 (m, 1H), 7.23 (t, J =4.8hz, 1h), 7.01 (dd, J =8.4,5.6hz, 1h), 6.87-6.81 (m, 1H), 6.59 (ddd, J =8.5,7.9,2.7hz, 1H), 5.03 (dt, J =10.1,3.3hz, 1H), 4.15-4.10 (m, 1H), 3.65 (dt, J =10.8,3.2hz, 1H), 3.44-3.38 (m, 1H), 2.69-2.62 (m, 1H), 2.29-2.18 (m, 1H), 1.48-1.37 (m, 2H), 1.34-1.23 (m, 1H).
Example 27: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-2. C 23 H 18 F 4 N 4 O 2 The mass calculation value of MS (ESI) is 458.1. M/z, and the measured value is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 28: (5-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-19. C 21 H 19 F 3 N 6 O 2 The mass calculation value of MS (ESI) is 444.2m/z, and the measured value is 445.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as optical isomer)Mixture (0.86.
Example 29: (6-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-3. C 21 H 19 F 3 N 6 O 2 The mass calculation value of MS (ESI) is 444.2m/z, and the measured value is 445.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.83.
Example 30: (3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-28. C 20 H 17 F 3 N 6 O 2 The mass calculation value of MS (ESI) is 430.1m/z, and the measured value is 431.2M +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.80.4,1.5Hz,1H),7.95-7.91(m,1H),7.88-7.81(m,3H),7.72(dd,J＝8.7,2.6Hz,1H),7.20(dd,J＝8.3,4.7Hz,1H),6.86(d,J＝8.8Hz,1H),5.03(dt,J＝10.2,3.2Hz,1H),4.27-4.23(m,1H),3.74-3.68(m,1H),3.47(dd,J＝11.0,1.3Hz,1H),2.71-2.66(m,1H),2.29-2.19(m,1H),1.64-1.48(m,3H)。
Example 31: (3-fluoro-2-methoxyphenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-18. C 20 H 18 F 4 N 2 O 3 Calculated value of MS (ESI) by mass is 410.1m/z found 411.1M + H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.83.
Example 32: (3-methyl-2-, (Oxazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-27. C 23 H 20 F 3 N 3 O 3 The mass calculation value of MS (ESI) is 443.1m/z, the measured value is 444.2[ M ] +H] + 。 1 H NMR(400MHz，Chloroform-d, compound present as a mixture of optical isomers (0.81-0.19), reporting major optical isomers) δ 8.07-8.03 (m, 1H), 7.81-7.73 (m, 2H), 7.30-7.25 (m, 1H), 7.18-7.13 (m, 1H), 6.91-6.80 (m, 3H), 5.04 (dt, J =10.2,3.2hz, 1H), 4.22-4.17 (m, 1H), 3.49-3.41 (m, 1H), 3.40-3.33 (m, 1H), 2.63-2.57 (m, 1H), 2.44 (s, 3H), 2.26-2.16 (m, 1H), 1.49 (d, J =10.4hz, 1H), 1.41-1.26 (m, 2H).
Example 33: (3-fluoro-2- (1H-1,2,3-triazol-1-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-33. C 21 H 17 F 4 N 5 O 2 The calculated mass value of MS (ESI) is 447.1m/z, and the measured value is 448.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.76, 0.24), reporting major optical isomers) δ 8.20-8.15 (m, 1H), 7.92-7.88 (m, 1H), 7.87-7.80 (m, 2H), 7.24-7.16 (m, 1H), 7.07-6.99 (m, 1H), 6.92-6.85 (m, 2H), 5.14 (dt, J =9.9,3.2hz, 1H), 4.28-4.24 (m, 1H), 3.37-3.31 (m, 1H), 3.30-3.24 (m, 1H), 2.62-2.56 (m, 1H), 2.32-2.21 (m, 1H), 1.42-1.31 (m, 2H), 0.94-0.89 (m, 1H).
Example 34: (6-methyl-2- (1H-1,2,3-triazol-1-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-4. C 21 H 19 F 3 N 6 O 2 The mass calculation value of MS (ESI) is 444.2m/z, and the measured value is 445.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.87Isomers) δ 8.44 (d, J =1.2hz, 1h), 8.09-8.05 (m, 1H), 7.84-7.78 (m, 2H), 7.28 (d, J =7.8hz, 1h), 6.88-6.83 (m, 1H), 6.65 (d, J =7.8hz, 1h), 5.05 (dt, J =10.1,3.3hz, 1h), 4.13-4.06 (m, 1H), 3.73 (dt, J =11.0, 3.21h), 3.38 (dd, J =10.9,1.5hz, 1h), 2.72-2.65 (m, 1H), 2.50 (s, 3H), 2.31-2.21 (m, 1H), 1.73-1.67 (m, 1H), 1.51-1.40H (m, 1H).
Example 35: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 25, substituting intermediate A-20 with intermediate A-16. C 21 H 17 F 4 N 5 O 2 The calculated mass value of MS (ESI) is 447.1m/z, and the measured value is 448.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.85.
Example 36: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-1. C 21 H 18 F 3 N 5 O 2 The mass calculation value of MS (ESI) is 429.1m/z, and the measured value is 430.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.87.28(m,1H),7.02(dd,J＝7.7,1.5Hz,1H),6.85-6.77(m,2H),4.99(dt,J＝10.2,3.3Hz,1H),4.10-4.00(m,1H),3.61(dt,J＝10.9,3.3Hz,1H),3.40(dd,J＝10.9,1.5Hz,1H),2.67-2.58(m,1H),2.26-2.15(m,1H),1.47-1.23(m,3H)。
Example 37: (3-ethoxy-6-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-8. C 21 H 22 F 3 N 3 O 3 The calculated mass value of MS (ESI) is 421.2m/z, measured value is 422.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.83.
Example 38: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate a-20 was replaced with intermediate a-6 and purification was carried out using silica gel chromatography (15-80% etoac (10% meoh in hexane)) instead of Agilent preparation method X. C 23 H 18 F 4 N 4 O 2 Mass calculated value of MS (ESI) of 458.1; the measured value of m/z is 459.1[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.78Optical isomers) δ 8.81 (d, J =4.9hz, 2h), 8.11-8.05 (m, 1H), 8.05-8.00 (m, 1H), 7.77 (dd, J =8.7,2.3hz, 1h), 7.31-7.27 (m, 1H), 7.23 (t, J =4.8hz, 1h), 6.91 (d, J =8.7hz, 1h), 6.72-6.64 (m, 1H), 4.97 (dt, J =10.1,3.4hz, 1h), 4.14-4.09 (m, 1H), 3.68 (dt, J =10.9,3.2hz, 1h), 3.46 (dd, J =10.9,1.5hz, 1h), 2.65 (s, 1H), 2.28-2.18 (m, 1H), 1.48-1.38 (m, 2H), 1.25-1.18 (m, 1H).
Example 39: (2-methoxy-6- (1H-pyrazol-5-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-30. C 23 H 21 F 3 N 4 O 3 Mass calculated as 458.2 for MS (ESI); the measured value of m/z is 459.3[ M ] +H ] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers) δ 8.00 (s, 1H), 7.75 (dd, J =8.7,2.6hz, 1h), 7.62-7.57 (m, 1H), 7.34-7.26 (m, 1H), 7.25-7.21 (m, 1H), 6.76 (d, J =8.7hz, 1h), 6.53 (d, J =2.0hz, 1h), 6.46 (d, J =8.4hz, 1h), 4.84 (dt, J =10.2,3.4hz, 1h), 4.15 (s, 1H), 3.54-3.46 (m, 4H), 3.34 (d, J =10.8hz, 1h), 2.49 (s, 1H), 2.19-2.07 (m, 1H), 1.55-1H (m, 1H).
Example 40: (2-methoxy-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-24. C 24 H 21 F 3 N 4 O 3 Mass calculated MS (ESI) of 470.2; the measured value of m/z is 471.1[ m ] +H] + . Analytical HPLC using an Xbridge C18 column (5um, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, intoLine 2 min, then 2 min at 100% acn, flow 2.5mL/min (temperature =45 ℃). R at 254nm t And 2.01 and 2.24 minutes (major optical isomer).
Example 41: (2- (1,4-dimethyl-1H-pyrazol-5-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 25, substituting intermediate A-20 with intermediate A-31. C 24 H 23 F 3 N 4 O 2 Mass calculated as 456.2 for MS (ESI); measured value of m/z is 457.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.74.
Example 42: (1H-indol-7-yl) ((1S,4R,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate a-20 was replaced with intermediate a-29 and purification was carried out using silica gel chromatography (0-60% etoac (10% meoh in hexane)) instead of Agilent preparation method X. C 21 H 18 F 3 N 3 O 2 The mass calculation value of MS (ESI) of (1) was 401.1; measured value of m/z is 402.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.82(s,1H),7.92(br.s,1H),7.62(dd,J＝8.9,2.7Hz,1H),7.32(d,J＝7.9Hz,1H),7.21(t,J＝2.8Hz,1H),6.93(d,J＝7.3Hz,1H),6.69(t,J＝7.5Hz,1H),6.57(d,J＝8.7Hz,1H),6.32-6.25(m,1H),5.06(dt,J＝10.0,3.1Hz,1H),4.67(br.s,1H),3.60-3.53(m,1H),3.52-3.44(m,1H),2.70-2.62(m,1H),2.29-2.17(m,1H),2.06-1.99(m,1H),1.73(d,J＝10.2Hz,1H),1.30(dt,J＝13.4,3.5Hz,1H)。
Example 43: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 25, intermediate A-20 was replaced with intermediate A-10. C 21 H 17 F 4 N 5 O 2 Mass calculated as 447.2 for MS (ESI); the measured value of m/z is 448.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.91.
Example 44: (4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-12. C 21 H 17 F 4 N 5 O 2 Mass calculated as 447.2 for MS (ESI); the measured value of m/z is 448.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88,1H),7.63(dd,J＝9.5,2.5Hz,1H),7.02(dd,J＝8.5,5.9Hz,1H),6.82(d,J＝8.7Hz,1H),6.52(td,J＝8.1,2.5Hz,1H),5.01(dt,J＝10.2,3.3Hz,1H),4.03(s,1H),3.63(dt,J＝11.0,3.2Hz,1H),3.40(dd,J＝10.9,1.4Hz,1H),2.68-2.61(m,1H),2.28-2.16(m,1H),1.46-1.38(m,2H),1.38-1.28(m,1H)。
Example 45: (2-bromo-3-fluorophenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-32. C 19 H 15 BrF 4 N 2 O 2 Mass calculated as 458.0 for MS (ESI); the measured value of m/z is 459.1[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.82.
Example 46: (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-11. C 21 H 17 F 4 N 5 O 2 Mass calculated as 447.2 for MS (ESI); the measured value of m/z is 448.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.81(m,1H),7.77-7.72(m,1H),7.32-7.27(m,1H),6.89(d,J＝8.8Hz,1H),6.60(td,J＝8.4,1.0Hz,1H),4.96(dt,J＝10.1,3.4Hz,1H),4.06-3.96(m,1H),3.64(dt,J＝10.9,3.2Hz,1H),3.44(dd,J＝10.9,1.5Hz,1H),2.69-2.60(m,1H),2.28-2.16(m,1H),1.51-1.34(m,2H),1.30-1.22(m,1H)。
Example 47: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Step A: (1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (101mg, 0.474mmol) dissolved in DMF (3 mL) was added NaH (38mg, 0.95mmol,60% dispersion in mineral oil). After 5 minutes, the flask wall was washed with additional DMF (1.0 mL), then 5-bromo-2-fluoropyridine (0.078mL, 0.76mmol) was added and the mixture was heated to 70 ℃. After heating at 70 ℃ for 3.25h, the mixture was cooled to room temperature and quenched with saturated NH 4 Quenching with Cl solution and H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, washing with MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-25% EtOAc in hexane) afforded the title compound (149mg, 0.40mmol, 85%). C 16 H 21 BrN 2 O 3 Mass calculation of (ESI) of (2) is 368.1; the measured value of m/z is 369.1[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers (0.75: J =10.1,3.2hz, 0.75h), 4.57-4.49 (m, 1H), 3.43-3.31 (m, 1H), 3.19 (dd, J =9.5,1.3hz, 0.75h), 3.15-3.09 (m, 0.25H), 2.59-2.50 (m, 1H), 2.26-2.13 (m, 1H), 1.77-1.66 (m, 1H), 1.65-1.56 (m, 1H), 1.43 (s, 2H), 1.41-1.23 (m, 1H), 1.16 (s, 7H).
And B: (1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-nitrogenHeterobicyclics [2.2.1]Heptane xHCl to a solution of the title compound of step A (149mg, 0.404 mmol) in EtOAc (1.5 mL) was added 4M HCl in dioxane (5 mL). After 3.25h, the reaction was concentrated to obtain the title compound of step B (128 mg), which was used without further purification. C 11 H 13 BrN 2 MS (ESI) mass calculated for O is 268.0; the measured value of m/z is 269.0[ m ] +H] + 。
And C: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-6 (24mg, 0.11mmol) in DMF (1.5 mL) was added DIPEA (0.25mL, 1.45mmol) and HATU (41mg, 0.11mmol). After completion, the reaction is applied to H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (20 mg). C 22 H 18 BrFN 4 O 2 Mass calculation of (ESI) of (2) is 468.1; measured value of m/z is 469.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.79.
Example 48: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 47, intermediate a-6 was replaced with intermediate a-2. C 22 H 18 BrFN 4 O 2 MS (ESI) mass meterThe value is 468.1; measured value of m/z is 469.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88 1 H NMR (400 MHz, chloroform-d) δ 8.85 (d, J =4.9hz, 2h), 7.90-7.83 (m, 1H), 7.66 (dd, J =8.8,2.5hz, 1h), 7.29-7.26 (m, 1H), 7.16-7.07 (m, 1H), 7.05-6.96 (m, 1H), 6.91 (dd, J =7.5,1.3hz, 1h), 6.67 (d, J =8.7hz, 1h), 4.96 (dt, J =10.1,3.3hz, 1h), 4.27-4.16 (m, 1H), 3.34-3.24 (m, 2H), 2.52 (s, 1H), 2.23-2.11 (m, 1H), 1.40 (d, J = 10.1H), 1.31.31, 1H, 31.8H, 31, 31.87 hz, 0.87 hz, 0.31, 1H).
Example 49: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 47, intermediate A-6 was replaced with intermediate A-1. C 20 H 18 BrN 5 O 2 Mass calculated as 439.1 for MS (ESI); the measured value of m/z is 440.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.89, 0.11), reporting the major optical isomer) δ 7.85 (dd, J =8.2,1.1hz, 1h), 7.81 (s, 2H), 7.75 (dd, J =2.5,0.7hz, 1h), 7.64 (dd, J =8.7,2.6hz, 1h), 7.41-7.35 (m, 1H), 7.05 (dd, J =7.7,1.5hz, 1h), 6.91 (td, J =7.6,1.2hz, 1h), 6.65 (d, J =8.7hz, 1h), 4.89 (dt, J =10.2,3.3hz, 1h), 4.05-3.97 (m, 1H), 3.59 (dt, J =10.9,3.2hz, 1h), 3.38 (dd, J =10.9,1.4hz, 1h), 2.63-2.56 (m, 1H), 2.23-2.12 (m, 1H), 1.41-1.33 (m, 2H), 1.29-1.23 (m, 1H).
Example 50: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 47, intermediate A-6 was replaced with intermediate A-20。C 20 H 19 BrN 6 O 2 Calculated mass MS (ESI) of 454.1; measured value of m/z is 455.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.85.
Example 51: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (101mg, 0.474mmol) dissolved in DMF (3 mL) was added NaH (38mg, 0.95mmol,60% dispersion in mineral oil). After 5 minutes, the flask wall was washed with additional DMF (1.0 mL), then 2-fluoro-3- (trifluoromethyl) pyridine (0.091mL, 0.76mmol) was added and the mixture was heated to 70 ℃. After heating at 70 ℃ for 3h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-35% EtOAc in hexane) afforded the title compound as a white solid (87mg, 0.24mmol, 51%). C 17 H 21 F 3 N 2 O 3 Mass calculation of (ESI) of (2) is 358.2; the measured value of m/z is 303.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.68:. 0.32), reporting the major optical isomers) delta 8.35-8.25 (m, 1H), 7.90-7.82 (m, 1H)),6.96(dd,J＝7.5,5.0Hz,1H),5.32(dt,J＝10.1,3.1Hz,1H),4.64-4.58(m,1H),3.42(dt,J＝9.5,3.1Hz,1H),3.15(d,J＝9.5Hz,1H),2.61-2.56(m,1H),2.27-2.15(m,1H),1.76-1.66(m,1H),1.63(br.s,1H),1.48(dt,J＝13.5,3.5Hz,1H),1.08(s,9H)。
And B: (1S,4R,6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (86mg, 0.24mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (3 mL). After 2h, the reaction was concentrated to give the title compound of step B as a white solid (76.5 mg) and used without further purification. C 12 H 13 F 3 N 2 The calculated mass MS (ESI) value of O is 258.1; measured value of m/z is 259.1[ deg. ] M + H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (25 mg) and intermediate A-1 (18mg, 0.093mmol) in DMF (0.8 mL) were added DIPEA (75. Mu.L, 0.44 mmol) and HATU (36mg, 0.093mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-60% etoac in hexanes) afforded the title compound (29 mg). C 21 H 18 F 3 N 5 O 2 Mass calculation of MS (ESI) of 429.1; the measured value of m/z is 430.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.76: 5.04 (dt, J =10.2,3.4hz, 1h), 4.15-4.04 (m, 1H), 3.66 (dt, J =10.9,3.3hz, 1h), 3.38 (dd, J =10.9,1.4hz, 1h), 2.66-2.60 (m, 1H), 2.27-2.15 (m, 1H), 1.48 (dt, J =13.3,3.6hz, 1h), 1.44-1.37 (m, 1H), 1.36-1.28 (m, 1H).
Example 52: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 51, intermediate A-1 was replaced with intermediate A-20. C 21 H 19 F 3 N 6 O 2 Mass calculation of (ESI) of (2) is 444.2; the measured value of m/z is 445.0[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.72.
Example 53: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hepta-2-carboxylic acid tert-butyl ester. To a microwave vial containing degassed toluene (9 mL) at room temperature was added Pd (OAc) 2 (24mg, 0.035mmol) and racemic BINAP (22mg, 0.035mmol), and the reaction mixture was quenched with N 2 And purging for 5 minutes. 2-chloro-5- (trifluoromethyl) pyridine (159mg, 0.874mmol), intermediate B-10 (204 mg) and sodium tert-butoxide (121mg, 1.22mmol) were then added and the reaction mixture was heated at 70 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filter pad was washed with EtOAc. The filtrate was concentrated in vacuo, and the crude residue was directly subjected to silica gel chromatography (0-50% EtOAc in hexane) to obtain the title compound of step A (198mg, 0.554mmol, 63%). C 17 H 22 F 3 N 3 O 2 The mass calculation of MS (ESI) of (1) is 357.2; measured value of m/z is 358.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers) δ 8.33 (s, 1H), 7.55 (d, J =8.8hz, 1h), 6.37 (d, J =8.8hz, 1h), 5.11-4.97 (m, 1H), 4.41 (s, 1H), 4.27-4.18 (m, 1H), 3.44-3.36 (m, 1H), 3.08 (d, J =9.7hz, 1h), 2.62-2.55 (m, 1H), 2.39-2.26 (m, 1H), 1.68-1.61 (m, 1H), 1.45-1.43 (m, 1H), 1.48 and 1.22 (two s, 9H) were reported.
And B: and B, step B: (1S,4R,6R) -N- (5- (trifluoromethyl) pyridin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine. XHCl to a solution of the title compound of step A (198mg, 0.554 mmol) in EtOAc (3 mL) was added a 4M solution of HCl in dioxane (14 mL). After 1h, the reaction was concentrated to obtain the title compound of step B (183 mg), which was used without further purification. C 12 H 14 F 3 N 3 Mass calculated as 257.1 for MS (ESI); the measured value of m/z is 258.1[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-1 (19mg, 0.10mmol) in DMF (1 mL) were added DIPEA (94. Mu.L, 0.55 mmol) and HATU (38mg, 0.10mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 The O was quenched and the aqueous layer was extracted with 4. The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (25-100% etoac in hexane with 10% meoh) afforded the title compound (20 mg). C 21 H 19 F 3 N 6 Calculated mass MS (ESI) for O was 428.2; m/z value measured is 429.1[ M ] C +H ] + 。 1 H NMR(400MHz,DMSO-d 6 Compounds presented as mixtures of optical isomers, the major optical isomers reported) δ 8.10 (s, 2H), 7.94-7.77 (m, 1H), 7.70 (d, J =8.1hz, 1h), 7.67-7.49 (m, 2H), 7.28 (td, J =7.7,1.5hz, 1h), 6.96-6.82 (m, 1H), 6.77-6.56 (m, 2H), 3.96 (br.s, 1H), 3.64 (br.s, 1H), 3.33-3.25 (m, 1H), 1H) 3.23-3.14 (m, 1H), 2.15-2.00 (m, 1H), 1.44-1.33 (m, 1H), 1.23-1.03 (m, 2H), and 1H embedded in DMSO-d 6 Under the peak.
Example 54: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-20 and purification was performed using Agilent preparation X instead of silica gel chromatography. C 21 H 20 F 3 N 7 MS (ESI) mass calculated for O is 443.2; the measured value of m/z is 444.2[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =5.92 min (main optical isomer).
Example 55: (3-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-22 and purification was performed using Agilent preparation X instead of silica gel chromatography. C 22 H 21 F 3 N 6 MS (ESI) mass calculated for O is 442.2; the measured value of m/z is 443.2[ deg. ] M + H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.85 min (main optical isomer).
Example 56: (7-ethoxyquinolin-8-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-25 and purification was performed using Agilent preparation X instead of silica gel chromatography. C 24 H 23 F 3 N 4 O 2 Mass calculated as 456.2 for MS (ESI); measured value of m/z is 457.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.45 min (main optical isomer).
Example 57: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-10. C 21 H 18 F 4 N 6 Calculated mass MS (ESI) for O is 446.1; the measured value of m/z is 447.1[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 )δ7.95(s,2H),7.91-7.84(m,1H),7.81(dd,J＝9.0,4.7Hz,1H),7.56(d,J＝8.1Hz,1H),7.12-7.02(m,1H),6.78-6.67(m,1H),6.67-6.47(m,1H),4.02-3.91(m,1H),3.85(br.s,1H),3.42(dt,J＝11.1,3.2Hz,1H),3.30-3.27(m,1H),2.63-2.55(m,1H),2.26-2.14(m,1H),1.51-1.40(m,1H),1.28-1.16(m,2H)。
Example 58: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-7 and purification was performed using Agilent preparation X instead of silica gel chromatography. C 23 H 19 F 4 N 5 Calculated mass MS (ESI) for O is 457.2; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d 6 Compounds presented as mixtures of optical isomers (0.90, 0.10), the major optical isomers reported δ 8.87 (d, J =4.9hz, 2h), 8.03 (dd, J =8.8,5.6hz, 1h), 7.88 (br.s, 1H), 7.64-7.49 (m, 2H), 7.45 (t, J =4.9hz, 1h), 7.04 (td, J =8.6,2.8hz, 1h), 6.70-6.53 (m, 2H), 3.96 (br.s, 1H), 3.73 (br.s, 1H), 3.23-3.13 (m, 1H), 2.15-2.02 (m, 1H), 1.37 (d, J =9.7hz, 1h), 1.21-0.99 (m, 3H). *1H is embedded in DMSO-d 6 Under the peak.
Example 59: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-10 (44 mg) and 2-chloro-5- (trifluoromethyl) pyrazine (45mg, 0.25mmol) in DMF (2 mL) was added K 2 CO 3 (43mg, 0.31mmol) and the mixture was heated to 70 ℃. After heating at 70 ℃ for 3.5H, the mixture is cooled to room temperature and washed with H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-45% EtOAc in hexane) afforded the title compound (31mg, 0.087mmol, 42%). C 16 H 21 F 2 N 4 O 2 Mass calculated as 358.2 for MS (ESI); the measured value of m/z is 303.1[ m ] +2H-tBu] + 。 1 H NMR(500MHz, chloroform-d) delta 8.38-8.25 (m, 1H), 7.93-7.76 (m, 1H), 6.25-6.12 and 5.57-5.44 (2m, 1H), 4.50-4.38 (m, 1H), 4.34-4.11 (m, 1H), 3.46-3.33 (m, 1H), 3.16-3.01 (m, 1H), 2.66-2.57 (m, 1H), 2.42-2.29 (m, 1H), 1.95-0.80 (m, 12H).
And B: (1S,4R,6R) -N- (5- (trifluoromethyl) pyrazin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine. XHCl to a solution of the title compound of step A (31mg, 0.087 mmol) in EtOAc (0.5 mL) was added a 4M solution of HCl in dioxane (4 mL). After 1.5h, additional 4M HCl in dioxane (2 mL) was added. After another 1.25h, the reaction was concentrated to obtain the title compound of step B (31 mg), which was used without further purification. C 11 H 13 F 3 N 4 The mass calculation of MS (ESI) of (1) was 258.1; measured value of m/z is 259.1[ deg. ] M + H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (29 mg) and intermediate A-1 (18mg, 0.096mmol) in DMF (2.0 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (37mg, 0.096mmol). After completion, the reaction is applied to H 2 O diluted and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, brine, washing with MgSO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (8 mg). C 20 H 18 F 3 N 7 Calculated mass MS (ESI) for O429.2; measured value of m/z is 430.2[ 2 ], [ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.27 min (main optical isomer).
Example 60: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing a solution of intermediate B-10 (218mg, 1.03mmol) in MeCN (5 mL) was added 2-chloro-5- (trifluoromethyl) pyrimidine (225mg, 1.23mmol) and Et 3 N (0.21mL, 1.54mmol), and the reaction mixture was sealed and heated at 90 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature and washed with H 2 And (4) diluting with oxygen. The reaction mixture was extracted with EtOAc (3 ×). The combined organics were concentrated and the concentrate was directly subjected to silica gel chromatography (0-50% etoac in hexanes) to afford the title compound of step a (263mg, 0.734mmol, 71%). C 16 H 21 F 3 N 4 O 2 The mass calculation value of MS (ESI) is 358.2, and the found value of m/z is 303.1[ M ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers) delta 8.54-8.36 (m, 2H), 6.18-6.09 and 5.82-5.71 (two m, 1H), 4.49-4.36 (m, 1H), 4.34-4.23 (m, 1H), 3.45-3.31 (m, 1H), 3.12 (3.00,1H), 2.63-2.55 (m, 1H), 2.38-2.27 (m, 1H), 1.77-1.18 (m, 12H), 1.12-1.02 (m, 1H).
And B: (1S,4R,6R) -N- (5- (trifluoromethyl) pyrimidin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine. XHCl to a solution of the title compound of step A (263mg, 0.73mmol) in EtOAc (2 mL) was added a 4M solution of HCl in dioxane (6 mL) and the reaction mixture was stirred at room temperature for 5h. The reaction was concentrated to obtain the title compound of step B (230 mg), which was used without further purification. C 11 H 13 F 3 N 4 The mass calculation of MS (ESI) of (1) was 258.1; measured value of m/z is 259.1[ deg. ] M + H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (35 mg) and intermediate A-1 (25mg, 0.13mmol) in DMF (1 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (50mg, 0.13mmol) and the reaction mixture was stirred at room temperature for 1h. Will be provided withThe reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via agilent preparation method X to obtain the title compound (34 mg). MS (ESI): c 20 H 18 F 3 N 7 Calculated mass value of O is 429.2; the measured value of m/z is 430.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.18 min (main optical isomer).
Example 61: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 59, substituting intermediate A-1 with intermediate A-40. MS (ESI): c 20 H 19 F 3 N 8 Calculated mass of O is 444.2; the measured value of m/z is 445.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 62: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 20 H 19 F 3 N 8 Calculated mass of O is 444.2; the measured value of m/z is 445.9[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.73, 0.27), the major optical isomers reported are δ 8.52-8.44 (m, 1H), 8.36-8.30 (m, 1H), 8.21 (d, J =8.5hz, 1h), 7.99 (s, 2H), 7.39 (d, J =8.5hz, 1h), 4.24-4.15 (m, 1H), 4.12-4.00 (m, 1H), 3.60 (dt, J =11.1,3.3hz, 1h), 3.35-3.32 (m, 1H), 2.75-2.70 (m, 1H), 2.48 (s, 3H), 2.43-2.30 (m, 1H), 1.76-1.62 (m, 2H), 1.39-1.29 (m, 1H).
Example 63: (4-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 64: (4-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 65: (4-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 66: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 23 H 19 F 4 N 5 The calculated mass value of O is 457.2; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.93, 0.07), the major optical isomers reported δ 8.90 (d, J =5.0hz, 2h), 7.93 (s, 1H), 7.57 (dd, J =8.9,2.5hz, 1h), 7.49 (t, J =5.0hz, 1h), 7.10-7.03 (m, 1H), 6.91-6.83 (m, 1H), 6.84-6.76 (m, 1H), 6.60-6.52 (m, 1H), 4.17 (s, 1H), 4.14-4.03 (m, 1H), 3.23 (s, 2H), 2.57-2.49 (m, 1H), 2.27-2.17 (m, 1H), 1.54 (d, J = 11.3h), 1.26-1.17 (m, 1H), 1.04 (m, 10H, 10 hz).
Example 67: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.83. 1H is embedded in a solvent.
Example 68: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 60, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.9[ M ] +H] + 。 1 H NMR (600 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.89, 0.11), the major optical isomers reported were δ 8.91 (d, J =4.9hz, 2h), 8.55-8.50 (m, 1H), 8.24-8.19 (m, 1H), 7.49 (t, J =5.0hz, 1h), 7.16-7.08 (m, 1H), 7.06-6.96 (m, 1H), 6.89 (d, J =7.8hz, 1h), 4.16 (s, 1H), 4.14-4.07 (m, 1H), 3.28-3.26 (m, 1H), 3.26-3.21 (m, 1H), 2.58-2.52 (m, 1H), 2.24-2.14 (m, 1H), 1.54 (d, J =10.0hz, 1h), 1.34-1.28 (m, 1H), 1.01-1.01H), 1.01-1.1H, 1.14 (m, 1H).
Example 69: (2- (3-methyl-1,2,4-Oxadiazol-5-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 70: (3-fluoro-2- (3-methyl-1,2,4-Oxadiazol-5-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 71: (4-fluoro-2- (3-methyl-1,2,4-Oxadiazol-5-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 72: (3- (5-fluoropyrimidin-2-yl) -5-methylpyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 73: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-2. 35% EtOH + (0.2% TEA) using Chiralpak AZ-H column (5 μm, 250X 4.6 mm): 65% of CO 2 Mobile phase, and 2mL/min flow, for 45 minutes (temperature =40 ℃), the enantiomeric purity of the title compound was confirmed by analytical SFC. Elution was monitored by absorbance at 220 nm. Enantiomeric purity 100%, which elutes as the main peak (R) t =10.8 minutes). MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 473.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.18 min (main optical isomer).
Example 74: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 77, intermediate A-40 was replaced with intermediate A-2. MS (ESI): c 23 H 19 F 4 N 5 O 2 The calculated mass of (a) is 473.2; measured value of m/z is 474.1[ 2], [ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.39 min (main optical isomer).
Example 75: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 76: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Tert-butyl octyl-2-carboxylate. To intermediate C-5B (196mg, 0.862mmol) dissolved in DMF (7 mL) was added NaH (69mg, 1.7mmol,60% dispersion in mineral oil). After 5 min, 2-chloro-5- (trifluoromethyl) pyridine (250mg, 1.38mmol) was then added, and the mixture was stirred at room temperature for 90 min. The reaction mixture was washed with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-50% EtOAc in hexane) afforded the title compound (250mg, 0.671mmol, 78%). C 18 H 23 F 3 N 2 O 3 Mass calculated MS (ESI) of 372.2; the measured value of m/z is 373.0[ m ] +H] + 。
And B: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (250mg, 0.671mmol) in EtOAc (8 mL) was added a 4M HCl in dioxane (0.84 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was then concentrated to obtain the title compound of step B, which was used without further purification. C 13 H 15 F 3 N 2 Calculated mass MS (ESI) for O is 272.1; measured value of m/z is 273.1[ m ] +H] + 。
And C: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (35 mg) and intermediate A-40 (75mg, 0.15mmol,42% purity) in DMF (1 mL) was added DIPEA (0.13mL, 0.77mmol) and HATU (54mg, 0.14mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and directly subjected to purification using Agilent preparative method X to obtain the title compound (28 mg). MS (ESI): c 22 H 21 F 3 N 6 O 2 The calculated mass of (a) is 458.2; measured value of m/z is 459.2[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.14 min (main optical isomer).
Example 77: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl)) Oxy) -2-azabicyclo [2.2.2]Tert-butyl octyl-2-carboxylate. To intermediate C-5B (52mg, 0.23mmol) dissolved in DMF (2 mL) was added NaH (18mg, 0.46mmol,60% dispersion in mineral oil). After 5 min, 2-chloro-5- (trifluoromethyl) pyrazine (45 μ L,0.37 mmol) was then added and the mixture was stirred at room temperature for 1h. The reaction mixture was saturated with NH 4 Cl solution quenched and with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, washing with MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-50% EtOAc in hexane) afforded the title compound (75mg, 0.20mmol, 88%). C 17 H 22 F 3 N 3 O 3 Mass calculated as 373.1 for MS (ESI); the measured value of m/z is 317.9[ m ] +2H-tBu] + 。
And B: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (75mg, 0.20 mmol) in EtOAc (3 mL) was added a 4M solution of HCl in dioxane (0.25 mL), and the reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed unreacted starting materials. An additional equivalent of 4M HCl in dioxane (0.25 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to obtain the title compound of step B (55 mg), which was used without further purification. C 12 H 14 F 3 N 3 Calculated mass MS (ESI) for O was 273.1; measured value of m/z is 274.1[ 2], [ M ] +H] + 。
And C: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [ 2.2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (27 mg) and intermediate A-40 (58mg, 0.12mmol) in DMF (1 mL) was added DIPEA (0.1mL, 0.59mmol) and HATU (41mg, 0.11mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with MeOH and the crude reaction mixture was directly subjected to purification using Agilent preparative method X to obtain the title compound (5.2 mg). MS (ESI): c 21 H 20 F 3 N 7 O 2 The calculated mass of (a) is 459.2; measured value of m/z is 460.2[ 2], [ M ] +H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.28-8.24(m,1H),8.15-8.11(m,1H),8.08-8.02(m,1H),7.83-7.79(s,2H),7.13-7.09(d,J＝8.3Hz,1H),5.03-4.94(m,1H),3.84-3.75(m,2H),3.68-3.58(m,1H),2.77-2.63(m,1H),2.29-2.24(s,3H),2.25-2.18(m,3H),1.93-1.81(m,1H),1.71-1.62(m,1H),1.50-1.43(m,1H)。
Example 78: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 79: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 80: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 83, intermediate A-40 was replaced with intermediate A-2. MS (ESI): c 23 H 20 F 4 N 6 Calculated mass of O is 472.2; measured value of m/z is 472.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.44 min (main optical isomer).
Example 81: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 82: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 83: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2]Tert-butyl octyl-2-carboxylate. To a microwave vial containing intermediate C-7B (193mg, 0.853 mmol) in MeCN (4 mL) was added 2-chloro-5- (trifluoromethyl) pyrazine (0.1mL, 0.82mmol) and Et 3 N (0.14mL, 1.02mmol), and the reaction mixture was sealed and heated to reflux on the bench overnight. After completion of the reaction, the crude reaction mixture was concentrated and directly subjected to silica gel chromatography (0-50% etoac in hexanes) to afford the title compound of step a (24msg, 0.658mmol, 77%). C 17 H 23 F 3 N 4 O 2 The mass calculation value of MS (ESI) is 372.2, and the measured value of m/z is 373.2[ M ] +H] + 。
And B: (1S,4R,6R) -N- (5- (trifluoromethyl) pyrazin-2-yl) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (2458 mg, 0.658mmol) in EtOAc (8 mL) was added a 4M HCl solution in dioxane (0.82 mL) and the mixture was stirredThe reaction mixture was stirred at room temperature overnight. The reaction was concentrated to obtain the title compound of step B (179 mg), which was used without further purification. C 12 H 15 F 3 N 4 The calculated mass MS (ESI) of (5) is 272.1; the measured value of m/z is 273.1[ m ] +H] + 。
And C: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [ 2.2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (35 mg) and intermediate A-40 (75mg, 0.15mmol,42% purity) in DMF (1.3 mL) was added DIPEA (0.13mL, 0.77mmol) and HATU (54mg, 0.14mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with MeOH and the crude reaction mixture was directly subjected to purification using Agilent preparative method X to obtain the title compound (26 mg). MS (ESI): c 21 H 21 F 3 N 8 Calculated mass of O is 458.2; the measured value of m/z is 459.2[ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =5.97 min (main optical isomer).
Example 84: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 85: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) - (6-) 2 H) - ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation is analogous to example 27, wherein NaBD is used 4 Instead of lithium L-tri-sec-butylborohydride, the reduction of intermediate B-5 was carried out. MS (ESI): c 23 H 17 DF 4 N 4 O 2 The calculated mass of (a) is 459.1; the measured value of m/z is 460.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.83, 0.17), the major optical isomers reported δ 8.91 (d, J =5.0hz, 2h), 8.19-8.13 (m, 1H), 7.96 (dd, J =8.7,2.6hz, 1h), 7.50 (t, J =5.0hz, 1h), 7.18-7.13 (m, 1H), 7.06-6.97 (m, 2H), 6.88 (dd, J =7.6,1.1hz, 1h), 4.33-4.23 (m, 1H), 3.27-3.24 (m, 2H), 2.59-2.53 (m, 1H), 2.30-2.21 (m, 1H), 1.54 (d, J =10.6hz, 1h), 1.37 (dd, J =13.5, 3.91, 6H), 1.01H, 1.01-1H).
Example 86: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]-(3- 2 H, 2 H) -hept-2-yl) methanone.
Preparation is analogous to example 27, using formaldehyde-d 2 Instead of formaldehyde, a Diels-Alder reaction of intermediate B-1 was carried out. MS (ESI): c 23 H 16 D 2 F 4 N 4 O 2 The calculated mass value of (a) is 460.1; the measured value of m/z is 461.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 87: (2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-39. MS (ESI): c 20 H 17 F 3 N 6 O 2 The calculated mass value of (A) is 430.1; the measured value of m/z is 431.2[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88, 0.12), reporting the major optical isomers) δ 8.43 (dd, J =4.8,1.8hz, 1h), 8.18-8.11 (m, 1H), 8.11-8.02 (m, 2H), 7.95 (dd, J =8.6,2.5hz, 1h), 7.71-7.55 (m, 1H), 7.12-6.90 (m, 2H), 5.08 (dt, J =10.1,3.2hz, 1h), 4.01 (s, 1H), 3.57 (dt, J =11.1,3.2hz, 1h), 3.35 (dd, J =11.1,1.7hz, 1h), 2.75-2.64 (m, 1H), 2.37-2.24 (m, 1H), 1.57 (d, 10.4h), 1.35H, 1.53-1.53H, 1.35H, 1.53H, 1.75-2.53 hz, 1H).
Example 88: (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-38. MS (ESI): c 21 H 19 F 3 N 6 O 2 The calculated mass of (a) is 444.2; the measured value of m/z is 445.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.90, 0.10), the major optical isomers reported are δ 8.26-8.21 (m, 1H), 8.19-8.14 (m, 1H), 8.05 (s, 2H), 7.98 (dd, J =8.7,2.6hz, 1h), 7.50-7.46 (m, 1H), 6.99 (d, J =8.8hz, 1h), 5.06 (dt, J =10.4,3.2hz, 1h), 4.05-3.97 (m, 1H), 3.54 (dt, J =11.0,3.2hz, 1h), 3.35 (dd, J =11.1,1.6hz, 1h), 2.68-2.62 (m, 1H), 2.32-2.19 (m, 1H), 2.08 (s, 3H), 1.56 (s, 1h), 1.47H, 1H, 47H, 1H).
Example 89: (2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-34. MS (ESI): c 23 H 18 F 4 N 4 O 2 The calculated mass value of (a) is 458.1; the measured value of m/z is 459.1[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.85: J =7.5,1.2hz, 1H), 5.11 (dt, J =10.2,3.3hz, 1H), 4.16-4.10 (m, 1H), 3.61 (dt, J =10.9,3.2hz, 1H), 3.35-3.33 (m, 1H), 2.74-2.65 (m, 1H), 2.36-2.26 (m, 1H), 1.59-1.53 (m, 1H), 1.46 (dt, J =13.4,3.7hz, 1H), 1.41-1.32 (m, 1H).
Example 90: (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-35. MS (ESI): c 23 H 17 F 5 N 4 O 2 The calculated mass of (a) is 476.1; the measured value of m/z is 477.1[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.81: J =7.6,0.9hz, 1h), 5.17 (dt, J =10.2,3.3hz, 1h), 4.31-4.21 (m, 1H), 3.35-3.32 (m, 1H), 3.27-3.23 (m, 1H), 2.63-2.59 (m, 1H), 2.32-2.25 (m, 1H), 1.65-1.56 (m, 1H), 1.39 (dt, J =13.6,3.6hz, 1h), 1.20-1.05 (m, 1H).
Example 91: (2- (5-fluoropyrimidin-2-yl) -3-methylphenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 25, intermediate A-20 was replaced with intermediate A-36. MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 473.1[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.81, 0.19), the major optical isomers reported δ 8.85 (d, J =0.8hz, 2h), 8.21-8.10 (m, 1H), 7.96 (dd, J =8.8,2.6hz, 1h), 7.25-7.18 (m, 1H), 7.08-6.96 (m, 1H), 6.96-6.79 (m, 2H), 5.17 (dt, J =10.2,3.3hz, 1h), 4.33-4.23 (m, 1H), 3.27-3.16 (m, 2H), 2.58 (s, 1H), 2.33-2.22 (m, 4H), 1.62-1.56 (m, 1H), 1.37 (dt, J =13.5,3.6hz, 1H), 1.21-1.21H (m, 1H).
Example 92: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-41. MS (ESI): c 23 H 20 F 3 N 5 O 2 The calculated mass of (a) is 455.2; the measured value of m/z is 456.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.90: 1H), 4.99 (dt, J =10.3,3.4hz, 1h), 4.32-4.25 (m, 1H), 3.66 (dt, J =10.9,3.2hz, 1h), 3.39 (dd, J =10.9,1.6hz, 1h), 2.71-2.66 (m, 1H), 2.33-2.24 (m, 1H), 2.19 (s, 3H), 1.62-1.54 (m, 1H), 1.49 (dt, J =13.4,3.7hz, 1h), 1.44-1.32 (m, 1H).
Example 93: (3-Phenylpyrazin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-43. MS (ESI): c 23 H 19 F 3 N 4 O 2 The calculated mass value of (A) is 440.1; the measured value of m/z is 441.2[ M + ] H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers, reported as major optical isomers) δ 8.52 (d, J =2.4hz, 1h), 8.04-8.01 (m, 1H), 7.93 (d, J =2.5hz, 1h), 7.89 (dd, J =8.8,2.7hz, 1h), 7.75-7.71 (m, 2H), 7.56-7.53 (m, 3H), 6.91-6.84 (m, 1H), 4.95 (dt, J =10.3,3.3hz, 1h), 4.11-3.99 (m, 1H), 3.38-3.34 (m, 2H), 2.57-2.52 (m, 1H), 2.27-2.12 (m, 1H), 1.45-1.35 (m, 2H), 0.68-0.59 (m, 1H).
Example 94: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((6- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (50mg, 0.23mmol) dissolved in DMF (1 mL) was added NaH (19mg, 0.47mmol,60% dispersion in mineral oil). After 5 min, the flask wall solution was washed with additional DMF (1 mL), then 2-fluoro-6- (trifluoromethyl) pyridine (0.045mL, 0.38mmol) was added and the mixture was stirred at room temperature overnight. The mixture was washed with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-40% EtOAc in hexane) afforded the title compound as a clear oil (29mg, 0.080mmol, 34%). C 17 H 21 F 3 N 2 O 3 Mass calculated as 358.2 for MS (ESI); measured value of m/z is 303.1[ 2M + [2 ] H-tBu] + 。
And B: (1S,4R,6R) -6- ((6- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (28mg, 0.078 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (0.1 mL). After 4h, the reaction was concentrated to give the title compound of step B as a pink solid (23 mg) and used without further purification. C 12 H 13 F 3 N 2 The calculated mass MS (ESI) value of O is 258.1; measured value of m/z is 259.1[ deg. ] M + H] + 。
Step C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (23 mg) and intermediate A-2 (25mg, 0.094 mmol) in DMF (1.1 mL) was added DIPEA (81. Mu.L, 0.47 mmol) and HATU (33mg, 0.086 mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (15 mg). MS (ESI): c 23 H 18 F 4 N 4 O 2 The calculated mass value of (a) is 458.1; the measured value of m/z is 459.1[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.84: 6.86 (dd, J =7.9,1.0hz, 1h), 5.12 (dt, J =10.2,3.3hz, 1h), 4.29-4.25 (m, 1H), 3.26 (t, J =3.0hz, 1h), 3.25 (s, 1H), 2.58 (s, 1H), 2.32-2.24 (m, 1H), 1.60 (d, J =10.1hz, 1h), 1.38 (dt, J =13.5,3.6hz, 1h), 1.11-1.05 (m, 1H).
Example 95: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((4- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((4- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (101mg, 0.47mmol) dissolved in DMF (3 mL) was added NaH (38mg, 0.95mmol,60% dispersion in mineral oil). After 5 min, the flask walls were washed with additional DMF (1.0 mL), then 2-chloro-4- (trifluoromethyl) pyridine (0.10mL, 0.76mmol) was added, and the mixture was heated to 70 ℃. After heating at 70 ℃ for 3h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-40% etoac in hexanes) afforded the title compound as a tan solid (1695g, 0.045mmol, 10%). C 17 H 21 F 3 N 2 O 3 Mass calculated as 358.2 for MS (ESI); the measured value of m/z is 359.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.34-8.23 (m, 1H), 7.12-7.04 (m, 1H), 7.01-6.92 (m, 1H), 5.35 (dt, J =10.1,3.2hz, 1H), 4.56-4.49 (m, 1H), 3.41 (dt, J =9.5,3.1hz, 1H), 3.27-3.17 (m, 1H), 2.60-2.55 (m, 1H), 2.28-2.16 (m, 1H), 1.80-1.71 (m, 1H), 1.68-1.62 (m, 1H), 1.53-0.93 (m, 10H).
And B: (1S,4R,6R) -6- ((4- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (1695g, 0.045mmol) in EtOAc (0.1 mL) was added a 4M solution of HCl in dioxane (0.1 mL). After 3h, the reaction was concentrated to give the title compound of step B (16 mg) and used without further purification. C 12 H 13 F 3 N 2 MS (ESI) mass calculated for O was 258.1; measured value of m/z is 259.2[ m ] +H] + 。
And C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((4- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To the title compound of step B (16 mg) and intermediate A-2 (13mg, 0.060mmol) of DTo a solution of MF (0.6 mL) were added DIPEA (56. Mu.L, 0.33 mmol) and HATU (23mg, 0.060mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation X to obtain the title compound (3.4 mg). MS (ESI): c 23 H 18 F 4 N 4 O 2 The calculated mass value of (a) is 458.1; the measured value of m/z is 459.1[ M ] +H ] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.80, 0.20), the major optical isomers reported δ 8.90 (d, J =5.0hz, 2h), 8.07 (d, J =5.3hz, 1h), 7.49 (t, J =5.0hz, 1h), 7.20-7.11 (m, 3H), 7.03-6.97 (m, 1H), 6.91-6.87 (m, 1H), 5.16 (dt, J =10.2,3.3hz, 1h), 4.28-4.23 (m, 1H), 3.28-3.24 (m, 2H), 2.61-2.54 (m, 1H), 2.32-2.20 (m, 1H), 1.56 (d, J =10.6hz, 1h), 1.38 (m, J =13.6, 3.1h), 1.96, 96H, 1.04-0H).
Example 96: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (101mg, 0.47mmol) dissolved in DMF (3 mL) was added NaH (38mg, 0.95mmol,60% dispersion in mineral oil). After 5 min, the flask walls were washed with additional DMF (1 mL), then 2-fluoro-3- (trifluoromethyl) pyridine (0.10 mL, 0.76mmol) was added and the mixture was heated to 70 ℃. After heating at 70 ℃ for 3h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with O. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated.Purification by silica gel chromatography (0-35% EtOAc in hexane) afforded the title compound as a white solid (87mg, 0.24mmol, 51%). C 17 H 21 F 3 N 2 O 3 Mass calculated as 358.2 for MS (ESI); the measured value of m/z is 303.1[ m ] +2H-tBu] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.35-8.25 (m, 1H), 7.90-7.82 (m, 1H), 6.96 (dd, J =7.5,5.0hz, 1h), 5.32 (dt, J =10.1,3.1hz, 1h), 4.64-4.58 (m, 1H), 3.42 (dt, J =9.5,3.1hz, 1h), 3.15 (d, J =9.5hz, 1h), 2.61-2.56 (m, 1H), 2.27-2.15 (m, 1H), 1.76-1.66 (m, 2H), 1.48 (dt, J =13.5,3.5hz, 1h), 1.08 (s, 9H).
And B: (1S,4R,6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (86mg, 0.24mmol) in EtOAc (0.9 mL) was added 4M HCl in dioxane (3 mL). After 2h, the reaction was concentrated to give the title compound of step B (77 mg) and used without further purification. C 12 H 13 F 3 N 2 MS (ESI) mass calculated for O was 258.1; measured value of m/z is 259.1[ 2 ], [ M ] +H] + 。
And C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1 ]Hept-2-yl) methanone. To a solution of the title compound of step B (28 mg) and intermediate A-2 (23mg, 0.11mmol) in DMF (1 mL) was added DIPEA (98. Mu.L, 0.57 mmol) and HATU (40mg, 0.11mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 The aqueous layer was quenched with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine, washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation X to obtain the title compound (5.4 mg). MS (ESI): c 23 H 18 F 4 N 4 O 2 The calculated mass value of (a) is 458.1; the measured value of m/z is 459.1[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.86.11(m,1H),7.08-7.04(m,1H),6.96-6.90(m,1H),6.77(dd,J＝7.6,1.1Hz,1H),5.20(dt,J＝10.2,3.3Hz,1H),4.32-4.28(m,1H),3.29-3.26(m,1H),3.25-3.20(m,1H),2.60-2.54(m,1H),2.29-2.21(m,1H),1.53(d,J＝10.4Hz,1H),1.40(dt,J＝13.6,3.6Hz,1H),0.95-0.89(m,1H)。
Example 97: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (70mg, 0.33mmol) and 2,3-difluoro-5- (trifluoromethyl) pyridine (90mg, 0.49mmol) in DMF (3 mL) was added NaH (18mg, 0.46mmol,60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature overnight after which analysis of the reaction mixture showed the majority of starting material. Additional 2,3-difluoro-5- (trifluoromethyl) pyridine (0.05 mL) was then added and the reaction mixture was heated to 70 ℃ and stirred overnight after which time the starting material was still shown to remain under the atmosphere of the reaction mixture. Additional 2,3-difluoro-5- (trifluoromethyl) pyridine (0.05 mL) was added again and the reaction mixture was heated at 70 ℃ for an additional 4.5 hours before additional 2,3-difluoro-5- (trifluoromethyl) pyridine (0.05 mL) was added and the reaction was stirred overnight. Analysis thereafter still showed incomplete conversion, however the reaction was cooled to room temperature and washed with H 2 And O quenching. The aqueous layer was extracted with EtOAc (3X), and the combined organics were washed with 5% LiCl aqueous solution, brine, na 2 SO 4 Dried, filtered and concentrated. Purify via silica gel chromatography (0-25% etoac in hexanes) to obtain the title compound. C 17 H 20 F 4 N 2 O 3 The calculated mass MS (ESI) of (1) is 376.1; the measured value of m/z is 321.1[ m ] +2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.678.18(m,1H),7.51(dd,J＝9.5,2.1Hz,1H),5.37(dt,J＝10.1,3.2Hz,1H),4.57-4.50(m,1H),3.41(dt,J＝9.5,3.1Hz,1H),3.22(dd,J＝9.5,1.4Hz,1H),2.62-2.57(m,1H),2.30-2.19(m,1H),1.77-1.73(m,1H),1.67-1.63(m,1H),1.48(dt,J＝13.7,3.6Hz,1H),1.12(s,9H)。
And B: (1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (130mg, 0.345mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (3 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to give the title compound of step B as a yellow oil (114 mg) and used without further purification. C 12 H 12 F 4 N 2 Calculated mass MS (ESI) for O is 276.1; measured value of m/z is 277.1[ 2 ], [ M ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (28.5 mg) and intermediate A-1 (19mg, 0.1mmol) in DMF (0.9 mL) were added DIPEA (0.13mL, 0.73mmol) and HATU (38mg, 0.1mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (18 mg). MS (ESI): c 21 H 17 F 4 N 5 O 2 The calculated mass of (a) is 447.1; the measured value of m/z is 448.2[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers (0.81.
Example 98: (1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 97, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 21 H 18 F 4 N 6 O 2 The calculated mass value of (a) is 462.1; the measured value of m/z is 463.1[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.79.
Example 99: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 97, intermediate A-1 was replaced with intermediate A-37. MS (ESI): c 23 H 18 F 4 N 4 O 2 The calculated mass value of (a) is 458.1; the measured value of m/z is 459.1[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.81.
Example 100: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 97, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 23 H 17 F 5 N 4 O 2 The calculated mass of (a) is 476.1; measured value of m/z is 477.2[ m + H ]] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.81: J =7.1,1.7hz, 1h), 7.13-7.03 (m, 2H), 5.10 (dt, J =10.0,3.3hz, 1h), 4.31-4.24 (m, 1H), 3.45-3.29 (m, 2H), 2.65-2.53 (m, 1H), 2.35-2.23 (m, 1H), 1.48 (d, J =9.9hz, 1h), 1.40 (dt, J =13.6,3.7hz, 1h), 1.18-0.99 (m, 1H).
Example 101: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (101mg, 0.47mmol) dissolved in DMF (3 mL) was added NaH (38mg, 0.95mmol,60% dispersion in mineral oil). After 5 minutes, the flask wall was washed with additional DMF (1.0 mL), then 2-chloro-5-methylpyridine (0.08mL, 0.76mmol) was added and the mixture was heated to 70 ℃. After heating at 70 ℃ for 3h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine, washing with Na 2 SO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-35% EtOAc in hexane) afforded the title compound (1695g, 0.053mmol, 11%) as a white solid. C 17 H 24 N 2 O 3 Mass calculated MS (ESI) of (1) of 304.2; the measured value of m/z is 305.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers reported) δ 7.97-7.89 (m, 1H), 7.37 (dd, J =8.4,2.5hz, 1h), 6.61 (d, J =8.5hz, 1h), 5.25 (dt, J =10.1,3.2hz, 1h), 4.56-4.48 (m, 1H), 3.38 (dt, J =9.5,3.1hz, 1h), 3.19 (d, J = 9.51h), 2.59-2.52 (m, 1H), 2.23 (s, 3H), 2.20-2.14 (m, 1H), 1.76-1.68 (m, 1H), 1.65-1.60 (m, 1H), 1.35 (dt, J =13.4, 1h), 1.6H (m, 1H), 1.35 (J =13.4, 1H).
And B: (1S,4R,6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (1695g, 0.053 mmol) in EtOAc (0.1 mL) was added 4M HCl in dioxane (0.1 mL). After 3h, the reaction was concentrated to give the title compound of step B (15 mg) and used without further purification. C 12 H 16 N 2 Calculated mass MS (ESI) for O was 204.1; the measured value of m/z is 205.2[ m ] +H] + 。
And C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (16 mg) and intermediate A-2 (1695g, 0.07mmol) in DMF (1 mL) was added DIPEA (69. Mu.L, 0.40 mmol) and HATU (28mg, 0.073mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (6 mg). MS (ESI): c 23 H 21 FN 4 O 2 The calculated mass value of (a) is 404.2; the measured value of m/z is 405.1[ mu ] M + H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.85, 0.15), the major optical isomers reported δ 8.89 (d, J =4.9hz, 2h), 7.69-7.65 (m, 1H), 7.52 (dd, J =8.4,2.5hz, 1h), 7.48 (t, J =4.9hz, 1h), 7.21-7.14 (m, 1H), 7.07-7.00 (m, 1H), 6.92 (dd, J =7.6,1.1hz, 1h), 6.74 (d, J =8.4hz, 1h), 5.02 (dt, J =10.1, 3.hz, 1.02 (dt, J =10.1, 3.1 hz, 1H), 1.89 (d, J = 4hz, 1h), 1.5.5.5 (d, J =10.1, 3.hz, 1H)H),4.25-4.19(m,1H),3.26-3.18(m,2H),2.57-2.53(m,1H),2.25(s,3H),2.24-2.19(m,1H),1.56-1.51(m,1H),1.34-1.28(m,1H),1.08-1.02(m,1H)。
Example 102: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- (pyridin-2-yloxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- (pyridin-2-yloxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (150mg, 0.70mmol) dissolved in DMF (5 mL) was added NaH (37mg, 0.91mmol,60% dispersion in mineral oil). After 5 min, the flask walls were washed with additional DMF (1 mL), then 2-fluoropyridine (0.10mL, 1.13mmol) was added, and the mixture was heated to 70 ℃. After heating at 70 ℃ for 7h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-30% etoac in hexanes) afforded the title compound as a colorless solid (73mg, 0.25mmol, 36%). C 16 H 22 N 2 O 3 Mass calculated MS (ESI) of 290.2; m/z found to be 291.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers reported) δ 8.11 (ddd, J =5.1,2.0,0.8hz, 1h), 7.59-7.50 (m, 1H), 6.89-6.80 (m, 1H), 6.70 (dt, J =8.4,0.9hz, 1h), 5.29 (dt, J =10.1,3.2hz, 1h), 4.61-4.49 (m, 1H), 3.39 (dt, J =9.5,3.1hz, 1h), 3.20 (dd, J =9.5,1.3hz, 1h), 2.59-2.50 (m, 1H), 2.26-2.15 (m, 1H), 1.76-1.69 (m, 1H), 1.67-1.63 (m, 1H), 1.38 (dt, J =13.3,3.6hz, 1h), 1.12 (s, 9H).
And B, step B: (1S,4R,6R) -6- (pyridin-2-yloxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (73mg, 0.25mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (4 mL) and the reaction was mixedThe mixture was stirred overnight. The reaction was then concentrated to obtain the title compound of step B (68 mg), and used without further purification. C 11 H 14 N 2 Calculated mass MS (ESI) for O was 190.1; measured value of m/z is 191.1[ m ] +H] + 。
Step C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- (pyridin-2-yloxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (23 mg) and intermediate A-1 (18mg, 0.094mmol) in DMF (1 mL) were added DIPEA (0.17mL, 0.99mmol) and HATU (36mg, 0.094mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (22 mg). MS (ESI): c 20 H 19 N 5 O 2 The calculated mass value of (A) is 361.2; the measured value of m/z is 362.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.90: J =7.6,1.2hz, 1h), 6.82-6.77 (m, 1H), 6.74 (d, J =8.3hz, 1h), 5.03 (dt, J =10.3,3.2hz, 1h), 4.06-3.97 (m, 1H), 3.60 (dt, J =10.9,3.3hz, 1h), 3.39 (dd, J =10.8,1.4hz, 1h), 2.68-2.56 (m, 1H), 2.27-2.13 (m, 1H), 1.48-1.31 (m, 3H).
Example 103: (6-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- (pyridin-2-yloxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 102, substituting intermediate A-1 with intermediate A-3. MS (ESI): c 20 H 20 N 6 O 2 The calculated mass of (a) is 376.2; measured value of m/z is 377.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.92.
Example 104: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- (pyridin-2-yloxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 102, substituting intermediate A-1 with intermediate A-2. MS (ESI): c 22 H 19 FN 4 O 2 Mass calculated value of 390.1; the measured value of m/z is 391.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.89, 0.11), reporting major optical isomers) δ 8.84 (d, J =4.9hz, 2h), 7.92-7.85 (m, 1H), 7.63-7.56 (m, 1H), 7.28-7.24 (m, 2H), 7.09-6.96 (m, 2H), 6.85-6.80 (m, 1H), 6.76 (dt, J =8.3,0.9hz, 1h), 5.10 (dt, J =10.0,3.3hz, 1h), 4.26-4.15 (m, 1H), 3.34-3.30 (m, 2H), 2.59-2.48 (m, 1H), 2.27-2.15 (m, 1H), 1.45 (d, J = 11.10H), 1.31H, 13.13H, 13H, 1H).
Example 105: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Preparation was analogous to example 47, substituting intermediate A-6 with intermediate A-3. MS (ESI): c 20 H 19 BrN 6 O 2 The calculated mass value of (a) is 454.1; measured value of m/z is 455.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound appearing as spin)A mixture of optical isomers (0.93: 0.07), reporting major optical isomers) δ 7.87 (s, 2H), 7.76 (d, J =2.6hz, 1h), 7.64 (dd, J =8.7,2.6hz, 1h), 7.29 (d, J =7.8hz, 1h), 6.69 (d, J =7.7hz, 1h), 6.62 (d, J =8.7hz, 1h), 4.83 (dt, J =10.3,3.3hz, 1h), 4.05-3.94 (m, 1H), 3.59 (dt, J =11.0,3.2hz, 1h), 3.38 (d, J = 11.11 hz, 1h), 2.66-2.56 (m, 4H), 2.23-2.10 (m, 1H), 1.44-1.33 (m, 2.33, 1.23, 1.32 (m, 1H).
Example 106: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation was analogous to example 47, intermediate A-6 was replaced with intermediate A-16. MS (ESI): c 20 H 17 BrFN 5 O 2 The calculated mass value of (a) is 457.1; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.90.
Example 107: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation was analogous to example 47, intermediate A-6 was replaced with intermediate A-12. MS (ESI): c 20 H 17 BrFN 5 O 2 The calculated mass value of (a) is 457.1; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers(0.89: 0.11), main optical isomers) δ 7.85 (d, J =2.6hz, 1h), 7.82 (s, 2H), 7.71-7.61 (m, 2H), 7.05 (dd, J =8.5,5.9hz, 1h), 6.68-6.58 (m, 2H), 4.91 (dt, J =10.1,3.3hz, 1h), 4.00 (s, 1H), 3.61 (dt, J =10.9,3.3hz, 1h), 3.38 (dd, J =10.9,1.4hz, 1h), 2.69-2.59 (m, 1H), 2.26-2.14 (m, 1H), 1.47-1.25 (m, 3H) are reported.
Example 108: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation was analogous to example 47, intermediate A-6 was replaced with intermediate A-10. MS (ESI): c 20 H 17 BrFN 5 O 2 The calculated mass value of (a) is 457.1; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.91.
Example 109: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation was analogous to example 47, intermediate A-6 was replaced with intermediate A-11. MS (ESI): c 20 H 17 BrFN 5 O 2 The calculated mass value of (a) is 457.1; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88 5(dt,J＝8.2,1.0Hz,1H),7.63(dd,J＝8.8,2.5Hz,1H),7.39-7.31(m,1H),6.76-6.66(m,2H),4.85(dt,J＝10.1,3.4Hz,1H),4.01-3.92(m,1H),3.62(dt,J＝10.9,3.2Hz,1H),3.42(dd,J＝10.9,1.5Hz,1H),2.64-2.58(m,1H),2.24-2.14(m,1H),1.42-1.31(m,2H),1.30-1.17(m,1H)。
Example 110: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 47, intermediate a-6 was replaced with intermediate a-23. MS (ESI): c 22 H 18 BrFN 4 O 2 The calculated mass of (a) is 468.1; measured value of m/z is 469.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compounds presented as a mixture of optical isomers (0.88: 7.04 (dd, J =8.4,5.6hz, 1h), 6.70-6.64 (m, 2H), 4.93 (dt, J =10.1,3.3hz, 1h), 4.09-4.04 (m, 1H), 3.63 (dt, J =10.9,3.1hz, 1h), 3.43-3.34 (m, 1H), 2.66-2.59 (m, 1H), 2.26-2.15 (m, 1H), 1.46-1.33 (m, 2H), 1.31-1.23 (m, 1H).
Example 111: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 47, substituting intermediate a-6 with intermediate a-7. MS (ESI): c 22 H 18 BrFN 4 O 2 The calculated mass of (a) is 468.1; measured value of m/z is 469.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.90. 83(dd,J＝2.6,0.7Hz,1H),7.68(dd,J＝8.8,2.6Hz,1H),7.18(t,J＝4.9Hz,1H),7.08-7.02(m,1H),6.81(dd,J＝8.6,2.7Hz,1H),6.68(d,J＝8.8Hz,1H),4.93(dt,J＝10.0,3.3Hz,1H),4.14-4.06(m,1H),3.64(dt,J＝10.9,3.2Hz,1H),3.40(dd,J＝10.7,1.5Hz,1H),2.69-2.61(m,1H),2.30-2.15(m,1H),1.47-1.35(m,2H),1.34-1.24(m,1H)。
Example 112: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (150mg, 0.70mmol) dissolved in DMF (5 mL) was added NaH (37mg, 0.91mmol,60% dispersion in mineral oil). After 5 min, the flask walls were washed with additional DMF (1 mL), then 5-chloro-2-fluoropyridine (0.11mL, 1.13mmol) was added and the mixture was heated to 70 ℃. After heating at 70 ℃ for 7h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine, washing with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-25% EtOAc in hexane) afforded the title compound (149mg, 0.46mmol, 65%) as a colorless solid. C 16 H 21 ClN 2 O 3 Mass calculation of (ESI) of (2) is 324.1; the measured value of m/z is 325.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compounds presented as mixtures of optical isomers, only the major optical isomers reported) δ 8.06 (d, J =2.6hz, 1h), 7.51 (dd, J =8.8,2.7hz, 1h), 6.66 (d, J =8.7hz, 1h), 5.22 (dt, J =10.1,3.2hz, 1h), 4.52-4.49 (m, 1H), 3.38 (dt, J =9.6,3.1hz, 1h), 3.18 (dd, J =9.5,1.3hz, 1h), 2.58-2.54 (m, 1H), 2.23-2.12 (m, 1H), 1.75-1.68 (m, 1H), 1.64-1.59 (m, 1H), 1.36 (J =13.4, 3.4, 1H), 1.6, 6H, 1H), 1.36 (J =13, 13.4, 1H, 6H, 15H).
And B: (1S,4R,6R) -6- ((5-chloropyridine-2)-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (149mg, 0.46mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 3h. The reaction was then concentrated to give the title compound of step B as a colorless solid (129 mg) and used without further purification. C 11 H 13 ClN 2 Calculated mass MS (ESI) for O was 224.1; the measured value of m/z is 225.1[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (32 mg) and intermediate A-1 (25mg, 0.14mmol) in DMF (1 mL) was added DIPEA (0.25mL, 1.5mmol) and HATU (51mg, 0.135mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (34 mg). MS (ESI): c 20 H 18 ClN 5 O 2 The calculated mass of (a) is 395.1; measured value of m/z is 396.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.89, 0.11), reported as the major optical isomer) δ 7.85 (dd, J =8.2,1.1hz, 1h), 7.81 (s, 2H), 7.67 (d, J =2.6hz, 1h), 7.53 (dd, J =8.8,2.7hz, 1h), 7.40-7.34 (m, 1H), 7.07 (dd, J =7.6,1.5hz, 1h), 6.91 (td, J =7.5,1.2hz, 1h), 6.69 (d, J =8.8hz, 1h), 4.90 (dt, J =10.1,3.3hz, 1h), 4.07-3.97 (m, 1H), 3.59 (dt, J =10.9,3.2hz, 1h), 3.38 (dd, J =10.8,1.4hz, 1h), 2.65-2.56 (m, 1H), 2.26-2.12 (m, 1H), 1.42-1.34 (m, 2H), 1.31-1.23 (m, 1H).
Example 113: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation analogous to example 112, intermediate A-1 was converted to intermediate A-10 substitutions. MS (ESI): c 20 H 17 ClFN 5 O 2 The calculated mass value of (b) is 413.1; the measured value of m/z is 414.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.92: 6.70 (d, J =8.7hz, 1H), 4.91 (dt, J =10.1,3.4hz, 1H), 4.11-3.98 (m, 1H), 3.56 (dt, J =10.9,3.2hz, 1H), 3.37 (dd, J =10.9,1.5hz, 1H), 2.68-2.56 (m, 1H), 2.26-2.13 (m, 1H), 1.47-1.32 (m, 2H), 1.32-1.22 (m, 1H).
Example 114: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 112, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 20 H 19 ClN 6 O 2 The calculated mass value of (a) is 410.1; measured value of m/z is 411.1[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 115: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 112, substituting intermediate A-1 with intermediate A-2. MS (ESI): c 22 H 18 ClFN 4 O 2 Calculated mass of 424.1; measured value of m/z is 425.1[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.84: 1H), 6.95-6.81 (m, 2H), 5.02 (dt, J =10.1,3.3hz, 1h), 4.29-4.20 (m, 1H), 3.28-3.17 (m, 2H), 2.59-2.50 (m, 1H), 2.29-2.17 (m, 1H), 1.52 (d, J =10.6hz, 1h), 1.33 (dt, J =13.5,3.6hz, 1h), 1.04-0.89 (m, 1H).
Example 116: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 112, substituting intermediate A-1 with intermediate A-34. MS (ESI): c 22 H 18 ClFN 4 O 2 Calculated mass of 424.1; the measured value of m/z is 425.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88, 0.12), the major optical isomers reported are δ 8.81 (d, J =0.6hz, 2h), 8.21-8.15 (m, 1H), 7.73-7.67 (m, 2H), 7.44-7.39 (m, 1H), 7.02-6.99 (m, 2H), 6.85 (d, J =8.7hz, 1h), 5.00 (dt, J =10.2,3.3hz, 1h), 4.13-4.06 (m, 1H), 3.60 (dt, J =11.0,3.2hz, 1h), 3.34-3.32 (m, 1H), 2.71-2.64 (m, 1H), 2.31-2.22 (m, 1H), 1.58-1.50 (m, 1H), 1.41 (dt, 3.13, 1H), 1.38 (m, 1H), 1H).
Example 117: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 112, substituting intermediate A-1 with intermediate A-35. MS (ESI): c 22 H 17 ClF 2 N 4 O 2 The calculated mass of (A) is 442.1; the measured value of m/z is 443.1[ deg. ] M + H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.82: J =7.6,1.4hz, 1H), 6.87 (dd, J =8.8,0.7hz, 1H), 5.06 (dt, J =10.1,3.3hz, 1H), 4.26-4.20 (m, 1H), 3.26-3.20 (m, 1H), 2.61-2.57 (m, 1H), 2.31-2.22 (m, 1H), 1.61-1.55 (m, 1H), 1.35 (dt, J =13.5,3.6hz, 1H), 1.17-1.09 (m, 1H). 1H is buried under the solvent peak.
Example 118: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-fluoropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-fluoropyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (200mg, 0.94mmol) dissolved in DMF (3 mL) was added NaH (41mg, 1.03mmol,60% dispersion in mineral oil). After 5 minutes, the flask walls were washed with additional DMF (1 mL), 2,5-difluoropyridine (0.11mL, 1.22mmol) was then added, and the mixture was heated to 60 ℃. After heating at 60 ℃ for 3h, the mixture was cooled to room temperature and quenched with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-30% EtOAc in hexane) afforded the title compound as a colorless solid (193mg, 0.63mmol, 67%). C 16 H 21 FN 2 O 3 The calculated mass MS (ESI) of (1) is 308.2; the measured value of m/z is 309.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, only the major optical isomer reported) delta 7.95 (d, J =3.1Hz, 1H), 7.37-7.30 (m, 1H), 6.67 (dd),J＝9.0,3.6Hz,1H),5.21(dt,J＝10.2,3.2Hz,1H),4.53-4.50(m,1H),3.39(dt,J＝9.6,3.1Hz,1H),3.19(dd,J＝9.5,1.4Hz,1H),2.58-2.53(m,1H),2.24-2.12(m,1H),1.77-1.69(m,1H),1.64-1.59(m,1H),1.36(dt,J＝13.4,3.6Hz,1H),1.15(s,9H)。
And B: (1S,4R,6R) -6- ((5-fluoropyridin-2-yl) oxy) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (193mg, 0.63mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 2h. The reaction was concentrated to give the title compound of step B as an off-white solid (182 mg) and used without further purification. C 11 H 13 FN 2 MS (ESI) mass calculated for O is 208.1; the measured value of m/z is 209.1[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-fluoropyridin-2-yl) oxy) -2-azabicyclo [2.2.1 ]Hept-2-yl) methanone. To a solution of the title compound of step B (32 mg) and intermediate A-1 (27mg, 0.13mmol) in DMF (1 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (48mg, 0.13mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (31 mg). MS (ESI): c 20 H 18 FN 5 O 2 The calculated mass of (a) is 379.1; the measured value of m/z is 380.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88, 0.12), reporting the major optical isomers) δ 7.85 (dd, J =8.2,1.1hz, 1h), 7.81 (s, 2H), 7.60 (d, J =3.1hz, 1h), 7.39-7.31 (m, 2H), 7.12 (dd, J =7.7,1.5hz, 1h), 6.92 (td, J =7.6,1.2hz, 1h), 6.70 (dd, J =9.0,3.6hz, 1h), 4.91 (dt, J =10.1,3.3hz, 1h), 4.04-3.95 (m, 1H), 3.59 (dt, J =10.9,3.2hz, 1h), 3.38 (dd, 11.0, 4h), 2.65, 2.58, 2H, 1.58-1H), 2.20H, 1m, 1H, 2H, 13.60 (dd, 13-20H, 13.1H).
Example 119: ((1S,4R,6R) -6- ((5-fluoropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation was analogous to example 118, substituting intermediate A-1 with intermediate A-40. MS (ESI): c 20 H 19 FN 6 O 2 Calculated mass of (a) is 394.2; the measured value of m/z is 395.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88, 0.12), reports the major optical isomers) δ 8.03 (d, J =8.4hz, 1H), 7.82 (s, 2H), 7.53 (d, J =3.1hz, 1H), 7.29-7.22 (m, 1H), 7.13 (d, J =8.4hz, 1H), 6.71 (dd, J =9.0,3.7hz, 1H), 4.84 (dt, J =10.3, 3.21h), 4.19-4.15 (m, 1H), 3.65 (dt, J =11.0,3.2hz, 1H), 3.44 (J, J =10.8,1.4hz, 1H), 2.63-2.58 (m, 1H), 2.30 (s, 3H), 2.23-2.23, 1H, 13.47 (m, 3H), 1H, 33H).
Example 120: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-fluoropyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 118, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 18 F 2 N 4 O 2 The calculated mass value of (A) is 408.1; the measured value of m/z is 409.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.89: 2H), 6.72 (dd, J =9.0,3.6hz, 1h), 4.98 (dt, J =10.0,3.3hz, 1h), 4.26-4.15 (m, 1H), 3.35-3.26 (m, 2H), 2.60-2.48 (m, 1H), 2.25-2.14 (m, 1H), 1.42 (d, J =10.3hz, 1h), 1.30 (dt, J =13.4,3.5hz, 1h), 1.00-0.92 (m, 1H).
Example 121: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (200mg, 0.94mmol) dissolved in DMF (3 mL) was added NaH (41mg, 1.03mmol,60% dispersion in mineral oil). After 5 minutes, the flask walls were washed with additional DMF (1.0 mL), then 2-chloro-5- (difluoromethyl) pyridine (0.15ml, 1.22mmol) was added and the mixture was heated to 60 ℃. After heating at 60 ℃ for 3h, the mixture was cooled to room temperature and saturated NH was added 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine, washing with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-20% EtOAc in hexane) afforded the title compound as a colorless solid (76mg, 0.22mmol, 24%). C 17 H 22 F 2 N 2 O 3 The calculated mass MS (ESI) of (1) was 340.2; the measured value of m/z is 341.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, only the major optical isomers) δ 8.27-8.23 (m, 1H), 7.72 (dd, J =8.7,2.5hz, 1h), 6.83-6.46 (m, 2H), 5.32 (dt, J =10.1,3.2hz, 1h), 4.57-4.52 (m, 1H), 3.40 (dt, J =9.6,3.1hz, 1h), 3.20 (dd, J =9.5,1.3hz, 1h), 2.61-2.55 (m, 1H), 2.26-2.15 (m, 1H), 1.77-1.71 (m, 1H), 1.67-1.60 (m, 1H), 1.40 (dd, J =13.5,3.8h, 1H), 1.12H (9, 12 hz).
And B: (1S,4R,6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (76mg, 0.22mmol) in EtOAc (4 mL) was added 4M HCl in dioxane (1 mL) and the reaction mixture was stirred at room temperature for 2h. The reaction was concentrated to give the title compound of step B as an off-white solid (74 mg) and used without further purification. C 12 H 14 F 2 N 2 Calculated mass MS (ESI) for O was 240.1; the measured value of m/z is 241.1[ mu ] M + H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (24 mg) and intermediate A-1 (20mg, 0.095mmol) in DMF (1 mL) were added DIPEA (0.1mL, 0.58mmol) and HATU (36mg, 0.095mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine, washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparative method X to obtain the title compound (29 mg). MS (ESI): c 21 H 19 F 2 N 5 O 2 The calculated mass of (a) is 411.2; the measured value of m/z is 412.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.89, 0.11), reporting major optical isomers) δ 7.88-7.85 (m, 1H), 7.83 (dd, J =8.3,1.1hz, 1H), 7.81 (s, 2H), 7.77-7.70 (m, 1H), 7.34-7.28 (m, 1H), 7.05 (dd, J =7.6,1.5hz, 1H), 6.85-6.79 (m, 2H), 6.60 (t, J =56.0hz, 1H), 5.00 (dt, J =10.2,3.3hz, 1H), 4.09-3.99 (m, 1H), 3.60 (dt, J =11.0, 3.2hj, 1H), 3.40 (dd, J =10.9, 1.56, 1H), 4.09-3.99 (m, 1H), 3.60 (dt, J =11.0,3.2H, 1H), 13.25H, 1H, 13.25H, 13.28 (m, 2H).
Example 122: ((1S, 4R, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 121, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 21 H 20 F 2 N 6 O 2 The calculated mass value of 426.2; the measured value of m/z is 427.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.86,2.4Hz,1H),7.06(d,J＝8.4Hz,1H),6.81(d,J＝8.6Hz,1H),6.57(t,J＝56.0Hz,1H),4.95(dt,J＝10.4,3.3Hz,1H),4.25-4.17(m,1H),3.67(dt,J＝11.0,3.2Hz,1H),3.46(dd,J＝11.0,1.4Hz,1H),2.68-2.61(m,1H),2.27-2.16(m,4H),1.50-1.40(m,3H)。
example 123: ((1S, 4R, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 121, replacing intermediate a-1 with intermediate a-2. MS (ESI): c 23 H 19 F 3 N 4 O 2 The calculated mass value of (A) is 440.1; measured value of m/z is 441.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88.
Example 124: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (125mg, 0.59mmol) dissolved in DMF (5 mL) was added NaH (47mg, 1.17mmol,60% dispersion in mineral oil). After 5 min, the flask-wall solution was washed with additional DMF (1 mL), then 2-chloro-5- (trifluoromethyl) pyrazine (0.12mL, 0.94mmol) was added and the reaction mixture was washed with water Stir at room temperature overnight. Then, the mixture was saturated with NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-40% EtOAc in hexane) afforded the title compound as a colorless solid (89mg, 0.25mmol, 42%). C 16 H 20 F 3 N 3 O 3 Mass calculated as 359.2 for MS (ESI); the measured value of m/z is 304.0[ M ] +2H-tBu] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ8.60(s,1H),8.35-8.26(m,1H),5.49-5.39(m,1H),4.59-4.53(m,1H),3.39(dt,J＝9.6,3.2Hz,1H),3.15(d,J＝9.5Hz,1H),2.67-2.62(m,1H),2.37-2.22(m,1H),1.80-1.73(m,3H),1.08(s,9H)。
And B: (1S,4R,6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (89mg, 0.25mmol) in EtOAc (3 mL) was added a 4M solution of HCl in dioxane (0.3 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to give the title compound of step B as a yellow oil (80 mg) and used without further purification. C 11 H 12 F 3 N 3 MS (ESI) mass calculated for O is 259.1; the measured value of m/z is 260.1[ m ] +H] + 。
And C: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (24 mg) and intermediate A-10 (20mg, 0.097mmol) in DMF (1 mL) were added DIPEA (84. Mu.L, 0.49 mmol) and HATU (34mg, 0.089mmol), and the reaction mixture was stirred at room temperature overnight. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Gilson preparation method X to obtain the title compound (17 mg). MS (ESI): c 20 H 16 F 4 N 6 O 2 The calculated mass of (a) is 448.1; the measured value of m/z is 449.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.83, 0.17), the main optical isomers reported are δ 8.40 (s, 1H), 8.23 (s, 1H), 7.96 (s, 2H), 7.90 (dd, J =9.0,4.7hz, 1h), 7.22-7.14 (m, 1H), 6.87 (d, J =8.1hz, 1h), 5.10 (dt, J =10.2,3.3hz, 1h), 4.02 (s, 1H), 3.52 (dt, J =10.9,3.3hz, 1h), 3.35 (dd, J =11.1,1.6hz, 1h), 2.71-2.63 (m, 1H), 2.35-2.24 (m, 1H), 1.59-1.51 (m, 1H), 1.49 (J =13.5, 1H), 1.46H, 1H).
Example 125: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 124, substituting intermediate A-10 with intermediate A-40. MS (ESI): c 20 H 18 F 3 N 7 O 2 The calculated mass value of (a) is 445.1; measured value of m/z is 446.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.90.
Example 126: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 124, substituting intermediate a-10 with intermediate a-2. MS (ESI): c 22 H 17 F 4 N 5 O 2 The calculated mass of (a) is 459.1; measured value of m/z is 460.1[ 2 ], [ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.76: 0.24), the major optical isomers reported δ 8.91 (d, J =5.0hz, 2h), 8.42 (d, J =1.3hz, 1h), 8.26-8.23 (m, 1H), 7.50 (t, J =5.0hz, 1h), 7.21-7.15 (m, 1H), 7.07-7.00 (m, 1H), 6.95 (dd, J =7.6,1.2hz, 1h), 5.14 (dt, J =10.2,3.3hz, 1h), 4.33-4.24 (m, 1H), 3.29-3.27 (m, 2H), 2.63-2.56 (m, 1H), 2.34-2.25 (m, 1H), 1.56 (d, J =11.1hz, 1h), 1.44 (dt, J =13.7,3.6hz, 1h), 1.05-0.91 (m, 1H).
Example 127: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 124, intermediate A-10 was replaced with intermediate A-23. MS (ESI): c 22 H 17 F 4 N 5 O 2 The calculated mass of (a) is 459.1; the measured value of m/z is 460.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.80, 0.20), the main optical isomer was reported as δ 8.88 (d, J =4.9hz, 2h), 8.40 (s, 1H), 8.20 (s, 1H), 7.92 (dd, J =10.1,2.7hz, 1h), 7.46-7.41 (m, 1H), 7.08 (dd, J =8.4,5.5hz, 1h), 6.66 (td, J =8.2,2.7hz, 1H), 5.09 (dt, J =10.2,3.3hz, 1H), 4.11 (s, 1H), 3.60 (dt, J =11.0,3.2hz, 1H), 3.36 (dd, J =11.0,1.6hz, 1H), 2.74-2.65 (m, 1H), 2.35-2.27 (m, 1H), 1.56-1.47 (m, 2H), 1.35-1.27 (m, 1H).
Example 128: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 124, intermediate A-10 was replaced with intermediate A-7. MS (ESI): c 22 H 17 F 4 N 5 O 2 The calculated mass of (a) is 459.1; the measured value of m/z is 460.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.85, 0.15), the major optical isomers reported δ 8.85 (d, J =4.9hz, 2h), 8.40 (s, 1H), 8.26 (dd, J =8.8,5.5hz, 1h), 8.22 (s, 1H), 7.39 (t, J =4.9hz, 1h), 7.15-7.09 (m, 1H), 6.78 (dd, J =8.6,2.7hz, 1H), 5.11 (dt, J =10.2,3.4hz, 1H), 4.14 (s, 1H), 3.61 (dt, J =11.0,3.2hz, 1H), 3.36 (dd, J =10.9,1.6hz, 1H), 2.74-2.66 (m, 1H), 2.36-2.26 (m, 1H), 1.58-1.54 (m, 1H), 1.52 (dt, J =13.6,3.6, 1H), 1.40-1.33 (m, 1H).
Example 129: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 124, intermediate A-10 was replaced with intermediate A-6. MS (ESI): c 22 H 17 F 4 N 5 O 2 The calculated mass of (a) is 459.1; the measured value of m/z is 460.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.74-0.26), the major optical isomers are reported as δ 8.88 (d, J =4.9hz, 2h), 8.35-8.33 (m, 1H), 8.17-8.12 (m, 2H), 7.43 (t, J =4.9hz, 1h), 7.41-7.35 (m, 1H), 6.70-6.64 (m, 1H), 5.07 (dt, J =10.2,3.4hz, 1h), 4.13-4.10 (m, 1H), 3.64 (dt, J =11.0,3.2hz, 1h), 3.39 (dd, J =11.0,1.6hz, 1h), 2.72-2.68 (m, 1H), 2.36-2.27 (m, 1H), 1.87-1.83 (m, 1H), 1.53-1.53 (m, 1H), 1H, 1 m, 1H), 1H (m, 1H).
Example 130: (2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 124, intermediateA-10 is replaced by intermediate A-37. MS (ESI): c 22 H 18 F 3 N 5 O 2 The calculated mass value of (a) is 441.1; the measured value of m/z is 442.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.85, 0.15), reported as the major optical isomers) δ 8.86 (d, J =4.9hz, 2h), 8.38 (s, 1H), 8.16 (dd, J =8.0,1.2hz, 1h), 8.11 (s, 1H), 7.44-7.33 (m, 2H), 7.01 (dd, J =7.7,1.4hz, 1h), 6.91 (t, J =7.5,1.3hz, 1h), 5.08 (dt, J =10.2,3.3hz, 1h), 4.12 (s, 1H), 3.58 (dt, J =10.9,3.2hz, 1h), 3.37 (dd, J =10.9,1.6hz, 1h), 2.73-2.66 (m, 1H), 2.35-2.22 (m, 1H), 1.56-1.48 (m, 2H), 1.28-1.21 (m, 1H).
Example 131: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (106mg, 0.497mmol) and 2-chloro-5-methylpyrimidine (93mg, 0.72mmol) dissolved in DMF (2 mL) was added NaH (40mg, 0.99mmol,60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature for 2h. Then the mixture is taken up with H 2 Quench O, dilute with EtOAc, and extract the aqueous layer with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine, washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed by silica gel chromatography (0-60% EtOAc in hexane) to obtain the title compound (129mg, 0.422mmol, 85%) as a colorless solid. C 16 H 23 N 3 O 3 Mass calculated MS (ESI) of 305.2; measured value of m/z is 306.2[ 2 ], [ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers (0.68,2.21(s,3H),2.17-2.11(m,1H),1.69-1.67(m,1H),1.63-1.59(m,1H),1.54-1.47(m,1H),1.07(s,9H)。
And B: (1S,4R,6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (129mg, 0.422mmol) in EtOAc (2 mL) was added a 4M solution of HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 1h. The reaction was concentrated to give the title compound of step B as a colorless solid (147 mg) and used without further purification. C 11 H 15 N 3 Calculated mass MS (ESI) for O was 205.1; measured value of m/z is 206.1[ 2 ], [ M ] +H ] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (34 mg) and intermediate A-1 (29mg, 0.16mmol) in DMF (0.8 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (59mg, 0.16mmol), and the reaction mixture was stirred at room temperature for 6h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (20 mg). MS (ESI): c 20 H 20 N 6 O 2 The calculated mass of (a) is 376.2; measured value of m/z is 377.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.78.
Example 132: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 131, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 20 H 21 N 7 O 2 The calculated mass value of (A) is 391.2; measured value of m/z is 392.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.74.
Example 133: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 131, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 20 FN 5 O 2 Mass calculated value of (a) is 405.2; the measured value of m/z is 406.1[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.75. 1H is buried under the water peak.
Example 134: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 131, intermediate A-1 was replaced with intermediate A-47. MS (ESI): c 22 H 22 N 6 O 2 Mass calculated value of (2) is 402.2; the measured value of m/z is 403.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.60. 1H is embedded in the solvent.
Example 135: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (120mg, 0.5631 mmol) and 2-chloro-5-ethylpyrimidine (128mg, 0.9mmol) in DMF (4 mL) was added NaH (29mg, 0.73mmol,60% dispersion in mineral oil), and the mixture was stirred at room temperature for 1h. Subjecting the reaction mixture to hydrogenation with H 2 Quench O, dilute with EtOAc, and extract the aqueous layer with EtOAc (3 ×). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed by silica gel chromatography (0-50% etoac in hexanes) to give the title compound as a colorless solid (160mg, 0.501mmol, 89%). C 17 H 25 N 3 O 3 Mass calculated as 319.2 for MS (ESI); the measured value of m/z is 320.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers, only the major optical isomer being reported) delta 8.34 (s, 2H),5.21(dt,J＝10.3,3.4Hz,1H),4.60-4.55(m,1H),3.40(dt,J＝9.5,3.1Hz,1H),3.23(dd,J＝9.5,1.4Hz,1H),2.61-2.55(m,3H),2.22-2.15(m,1H),1.75-1.69(m,1H),1.65-1.62(m,1H),1.55(dt,J＝13.5,3.8Hz,1H),1.25-1.22(m,3H),1.09(s,9H)。
And B: (1S,4R,6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (160mg, 0.501mmol) in EtOAc (1.5 mL) was added 4M HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 1h. The reaction was then concentrated to give the title compound of step B as a colorless solid (148 mg), and used without further purification. C 12 H 17 N 3 MS (ESI) mass calculation of O was 219.1; measured value of m/z is 220.1[ m ] +H] + 。
Step C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1 ]Hept-2-yl) methanone. To a solution of the title compound of step B (37 mg) and intermediate A-1 (30mg, 0.16mmol) in DMF (1 mL) was added DIPEA (0.1mL, 0.6mmol) and HATU (61mg, 0.16mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 The aqueous layer was quenched with EtOAc (3 ×). The combined organics were concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (33 mg). MS (ESI): c 21 H 22 N 6 O 2 Mass calculated value of 390.2; the measured value of m/z is 391.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.81.
Example 136: ((1S, 4R, 6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 135, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 21 H 23 N 7 O 2 Mass calculated value of (a) is 405.2; the measured value of m/z is 406.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.69.
Example 137: ((1S, 4R, 6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 135, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 23 H 22 FN 5 O 2 Calculated mass of 419.2; the measured value of m/z is 420.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.78. 1H is embedded in the solvent.
Example 138: ((1S, 4R, 6R) -6- ((5-ethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 135, intermediate A-1 was replaced with intermediate A-41. MS (ESI): c 23 H 24 N 6 O 2 Mass calculated of 416.2; the measured value of m/z is 417.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.63.
Example 139: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1]Hepta-2-carboxylic acid tert-butyl ester. To intermediate B-5 (106mg, 0.457 mmol) and 3-chloro-6- (trifluoromethyl) pyridazine (120mg, 0.66mmol) dissolved in DMF (2 mL) was added NaH (40mg, 0.99mmol,60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature for 2h. The mixture was then saturated with NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, brine and washed with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed via silica gel chromatography (0-50% etoac in hexanes) to give the title compound as an off-white solid (189 mg). C 16 H 20 F 3 N 3 O 3 Mass calculated as 359.2 for MS (ESI); the measured value of m/z is 304.1[ m ] +2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d, compound No.)Now, as a mixture of optical isomers (0.74, 0.26), the main optical isomers are reported to be δ 7.70 (d, J =9.2hz, 1h), 7.07 (d, J =9.2hz, 1h), 5.59 (dt, J =10.1,3.1hz, 1h), 4.76-4.67 (m, 1H), 3.43 (dt, J =9.6,3.1hz, 1h), 3.23-3.17 (m, 1H), 2.64-2.60 (m, 1H), 2.34-2.26 (m, 1H), 1.81-1.76 (m, 1H), 1.68-1.65 (m, 1H), 1.50-1.45 (m, 1H), 1.10 (s, 9H).
And B: (1S,4R,6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (189mg, 0.53mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 6h. The reaction was concentrated to give the title compound of step B as an off-white solid (146 mg) and used without further purification. C 11 H 12 F 3 N 3 Calculated mass MS (ESI) for O is 259.1; the measured value of m/z is 260.1[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (34 mg) and intermediate A-1 (24mg, 0.126mmol) in DMF (0.5 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (48mg, 0.126mmol) and the reaction mixture was stirred at room temperature for 1h. Analysis of the reaction mixture showed unreacted starting material and additional intermediate a-1 (10 mg) was added. The reaction mixture was stirred at room temperature for a further 15 minutes. The reaction was then quenched by addition of H 2 O quenched and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were concentrated and directly subjected to purification using Agilent preparative method X to give the title compound (33 mg). MS (ESI): c 20 H 17 F 3 N 6 O 2 The calculated mass value of (A) is 430.1; the measured value of m/z is 431.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.08 min (main optical isomer).
Example 140: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 139, substituting intermediate A-1 with intermediate A-40. MS (ESI): c 20 H 18 F 3 N 7 O 2 The calculated mass value of (a) is 445.1; measured value of m/z is 446.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.82.
Example 141: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 139, substituting intermediate A-1 with intermediate A-2. MS (ESI): c 22 H 17 F 4 N 5 O 2 The calculated mass of (a) is 459.1; measured value of m/z is 460.1[ 2 ], [ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.78.
Example 142: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 139, intermediate A-1 was replaced with intermediate A-41. MS (ESI): c 22 H 19 F 3 N 6 O 2 The calculated mass of (a) is 456.2; measured value of m/z is 457.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.78.
Example 143: (6-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 53, substituting intermediate A-1 with intermediate A-3. MS (ESI): c 21 H 20 F 3 N 7 The calculated mass value of O is 443.2; measured value of m/z is 444.2[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =5.80 min (main optical isomer).
Example 144: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-16. MS (ESI): c 21 H 18 F 4 N 6 The calculated mass value of O is 446.1; measured value of m/z is 447.1[ alpha ], [ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds presented as mixtures of optical isomers, reporting the major optical isomer) δ 8.00 (s, 2H), 7.91 (s, 1H), 7.58 (dd, J =8.9,2.6hz, 1h), 7.23-7.16 (m, 1H), 6.92-6.84 (m, 1H), 6.80 (d, J =7.6hz, 1h), 6.64-6.53 (m, 1H), 4.15-3.93 (m, 2H), 3.27-3.18 (m, 2H), 2.56-2.50 (m, 1H), 2.28-2.14 (m, 1H), 1.55 (d, J =10.2hz, 1h), 1.29-1.09 (m, 2H).
Example 145: (4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-12. MS (ESI): c 21 H 18 F 4 N 6 The calculated mass value of O is 446.1; measured value of m/z is 447.1[ alpha ], [ M ] +H ] + . Analytical HPLC using an Xbridge C18 column (5um, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 2 min, then 2 min under 100% ACN, at a flow rate of 2.5mL/min (temperature =45 ℃). R at 254nm t =2.05 min.
Example 146: (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 53, substituting intermediate A-1 with intermediate A-11. MS (ESI): c 21 H 18 F 4 N 6 The calculated mass value of O is 446.1; the measured value of m/z is 447.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as major optical isomers) δ 7.98 (s, 2H), 7.78 (s, 1H), 7.75 (dt, J =8.3,0.9hz, 1h), 7.56 (dd, J =8.8,2.4hz, 1h), 7.35-7.27 (m, 1H), 6.66-6.56 (m, 1H), 6.49 (t, J =8.6hz, 1h), 3.98-3.89 (m, 1H), 3.88-3.82 (m, 1H), 3.49 (dt, J =11.0,3.2hz, 1h), 3.34-3.32 (m, 1H), 2.63-2.55 (m, 1H), 2.27-2.15 (m, 1H), 1.44 (d, J = 10.1h), 1.19-2H (m, 1H).
Example 147: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-6. MS (ESI): c 23 H 19 F 4 N 5 The calculated mass value of O is 457.2; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as major optical isomers) δ 8.86 (d, J =4.9hz, 2H), 8.06 (dd, J =7.9,1.0hz, 1H), 7.83-7.73 (m, 1H), 7.56 (dd, J =8.9,2.4hz, 1H), 7.41 (t, J =4.9hz, 1H), 7.31-7.24 (m, 1H), 6.66-6.59 (m, 1H), 6.58-6.53 (m, 1H), 3.99-3.90 (m, 2H), 3.55 (dt, J =10.9,3.2hz, 1H), 3.35-3.32 (m, 1H), 2.64-2.58 (m, 1H), 2.26-2.16 (m, 1H), 1.44 (d = 44, 10.19, 1H), 1.19 (m, 1H), 1H, 13H, 1H).
Example 148: (2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
The preparation was carried out analogously to example 53,intermediate A-1 was replaced with intermediate A-37. MS (ESI): c 23 H 20 F 3 N 5 The calculated mass value of O is 439.2; the measured value of m/z is 440.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.91: J =7.7,1.4hz, 1H), 6.98-6.87 (m, 1H), 6.87-6.76 (m, 1H), 6.66-6.49 (m, 1H), 4.08-3.92 (m, 1H), 3.52 (dt, J =10.9,3.3hz, 1H), 2.66-2.59 (m, 1H), 2.30-2.19 (m, 1H), 1.54-1.45 (m, 1H), 1.35-1.19 (m, 3H). 1H is buried under the solvent peak.
Example 149: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-47. MS (ESI): c 23 H 21 F 3 N 6 The calculated mass value of O is 454.2; the measured value of m/z is 455.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.89: 7.28 (t, J =4.9hz, 1h), 6.38 (d, J =8.8hz, 1h), 4.32-4.28 (m, 1H), 4.22-4.11 (m, 1H), 3.72 (dt, J =10.9,3.2hz, 1h), 3.32 (dd, J =10.9,1.5hz, 1h), 2.83-2.72 (m, 1H), 2.46-2.36 (m, 4H), 1.94-1.87 (m, 1H), 1.71 (d, J =10.0hz, 1h), 1.20 (dt, J =13.0,3.5hz, 1h).
Example 150: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-41. MS (ESI): c 23 H 21 F 3 N 6 The calculated mass value of O is 454.2; measured value of m/z is 455.2[ 2 ], [ M ] +H ] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.91.
Example 151: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-46. MS (ESI): c 23 H 21 F 3 N 6 The calculated mass value of O is 454.2; the measured value of m/z is 455.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 line using an Xbridge C18 column (5 μm,100x4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =5.33 min (main optical isomer).
Example 152: (4-fluoro-2- (3-methyl-1,2,4-Oxadiazol-5-yl) phenyl) ((1S,4S,6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-51. MS (ESI): c 22 H 19 F 4 N 5 O 2 Calculated mass of 461.1; the measured value of m/z is 462.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers, the major optical isomers reported) δ 7.84 (s, 1H), 7.70 (dd, J =9.1,2.6hz, 1h), 7.59-7.53 (m, 1H), 7.02 (dd, J =8.5,5.3hz, 1h), 6.72 (td, J =8.2,2.6hz, 1h), 6.62-6.47 (m, 1H), 4.06-3.97 (m, 2H), 3.61 (dt, J =11.1,3.2hz, 1h), 3.41-3.35 (m, 1H), 2.76-2.67 (m, 1H), 2.44 (s, 3H), 2.34-2.23 (m, 1H), 1.74-1.60 (m, 2H), 1.35-1.26 (m, 1H).
Example 153: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
To the title compound of example 53 (10mg, 0.023mmol) dissolved in DMF (0.5 mL) was added NaOtBu (2.5mg, 0.026mmol). After 5 min, meI (1.5. Mu.L, 0.025 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was then washed with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (2 ×). The combined organic matter is treated with H 2 O washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound (3 mg) as a brown solid. MS (ESI): c 22 H 21 F 3 N 6 The calculated mass value of O is 442.2; the measured value of m/z is 443.1[ deg. ] M + H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.916(m,1H),3.88(s,1H),3.49-3.42(m,2H),3.11(s,3H),2.69(s,1H),2.09-1.98(m,1H),1.99-1.88(m,1H),1.49(d,J＝9.9Hz,1H),1.27-1.17(m,1H)。
Example 154: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-16, followed by the alkylation step of example 153. MS (ESI): c 22 H 20 F 4 N 6 Calculated mass of O is 460.2; the measured value of m/z is 461.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.86, 0.14), the major optical isomers reported δ 7.98 (s, 3H), 7.76-7.70 (m, 1H), 7.65 (dd, J =9.1,2.5hz, 1h), 7.33-7.26 (m, 1H), 6.70 (d, J =9.1hz, 1h), 6.59-6.50 (m, 1H), 4.49-4.40 (m, 1H), 3.99-3.93 (m, 1H), 3.51 (dt, J =11.4,3.0hz, 1h), 3.43 (dd, J =11.4,1.6hz, 1h), 3.09 (d, J =1.3hz, 3h), 2.69 (s, 1H), 2.08-1.93 (m, 2H), 1.46.46J = 1.19, 1H, 12H (m, 1H).
Example 155: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 53, substituting intermediate a-1 with intermediate a-10, followed by the alkylation step of example 153. MS (ESI): c 22 H 20 F 4 N 6 Calculated mass of O is 460.2; the measured value of m/z is 461.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.93, 0.07), the main optical isomers reported δ 8.08 (s, 1H), 7.95 (s, 2H), 7.79 (dd, J =9.0,4.7hz, 1h), 7.63 (dd,J＝9.1,2.6Hz,1H),7.07-6.99(m,1H),6.69(dd,J＝8.1,2.9Hz,1H),6.66(d,J＝9.1Hz,1H),4.52-4.44(m,1H),3.92-3.87(m,1H),3.44-3.40(m,2H),3.10(s,3H),2.70-2.65(m,1H),2.08-1.99(m,1H),1.97-1.90(m,1H),1.52-1.45(m,1H),1.19-1.11(m,1H)。
Example 156: ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-40, followed by the alkylation step of example 153. MS (ESI): c 22 H 22 F 3 N 7 The calculated mass value of O is 457.2; measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.93: 0.07), the major optical isomers reported δ 8.09 (d, J =8.4hz, 1h), 8.07 (s, 1H), 7.97 (s, 2H), 7.66 (dd, J =9.1,2.6hz, 1h), 7.17 (d, J =8.4hz, 1h), 6.68 (d, J =9.1hz, 1h), 4.72-4.63 (m, 1H), 3.95-3.87 (m, 1H), 3.54 (dt, J =11.4,3.1hz, 1h), 3.51-3.42 (m, 1H), 3.12 (s, 3H), 2.77-2.69 (m, 1H), 2.15 (s, 3H), 2.11-1.99 (m, 1H), 1.92-1.80 (m, 1H), 1.57 (d, J =10.4hz, 1h), 1.47-1.38 (m, 1H).
Example 157: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-2, followed by the alkylation step of example 153. MS (ESI): c 24 H 21 F 4 N 5 The calculated mass value of O is 471.2; the measured value of m/z is 472.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds are presented as optical isomersMixture of (0.90).
Example 158: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 53, intermediate a-1 was replaced with intermediate a-7, followed by the alkylation step of example 153. MS (ESI): c 24 H 21 F 4 N 5 The calculated mass value of O is 471.2; measured value of m/z is 472.2[ m ] +H ] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.91, 0.09), the main optical isomer being reported as δ 8.83 (d, J =4.9hz, 2h), 8.15 (dd, J =8.8,5.5hz, 1h), 8.08 (s, 1H), 7.63 (dd, J =9.1,2.6hz, 1h), 7.38 (t, J =4.9hz, 1h), 6.98 (ddd, J =8.8,8.1,2.7hz, 1h), 6.66 (d, J =9.1hz, 1h), 6.58 (dd, J =8.4,2.7hz, 1H), 4.55-4.45 (m, 1H), 4.02-3.95 (m, 1H), 3.51 (dt, J =11.3,3.1hz, 1H), 3.48-3.41 (m, 1H), 3.14 (s, 3H), 2.75-2.67 (m, 1H), 2.10-2.00 (m, 1H), 1.99-1.92 (m, 1H), 1.49 (d, J =10.1hz, 1H), 1.19-1.09 (m, 1H).
Example 159: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate a-1 was replaced with intermediate a-6, followed by the alkylation step of example 153. MS (ESI): c 24 H 21 F 4 N 5 The calculated mass value of O is 471.2; the measured value of m/z is 472.2[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.85, 0.15), the major optical isomers reported δ 8.86 (d, J =4.9hz, 2h), 8.02 (dd, J =7.8,1.0hz, 1h), 7.98 (s, 1H), 7.63 (dd, J =9.2,2.6hz, 1h), 7.42 (t, J =4.9hz, 1h), 7.28-7.22 (m, 1H), 6.68 (d, J =9.2hz, 1h), 6.63-6.58 (m, 1H), 4.48-4.40 (m, 1H), 4.08-4.00 (m, 1H), 3.55 (dt, J =11.3,3.0hz, 1h), 3.46-3.41 (m, 1H), 3.11-3.09 (m, 3H), 2.72-2.68 (m, 1H), 2.07-1.94 (m, 2H), 1.48-1.42 (m, 1H), 1.07-1.02 (m, 1H).
Example 160: (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
To the title compound of example 66 (38mg, 0.066 mmol) dissolved in DMF (1.3 mL) was added NaOtBu (7 mg, 0.072mmol). After 5 min, etI (5.5. Mu.L, 0.069 mmol) was added and the reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed that the starting material (example 66) remained. NaH (5mg, 0.13mmol,60% dispersion in mineral oil) and additional EtI (5.5. Mu.L, 0.069 mmol) were added to the reaction flask and the reaction mixture was stirred at room temperature for 2h. The mixture was then washed with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (2 ×). The combined organic matter is treated with H 2 O washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Agilent preparation method X to obtain the title compound as a white solid (16 mg). MS (ESI): c 25 H 23 F 4 N 5 Calculated mass of O is 485.2; the measured value of m/z is 486.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.93 ,7.03-6.96(m,1H),6.83-6.76(m,1H),6.71-6.64(m,2H),4.48-4.39(m,1H),4.13(s,1H),3.88-3.75(m,1H),3.36-3.32(m,2H),3.16(dt,J＝11.4,3.2Hz,1H),2.61(s,1H),2.14-2.05(m,1H),1.83-1.75(m,1H),1.53(d,J＝10.1Hz,1H),1.17(t,J＝7.0Hz,3H),0.86-0.79(m,1H)。
Example 161: ((1S, 4S, 6R) -6- ((cyclopropylmethyl) (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
To the title compound of example 66 (30mg, 0.053 mmol) dissolved in DMF (1 mL) was added NaH (6 mg,0.16mmol,60% dispersion in mineral oil). After 10 min, (bromomethyl) cyclopropane (10 μ L,0.11 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was then washed with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (2 ×). The combined organic matter is treated with H 2 O washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Gilson preparation method X to obtain the title compound (19 mg) as a white solid. MS (ESI): c 27 H 25 F 4 N 5 Calculated mass of O is 511.2; measured value of m/z is 512.3[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.93: 0.07), the major optical isomers reported δ 8.89 (d, J =4.9hz, 2h), 8.13 (s, 1H), 7.61 (dd, J =9.1,2.6hz, 1h), 7.48 (t, J =5.0hz, 1h), 7.02-6.95 (m, 1H), 6.85-6.78 (m, 1H), 6.75 (d, J =9.1hz, 1h), 6.68 (dd, J =7.6,1.1hz, 1h), 4.51-4.41 (m, 1H), 4.20-4.10 (m, 1H), 3.85-3.73 (m, 1H), 3.28-3.23 (m, 1H), 3.20-3.11 (m, 1H), 2.63-2.58 (m, 1H), 2.19-2.08 (m, 1H), 1.90-1.82 (m, 1H), 1.57-1.51 (m, 1H), 1.29 (s, 1H), 0.99-0.90 (m, 1H), 0.86-0.77 (m, 1H), 0.62-0.49 (m, 2H), 0.49-0.42 (m, 1H), 0.37-0.28 (m, 1H).
Example 162: n- ((1S, 4R, 6R) -2- (3-fluoro-2- (pyrimidin-2-yl) benzoyl) -2-azabicyclo [2.2.1] hept-6-yl) -N- (5- (trifluoromethyl) pyridin-2-yl) acetamide.
To the title compound of example 66 (30mg, 0.053 mmol) was added Ac 2 O (0.1mL, 1.05mmol), and the reaction mixture was stirred at 100 ℃ overnight. The mixture was then concentrated and the concentrate was directly purified using Gilson preparation method X to obtain the title compound. MS (ESI): c 25 H 21 F 4 N 5 O 2 The calculated mass of (a) is 499.2; the measured value of m/z is 500.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.79-0.21), reporting major optical isomers) δ 9.02-8.98 (m, 1H), 8.89 (d, J =4.9hz, 2H), 8.31 (dd, J =8.1,2.5hz, 1h), 7.64-7.46 (m, 4H), 7.38-7.32 (m, 1H), 4.55-4.48 (m, 1H), 4.38-4.33 (m, 1H), 3.08 (dt, J =11.1,3.2hz, 1h), 2.68 (d, J =11.2hz, 1h), 2.39 (s, 1H), 1.91-1.81 (m, 1H), 1.75 (s, 3H), 1.52 (d, J =10.4hz, 1h), 0.96-0.90 (m, 1H), 0.69-0.61H (m, 1H).
Example 163: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((2-methoxyethyl) (5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
To the title compound of example 66 (43mg, 0.094mmol) dissolved in DMF (2 mL) was added NaH (19mg, 0.47mmol,60% dispersion in mineral oil). After 10 min, 2-chloroethylmethyl ether (26 μ L,0.28 mmol) was added and the reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed that the starting material (example 66) remained. NaH (19mg, 0.47mmol,60% dispersion in mineral oil) and additional 2-chloroethylmethyl ether (26. Mu.L, 0.28 mmol) were added to the reaction flask and the reaction mixture was stirred at 50 ℃ for 3h. The mixture was then washed with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (2 ×). The combined organic matter is treated with H 2 O washing with Na 2 SO 4 Dried, filtered and concentrated. Purification of the concentrate was performed using Gilson preparation X to obtain the title compound as an off-white solid (10 mg). MS (ESI): c 26 H 25 F 4 N 5 O 2 The calculated mass value of (A) is 515.2; the measured value of m/z is 516.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.92: J =7.6,1.1hz, 1h), 4.46-4.36 (m, 1H), 4.16 (s, 1H), 4.04-3.90 (m, 1H), 3.61-3.43 (m, 3H), 3.38-3.32 (m, 3H), 3.16 (dt, J =12.1,3.1hz, 1h), 2.65-2.56 (m, 1H), 2.14-2.02 (m, 1H), 1.91-1.82 (m, 1H), 1.54 (d, J =10.3hz, 1h), 0.83 (d, J =10.3hz, 1h). 1H was buried under the solvent peak.
Example 164: (2-methyl-4- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 165: (6-methyl-4- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 166: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate.To a microwave vial containing 5-bromo-2-iodopyridine (669mg, 2.36mmol) and degassed THF (12 mL) were added NaOtBu (453mg, 4.71mmol), xantphos (98mg, 0.17mmol) and Pd 2 (dba) 3 (86mg, 0.094mmol). The reaction mixture is treated with N 2 Purge for 10 min, then intermediate B-10 (500mg, 2.36mmol) was added and the reaction mixture was heated at 90 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the crude residue was directly subjected to silica gel chromatography (0-60% etoac in hexanes) to afford the title compound of step a (91 mg). 0-10% MeOH (having a content of 10%2M NH) 3 ) Further performing flash column chromatography on the DCM solution to obtain (1S, 4R, 6R) -N- (5-bromopyridin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine (483 mg). (1S,4S,6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hepta-2-carboxylic acid tert-butyl ester: c 16 H 22 BrN 3 O 2 Mass calculation of (ESI) of (2) is 367.1; measured value of m/z is 370.0[ m ] +H ] + 。 1 H NMR (500 MHz, methanol-d) 4 ) δ 7.98 (d, J =2.5hz, 1h), 7.49 (dd, J =9.0,2.5hz, 1h), 6.51 (d, J =8.9hz, 1h), 4.46-4.41 (m, 1H), 4.12-4.05 (m, 1H), 3.29-3.27 (m, 1H), 3.07 (d, J =9.6hz, 1h), 2.57-2.51 (m, 1H), 2.27-2.18 (m, 1H), 1.70-1.67 (m, 2H), 1.18-1.09 (m, 10H). (1S,4R,6R) -N- (5-bromopyridin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine: 1 h NMR (500 MHz, methanol-d) 4 )δ8.11(dd,J＝2.5,0.7Hz,1H),7.58(dd,J＝8.9,2.5Hz,1H),6.65(dd,J＝8.9,0.7Hz,1H),4.44(dd,J＝3.1,2.0Hz,1H),4.14-4.10(m,1H),3.21(dt,J＝10.9,3.4Hz,1H),3.11(dd,J＝10.9,1.8Hz,1H),2.74-2.70(m,1H),2.39-2.29(m,1H),2.05-2.02(m,1H),1.90-1.83(m,1H),1.38(dt,J＝13.4,3.5Hz,1H)。
And B: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To (1S,4R,6R) -N- (5-bromopyridin-2-yl) -2-azabicyclo [ 2.2.1) from step A]To a solution of hept-6-amine (70mg, 0.26mmol) and intermediate A-1 (63mg, 0.33mmol) in DMF (2 mL) were added DIPEA (0.27mL, 1.57mmol) and HATU (109mg, 0.29mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and subjected to purification via Gilson preparation X to give the title compound as an off-white powder (42 mg). MS (ESI): c 20 H 19 BrN 6 Calculated mass of O is 438.1; the measured value of m/z is 439.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as major optical isomers) δ 7.94 (s, 2H), 7.83 (d, J =7.8hz, 1h), 7.60-7.55 (m, 1H), 7.50-7.43 (m, 1H), 7.40 (td, J =7.9,1.5hz, 1h), 6.96 (s, 1H), 6.82 (s, 1H), 6.46 (s, 1H), 3.85 (s, 2H), 3.50-3.41 (m, 1H), 3.28 (dd, J =11.1,1.6hz, 1h), 2.58 (s, 1H), 2.26-2.15 (m, 1H), 1.53-1.38 (m, 1H), 1.35-1.24 (m, 1H), 1.23-1.14 (m, 1H).
Example 167: ((1S, 4S, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 166, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 19 BrFN 5 Calculated mass of O is 467.1; the measured value of m/z is 470.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.81-0.19), the major optical isomers were reported as δ 8.86 (d, J =4.9hz, 2h), 8.07 (dd, J =8.0,1.0hz, 1h), 7.52 (d, J =2.4hz, 1h), 7.46-7.32 (m, 3H), 6.70-6.62 (m, 1H), 6.47 (d, J =9.4hz, 1h), 3.96-3.89 (m, 1H), 3.87-3.78 (m, 1H), 3.53 (dt, J =10.9,3.2hz, 1h), 2.62-2.55 (m, 1H), 2.24-2.14 (m, 1H), 1.44-1.39 (m, 1H), 1.29-1.18 (m, 1H), 1.16-1H (m, 1H), 1.11H). 1H is buried under the solvent peak.
Example 168: ((1S, 4S, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 166, substituting intermediate A-1 with intermediate A-6. MS (ESI): c 22 H 19 BrFN 5 Calculated mass of O is 467.1; measured value of m/z is 468.0[ 2 ] M + H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.92, 0.08), the major optical isomers reported δ 8.89 (d, J =4.9hz, 2h), 7.69 (d, J =2.5hz, 1h), 7.48 (t, J =5.0hz, 1h), 7.45 (dd, J =8.9,2.5hz, 1h), 7.17-7.10 (m, 1H), 6.99-6.92 (m, 1H), 6.81 (d, J =7.5hz, 1h), 6.43 (d, J =8.9hz, 1h), 4.15 (s, 1H), 4.01-3.91 (m, 1H), 3.25-3.18 (m, 2H), 2.52 (s, 1H), 2.27-2.15 (m, 1H), 1.52 (d, 1j = 11.11, 1H), 1.25-3.18 (m, 2H), 2.52 (s, 1H), 2.27-2.15 (m, 1H), 1.52 (d, 1J = 11.06, 1H), 1.06, 1H).
Example 169: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing degassed toluene (3 mL) at room temperature was added Pd (OAc) 2 (6mg, 0.028mmol) and racemic BINAP (17mg, 0.028mmol), and the reaction mixture was treated with N 2 Purge 5 minutes. 2-bromo-5-chloropyridine (90mg, 0.47mmol), intermediate B-10 (109 mg), and sodium tert-butoxide (63mg, 0.66mmol) were then added and the reaction mixture was heated at 90 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the crude residue was subjected directly to silica gel chromatography (0-10% MeOH (having 10%2N NH) 3 ) DCM) to obtain the title compound of step a. C 16 H 22 ClN 3 O 2 Mass calculated value of MS (ESI) of (2) is 323.1; measured value of m/z is 324.1[ 2 ], [ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ7.90(d,J＝2.6Hz,1H),7.39(dd,J＝8.9,2.7Hz,1H),6.54(d,J＝9.0Hz,1H),4.43(s,1H),4.12-4.06(m,1H),3.30-3.27(m,1H),3.09-3.05(m,1H),2.57-2.50(m,1H),2.28-2.17(m,1H),1.70-1.67(m,2H),1.48-1.38(m,2H),1.12(s,9H)。
And B: (1S,4R,6R) -N- (5-chloropyridin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine xHCl to a solution of the title compound of step A (252mg, 0.701mmol) in EtOAc (9 mL) was added a 4M HCl in dioxane (0.9 mL). After 1h, the reaction was concentrated to obtain the title compound of step B (231mg, 90% purity), which was used without further purification. C 11 H 14 ClN 3 Mass calculation of MS (ESI) of 223.1; the measured value of m/z is 224.1[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (40 mg) and intermediate A-1 (28mg, 0.15mmol) in DMF (1 mL) was added DIPEA (0.2mL, 1.2mmol) and HATU (56mg, 0.15mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (4 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Agilent preparative method X to give the title compound (30 mg). MS (ESI): c 20 H 19 ClN 6 Calculated mass of O is 394.1; the measured value of m/z is 395.2[ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.25 min (main optical isomer).
Example 170: ((1S,4S,6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 169, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 19 ClFN 5 Calculation of the mass of OA value of 423.1; the measured value of m/z is 424.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.84.
Example 171: ((1S,4S,6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 169, intermediate A-1 was replaced with intermediate A-23. MS (ESI): c 22 H 19 ClFN 5 The calculated mass value of O is 423.1; measured value of m/z is 424.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as major optical isomers) δ 8.86 (d, J =4.9hz, 2h), 7.88 (dd, J =10.1,2.7hz, 1h), 7.58 (d, J =2.6hz, 1h), 7.44-7.35 (m, 2H), 6.98-6.92 (m, 1H), 6.64-6.56 (m, 1H), 6.51-6.43 (m, 1H), 3.93 (s, 1H), 3.91-3.86 (m, 1H), 3.52 (dt, J =10.9,3.3hz, 1h), 3.30-3.28 (m, 1H), 2.63-2.58 (m, 1H), 2.27-2.17 (m, 1H), 1.47 (d, J = 10.1h), 1.33-1H, 1.26, 1H), 1.26-1H (m, 1H).
Example 172: ((1S, 4S, 6R) -6- ((5-Chloropyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 169, substituting intermediate A-1 with intermediate A-7. MS (ESI): c 22 H 19 ClFN 5 Calculated mass of O is 423.1; the measured value of m/z is 424.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.91, 0.09), the main optical isomers reported δ 8.83 (d, J =4.8hz, 2h), 8.19 (dd, J =8.8,5.5hz, 1h), 7.55 (d, J =2.6hz, 1h), 7.39-7.32 (m, 2H), 7.08 (td, J =8.5,2.7hz, 1h), 6.72-6.64 (m, 1H), 6.50-6.42 (m, 1H), 3.95 (s, 1H), 3.92-3.86 (m, 1H), 3.50 (dt, J =11.0,3.2Hz, 1H), 3.30-3.28 (m, 1H), 2.62-2.58 (m, 1H), 2.26-2.18 (m, 1H), 1.46 (d, J =10.1Hz, 1H), 1.28-1.17 (m, 2H).
Example 173: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5- (difluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing degassed toluene (6 mL) at room temperature was added Pd (OAc) 2 (25mg, 0.038mmol) and racemic BINAP (27mg, 0.043mmol), and the reaction mixture was quenched with N 2 Purge 5 minutes. 2-chloro-5- (difluoromethyl) pyridine (70. Mu.L, 0.59 mmol), intermediate B-10 (137 mg), and sodium tert-butoxide (81mg, 0.82mmol) were then added and the reaction mixture was heated at 90 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the crude residue was directly subjected to silica gel chromatography (0-60% etoac in hexanes) to afford the title compound of step a (71mg, 0.21mmol, 36%). C 17 H 23 F 2 N 3 O 2 Calculated mass MS (ESI) of 339.2; the measured value of m/z is 340.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 ) δ 8.12-8.07 (m, 1H), 7.56 (dd, J =8.6,2.3hz, 1h), 6.80-6.49 (m, 2H), 4.49-4.44 (m, 1H), 4.23-4.14 (m, 1H), 3.09 (d, J =9.5hz, 1h), 2.59-2.54 (m, 1H), 2.31-2.18 (m, 1H), 1.74-1.68 (m, 2H), 1.22-1.16 (m, 1H), 1.09 (s, 9H). 1H is buried under the solvent peak.
And B: (1S,4R,6R) -N- (5- (difluoromethyl) pyridin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine. XHCl to a solution of the title compound of step A (71mg, 0.21mmol) in EtOAc (3 mL) was added a 4M HCl solution in dioxane (0.3 mL). After 1h, the reaction was concentrated to obtain the title compound of step B (65 mg), which was used without further purification. C 12 H 15 F 2 N 3 The mass calculation value of MS (ESI) of (1) is 239.1; the measured value of m/z is 240.1[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (33 mg) and intermediate A-1 (24mg, 0.13mmol) in DMF (1.5 mL) were added DIPEA (0.11mL, 0.63mmol) and HATU (44mg, 0.12mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Agilent preparative method X to give the title compound (27 mg). MS (ESI): c 21 H 20 F 2 N 6 The calculated mass value of O is 410.2; the measured value of m/z is 411.1[ m ] +H] + . Analytical HPLC using an Xbridge C18 column (5um, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 2 min, then 2 min under 100% ACN, at a flow rate of 2.5mL/min (temperature =45 ℃). R at 254nm t =1.83 and 2.03 minutes (main optical isomer).
Example 174: ((1S, 4S, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 173, substituting intermediate A-1 with intermediate A-2. MS (ESI): c 23 H 20 F 3 N 5 Calculated mass of O is 439.2; the measured value of m/z is 440.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds being present as optical isomersMixture (0.92, 0.08), reported as major optical isomers) δ 8.89 (d, J =5.0hz, 2h), 7.81 (s, 1H), 7.53 (dd, J =8.8,2.4hz, 1h), 7.48 (t, J =4.9hz, 1h), 7.10-7.02 (m, 1H), 6.91-6.82 (m, 1H), 6.82-6.51 (m, 3H), 4.20-4.13 (m, 1H), 4.11-4.01 (m, 1H), 3.27-3.22 (m, 2H), 2.58-2.51 (m, 1H), 2.29-2.18 (m, 1H), 1.55 (d, J =9.6hz, 1h), 1.25-1.17 (m, 1H), 1.11 (d, J =9.6hz, 1h), 1.25-1.17 (m, 1H), 1.11 (d, J = 9.9, 1h).
Example 175: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methoxypyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5-methoxypyridin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing degassed toluene (4 mL) at room temperature was added Pd (OAc) 2 (9mg, 0.038mmol) and racemic BINAP (24mg, 0.038mmol), and the reaction mixture was stirred with N 2 Purge 5 minutes. 2-chloro-5-methoxypyridine (75. Mu.L, 0.63 mmol), intermediate B-10 (148mg, 0.695mmol), and sodium tert-butoxide (85mg, 0.89mmol) were then added and the reaction mixture was heated at 90 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the crude residue was directly subjected to silica gel chromatography (0-10% meoh (with 10% 2N NH) 3 ) DCM) to obtain the title compound of step a (158mg, 0.49mmol,90% purity, 70%). C 17 H 25 N 3 O 3 Mass calculated as 319.2 for MS (ESI); the measured value of m/z is 320.3[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ7.65(d,J＝3.0Hz,1H),7.18(dd,J＝9.1,3.0Hz,1H),6.55(d,J＝9.1Hz,1H),4.44-4.40(m,1H),4.09-4.01(m,1H),3.75(s,3H),3.30-3.26(m,1H),3.07(d,J＝9.4Hz,1H),2.57-2.49(m,1H),2.30-2.19(m,1H),1.71-1.67(m,2H),1.48-1.45(m,1H),1.11(s,9H)。
And B: (1S,4R,6R) -N- (5-methoxypyridin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine. XHCl to the title compound of step A (176 mg,0.49mmol,90% purity) in EtOAc (6 mL) is added a 4M HCl in dioxane (0.6 mL). After 3h, the reaction was concentrated to obtain the title compound of step B (150 mg), which was used without further purification. C 12 H 17 N 3 Calculated mass MS (ESI) for O is 219.1; the measured value of m/z is 220.2[ m ] +H] + 。
Step C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methoxypyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-1 (21mg, 0.11mmol) in DMF (1 mL) were added DIPEA (0.10mL, 0.55mmol) and HATU (39mg, 0.10mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Gilson preparation method X to obtain the title compound (17 mg). MS (ESI): c 21 H 22 N 6 O 2 Mass calculated value of 390.2; the measured value of m/z is 391.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.87-0.13), the major optical isomers reported δ 7.93 (s, 2H), 7.82 (d, J =8.1hz, 1H), 7.39-7.33 (m, 1H), 7.29 (d, J =2.4hz, 1H), 7.17-7.10 (m, 1H), 7.02-6.92 (m, 1H), 6.85-6.69 (m, 1H), 6.57-6.38 (m, 1H), 3.93-3.80 (m, 2H), 3.76 (s, 3H), 3.49-3.41 (m, 1H), 3.30-3.26 (m, 1H), 2.57 (s, 1H), 2.27-2.16 (m, 1H), 1.53-1.43 (m, 1H), 1.41-1.26 (m, 1H), 1.20-1H), 1.26 (m, 1H).
Example 176: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methoxypyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 175, intermediate a-1 was replaced with intermediate a-2. MS (ESI): c 23 H 22 FN 5 O 2 Calculated mass of 419.2; the measured value of m/z is 420.1[ m ] +H] + 。 1 H NMR(500MHz，Methanol-d 4 Compounds presented as a mixture of optical isomers (0.88: 6.44 (d, J =9.1hz, 1h), 4.18-4.11 (m, 1H), 3.98-3.92 (m, 1H), 3.76 (s, 3H), 3.23 (t, J =3.0hz, 1h), 3.22-3.20 (m, 1H), 2.55-2.50 (m, 1H), 2.29-2.19 (m, 1H), 1.57 (d, J =11.2hz, 1h), 1.22-1.16 (m, 1H), 1.16-1.11 (m, 1H).
Example 177: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing intermediate B-10 (170mg, 0.801mmol) in DMF (2.5 mL) was added 2,3-difluoro-5- (trifluoromethyl) pyridine (176mg, 0.961mmol) and Et 3 N (0.17mL, 1.20mmol), and the reaction mixture was sealed and heated on a bench overnight at 90 ℃. After completion of the reaction, the mixture was cooled to room temperature and directly subjected to silica gel chromatography (0-30% etoac in hexanes) to obtain the title compound of step a (322 mg). C 17 H 21 F 4 N 3 O 2 The mass calculation value of MS (ESI) is 375.16, and the measured value of m/z is 376.0[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomers) δ 8.15 (s, 1H), 7.33-7.28 (m, 1H), 5.37-5.23 (m, 1H), 4.42-4.34 (m, 2H), 3.44-3.39 (m, 1H), 3.11 (d, J =9.3hz, 1h), 2.64-2.60 (m, 1H), 2.42-2.31 (m, 1H), 1.69-1.63 (m, 1H), 1.26 (s, 9H), 1.10-1.04 (m, 1H) were reported.
And B: (1S,4R,6R) -N- (3-fluoro-5- (trifluoromethyl) pyridin-2-yl) -2-azabicyclo [2.2.1 ]Heptan-6-amine xHCl to a solution of the title compound of step A (322 mg) in EtOAc (1 mL) was added a 4M HCl solution in dioxane (3 mL) and the reactionThe mixture was stirred at room temperature for 2h. The reaction was concentrated to obtain the title compound of step B (327 mg), which was used without further purification. C 12 H 13 F 4 N 3 Mass calculated as 275.1 for MS (ESI); the measured value of m/z is 276.0[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (40 mg) and intermediate A-1 (24mg, 0.126mmol) in DMF (0.5 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (48mg, 0.13mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Agilent preparative method X to give the title compound (26 mg). MS (ESI): c 21 H 18 F 4 N 6 The calculated mass value of O is 446.1; the measured value of m/z is 447.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.87, 0.13), reported as the major optical isomers) δ 7.95 (s, 2H), 7.81 (d, J =8.2hz, 1h), 7.66 (s, 1H), 7.58-7.44 (m, 1H), 7.30 (t, J =7.8hz, 1h), 7.04-6.95 (m, 1H), 6.83-6.72 (m, 1H), 4.11-4.03 (m, 1H), 3.88-3.79 (m, 1H), 3.50-3.33 (m, 2H), 2.63-2.57 (m, 1H), 2.22-2.12 (m, 1H), 1.51-1.41 (m, 2H), 1.29-1.18 (m, 1H). On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.81 min (main optical isomer).
Example 178: ((1S,4S,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 177, substituting intermediate A-1 with intermediate A-40. MS (ESI): c 21 H 19 F 4 N 7 Calculated mass value of O is 461.2; the measured value of m/z is 462.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds presented as a mixture of optical isomers (0.88-0.12), reported as the major optical isomers) δ 8.14 (d, J =8.4hz, 1h), 7.98 (s, 2H), 7.84-7.78 (m, 1H), 7.43 (dd, J =11.1,2.0hz, 1h), 7.31 (d, J =8.6hz, 1h), 4.25-4.19 (m, 1H), 4.12-4.04 (m, 1H), 3.56 (dt, J =11.0,3.2hz, 1h), 3.35 (dd, J =10.9,1.4hz, 1h), 2.72-2.67 (m, 1H), 2.37 (s, 3H), 2.35-2.27 (m, 1H), 1.65-1.61 (m, 2H), 1.44-1.38 (m, 1H).
Example 179: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 177, substituting intermediate a-1 with intermediate a-2. MS (ESI): c 23 H 18 F 5 N 5 Calculated mass of O is 475.1; m/z found at 476.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88-0.12), the main optical isomers reported δ 8.90 (d, J =4.9hz, 2h), 7.80-7.73 (m, 1H), 7.52-7.46 (m, 2H), 7.08-7.01 (m, 1H), 6.95-6.87 (m, 1H), 6.80 (d, J =7.7hz, 1h), 4.20 (s, 1H), 4.17-4.10 (m, 1H), 3.33-3.32 (m, 1H), 3.19 (dt, J =11.1,3.2hz, 1h), 2.57-2.49 (m, 1H), 2.23-2.13 (m, 1H), 1.52 (d, J =9.8hz, 1h), 1.45-1.36 (m, 1H), 0.93 (d, 1h), 0.1d, 10H).
Example 180: ((1S,4S,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
The preparation was carried out analogously to example 177,intermediate A-1 was replaced with intermediate A-34. MS (ESI): c 23 H 18 F 5 N 5 Calculated mass of O is 475.1; m/z found at 476.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds presented as a mixture of optical isomers (0.88: 6.90-6.79 (m, 1H), 4.16-4.08 (m, 1H), 4.07-3.95 (m, 1H), 3.53 (dt, J =10.8,3.2Hz, 1H), 3.40 (dd, J =10.8,1.6Hz, 1H), 2.68-2.63 (m, 1H), 2.26-2.16 (m, 1H), 1.58-1.51 (m, 1H), 1.51-1.45 (m, 1H), 1.38-1.28 (m, 1H).
Example 181: ((1S,4S,6R) -6- (benzo [ d)]Azol-2-ylamino) -2-azabicyclo [2.2.1]Hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Step A: (1S, 4S) -6- (benzo [ d ]]Azol-2-ylamino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing intermediate B-10 (183mg, 0.862mmol) in MeCN (2 mL) was added 2-chlorobenzoAzole (0.12mL, 1.03mmol) and Et 3 N (0.18mL, 1.29mmol), and the reaction mixture was sealed and heated on a bench overnight at 100 ℃. After completion of the reaction, the mixture was cooled to room temperature and washed with H 2 And (4) diluting with oxygen. The reaction mixture was extracted with EtOAc (3 ×). The combined organics were concentrated and the concentrate was directly subjected to silica gel chromatography (0-50% EtOAc in hexane) to obtain the title compound of step A (199mg, 0.604mmol, 70%). C 18 H 23 N 3 O 3 Calculated value of MS (ESI) by mass is 329.2m/z, found 330.2M + H] + 。 1 H NMR (400 MHz, chloroform-d, compound present as a mixture of optical isomers) delta 7.40-7.34 (m, 1H), 7.26-7.20 (m, 1H), 7.20-7.12 (m, 1H), 7.07-6.99 (m, 1H), 5.88-5.78 and 5.29-5.19 (two m, 1H), 4.51-4.43 (m, 1H), 4.33-4.19 (m, 1H), 3.45-3.33 (m, 1H), 3.15-3.04 (m, 1H), 2.64-2.57 (m, 1H), 2.46-2.31 (m, 1H), 1.80-0.99 (a series of m, 12H).
And B: n- ((1S, 4R) -2-azabicyclo [2.2.1]Hept-6-yl) benzo [ d]Azole-2-amine. XHCl to a solution of the title compound of step A (199mg, 0.604mmol) in EtOAc (1.5 mL) was added a solution of 4M HCl in dioxane (4 mL). After 1h, the reaction was concentrated to obtain the title compound of step B (194 mg), which was used without further purification. C 13 H 15 N 3 MS (ESI) mass calculated for O is 229.1; measured value of m/z is 230.1[ 2 ], [ M ] +H] + 。
And C: ((1S,4S,6R) -6- (benzo [ d)]Azol-2-ylamino) -2-azabicyclo [2.2.1]Hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone. To a solution of the title compound of step B (40 mg) and intermediate A-40 (30mg, 0.15mmol) in DMF (1 mL) was added DIPEA (0.13mL, 0.75mmol) and HATU (55mg, 0.15mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Agilent preparative method X to give the title compound (24 mg). MS (ESI): c 22 H 21 N 7 O 2 The calculated mass value of (b) is 415.2; the measured value of m/z is 416.2[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.81 ),4.26-4.21(m,1H),3.98-3.88(m,1H),3.59(dt,J＝11.0,3.2Hz,1H),3.35(d,J＝11.0Hz,1H),2.76-2.68(m,1H),2.40-2.28(m,1H),2.09(s,3H),1.68-1.60(m,2H),1.40-1.33(m,1H)。
Example 182: ((1S,4S,6R) -6- (benzo [ d)]Azol-2-ylamino) -2-azabicyclo [2.2.1]Hept-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation was analogous to example 181, intermediate A-40 was replaced with intermediate A-16. MS (ESI): c 22 H 19 FN 6 O 2 Calculated mass of 418.2; the measured value of m/z is 419.2[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.93, 0.07), the major optical isomers reported δ 8.00 (s, 2H), 7.37-7.31 (m, 1H), 7.20-7.16 (m, 1H), 7.12 (d, J =7.1hz, 2h), 6.91 (d, J =8.2hz, 2h), 6.49-6.37 (m, 1H), 4.12 (s, 1H), 4.01-3.88 (m, 1H), 3.63 (s, 1H), 3.27-3.22 (m, 1H), 2.60-2.54 (m, 1H), 2.31-2.21 (m, 1H), 1.59 (d, J =10.3hz, 1h), 1.32-1.19 (m, 2H).
Example 183: ((1S,4S,6R) -6- (benzo [ d)]Azol-2-ylamino) -2-azabicyclo [2.2.1]Hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 181, intermediate A-40 was replaced with intermediate A-2. MS (ESI): c 24 H 20 FN 5 O 2 Calculated mass value of 429.2; the measured value of m/z is 430.2[ m ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 The compounds exhibit optical isomerismMixture of bodies (0.93, 0.07), reporting major optical isomers) δ 8.91 (d, J =5.0hz, 2h), 7.49 (t, J =5.0hz, 1h), 7.30 (d, J =7.9hz, 1h), 7.21-7.06 (m, 3H), 6.93 (d, J =7.5hz, 1h), 6.86-6.79 (m, 1H), 6.62-6.49 (m, 1H), 4.27 (s, 1H), 4.05-3.97 (m, 1H), 3.29-3.28 (m, 1H), 3.27 (s, 1H), 2.67-2.56 (m, 1H), 2.37-2.25 (m, 1H), 1.63 (d, J =10.2hz, 1h), 1.35-1.23 (m, 2H).
Example 184: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (p-tolylamino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S, 4S) -6- (p-tolylamino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing degassed dioxane (2 mL), intermediate B-10 (60mg, 0.28mmol) and 4-bromotoluene (73mg, 0.42mmol) were added Brettphos Palladacycle (11mg, 0.014mmol), brettphos (8mg, 0.014mmol) and sodium t-butoxide (33mg, 0.34mmol). The reaction mixture was heated on the bench for 3h at 90 ℃. After completion of the reaction, the mixture was cooled to room temperature and washed with H 2 O and EtOAc dilution. The reaction mixture was extracted with EtOAc (3 ×), and the combined organics were washed with brine, dried (Na) 2 SO 4 ) And filtered. The filtrate was concentrated in vacuo, and the crude residue was directly subjected to silica gel chromatography (0-40% etoac in hexanes) to afford the title compound of step a (68mg, 0.22mmol, 80%). C 18 H 26 N 2 O 2 Mass calculated MS (ESI) of 302.2; the measured value of m/z is 303.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as the major optical isomer) δ 6.91 (d, J =8.1hz, 2h), 6.55 (d, J =8.3hz, 2h), 4.39 (s, 1H), 3.86-3.73 (m, 1H), 3.27 (dt, J =9.4,3.2hz, 1h), 3.05 (d, J =9.3hz, 1h), 2.52-2.48 (m, 1H), 2.28-2.21 (m, 1H), 2.18 (s, 3H), 1.74-1.40 (m, 3H), 1.08 (s, 9H).
And B: (1S, 4R) -N- (p-tolyl) -2-azabicyclo [2.2.1]Addition of hept-6-amine. XHCl to the title compound of step A (68 mg)0.22 mmol) in EtOAc (3 mL), a solution of 4M HCl in dioxane (0.3 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction was concentrated to obtain the title compound of step B (70 mg), which was used without further purification. C 13 H 18 N 2 The mass calculation of MS (ESI) of (1) was 202.2; the measured value of m/z is 203.3[ m ] +H] + 。
And C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (p-tolylamino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (61 mg) and intermediate A-2 (71mg, 0.27mmol,82% pure) in DMF (2 mL) was added DIPEA (0.23mL, 1.33mmol) and HATU (93mg, 0.24mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate was directly subjected to purification via Gilson preparation method X to obtain the title compound (31 mg). MS (ESI): c 24 H 23 FN 4 The calculated mass value of O is 402.2; measured value of m/z is 403.2[ 2 ], [ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.88, 0.12), reported as the major optical isomers) δ 8.88 (d, J =5.0hz, 2h), 7.48 (t, J =5.0hz, 1h), 7.09-7.02 (m, 1H), 6.85-6.77 (m, 4H), 6.34-6.27 (m, 2H), 4.10 (s, 1H), 3.73-3.64 (m, 1H), 3.29-3.11 (m, 2H), 2.57-2.48 (m, 1H), 2.32-2.23 (m, 1H), 2.21 (s, 3H), 1.60 (d, J =10.1hz, 1h), 1.26-1.19 (m, 1H), 1.15-1.09 (m, 1H).
Example 185: (1H-indol-7-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-29. MS (ESI): c 21 H 19 F 3 N 4 The calculated mass value of O is 400.2; the measured value of m/z is 401.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 To transform intoThe compounds presented as mixtures of optical isomers reported as the major optical isomers δ 7.53 (s, 1H), 7.32-7.25 (m, 1H), 7.23 (d, J =3.1hz, 1h), 7.17 (dt, J =8.0,1.0hz, 1h), 6.70-6.60 (m, 2H), 6.37 (dd, J =3.1,0.9hz, 1h), 6.33 (s, 1H), 4.59 (s, 1H), 3.98-3.89 (m, 1H), 3.63 (dt, J =11.1,3.3hz, 1h), 3.51 (dd, J =11.2,1.6hz, 1h), 2.76-2.66 (m, 1H), 2.33-2.20 (m, 1H), 2.05-1.95 (m, 1H), 1.81, 1.74, 1.25 (m, 1H).
Example 186: (1H-indazol-7-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 53, intermediate A-1 was replaced with intermediate A-44. MS (ESI): c 20 H 18 F 3 N 5 The calculated mass value of O is 401.1; the measured value of m/z is 402.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ7.88(s,1H),7.55(d,J＝8.1Hz,1H),7.52(s,1H),7.22(d,J＝7.1Hz,1H),7.09(dd,J＝8.9,2.5Hz,1H),6.89-6.80(m,1H),6.11(d,J＝8.9Hz,1H),4.76(s,1H),4.00-3.92(m,1H),3.67-3.56(m,2H),2.76-2.68(m,1H),2.36-2.25(m,1H),2.17-2.08(m,1H),1.83(d,J＝10.4Hz,1H),1.33-1.22(m,1H)。
Example 187: (5-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 59, substituting intermediate A-1 with intermediate A-19. MS (ESI): c 20 H 19 F 3 N 8 The calculated mass value of O is 444.2; measured value of m/z is 445.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.85,3H),7.56(s,1H),4.31(s,1H),4.26-4.12(m,1H),3.72(dt,J＝11.0,3.2Hz,1H),3.35(dd,J＝11.0,1.7Hz,1H),2.85-2.72(m,1H),2.47-2.36(m,4H),1.98-1.89(m,1H),1.72(d,J＝10.5Hz,1H),1.21(dt,J＝13.4,4.0Hz,1H)。
Example 188: (2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-39. MS (ESI): c 19 H 17 F 3 N 8 The calculated mass value of O is 430.1; the measured value of m/z is 431.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds presented as a mixture of optical isomers (0.91-0.09), main optical isomers) δ 8.36 (dd, J =4.8,1.8hz, 1h), 8.07 (s, 2H), 7.98-7.83 (m, 2H), 7.61-7.48 (m, 1H), 6.89-6.75 (m, 1H), 4.01-3.89 (m, 1H), 3.85-3.70 (m, 1H), 3.51 (dt, J =11.2,3.2hz, 1h), 3.35 (dd, J =11.1,1.7hz, 1h), 2.64 (s, 1H), 2.30-2.19 (m, 1H), 1.57-1.47 (m, 1H), 1.43-1.32 (m, 1H), 1.32-1.21H) were reported.
Example 189: (3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-42. MS (ESI): c 21 H 18 F 3 N 7 Calculated mass of O is 441.2; the measured value of m/z is 442.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.85, 0.15), the major optical isomers reported δ 8.89 (d, J =4.9hz, 2h), 8.53 (dd, J =8.0,1.6hz, 1h), 8.02 (d, J =4.8hz, 1h), 7.94-7.86 (m, 2H), 7.44 (t, J =4.9hz, 1h), 7.37 (dd, J =8.0,4.8Hz,1H),4.20-4.14(m,1H),4.11-4.01(m,1H),3.63(dt,J＝10.9,3.2Hz,1H),3.35(d,J＝10.9Hz,1H),2.77-2.68(m,1H),2.36-2.30(m,1H),1.70-1.54(m,2H),1.40-1.30(m,1H)。
Example 190: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-47. MS (ESI): c 22 H 20 F 3 N 7 Calculated mass of O is 455.2; the measured value of m/z is 456.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88-0.12), the major optical isomers reported δ 8.88 (d, J =4.9hz, 2h), 8.33 (dd, J =2.1,0.9hz, 1h), 7.90 (s, 1H), 7.89-7.88 (m, 1H), 7.82 (s, 1H), 7.43 (t, J =4.9hz, 1h), 4.20-4.15 (m, 1H), 4.10-3.99 (m, 1H), 3.60 (dt, J =10.9,3.2hz, 1h), 3.35 (dd, J =11.0,1.5hz, 1h), 2.73-2.67 (m, 1H), 2.33 (s, 3H), 2.32-2.26 (m, 1H), 1.66-1.51, 1H), 1.31, 1H (m, 1H), 1.31H).
Example 191: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-41. MS (ESI): c 22 H 20 F 3 N 7 Calculated mass of O is 455.2; the measured value of m/z is 456.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.86, 0.14), the major optical isomer was reported to be δ 7.37 (d, J =4.9hz, 2h), 6.88 (d, J =8.1hz, 1h), 6.45 (s, 1H), 6.33 (d, J =1.4hz, 1h), 5.91 (t, J =4.9hz, 1h), 5.74 (d, J =8.1hz, 1h), 2.76-2.67 (m, 1H), 2.59-2.48(m,1H),2.11(dt,J＝11.0,3.2Hz,1H),1.83(dd,J＝10.9,1.6Hz,1H),1.20-1.18(m,1H),0.87-0.75(m,4H),0.17--0.00(m,2H),-0.13--0.27(m,1H)。
Example 192: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-16. MS (ESI): c 20 H 17 F 4 N 7 The calculated mass value of O is 447.1; measured value of m/z is 448.2[ 2 ], [ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.35 min (main optical isomer).
Example 193: (4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-12. MS (ESI): c 20 H 17 F 4 N 7 The calculated mass value of O is 447.1; the measured value of m/z is 448.2[ M ] +H] + 。] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.56 min (main optical isomer).
Example 194: ((5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-10. MS (ESI): c 20 H 17 F 4 N 7 Calculated mass of O is 447.1; the measured value of m/z is 448.2[ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.36 min (main optical isomer).
Example 195: (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 59, substituting intermediate A-1 with intermediate A-11. MS (ESI): c 20 H 17 F 4 N 7 Calculated mass of O is 447.1; the measured value of m/z is 448.2[ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.41 min (main optical isomer).
Example 196: (3-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-22. MS (ESI): c 21 H 20 F 3 N 7 Calculated mass of O is 443.2; the measured value of m/z is 444.2[ m ] +H] + 。] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.61 min (main optical isomer).
Example 197: (4-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-5. MS (ESI): c 21 H 20 F 3 N 7 O 2 The calculated mass of (a) is 459.2; the measured value of m/z is 460.1[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.30 min (main optical isomer).
Example 198: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-23. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the value of m/z is 459.2M+H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.24 min (main optical isomer).
Example 199: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-7. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; measured value of m/z is 459.9[ m ] +H] + 。 1 H NMR (600 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.93, 0.07), reported as the major optical isomers) δ 8.84 (d, J =4.8hz, 2h), 8.19 (dd, J =8.8,5.5hz, 1h), 7.95-7.87 (m, 2H), 7.38 (t, J =4.9hz, 1h), 7.04 (td, J =8.4,2.7hz, 1h), 6.74-6.64 (m, 1H), 4.04-3.93 (m, 2H), 3.54 (dt, J =11.0,3.2hz, 1h), 3.36-3.33 (m, 1H), 2.66-2.62 (m, 1H), 2.30-2.22 (m, 1H), 1.50 (d, J = 10.01h), 1.34-1.24 (m, 2H).
Example 200: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-6. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.2[ M ] +H] + 。] + . Analytical HPLC was obtained on an Agilent 1100 line using an Xbridge C18 column (5 μm,100x4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OHFor 8 minutes, then held at 100% acn for 3 minutes at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.16 min (main optical isomer).
Example 201: (2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-37. MS (ESI): c 22 H 19 F 3 N 6 The calculated mass value of O is 440.2; the measured value of m/z is 441.9[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.93-0.07), the major optical isomers reported δ 8.86 (d, J =4.9hz, 2h), 8.12 (d, J =7.6hz, 1h), 7.94-7.87 (m, 1H), 7.86-7.78 (m, 1H), 7.40 (t, J =4.9hz, 1h), 7.30 (td, J =7.7,1.4hz, 1h), 7.02-6.92 (m, 1H), 6.87-6.75 (m, 1H), 4.06-3.90 (m, 2H), 3.52 (dt, J =11.0,3.1hz, 1h), 3.36-3.33 (m, 1H), 2.67-2.60 (m, 1H), 2.31-2.20 (m, 1H), 1.47, 10.1h, 1H), 1.26-1H (m, 1H).
Example 202: (5-fluoro-2-, (Oxazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-49. MS (ESI): c 21 H 17 F 4 N 5 O 2 The calculated mass of (a) is 447.1; the measured value of m/z is 448.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, main optical isomer reported) delta 8.30 (s, 1H),8.11(dd,J＝8.8,5.3Hz,1H),7.99-7.89(m,1H),7.85(d,J＝1.4Hz,1H),7.80(d,J＝0.9Hz,1H),7.29-7.26(m,1H),7.21(ddd,J＝8.9,7.9,2.7Hz,1H),7.05(dd,J＝8.3,2.6Hz,1H),4.88(s,1H),4.85-4.70(m,1H),3.22(dt,J＝8.9,2.9Hz,1H),2.95(dd,J＝8.9,1.5Hz,1H),2.63-2.55(m,1H),2.49-2.31(m,1H),1.90-1.75(m,2H),1.18-1.11(m,1H)。
example 203: (2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-34. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 The compounds were presented as a mixture of optical isomers (0.93, 0.07), reporting the major optical isomers) δ 8.81 (s, 2H), 8.12 (d, J =7.9hz, 1h), 7.97-7.87 (m, 1H), 7.86-7.76 (m, 1H), 7.29 (td, J =7.7,1.4hz, 1h), 6.95 (d, J =7.5hz, 1h), 6.85-6.70 (m, 1H), 4.08-3.90 (m, 2H), 3.55 (dt, J =10.9,3.2hz, 1h), 3.38-3.32 (m, 1H), 2.66 (s, 1H), 2.31-2.18 (m, 1H), 1.51 (d, J =10.0hz, 1h), 1.41-1.24 (m, 2H).
Example 204: (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-35. MS (ESI): c 22 H 17 F 5 N 6 Calculated mass of O is 476.1; measured value of m/z is 477.9[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.91, 0.09), the major optical isomer was reported as δ 8.88 (d, J =0.7Hz,2H),7.96-7.89(m,2H),7.11-7.03(m,1H),6.93-6.81(m,2H),4.20(s,1H),4.10-4.02(m,1H),3.28-3.25(m,2H),2.58(s,1H),2.32-2.19(m,1H),1.57(d,J＝10.1Hz,1H),1.32-1.21(m,1H),1.15-1.02(m,1H)。
example 205: (3-Phenylpyrazin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate A-1 was replaced with intermediate A-43. MS (ESI): c 22 H 19 F 3 N 6 The calculated mass value of O is 440.2; the measured value of m/z is 441.2[ M + ] H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as major optical isomers) δ 8.48 (d, J =2.4hz, 1h), 7.93 (s, 1H), 7.84 (s, 1H), 7.78 (d, J =2.4hz, 1h), 7.73-7.66 (m, 2H), 7.56-7.50 (m, 3H), 3.90-3.82 (m, 1H), 3.81-3.73 (m, 1H), 3.34 (dd, J =11.3,1.6hz, 1h), 3.27 (dt, J =11.3,3.2hz, 1h), 2.53-2.48 (m, 1H), 2.20-2.08 (m, 1H), 1.38-1.28 (m, 1H), 1.29-1.19 (m, 1H), 0.66-0.55 (m, 1H).
Example 206 [1,1' -diphenyl ] -2-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59 intermediate A-1 was substituted with [1,1' -diphenyl]-2-carboxylic acid substitution. MS (ESI): c 24 H 21 F 3 N 4 Calculated mass of O is 438.2; the measured value of m/z is 439.2[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ7.91(br.s,1H),7.76(br.s,1H),7.49-7.33(m,6H),7.25(td,J＝7.6,1.4Hz,1H),6.87(dd,J＝7.6,1.3Hz,1H),6.68(td,J＝7.5,1.3Hz,1H),3.93-3.72(m,2H),3.25(dd,J＝11.2,1.6Hz,1H),3.09(dt,J＝11.2,3.2Hz,1H),2.43-2.33(m,1H),2.16-2.05(m,1H),1.26-1.11(m,3H)。
Example 207: (3-Phenylfuran-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 59, substituting intermediate A-1 with intermediate A-45. MS (ESI): c 22 H 19 F 3 N 4 O 2 Calculated mass of 428.1; m/z is measured as 429.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.93, 0.07), the major optical isomers reported δ 8.09-8.05 (m, 1H), 7.74 (d, J =1.4hz, 1H), 7.43-7.36 (m, 4H), 7.36-7.31 (m, 1H), 7.06 (d, J =1.8hz, 1H), 6.41 (d, J =1.8hz, 1H), 4.50-4.46 (m, 1H), 4.04-3.96 (m, 1H), 3.49-3.45 (m, 2H), 2.64-2.58 (m, 1H), 2.28-2.20 (m, 1H), 1.61-1.49 (m, 2H), 1.32-1.24 (m, 1H).
Example 208: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 59, intermediate a-1 was replaced with intermediate a-2, followed by the alkylation step of example 153. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 473.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.88: J =7.6,1.2hz, 1H), 4.56-4.47 (m, 1H), 4.15-4.09 (m, 1H), 3.37 (dd, J =11.5,1.6hz, 1H), 3.22-3.16 (m, 4H), 2.63-2.59 (m, 1H), 2.08-1.98 (m, 1H), 1.97-1.88 (m, 1H), 1.55-1.48 (m, 1H), 0.84-0.77 (m, 1H).
Example 209: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- (methyl (5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 208, intermediate a-2 was replaced with intermediate a-7. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 473.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.89, 0.11), the major optical isomers reported δ 8.84 (d, J =4.9hz, 2h), 8.18 (dd, J =8.8,5.5hz, 1h), 8.15 (s, 1H), 8.09-8.04 (m, 1H), 7.39 (t, J =4.9hz, 1h), 7.05-6.96 (m, 1H), 6.64 (dd, J =8.5,2.7hz, 1H), 4.51-4.41 (m, 1H), 4.03-3.95 (m, 1H), 3.54 (dt, J =11.3,3.1hz, 1H), 3.45 (dd, J =11.3,1.6hz, 1H), 3.24 (s, 3H), 2.78-2.69 (m, 1H), 2.13-1.97 (m, 2H), 1.57-1.46 (m, 1H), 1.23-1.11 (m, 1H).
Example 210: ((1S,4S,6R) -6- (methyl (5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 208, intermediate A-2 was replaced with intermediate A-37. MS (ESI): c 23 H 21 F 3 N 6 The calculated mass value of O is 454.2; the measured value of m/z is 455.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.88, 0.12), the major optical isomers reported δ 8.85 (d, J =4.9hz, 2h), 8.10 (dd, J =7.9,1.2hz, 1h), 8.08 (s, 2H), 7.39 (t, J =4.9hz, 1h), 7.26 (td, J =7.7,1.4hz, 1h), 6.92 (dd, J =7.6,1.3hz, 1h), 6.82 (td, J =7.5,1.3hz, 1h), 4.50-4.43 (m, 1H), 3.99-3.92 (m, 1H), 3.52 (dt, J =11.3,3.1hz, 1h), 3.44 (dd, J =11.3,1.5hz, 1h), 3.23 (s, 3H), 2.76-2.67 (m, 1H), 2.12-1.91 (J =11.3,1.5hz, 1h) ((s, 3H) m,2H),1.52-1.42(m,1H),1.19-1.07(m,1H)。
Example 211: ((1S, 4S, 6R) -6- ((cyclopropylmethyl) (5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 59, intermediate a-1 was replaced with intermediate a-2, followed by the alkylation step of example 161. MS (ESI): c 26 H 24 F 4 N 6 Calculated mass of O is 512.2; the measured value of m/z is 513.2[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.93, 0.07), the major optical isomer being reported as δ 8.89 (d, J =4.9hz, 2h), 8.18 (br.s, 1H), 8.15 (br.s, 1H), 7.49 (t, J =5.0hz, 1h), 7.04-6.98 (m, 1H), 6.89-6.81 (m, 1H), 6.78 (dd, J =7.6,1.2hz, 1h), 4.48-4.40 (m, 1H), 4.18-4.14 (m, 1H), 3.84 (dd, J =16.1,5.9hz, 1H), 3.39-3.33 (m, 2H), 3.14 (dt, J =11.4,3.2hz, 1H), 2.63-2.58 (m, 1H), 2.19-2.08 (m, 1H), 1.91-1.84 (m, 1H), 1.53 (d, J =10.3hz, 1H), 1.01-0.92 (m, 1H), 0.77-0.70 (m, 1H), 0.65-0.52 (m, 2H), 0.51-0.43 (m, 1H), 0.38-0.30 (m, 1H).
Example 212: ((1S, 4S, 6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Step A: (1S,4S,6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [2.2.1 ]Tert-butyl hepta-2-carboxylate. To a microwave vial containing intermediate B-10 (300mg, 1.41mmol) in MeCN (3 mL) was added 2,5-dichloropyrazine (0.17mL, 1.70mmol) and Et 3 N (0.30mL, 2.12mmol), and the reaction mixture was sealed and heated on a 90 ℃ bench overnight. After completion of the reaction, the mixture was cooled to room temperature and washed with H 2 And (4) diluting with oxygen. The reaction mixture was extracted with EtOAc(3X). The combined organics were concentrated and the concentrate was directly subjected to silica gel chromatography (0-60% etoac in hexanes) to afford the title compound of step a (153mg, 0.471mmol, 33%). C 15 H 21 ClN 4 O 2 The mass calculation value of MS (ESI) is 324.1, the found value of m/z is 269.1[ M ] +2H-tBu] + 。 1 H NMR (500 MHz, methanol-d) 4 ) δ 7.99 (d, J =1.4hz, 1h), 7.71 (d, J =1.4hz, 1h), 4.45-4.39 (m, 1H), 4.16-4.12 (m, 1H), 3.08 (d, J =10.1hz, 1h), 2.62-2.50 (m, 1H), 2.29-2.19 (m, 1H), 1.74-1.64 (m, 2H), 1.22-1.16 (m, 1H), 1.11 (s, 9H). 1H is embedded under a solvent.
And B: (1S,4R,6R) -N- (5-chloropyrazin-2-yl) -2-azabicyclo [2.2.1]Hept-6-amine xHCl to a solution of the title compound of step A (150mg, 0.46mmol) in EtOAc (5 mL) was added 4M HCl in dioxane (0.6 mL) and the reaction mixture was stirred overnight. The reaction was concentrated to obtain the title compound of step B (137 mg), which was used without further purification. C 10 H 13 ClN 4 The calculated mass MS (ESI) of (a) was 224.1; measured value of m/z is 225.1[ 2 ], [ M ] +H] + 。
Step C: ((1S,4S,6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [ 2.2.1)]Hept-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone. To a solution of the title compound of step B (34 mg) and intermediate A-16 (28mg, 0.14mmol) in DMF (1 mL) were added DIPEA (0.12mL, 0.69mmol) and HATU (48mg, 0.13mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Gilson preparation method X to obtain the title compound (35 mg). MS (ESI): c 19 H 17 ClFN 7 The calculated mass value of O is 413.1; the measured value of m/z is 414.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.92, 0.08), the major optical isomers reported are δ 8.01 (s, 2H), 7.70-7.66 (m, 1H), 7.62 (d, J =1.4hz, 1H), 7.33-7.27 (m, 1H), 7.02-6.93 (m, 1H), 6.87 (d, J =7.7hz, 1H), 4.02 (s, 1H), 3.95-3.86 (m, 1H), 3.24-3.20 (m, 2H), 2.53 (s, 1H), 2.27-2.15 (m,1H),1.52(d,J＝10.3Hz,1H),1.22-1.05(m,2H)。
example 213:1S,4S, 6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation analogous to example 212, intermediate A-16 was replaced with intermediate A-10. MS (ESI): c 19 H 17 ClFN 7 The calculated mass value of O is 413.1; the measured value of m/z is 414.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as the major optical isomers) δ 7.95 (s, 2H), 7.84 (dd, J =9.0,4.7hz, 1h), 7.69-7.62 (m, 1H), 7.60 (d, J =1.4hz, 1h), 7.22-7.15 (m, 1H), 6.81-6.70 (m, 1H), 3.92-3.74 (m, 1H), 3.48-3.39 (m, 1H), 3.29-3.27 (m, 1H), 2.59 (s, 1H), 2.27-2.16 (m, 1H), 1.51-1.41 (m, 1H), 1.29-1.16 (m, 2H). 1H is buried under the solvent peak.
Example 214: ((1S, 4S, 6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 212, intermediate A-16 was replaced with intermediate A-2. MS (ESI): c 21 H 18 ClFN 6 The calculated mass value of O is 424.1; the measured value of m/z is 425.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.91, 0.09), the major optical isomers reported δ 8.91 (d, J =5.0hz, 2h), 7.63 (dd, J =9.3,1.5hz, 2h), 7.50 (t, J =5.0hz, 1h), 7.19-7.12 (m, 1H), 7.01-6.93 (m, 1H), 6.85 (d, J =6.9hz, 1h), 4.15 (s, 1H), 3.97-3.91 (m, 1H), 3.24-3.20 (m, 2H), 2.56-2.48 (m, 1H), 2.27-2.17 (m, 1H), 1.50 (d, J =10.3hz, 1h), 1.22-1.15 (m, 1H), 0.94 (d, 1j = 10.10H, 2h).
Example 215: ((1S, 4S, 6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 212, intermediate A-16 was replaced with intermediate A-37. MS (ESI): c 21 H 19 ClN 6 The calculated mass value of O is 406.1; the measured value of m/z is 407.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds presented as a mixture of optical isomers (0.92-0.08), the major optical isomers reported were δ 8.85 (d, J =4.9hz, 2h), 8.12 (d, J =8.0hz, 1h), 7.68-7.61 (m, 1H), 7.54-7.50 (m, 1H), 7.43-7.34 (m, 2H), 6.97 (d, J =7.6hz, 1h), 6.95-6.85 (m, 1H), 3.94 (s, 1H), 3.91-3.84 (m, 1H), 3.50 (dt, J =11.0,3.2hz, 1h), 3.30-3.29 (m, 1H), 2.66-2.58 (m, 1H), 2.28-2.17 (m, 1H), 1.51-1.42 (m, J = 10.1h), 1.27-2.27H, 1H), 1.51-1H, 1.10, 1H, and 1.27H.
Example 216: ((1S, 4S, 6R) -6- ((5-chloropyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 212, intermediate A-16 was replaced with intermediate A-35. MS (ESI): c 23 H 18 F 5 N 5 Calculated mass of O is 475.1; m/z found at 476.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.92, 0.08), the major optical isomers reported δ 8.87 (s, 2H), 7.93 (s, 1H), 7.58 (dd, J =8.9,2.5hz, 1h), 7.13-7.00 (m, 1H), 6.90-6.82 (m, 1H), 6.82-6.75 (m, 1H), 6.65-6.54 (m, 1H), 4.17 (s, 1H), 4.13-4.04 (m, 1H), 3.28-3.21 (m, 2H), 2.61-2.50 (m, 1H), 2.31-2.16 (m, 1H), 1.59 (d, J =10.2hz, 1h), 1.27-1.08 (m, 2H).
Example 217: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methylpyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((5-methylpyrazin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing degassed toluene (9 mL) at room temperature was added Pd (OAc) 2 (24mg, 0.035mmol) and racemic BINAP (22mg, 0.035mmol), and the reaction mixture was purified with N 2 Purge 5 minutes. 2-chloro-5-methylpyrazine (112mg, 0.87mmol), intermediate B-10 (204 mg) and sodium tert-butoxide (121mg, 1.22mmol) were then added and the reaction mixture was heated at 70 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo and the crude residue was directly subjected to silica gel chromatography (10-80% etoac in hexane) to obtain the title compound of step a (139mg, 0.457mmol, 52%). C 16 H 24 N 4 O 2 Mass calculated MS (ESI) of (1) of 304.2; measured value of m/z is 305.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 ) δ 7.93-7.79 (m, 2H), 4.45-4.40 (m, 1H), 4.16-4.12 (m, 1H), 3.09 (dd, J =9.5,1.2hz, 1h), 2.60-2.53 (m, 1H), 2.33 (s, 3H), 2.29-2.20 (m, 1H), 1.74-1.64 (m, 2H), 1.20-1.15 (m, 1H), 1.08 (s, 9H). 1H is embedded under a solvent.
And B: (1S,4R,6R) -N- (5-methylpyrazin-2-yl) -2-azabicyclo [2.2.1]Heptan-6-amine xHCl to a solution of the title compound of step A (139mg, 0.46mmol) in EtOAc (5 mL) was added a 4M HCl solution in dioxane (0.6 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to obtain the title compound of step B (140 mg), which was used without further purification. C 11 H 16 N 4 The calculated mass MS (ESI) of (a) was 204.1; the measured value of m/z is 205.2[ m ] +H] + 。
And C: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methylpyrazin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To the title compound of step B (31 mg) and intermediate A-16 (28mg, 0.13mmol) in DMF (1 mL)) To the solution, DIPEA (0.12mL, 0.67mmol) and HATU (47mg, 0.12mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Gilson preparation method X to obtain the title compound (18 mg). MS (ESI): c 20 H 20 FN 7 The calculated mass value of O is 393.2; m/z found to be 394.2[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers, the major optical isomers reported) δ 8.00 (s, 2H), 7.80-7.75 (m, 1H), 7.55-7.49 (m, 1H), 7.29-7.22 (m, 1H), 6.93-6.78 (m, 2H), 4.10-3.97 (m, 1H), 3.97-3.89 (m, 1H), 3.25-3.20 (m, 2H), 2.53 (s, 1H), 2.33 (s, 3H), 2.27-2.17 (m, 1H), 1.54 (d, J =10.1hz, 1h), 1.23-1.11 (m, 2H).
Example 218: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methylpyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 217, intermediate A-16 was replaced with intermediate A-10. MS (ESI): c 20 H 20 FN 7 The calculated mass value of O is 393.2; m/z found to be 394.5[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as the major optical isomers) δ 7.95 (s, 2H), 7.82 (dd, J =9.0,4.7hz, 1h), 7.78 (s, 1H), 7.50-7.45 (m, 1H), 7.19-7.11 (m, 1H), 6.69 (s, 1H), 3.91-3.77 (m, 2H), 3.48-3.38 (m, 1H), 2.58 (s, 1H), 2.32 (s, 3H), 2.27-2.18 (m, 1H), 1.50-1.38 (m, 1H), 1.29-1.14 (m, 2H). 1H is embedded in the solvent.
Example 219: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5-methylpyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 217, intermediate A-16 was replaced with intermediate A-2. MS (ESI): c 22 H 21 FN 6 The calculated mass value of O is 404.2; the measured value of m/z is 405.5[ deg. ] M + H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.91-0.09), reported as the major optical isomers) δ 8.90 (d, J =5.0hz, 2h), 7.75 (d, J =1.5hz, 1h), 7.55-7.52 (m, 1H), 7.49 (t, J =5.0hz, 1h), 7.15-7.09 (m, 1H), 6.92-6.86 (m, 1H), 6.85-6.82 (m, 1H), 4.18-4.13 (m, 1H), 4.01-3.93 (m, 1H), 3.27-3.20 (m, 2H), 2.53 (s, 1H), 2.33 (s, 3H), 2.27-2.19 (m, 1H), 1.53 (d, J = 10.3hz), 1.21-1.14 (m, 1H), 1.06H, 1.06 (m, 1H).
Example 220: ((1S,4S,6R) -6- ((5-methylpyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 217, intermediate A-16 was replaced with intermediate A-37. MS (ESI): c 22 H 22 N 6 Calculated mass of O is 386.2; the measured value of m/z is 387.1[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88, 0.12), the major optical isomers reported were δ 8.85 (d, J =4.9hz, 2h), 8.11 (d, J =7.9hz, 1h), 7.75 (s, 1H), 7.43 (s, 1H), 7.39 (t, J =4.9hz, 1h), 7.33 (t, J =7.7hz, 1h), 6.96 (d, J =7.5hz, 1h), 6.87-6.76 (m, 1H), 4.03-3.84 (m, 2H), 3.51 (dt, J =11.1,3.2hz, 1h), 2.67-2.57 (m, 1H), 2.33 (s, 3H), 2.28-2.14 (m, 1H), 1.48 (d, J =9.8, 1H), 1.18-1.18H (m, 1H). 1H is buried under the solvent peak.
Example 221- (((1S, 4S, 6R) -2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2-azabicyclo [2.2.1] hept-6-yl) amino) pyrazine-2-carboxylic acid methyl ester
Step A: (1S,4S,6R) -6- ((5- (methoxycarbonyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing intermediate B-10 (100mg, 0.471mmol) in DMF (2 mL) was added methyl 5-chloropyrazine-2-carboxylate (98mg, 0.57mmol) and Et 3 N (0.1mL, 0.72mmol), and the reaction mixture was sealed and heated on a 70 ℃ bench overnight. After 14 hours LCMS analysis of the reaction mixture showed incomplete conversion of the starting material. The temperature was raised to 100 ℃ and the reaction mixture was heated overnight. After completion of the reaction, the mixture was cooled to room temperature and directly subjected to silica gel chromatography (0-50% etoac in hexanes) to obtain the title compound of step a (112 mg). C 17 H 24 N 4 O 4 The mass calculation value of MS (ESI) is 348.2, and the measured value of m/z is 349.2[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers) Δ 8.78-8.68 (m, 1H), 7.93-7.74 (m, 1H), 6.30-6.18 and 5.90-5.77 (two m, 1H), 4.46-4.36 (m, 1H), 4.33-4.12 (m, 1H), 3.91 (s, 3H), 3.41-3.30 (m, 1H), 3.11-2.99 (m, 1H), 2.63-2.51 (m, 1H), 2.39-2.25 (m, 1H), 1.78-1.59 (m, 2H), 1.51-1.01 (m, 10H).
And B:5- ((1S, 4R, 6R) -2-azabicyclo [2.2.1]Hept-6-ylamino) pyrazine-2-carboxylic acid methyl ester xHCl to a solution of the title compound of step A (112mg, 0.321mmol) in EtOAc (1 mL) was added a 4M solution of HCl in dioxane (3 mL) and the reaction mixture was stirred at room temperature for 2h. The reaction was concentrated to obtain the title compound of step B (99 mg), which was used without further purification. C 12 H 16 N 4 O 2 The mass calculation value of MS (ESI) of (4) is 248.1; the measured value of m/z is 249.1[ m ] +H] + 。
And C:5- (((1S,4S,6R) -2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2-azabicyclo [2.2.1]Hept-6-yl) amino) pyrazine-2-carboxylic acid methyl ester. To a solution of the title compound of step B (99 mg) and intermediate A-1 (70mg, 0.37mmol) in DMF (2 mL) was added DIPEA (0.3mL, 1.7 mmol) and HATU (129mg, 0.339mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics are concentrated andand the concentrate was directly subjected to purification via Gilson preparation method X to obtain the title compound. MS (ESI): c 21 H 21 N 7 O 3 The calculated mass value of (a) is 419.2; the measured value of m/z is 420.2[ m ] +H] + . Analytical HPLC was obtained on the Agilent 1100 line using an Xbridge C18 column (5 μm,100x4.6 mM) with mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =4.75 min (main optical isomer).
Example 222: (2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-39. MS (ESI): c 19 H 17 F 3 N 8 The calculated mass value of O is 430.1; the measured value of m/z is 430.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =5.15 min (main optical isomer).
Example 223: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 60, substituting intermediate A-1 with intermediate A-16. MS (ESI): c 20 H 17 F 4 N 7 The calculated mass value of O is 447.1; measured value of m/z is 448.9[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88-0.12), the major optical isomers reported δ 8.56 (d, J =3.2hz, 1h), 8.20 (d, J =3.1hz, 1h), 8.01 (s, 2H), 7.28-7.19 (m, 1H), 7.06-6.95 (m, 1H), 6.93-6.85 (m, 1H), 4.10-3.99 (m, 2H), 3.29-3.26 (m, 1H), 3.20 (dt, J =11.2,3.2hz, 1h), 2.57-2.51 (m, 1H), 2.25-2.12 (m, 1H), 1.54 (d, J =10.3hz, 1h), 1.39-1.28 (m, 1H), 1.23-1.08 (m, 1H).
Example 224: (4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-12. MS (ESI): c 20 H 17 F 4 N 7 Calculated mass of O is 447.1; the measured value of m/z is 448.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers reported as major optical isomers) δ 8.56 (s, 1H), 8.22-8.13 (m, 1H), 7.98 (s, 2H), 7.64 (dd, J =9.6,2.6hz, 1h), 7.12-6.99 (m, 1H), 6.68-6.50 (m, 1H), 4.07-3.95 (m, 1H), 3.80 (s, 1H), 3.54-3.43 (m, 1H), 3.36 (dd, J =10.9,1.6hz, 1h), 2.62 (s, 1H), 2.26-2.14 (m, 1H), 1.52-1.42 (m, 1H), 1.38-1.29 (m, 2H).
Example 225: (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-10. MS (ESI): c 20 H 17 F 4 N 7 The calculated mass value of O is 447.1; m/z value measured is 447.9[ M ] C + H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers, reporting the major optical isomer)) delta 8.52(s,1H),8.17(d,J＝3.1Hz,1H),7.95(s,2H),7.85(dd,J＝9.0,4.8Hz,1H),7.16-7.06(m,1H),6.86-6.74(m,1H),4.07-3.97(m,1H),3.80(s,1H),3.47-3.33(m,2H),2.65-2.54(m,1H),2.25-2.15(m,1H),1.47(d,J＝10.2Hz,1H),1.38-1.31(m,1H),1.31-1.21(m,1H)。
Example 226: (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-11. MS (ESI): c 20 H 17 F 4 N 7 Calculated mass of O is 447.1; measured value of m/z is 447.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 line using an Xbridge C18 column (5 μm,100x4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.18 min (main optical isomer).
Example 227: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 60, substituting intermediate A-1 with intermediate A-23. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.9[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88, 0.12), the main optical isomer reported δ 8.88 (d, J =4.9hz, 2h), 8.64-8.47 (m, 1H), 8.16 (d, J =3.1hz, 1h), 7.89 (dd, J =10.0,2.7hz, 1h), 7.42 (t, J =4.9hz, 1h), 7.12-6.93 (m, 1H), 6.68 (s, 1H), 4.09-3.85 (m, 2H), 3.53 (dt, J =10.9,3.2hz, 1h), 3.36 (dd, J = 1H)10.9,1.6Hz,1H),2.69-2.61(m,1H),2.30-2.16(m,1H),1.54-1.43(m,1H),1.41-1.34(m,1H),1.33-1.23(m,1H)。
Example 228: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-7. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.9[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.91: 6.80-6.71 (m, 1H), 4.10-4.00 (m, 1H), 3.94 (s, 1H), 3.52 (dt, J =10.7,3.1Hz, 1H), 3.36 (dd, J =10.9,1.6Hz, 1H), 2.68-2.60 (m, 1H), 2.27-2.15 (m, 1H), 1.49 (d, J =10.1Hz, 1H), 1.41-1.33 (m, 1H), 1.33-1.23 (m, 1H).
Example 229: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-6. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.9[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers, the major optical isomers reported) δ 8.87 (d, J =4.9hz, 2h), 8.56-8.51 (m, 1H), 8.12-8.04 (m, 2H), 7.42 (t, J =4.9hz, 1h), 7.36-7.30 (m, 1H), 6.73-6.67 (m, 1H), 4.03-3.97 (m, 1H), 3.97-3.90 (m, 1H), 3.56 (dt, J =10.9,3.2hz, 1h), 3.36 (dd, J = 10.9H) ,1.7Hz,1H),2.65-2.60(m,1H),2.25-2.14(m,1H),1.49-1.39(m,2H),1.20-1.14(m,1H)。
Example 230: (2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-37. MS (ESI): c 22 H 19 F 3 N 6 The calculated mass value of O is 440.2; the measured value of m/z is 441.9[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88-0.12), the major optical isomers reported δ 8.86 (d, J =4.9hz, 2h), 8.56-8.48 (m, 1H), 8.15 (d, J =8.0hz, 1h), 8.10 (s, 1H), 7.39 (t, J =4.9hz, 1h), 7.36-7.28 (m, 1H), 7.01 (s, 1H), 6.95 (s, 1H), 4.11-3.91 (m, 2H), 3.52 (dt, J =11.0,3.3hz, 1h), 3.35 (dd, J =10.9,1.6hz, 1h), 2.64 (s, 1H), 2.28-2.16 (m, 1H), 1.56-1.44 (m, 1H), 1.41-1.16 (m, 1H), 1.16 (m, 2H).
Example 231: (2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-34. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.9[ M ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.88, 0.12), the major optical isomers reported δ 8.82 (s, 2H), 8.58-8.47 (m, 1H), 8.15 (d, J =7.8hz, 1h), 8.13-8.04 (m, 1H), 7.32 (t, J =7.6hz, 1h), 7.10-6.83 (m, 2H), 4.12-4.03 (m, 1H), 4.04-3.89 (m, 1H), 3.56 (dt, J =10.9,3.3hz, 1h), 3.36 (dd, J =10.9,1.6hz, 1h), 2.70-2.62 (m, 1H), 2.29-2.17 (m, 1H), 1.61-1.14 (m, 3H).
Example 232: (2-fluoro-6-)Oxazol-2-yl) phenyl) ((1S,4S,6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation was analogous to example 60, substituting intermediate A-1 with intermediate A-50. MS (ESI): c 21 H 17 F 4 N 5 O 2 The calculated mass of (a) is 447.1; measured value of m/z is 447.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.15 min (main optical isomer).
Example 233: (3-ethoxy-6-methylpyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 60, intermediate A-1 was replaced with intermediate A-8. MS (ESI): c 20 H 22 F 3 N 5 O 2 The calculated mass of (a) is 421.2; measured value of m/z is 422.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.85-0.15), the major optical isomers reported δ 8.47 (d, J =3.2hz, 1h), 8.11 (d, J =3.1hz, 1h), 7.23 (d, J =8.6hz, 1h), 7.06 (d, J =8.9hz, 1h), 4.47-4.42 (m, 1H), 4.08-3.95 (m, 3H), 3.60 (dt, J =11.1,3.2hz, 1h), 3.38 (dd, J =11.1,1.6hz, 1h), 2.77-2.69 (m, 1H), 2.36-2.28 (m, 1H), 2.26 (s, 3H), 1.92-1.87 (m, 1H), 1.83-1.78 (m, 1H), 1.42-1.42 (m, 4H).
Example 234: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Step A: (1S,4S,6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing a solution of intermediate B-10 (305mg, 1.44mmol) in DMF (6 mL) was added 2,5-dichloropyrimidine (257mg, 1.72mmol) and DIPEA (0.99ml, 5.75mmol) and the reaction mixture was sealed and heated on an 80 ℃ bench overnight. After completion of the reaction, the mixture was cooled to room temperature and washed with H 2 And (4) diluting with O. The reaction mixture was extracted with EtOAc (3 ×). The combined organics were washed with 5% aqueous LiCl solution and dried (Na) 2 SO 4 ) Filtered and concentrated. The concentrate was directly subjected to silica gel chromatography (10-90% EtOAc in hexane) to obtain the title compound of step A (433mg, 1.33mmol, 93%). C 15 H 21 ClN 4 O 2 The mass calculation value of MS (ESI) is 324.1, the found value of m/z is 269.1[ M ] +2H-tBu] + 。
And B: (1S,4R,6R) -N- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1]To a solution of the title compound of step A (433mg, 1.33mmol) in EtOAc (7 mL) was added 4M HCl in dioxane (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to obtain the title compound of step B (370 mg), which was used without further purification. C 10 H 13 ClN 4 Mass calculated MS (ESI) of 224.1; measured value of m/z is 225.1[ 2 ], [ M ] +H] + 。
And C: ((1S,4S,6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [ 2.2.1)]Hept-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-16 (25mg, 0.12mmol) in DMF (1 mL) were added DIPEA (0.10mL, 0.61mmol) and HATU (42mg, 0.11mmol), and the reaction mixture was stirred at room temperatureStirring for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate was directly subjected to purification via Gilson preparation method X to obtain the title compound (32 mg). MS (ESI): c 19 H 17 ClFN 7 The calculated mass value of O is 413.1; the measured value of m/z is 414.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.89-0.11), reporting the major optical isomers) δ 8.35-8.20 (m, 1H), 8.00 (s, 2H), 7.94-7.82 (m, 1H), 7.33-7.24 (m, 1H), 7.08-7.00 (m, 1H), 6.88 (d, J =7.7hz, 1h), 4.01 (s, 1H), 3.98-3.92 (m, 1H), 3.27 (dd, J =11.1, 1.6h), 3.18 (dt, J =10.8,3.0hz, 1h), 2.55-2.48 (m, 1H), 2.22-2.12 (m, 1H), 1.52 (d, J =10.3hz, 1h), 1.30-1.22 (m, 1H), 1.18-1.18H, 1m, 1H).
Example 235: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Preparation was analogous to example 234, intermediate A-16 was replaced with intermediate A-10. MS (ESI): c 19 H 17 ClFN 7 The calculated mass value of O is 413.1; the measured value of m/z is 414.0[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 )δ8.25(s,1H),8.14-8.01(m,1H),7.95(s,2H),7.85(dd,J＝9.0,4.8Hz,1H),7.17(ddd,J＝9.0,7.8,2.9Hz,1H),6.84-6.75(m,1H),3.98-3.86(m,1H),3.85-3.75(m,1H),3.44-3.38(m,1H),3.36-3.32(m,1H),2.63-2.54(m,1H),2.23-2.12(m,1H),1.49-1.41(m,1H),1.34-1.20(m,2H)。
Example 236: ((1S,4S,6R) -6- ((5-chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 234, intermediate A-16 is replaced by intermediate a-2. MS (ESI): c 21 H 18 ClFN 6 The calculated mass value of O is 424.1; the measured value of m/z is 425.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds were presented as a mixture of optical isomers (0.89, 0.11), reporting the major optical isomers) δ 8.91 (d, J =5.0hz, 2h), 8.35-8.15 (m, 1H), 8.02-7.85 (m, 1H), 7.49 (t, J =5.0hz, 1h), 7.20-7.12 (m, 1H), 7.10-7.01 (m, 1H), 6.88 (d, J =7.9hz, 1h), 4.14 (s, 1H), 4.05-3.95 (m, 1H), 3.26-3.21 (m, 1H), 2.56-2.48 (m, 1H), 2.24-2.12 (m, 1H), 1.52 (d, J =9.5hz, 1h), 1.31-1.18 (m, 1H), 1.03 (d, J = 9.1h), 1.03 (d, 10H, 1h). 1H is embedded in the solvent.
Example 237: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 234, intermediate a-16 was replaced with intermediate a-23. MS (ESI): c 21 H 18 ClFN 6 The calculated mass value of O is 424.1; the measured value of m/z is 425.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers, the major optical isomers) δ 8.87 (d, J =4.9hz, 2h), 8.34-8.19 (m, 1H), 8.03-7.76 (m, 2H), 7.41 (t, J =4.9hz, 1h), 7.10-6.98 (m, 1H), 6.80-6.67 (m, 1H), 4.01-3.85 (m, 2H), 3.51 (dt, J =11.0,3.2hz, 1h), 3.37-3.31 (m, 1H), 2.62 (s, 1H), 2.25-2.14 (m, 1H), 1.47 (d, J =9.9hz, 1h), 1.37-1.20 (m, 2H) are reported.
Example 238: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 234, intermediate A-16 was replaced with intermediate A-7. MS (ESI): c 21 H 18 ClFN 6 The calculated mass value of O is 424.1; m-z is measured value of 425.1[ deg. ] M +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.87, 0.13), reported as the major optical isomers) δ 8.84 (d, J =4.8hz, 2h), 8.29-8.19 (m, 2H), 7.86 (br.s, 1H), 7.38 (t, J =4.9hz, 1h), 7.11 (td, J =8.5,2.7hz, 1h), 6.79-6.70 (m, 1H), 3.98-3.88 (m, 2H), 3.50 (dt, J =10.9,3.2hz, 1h), 3.34 (dd, J =11.0,1.7hz, 1h), 2.64-2.59 (m, 1H), 2.24-2.15 (m, 1H), 1.47 (d, J = 10.0h), 1.35-1.19 (m, 2H).
Example 239: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 234, intermediate A-16 was replaced with intermediate A-6. MS (ESI): c 21 H 18 ClFN 6 The calculated mass value of O is 424.1; the measured value of m/z is 425.1[ m ] +H] + . Analytical HPLC used an Xbridge C18 column (5 μm, 100x4.6mm) with a mobile phase of 10-100% ACN in 20mM NH 4 In OH, 2 minutes and then 2 minutes at 100% acn, at a flow rate of 2.5mL/min (temperature =45 ℃). R at 254nm t And =1.85 and 2.12 minutes (main optical isomer).
Example 240: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 234, intermediate A-16 was replaced with intermediate A-37. MS (ESI): c 21 H 19 ClN 6 The calculated mass value of O is 406.1; measured value of m/z is 407.1[ 2 ], [ M + H ]] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as a mixture of optical isomers (0.88 hz, 0.12), the major optical isomer reported δ 8.85 (d, J =4.9hz, 2h), 8.29-8.18 (m, 1H), 8.14 (dt, J =8.0,0.9hz, 1h),7.92-7.70(m,1H),7.42-7.35(m,2H),7.07-6.92(m,2H),4.10-3.86(m,2H),3.50(dt,J＝10.8,3.3Hz,1H),3.35-3.32(m,1H),2.65-2.59(m,1H),2.27-2.13(m,1H),1.54-1.43(m,1H),1.36-1.19(m,2H)。
example 241: ((1S, 4S, 6R) -6- ((5-Chloropyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 234, intermediate A-16 was replaced with intermediate A-34. MS (ESI): c 21 H 18 ClFN 6 The calculated mass value of O is 424.1; the measured value of m/z is 425.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.87, 0.13), the major optical isomers are reported as δ 8.81 (s, 2H), 8.38-8.17 (m, 1H), 8.17-8.13 (m, 1H), 7.93-7.75 (m, 1H), 7.44-7.32 (m, 1H), 7.11-6.91 (m, 2H), 4.06-3.86 (m, 2H), 3.54 (dt, J =10.8,3.3hz, 1H), 3.34 (dd, J =11.0,1.7hz, 1H), 2.71-2.61 (m, 1H), 2.29-2.15 (m, 1H), 1.59-1.46 (m, 1H), 1.45-1.27 (m, 2H).
Example 242: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a vial containing a solution of intermediate B-10 (100mg, 0.471mmol) in MeCN (2 mL) was added 3-chloro-6- (trifluoromethyl) pyridazine (103mg, 0.565mmol) and Et 3 N (0.15ml, 1.1mmol), and the reaction mixture was sealed and heated on a 90 ℃ bench overnight. After completion of the reaction, the mixture was cooled to room temperature and directly subjected to silica gel chromatography (0-50% etoac in hexanes) to obtain the title compound of step a (143 mg) containing a small amount of impurities. Title to be written The compound was carried forward to the next step. C 16 H 21 F 3 N 4 O 2 The mass calculation value of MS (ESI) is 358.2, and the found value of m/z is 359.2[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers) Δ 7.45-7.33 (m, 1H), 6.71-6.56 (m, 1H), 6.12 and 5.60 (2 br.s, 1H), 4.53-4.21 (m, 2H), 3.44-3.29 (m, 1H), 3.13-3.01 (m, 1H), 2.63-2.56 (m, 1H), 2.50-2.28 (m, 1H), 1.77-1.06 (m, 12H).
And B, step B: (1S,4R,6R) -N- (6- (trifluoromethyl) pyridazin-3-yl) -2-azabicyclo [2.2.1]Hepta-6-amine xHCl to a solution of the title compound of step A (143mg, 0.399mmol) in EtOAc (1 mL) was added a 4M solution of HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 1.5h. The reaction was concentrated to obtain the title compound of step B (130 mg), which was used without further purification. C 11 H 13 F 3 N 4 The mass calculation of MS (ESI) of (1) was 258.1; measured value of m/z is 259.2[ m ] +H] + 。
And C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (33 mg) and intermediate A-1 (21mg, 0.11mmol) in DMF (0.5 mL) were added DIPEA (0.1mL, 0.58mmol) and HATU (42mg, 0.11mmol) and the reaction mixture was stirred at room temperature for 1h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Agilent preparative method X to give the title compound (26 mg). MS (ESI): c 20 H 18 F 3 N 7 Calculated mass value of O is 429.2; the measured value of m/z is 430.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =5.48 min (main optical isomer).
Example 243: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 242, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 20 H 19 F 3 N 8 Calculated mass of O is 444.2; the measured value of m/z is 445.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.86.
Example 244: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 242, intermediate A-1 was replaced with intermediate A-41. MS (ESI): c 22 H 20 F 3 N 7 Calculated mass of O is 455.2; the measured value of m/z is 456.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.93.
Example 245: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridazin-3-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 242, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 22 H 18 F 4 N 6 The calculated mass value of O is 458.1; the measured value of m/z is 459.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.85.
Example 246: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridin-3-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Step A: (1S,4S,6R) -6- ((6- (trifluoromethyl) pyridin-3-yl) amino) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To a microwave vial containing degassed toluene (2 mL) solution at room temperature were added 5-bromo-2- (trifluoromethyl) pyridine (116mg, 0.514mmol), intermediate B-10 (120 mg), and racemic BINAP (13mg, 0.021mmol), and the reaction mixture was quenched with N 2 Degassing for 5 minutes. Then Pd (OAc) is added 2 (14mg, 0.021mmol) and sodium tert-butoxide (71mg, 0.72mmol), and the reaction mixture was heated at 70 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature and the crude material was directly subjected to silica gel chromatography (0-50% etoac in hexanes) to obtain the title compound of step a (184 mg). C 17 H 22 F 3 N 3 O 2 The mass calculation of MS (ESI) of (1) is 357.2; the measured value of m/z is 358.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers) Δ 8.02 and 7.90 (two s, 1H), 7.46-7.35 (m, 1H), 6.88-6.81 and 6.77-6.68 (two m, 1H), 5.39-5.29 and 4.72-4.62 (two m, 1H), 4.47-4.33 (m, 1H), 3.87-3.72 (m, 1H), 3.41-3.31 (m, 1H), 3.11-2.99 (m, 1H), 2.64-2.56 (m, 1H), 2.37-2.17 (m, 1H), 1.81-1.67 (m, 1H), 1.66-1.60 (m, 1H), 1.53-1.01 (m, 11H).
And B: (1S,4R,6R) -N- (6- (trifluoromethyl) pyridin-3-yl) -2-azabicyclo [2.2.1]Heptan-6-amine xHCl to a solution of the title compound of step A (77mg, 0.22mmol) in EtOAc (0.6 mL) was added a 4M solution of HCl in dioxane (3 mL) and the reaction mixture was stirred at room temperature for 2.5h. The reaction was concentrated to obtain the title compound of step B (72 mg), which was used without further purification. C 12 H 14 F 3 N 3 Mass calculated as 257.1 for MS (ESI); the measured value of m/z is 258.1[ m ] +H] + 。
Step C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridin-3-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone. To a solution of the title compound of step B (36 mg) and intermediate A-1 (25mg, 0.13mmol) in DMF (1 mL) was added DIPEA (0.2mL, 1.2mmol) and HATU (46mg, 0.12mmol), and the reaction mixture was stirred at room temperature for 1.5h. The reaction is carried out by adding H 2 O quenched and the aqueous layer was extracted with EtOAc (2 ×). The combined organics were concentrated and the concentrate directly subjected to purification via Gilson preparation method X to obtain the title compound (29 mg). MS (ESI): c 21 H 19 F 3 N 6 Calculated mass of O is 428.2; m/z is measured as 429.2[ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.07 min (main optical isomer).
Example 247: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((6- (trifluoromethyl) pyridin-3-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 246, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 23 H 19 F 4 N 5 The calculated mass value of O is 457.2; the measured value of m/z is 458.1[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers (0.89, 0.11), the major optical isomers reported δ 8.91 (d, J =5.0hz, 2h), 7.87 (d, J =2.7hz, 1h), 7.50 (t, J =5.0hz, 1h), 7.31 (d, J =8.7hz, 1h), 7.06-6.99 (m, 1H), 6.87-6.80 (m, 2H), 6.73 (dd, J =8.7,2.8hz, 1h), 4.11 (s, 1H), 3.80-3.71 (m, 1H), 3.28-3.22 (m, 2H), 2.60-2.52 (m, 1H), 2.34-2.25 (m, 1H), 1.59 (d, J =10.8, 1h), 1.24-1.18 (m, 1H), 3.11H, 1H, 1.11H), 3.11-1H (d, 1H).
Example 248: (R/S) - (3-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (R/S) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-carboxylic acid tert-butyl ester. To intermediate C-5A (50mg, 0.22mmol) in DMF (2 mL) was added NaH (18mg, 0.44mmol,60% dispersion in mineral oil). After 5 min, 2-chloro-5- (trifluoromethyl) pyridine (64mg, 0.35mmol) was then added, and the mixture was stirred at room temperature for 3h. The reaction mixture was saturated with NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, washing with MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-40% EtOAc in hexane) afforded the title compound (67mg, 0.18mmol, 82%). C 18 H 23 F 3 N 2 O 3 Mass calculated MS (ESI) of 372.2; the measured value of m/z is 373.2[ m ] +H] + 。 1 H NMR(500MHz, methanol-d 4 Compounds presented as mixtures of optical isomers (0.68-0.32), the major optical isomers reported were δ 8.49-8.45 (m, 1H), 7.94 (dd, J =8.8,2.6hz, 1h), 6.90 (d, J =8.7,0.8hz, 1h), 5.22 (dt, J =9.7,2.9hz, 1h), 4.48-4.41 (m, 1H), 3.42 (dt, J =10.9,2.5hz, 1h), 3.25 (dt, J =11.0,2.6hz, 1h), 2.27-2.18 (m, 1H), 2.09-2.04 (m, 1H), 1.97-1.87 (m, 1H), 1.77-1.71 (m, 1H), 1.68-1.59 (m, 3H), 1.13 (s, 9H).
And B: (R/S) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (67mg, 0.18 mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (0.23 mL). After 3h, the reaction was concentrated to obtain the title compound of step B, which was used without further purification. C 13 H 15 F 3 N 2 Calculated mass MS (ESI) for O is 272.1; the measured value of m/z is 273.1[ m ] +H ] + 。
And C: (R/S) - (3-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (46 mg) and intermediate A-2 (54mg, 0.20mmol,82% purity) in DMF (1.7 mL) were added DIPEA (0.18mL, 1.01mmol) and HATU (71mg, 0.19mmol), and the reaction mixture was stirred at room temperature overnight. Subjecting the reaction mixture to hydrogenation with H 2 O and EtOAc dilution. The aqueous layer was extracted with EtOAc (3 ×), and the combined organics were concentrated and directly subjected to purification using Gilson preparative method X to give the title compound (20 mg). MS (ESI): c 24 H 20 F 4 N 4 O 2 The calculated mass of (a) is 472.2; the measured value of m/z is 473.1[ m ] +H] + . Analytical HPLC using an Xbridge C18 column (5um, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 2 minutes and then 2 minutes at 100% acn, at a flow rate of 2.5mL/min (temperature =45 ℃). R at 254nm t =2.18 and 2.29 minutes (main optical isomer). Using Chiralpak AZ-H column (5 μm 250X 21 mm), 35% EtOH + (0.2% TEA): 65% CO 2 Mobile phase, and flow rate of 40mL/min (temperature =40 ℃), the enantiomer of example 248 was isolated via chiral SFC purification.
Example 249: (R/S) - (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 248, substituting intermediate A-2 with intermediate A-16. MS (ESI): c 22 H 19 F 4 N 5 O 2 Calculated mass of 461.2; the measured value of m/z is 461.9[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds presented as mixtures of optical isomers, the major optical isomers reported) δ 8.25 (s, 1H), 8.11-7.95 (m, 3H), 7.27 (t, J =9.3hz, 1h), 7.14-7.00 (m, 2H), 6.91 (d, J =7.8hz, 1h), 5.14-5.06 (m, 1H), 3.82 (s, 1H), 3.60 (d, J =12.8hz, 1h), 3.24 (d, J =12.7hz, 1h), 2.34-2.24 (m, 1H), 2.11 (s, 1H), 1.81-1.41 (a series of m, 5H).
Example 250: (R/S) - (4-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 248, substituting intermediate a-2 with intermediate a-23. MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 472.9[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 Compounds which are present as a mixture of optical isomers) δ 8.96-8.78 (m, 2H), 8.22-8.14 (m, 1H), 8.04-7.97 (m, 1H), 7.92 (dd, J =10.1,2.6hz, 1h), 7.49-7.42 (m, 1H), 7.10-6.88 (m, 2H), 6.76-6.58 (m, 1H), 5.05-4.98 (m, 1H), 3.85-3.73 (m, 1H), 3.69 (d, J =12.3hz, 1h), 3.55-3.48 (m, 1H), 2.33-2.24 (m, 1H), 2.21-2.07 (m, 1H), 1.86-1.77 (m, 1H), 1.74-1.37 (m, 3H), 1.27-1H (m, 1H).
Example 251: (R/S) - (2- (5-fluoropyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 248, substituting intermediate A-2 with intermediate A-34. MS (ESI): c 24 H 20 F 4 N 4 O 2 The calculated mass of (a) is 472.2; the measured value of m/z is 472.9[ m ] +H] + 。 1 H NMR (500 MHz, methanol-d) 4 The compounds are present as a mixture of optical isomers) delta 8.87-8.74 (m, 2H), 8.20-8.12 (m, 2H), 8.05-7.93 (m, 1H), 7.65-7.55 (m, 1H), 7.38-7.30 (m, 1H), 7.09-6.86 (m, 2H), 5.13-5.02 (m, 1H), 3.84-3.76 (m, 1H), 3.71-3.64 (m, 1H), 3.60-3.51 (m, 1H), 2.35-2.26 (m, 1H), 2.22-2.13 (m, 1H), 1.87-1.76 (m, 1H), 1.73-1.29 (m, 4H).
Example 252: (R/S) - (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (R/S) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2]Tert-butyl octyl-2-carboxylate. To a microwave vial containing a solution of C-7A (308mg, 1.36mmol) in MeCN (5 mL) was added 2-chloro-5- (trifluoromethyl) pyrazine (0.20mL, 1.63mmol) and Et 3 N (0.28mL, 2.04mmol), and the reaction mixture was sealed and heated on a 70 ℃ bench overnight. Analysis of the reaction mixture still showed unreacted starting material. An additional equivalent of 2-chloro-5- (trifluoromethyl) pyrazine (0.20mL, 1.63mmol) and Et was added 3 N (0.28mL, 2.04mmol), and the reaction mixture was again heated on the 70 ℃ bench overnight. After completion of the reaction, the mixture was cooled to room temperature and washed with H 2 And (4) diluting with oxygen. The reaction mixture was extracted with EtOAc (3 ×). The combined organics were concentrated and the concentrate was directly subjected to silica gel chromatography (0-30% EtOAc in hexane) to afford the title compound of step A (2450 mg,0.658mmol, 48)％)。C 17 H 23 F 3 N 4 O 2 The mass calculation value of MS (ESI) is 372.2, the found value of m/z is 371.1[ m ] +2H-tBu] + 。
And B: (R/S) -N- (5- (trifluoromethyl) pyrazin-2-yl) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (24mgs, 0.658mmol) in EtOAc (1 mL) was added a 4M solution of HCl in dioxane (4 mL), and the reaction mixture was stirred at room temperature for 3h. The reaction was concentrated to obtain the title compound of step B (249 mg), which was used without further purification. C 12 H 15 F 3 N 4 The calculated mass MS (ESI) of (a) is 272.1; the measured value of m/z is 273.0[ m ] +H] + 。
And C: (R/S) - (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (50 mg) and intermediate A-40 (36mg, 0.18mmol) in DMF (0.5 mL) was added DIPEA (0.15mL, 0.87mmol) and HATU (68mg, 0.18mmol), and the reaction mixture was stirred at room temperature for 3h. The reaction was diluted with MeOH and the crude reaction mixture was directly subjected to purification using Agilent preparative method X to give the title compound (25 mg). MS (ESI): c 21 H 21 F 3 N 8 Calculated mass of O is 458.2; the measured value of m/z is 458.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.45 min (main optical isomer).
Example 253: (R/S) - (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 252 at HIsolated from step C during PLC purification. MS (ESI): c 21 H 21 F 3 N 8 Calculated mass of O is 458.2; measured value of m/z is 459.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.26 min (main optical isomer).
Example 254: (R/S) - (2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 252, intermediate A-40 was replaced with intermediate A-1. MS (ESI): c 21 H 20 F 3 N 7 Calculated mass of O is 443.2; the measured value of m/z is 443.9[ deg. ] M + H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.65 min (main optical isomer).
Example 255: (R/S) - (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 252, intermediate A-40 was replaced with intermediate A-16. MS (ESI): c 21 H 19 F 4 N 7 Calculated mass value of O is 461.2; the measured value of m/z is 461.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mm) with a mobile phase of10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.65 min (main optical isomer).
Example 256: (R/S) - (3-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 252, intermediate A-40 was replaced with intermediate A-22. MS (ESI): c 22 H 22 F 3 N 7 The calculated mass value of O is 457.2; the measured value of m/z is 458.0[ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.96 min (main optical isomer).
Example 257: (R/S) - (3-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 252, substituting intermediate A-40 with intermediate A-2. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 472.9[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.49 min (main optical isomer).
Example 258: (R/S) - (4-fluoro-2- (pyrimidin-2-yl) phenyl) (6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 252, intermediate A-40 was replaced with intermediate A-23. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 472.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.57 min (main optical isomer).
Example 259: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-23. MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 473.2[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.28 min (main optical isomer).
Example 260: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-7. MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 473.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.59 min (main optical isomer).
Example 261: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-6. MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 473.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.41 min (main optical isomer).
Example 262: (2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-34. MS (ESI): c 24 H 20 F 4 N 4 O 2 Calculated mass of (d) is 472.2; the measured value of m/z is 473.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.83 min (main optical isomer).
Example 263: (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-35. MS (ESI): c 24 H 19 F 5 N 4 O 2 The calculated mass value of (A) is 490.1; the measured value of m/z is 491.2[ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.78 min (main optical isomer).
Example 264: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 76, intermediate A-40 was replaced with intermediate A-47. MS (ESI): c 24 H 22 F 3 N 5 O 2 The calculated mass of (a) is 469.2; the measured value of m/z is 470.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then held at 100% ACN for 3 minutes at a flow rate of 1mL/min (temperature)=30 ℃). R at 254nm t =6.999 min (main optical isomer).
Example 265: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 76, substituting intermediate A-40 with intermediate A-41. MS (ESI): c 24 H 22 F 3 N 5 O 2 The calculated mass of (a) is 469.2; the measured value of m/z is 470.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.73 min (main optical isomer).
Example 266: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2 ]Tert-butyl octyl-2-carboxylate. To intermediate C-5B (52mg, 0.23mmol) dissolved in DMF (2 mL) was added NaH (18mg, 0.46mmol,60% dispersion in mineral oil). After 5 min, 2,3-difluoro-5- (trifluoromethyl) pyridine (63mg, 0.34mmol) was then added and the mixture was stirred at room temperature for 1h. The reaction mixture was washed with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc in hexane) afforded the title compound (67)mg，0.17mmol，75％)。C 18 H 22 F 4 N 2 O 3 Mass calculated MS (ESI) of 390.2; the measured value of m/z is 336.1[ m ] +2H-tBu] + 。
And B: (1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (67mg, 0.17mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (0.22 mL) and the reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed most of the starting material. Additional 4M HCl in dioxane (0.5 mL) was added and the reaction mixture was stirred at room temperature for 5h. The reaction mixture was then concentrated to obtain the title compound of step B (30 mg), which was used without further purification. C 13 H 14 F 4 N 2 Calculated mass MS (ESI) for O is 290.1; m/z found to be 291.1[ m ] +H] + 。
And C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-2 (27mg, 0.12mmol) in DMF (1 mL) was added DIPEA (0.11mL, 0.62mmol) and HATU (43mg, 0.11mmol). After completion of the reaction, it was purified by Agilent preparation method X to obtain the title compound (11 mg). MS (ESI): c 24 H 19 F 5 N 4 O 2 The calculated mass of (a) is 490.2; the measured value of m/z is 491.1[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.35 min (main optical isomer).
Example 267: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Tert-butyl octyl-2-carboxylate. To intermediate C-5B (37mg, 0.16mmol) in DMF (1.4 mL) was added NaH (13mg, 0.33mmol,60% dispersion in mineral oil). After 5 min, 2-chloro-5-methylpyridine (0.03mL, 0.26mmol) was then added and the mixture was stirred at room temperature for 2h. Analysis of the reaction mixture only showed the presence of starting material. The reaction mixture was heated at 70 ℃ overnight. Analysis of the reaction mixture showed the formation of a small amount of product. Additional NaH was added and the reaction mixture was heated at 70 ℃ over the weekend. The reaction mixture was washed with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-50% EtOAc in hexane) afforded the title compound (8 mg,0.03mmol, 15%). C 18 H 26 N 2 O 3 Mass calculation of (ESI) of (2) is 318.2; the measured value of m/z is 319.2[ m ] +H] + 。
And B, step B: (1S,4R,6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (8 mg, 0.03mmol) in EtOAc (0.3 mL) was added a 4M solution of HCl in dioxane (0.03 mL), and the reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed that starting material was still present. Additional 4M HCl in dioxane (0.25 mL) was added and the reaction mixture was stirred at room temperature for 5h. The reaction was concentrated to obtain the title compound of step B, which was used without further purification. C 13 H 18 N 2 Calculated mass MS (ESI) for O is 218.1; the measured value of m/z is 219.2[ m ] +H] + 。
And C: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (5 mg) and intermediate A-2 (6 mg, 0.03mmol) in DMF (0.3 mL) were added DIPEA (0.02mL, 0.14mmol) and HATU (10mg, 0.03mmol), And the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and the crude reaction mixture was directly subjected to purification using Agilent preparative method X to give the title compound (1 mg). MS (ESI): c 24 H 23 FN 4 O 2 Calculated mass of 418.2; the measured value of m/z is 419.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.35 min (main optical isomer).
Example 268: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Tert-butyl octyl-2-carboxylate. To intermediate C-5B (37mg, 0.16mmol) dissolved in DMF (1.4 mL) was added NaH (13mg, 0.33mmol,60% dispersion in mineral oil). After 5 min, 5-bromo-2-fluoropyridine (0.03mL, 0.26mmol) was then added and the mixture was stirred at room temperature for 2h. The reaction mixture was washed with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc in hexane) afforded the title compound (63mg, 0.16mmol, 100%). C 17 H 23 BrN 2 O 3 Mass calculated as 382.1 for MS (ESI); the measured value of m/z is 383.1[ m ] +H] + 。
And B: (1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Octane. XHCl to a solution of the title compound of step A (63mg, 0.16mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (0.21 mL) and the mixture was addedThe reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed that starting material was still present. Additional 4M HCl in dioxane (0.21 mL) was added and the reaction mixture was stirred at room temperature for 5h. The reaction was concentrated to obtain the title compound of step B, which was used without further purification. C 12 H 15 BrN 2 Calculated mass MS (ESI) for O is 282.0; measured value of m/z is 283.0[ m ] +H] + 。
Step C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone. To a solution of the title compound of step B (23 mg) and intermediate A-1 (47mg, 0.25mmol) in DMF (0.8 mL) were added DIPEA (0.08mL, 0.49mmol) and HATU (34mg, 0.09mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and the crude reaction mixture was directly subjected to purification using Agilent preparative method X to obtain the title compound (7.7 mg). MS (ESI): c 21 H 20 BrN 5 O 2 The calculated mass of (a) is 453.1; the measured value of m/z is 454.1[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.51 min (main optical isomer).
Example 269: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation analogous to example 268, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 23 H 20 BrFN 4 O 2 Calculated mass of 482.1; the measured value of m/z is 483.1[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mMNH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.10 min (main optical isomer).
Example 270: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Step A: (1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2 ]Tert-butyl octyl-2-carboxylate. To intermediate C-5B (37mg, 0.16mmol) dissolved in DMF (1.4 mL) was added NaH (13mg, 0.33mmol,60% dispersion in mineral oil). After 5 min, 5-chloro-2-fluoropyridine (0.03mL, 0.26mmol) was then added and the mixture was stirred at room temperature for 1.5h. The reaction mixture was washed with saturated NH 4 Cl solution quenched with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-50% EtOAc in hexane) afforded the title compound (52mg, 0.15mmol, 94%). C 17 H 23 ClN 2 O 3 The calculated mass MS (ESI) of (2) was 338.1; measured value of m/z is 339.2[ m ] +H] + 。
And B: (1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Octane. XHCl to a solution of the title compound of step A (52mg, 0.15mmol) in EtOAc (2 mL) was added a 4M solution of HCl in dioxane (0.19 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to obtain the title compound of step B, which was used without further purification. C 12 H 15 ClN 2 Calculated mass MS (ESI) for O was 238.1; the measured value of m/z is 239.1[ m ] +H] + 。
Step C: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2 ]Oct-2-yl) methanone. To the title compound of step B (18)mg) and intermediate A-1 (44mg, 0.23mmol) in DMF (0.8 mL), DIPEA (0.08mL, 0.45mmol) and HATU (44mg, 0.23mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and the crude reaction mixture was directly subjected to purification using Agilent preparative method X to obtain the title compound (16 mg). MS (ESI): c 21 H 20 ClN 5 O 2 The calculated mass of (a) is 409.1; the measured value of m/z is 410.1[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.35 min (main optical isomer).
Example 271: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 270, intermediate A-1 was replaced with intermediate A-2. MS (ESI): c 23 H 20 ClFN 4 O 2 The calculated mass of (a) is 438.1; the measured value of m/z is 439.1[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.94 min (main optical isomer).
Example 272: (2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogously to example 77, intermediateA-40 is replaced by intermediate A-34. MS (ESI): c 23 H 19 F 4 N 5 O 2 The calculated mass of (a) is 473.1; the actual measurement value of m/z is 474.2[ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.16 min (main optical isomer).
Example 273: (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 77, intermediate A-40 was replaced with intermediate A-35. MS (ESI): c 23 H 18 F 5 N 5 O 2 The calculated mass of (a) is 491.1; the measured value of m/z is 492.2[ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.29 min (main optical isomer).
Example 274: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 83, intermediate A-40 was replaced with intermediate A-16. MS (ESI): c 21 H 19 F 4 N 7 Calculated mass value of O is 461.2; the measured value of m/z is 462.2[ m ] +H] + . On an Agilent 1100 series, obtained using an Xbridge C18 column (5 μm, 100X 4.6 mm)Analytical HPLC, mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.71 min (main optical isomer).
Example 275: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 83, intermediate A-40 was replaced with intermediate A-1. MS (ESI): c 21 H 20 F 3 N 7 The calculated mass value of O is 443.2; measured value of m/z is 444.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.67 min (main optical isomer).
Example 276: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1R, 4S, 6S) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 83, intermediate A-40 was replaced with intermediate A-2 (step C), and intermediate C-7B was replaced with its enantiomer (1R, 4S, 6S) -6-amino-2-azabicyclo [2.2.2]Tert-butyl octa-2-carboxylate (step A). MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; measured value of m/z is 472.9[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then held at 100% ACN for 3 minutes at a flow rate of 1mL/min (temperature)=30 ℃). R at 254nm t =6.39 min (main optical isomer).
Example 277: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 83, intermediate A-40 was replaced with intermediate A-23. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 473.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.62 min (main optical isomer).
Example 278: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 83, intermediate A-40 was replaced with intermediate A-7. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 473.2[ m ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.44 min (main optical isomer).
Example 279: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 83, intermediate A-40 was replaced with intermediate A-6. MS (ESI): c 23 H 20 F 4 N 6 The calculated mass value of O is 472.2; the measured value of m/z is 473.2[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 line using an Xbridge C18 column (5 μm,100x4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.27 min (main optical isomer) and 6.95 min.
Example 280: (2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation was analogous to example 83, intermediate A-40 was replaced with intermediate A-37. MS (ESI): c 23 H 21 F 3 N 6 The calculated mass value of O is 454.2; measured value of m/z is 455.4[ m ] +H] + . Analytical HPLC using an Xbridge C18 column (5 μm,100X4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 2 minutes and then 2 minutes at 100% acn, at a flow rate of 2.5mL/min (temperature =45 ℃). R at 254nm t And =2.01 and 1.98 minutes (main optical isomer).
Example 281: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Step A: (1S,4R,6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2 ]Oct-2-carboxylic acid tert-butyl ester. To intermediate C-5B (100mg, 0.44mmol) dissolved in DMF (4 mL) was added NaH (35mg, 0.88mmol,60% dispersion in mineral oil). After 5 min, 3-chloro-2-fluoro-5- (trifluoromethyl) pyridine (86 μ L,0.66 mmol) was then added and the mixture was stirred at room temperature over the weekend. Analysis of the reaction mixture showed most of the starting material. Additional NaH was added. The analysis still showed incomplete conversion, however the reaction mixture was saturated with NH 4 Cl solution quenched and with EtOAc and H 2 And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, brine, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc in hexane) afforded the title compound (38mg, 0.093mmol, 21%). C 18 H 22 ClF 3 N 2 O 3 Mass calculated MS (ESI) of 406.1; the measured value of m/z is 351.1[ m ] +2H-tBu] + 。
And B: (1S,4R,6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]To a solution of the title compound of step A (38mg, 0.093 mmol) in EtOAc (1.2 mL) was added 4M HCl in dioxane (0.12 mL) and the reaction mixture was stirred at room temperature overnight. Analysis of the reaction mixture showed that starting material was still present. Additional 4M HCl in dioxane (0.12 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to obtain the title compound of step B (29 mg), which was used without further purification. C 13 H 14 ClF 3 N 2 Calculated mass MS (ESI) for O is 306.1; the measured value of m/z is 307.1[ m ] +H] + 。
And C: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone. To a solution of the title compound of step B (27 mg) and intermediate A-2 (23mg, 0.11mmol) in DMF (0.9 mL) were added DIPEA (0.09mL, 0.53mmol) and HATU (37mg, 0.097mmol) and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was diluted with MeOH, filtered through syringe, and prepared using AgilentMethod X was directly subjected to purification to obtain the title compound (11 mg). MS (ESI): c 24 H 19 ClF 4 N 4 O 2 The calculated mass value of (A) is 506.1; the measured value of m/z is 507.1[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.87 min (main optical isomer).
Example 282: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 77, intermediate A-40 was replaced with intermediate A-47. MS (ESI): c 23 H 21 F 3 N 6 O 2 The calculated mass value of (A) is 470.2; the measured value of m/z is 471.2[ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =6.77 min (main optical isomer).
Example 283: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Preparation was analogous to example 266, substituting intermediate a-2 with intermediate a-47. MS (ESI): c 24 H 21 F 4 N 5 O 2 The calculated mass of (a) is 487.2; m/z found to be 488.2[ 2], [ M ] +H] + . In the Agilent 1100 systemOn the column, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =30 ℃). R at 254nm t =7.38 min (main optical isomer).
Example 284: ((1S, 4R, 6R) -6- ((5-Chloropyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Step A: (1S,4R,6R) -6- ((5-chloropyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (150mg, 0.70mmol) and 2,5-dichloropyrimidine (225mg, 1.51mmol) in DMF (2 mL) was added NaH (37mg, 0.91mmol,60% dispersion in mineral oil). After 3H, LCMS analysis showed that the reaction was incomplete and additional NaH (40mg, 1.0mmol,60% dispersion in mineral oil) was added and the reaction mixture was allowed to stir for an additional 45 minutes before quenching with H2O. The aqueous layer was extracted with EtOAc (3X). The combined organic matter is treated with H 2 O, 5% LiCl aqueous solution, and MgSO 4 Dried, filtered and concentrated. Purification by silica gel chromatography (0-40% EtOAc in hexane) afforded the title compound (211mg, 0.65mmol, 92%) as a colorless solid. C 15 H 20 ClN 3 O 3 The calculated mass value of MS (ESI) of (A) is 325.1; measured value of m/z is 370.1[ 2M + ] 2H-tBu] + 。 1 H NMR (500 MHz, chloroform-d, compounds presented as mixtures of optical isomers, reporting two optical isomers) Δ 8.44 and 8.39 (two s, 2H), 5.25-5.16 (m, 1H), 4.68-4.65 and 4.56-4.52 (two m, 1H), 3.42-3.37 and 3.35-3.31 (two m, 1H), 3.24-3.16 (m, 1H), 2.61-2.51 (m, 1H), 2.24-2.13 (m, 1H), 1.77-1.40 (m, 3H), 1.35 and 1.12 (2 s, 9H).
And B: (1S,4R,6R) -6- ((5-chloropyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1]Heptane xHCl to a solution of the title compound of step A (211mg, 0.65mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (4 mL) andthe reaction mixture was stirred at room temperature for 1.5h. The reaction was then concentrated to give the title compound of step B as an off-white solid (155 mg) and used without further purification. C 10 H 12 ClN 3 MS (ESI) mass calculated for O was 225.1; the measured value of m/z is 226.1[ m ] +H] + 。
And C: ((1S, 4R, 6R) -6- ((5-Chloropyrimidin-2-yl) oxy) -2-azabicyclo [ 2.2.1)]Hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-2 (27mg, 0.13mmol) in DMF (0.4 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (48mg, 0.13mmol) and the reaction mixture was stirred at room temperature for 2h. The reaction was diluted with MeOH, filtered, and purified using Agilent prep. X to obtain the title compound (27 mg). MS (ESI): c 21 H 17 ClFN 5 O 2 Calculated mass of 425.1; measured value of m/z is 426.1[ 2 ], [ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.72.
Example 285: ((1S, 4R, 6R) -6- ((5-Chloropyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 284, intermediate A-2 was replaced with intermediate A-41. MS (ESI): c 21 H 19 ClN 6 O 2 The calculated mass of (a) is 422.1; measured value of m/z is 423.2[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.63H),3.78(dt,J＝10.8,3.0Hz,1H),3.46(dd,J＝10.9,1.4Hz,1H),2.72-2.64(m,1H),2.30(s,3H),2.26-2.18(m,1H),1.67(dt,J＝13.5,3.6Hz,1H),1.56-1.45(m,2H)。
Example 286: ((1S,4R,6R) -6- ((1,8-naphthyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 287, intermediate A-1 was replaced with intermediate A-40. MS (ESI): c 23 H 21 N 7 O 2 The calculated mass of (a) is 427.2; measured value of m/z is 428.2[ 2 ], [ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.86 (dd, J =4.4,2.0hz, 1h), 8.06 (dd, J =7.9,2.0hz, 1h), 7.92 (d, J =8.7hz, 1h), 7.86 (d, J =8.4hz, 1h), 7.81 (s, 2H), 7.33 (dd, J =7.9,4.4hz, 1h), 7.03 (d, J =8.8hz, 1h), 6.67 (d, J =8.4hz, 1h), 5.39 (dt, J =9.9,3.1hz, 1h), 4.54-4.43 (m, 1H), 3.71 (dt, J =11.0,3.2hz, 1h), 3.49 (d, J =11.0hz, 1h), 2.69-2.66 (m, 1H), 2.39-2.23 (m, 1H), 2.03 (s, 3H), 1.58-1.50 (m, 3H).
Example 287: ((1S, 4R, 6R) -6- ((1,8-naphthyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Step A: (1S,4R,6R) -6- ((1,8-naphthyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate. To intermediate B-5 (150mg, 0.70mmol) and 2-chloro-1,8-naphthyridine (225mg, 1.37mmol) in DMF (2 mL) was added NaH (37mg, 0.91mmol,60% dispersion in mineral oil). After 50 minutes, the mixture is washed with H 2 The aqueous layer was quenched with EtOAc (3 ×). The combined organics were washed with 5% LiCl aqueous solution, brine, mgSO 4 Dried, filtered and concentrated. Purification via silica gel chromatography (0-100% etoac in hexanes) afforded the title compound (200 mg) as a colorless solid.C 19 H 23 N 3 O 3 Mass calculation of (ESI) of (2) is 341.2; measured value of m/z is 342.2[ m ] +H] + 。
And B:2- ((1S, 4R, 6R) -2-azabicyclo [2.2.1]Hept-6-yloxy) -1,8-naphthyridine xHCl to a solution of the title compound of step A (200mg, 0.59mmol) in EtOAc (2 mL) was added a 4M HCl in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 2h. The reaction was then concentrated to give the title compound of step B as a colorless solid (192 mg), and used without further purification. C 14 H 15 N 3 O 3 The calculated mass MS (ESI) of (1) is 241.1; the measured value of m/z is 242.1[ m ] +H] + 。
And C: ((1S, 4R, 6R) -6- ((1,8-naphthyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) (2- (2H-1,2,3-triazol-2-yl) phenyl) methanone. To a solution of the title compound of step B (30 mg) and intermediate A-1 (20mg, 0.11mmol) in DMF (0.5 mL) was added DIPEA (0.1mL, 0.58mmol) and HATU (40mg, 0.11mmol), and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with MeOH, filtered, and purified using Agilent prep. X to obtain the title compound (22 mg). MS (ESI): c 23 H 20 N 6 O 2 The calculated mass of (a) is 412.2; the measured value of m/z is 413.2[ m ] +H] + 。 1 H NMR (400 MHz, chloroform-d) delta 8.87 (dd, J =4.4,2.0Hz, 1H), 8.11 (dd, J =7.9,2.0Hz, 1H), 8.05 (d, J =8.8Hz, 1H), 7.82-7.74 (m, 3H), 7.35 (dd, J =7.9,4.4Hz, 1H), 7.10 (dd, J =7.7,1.5Hz, 1H), 7.03 (d, J =8.7Hz, 1H), 7.00-6.92 (m, 1H), 6.54 (t, J =7.6hz, 1h), 5.44 (dt, J =10.2,3.2hz, 1h), 4.28-4.19 (m, 1H), 3.65 (dt, J =10.9,3.2hz, 1h), 3.43 (d, J =9.5hz, 1h), 2.72-2.62 (m, 1H), 2.45-2.31 (m, 1H), 1.52-1.42 (m, 3H).
Example 288: ((1S,4R,6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 121, intermediate a-1 was replaced with intermediate a-47. MS (ESI): c 23 H 21 F 2 N 5 O 2 The calculated mass of (a) is 437.2; the measured value of m/z is 438.2[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.77 (d, J =4.9hz, 2h), 8.28-8.19 (m, 1H), 7.83-7.77 (m, 1H), 7.69 (dd, J =8.7,2.4hz, 1h), 7.66-7.64 (m, 1H), 7.21 (t, J =4.9hz, 1h), 6.91 (d, J =8.6hz, 1h), 6.59 (t, J =56.1hz, 1h), 5.02 (dt, J =10.3,3.4hz, 1h), 4.33-4.21 (m, 1H), 3.70 (dt, J =10.8,3.2hz, 1h), 3.46 (dd, J =10.7,1.4hz, 1h), 2.72-2.63 (m, 1H), 2.26 (s, 3H), 2.23-2.16 (m, 1H), 1.61-1.35 (m, 3H).
Example 289: (2-methoxy-6- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation was analogous to example 25, intermediate A-20 was replaced with intermediate A-13. MS (ESI): c 22 H 20 F 3 N 5 O 3 The calculated mass of (a) is 459.2; measured value of m/z is 460.2[ 2 ], [ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =45 ℃). R at 254nm t =6.84 min (main optical isomer).
Example 290: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-46. MS (ESI): c 23 H 20 F 3 N 5 O 2 Mass calculated value of455.2; the measured value of m/z is 456.4[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.87.
Example 291: (4-fluoro-2- (3-methyl-1,2,4-Oxadiazol-5-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-51. MS (ESI): c 22 H 18 F 4 N 4 O 3 The calculated mass value of (a) is 462.1; the measured value of m/z is 463.4[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d) delta 8.10-8.01 (m, 1H), 7.80 (dd, J =8.8,2.5Hz, 1H), 7.72 (dd, J =8.9,2.6Hz, 1H), 7.02 (dd, J =8.5,5.4Hz, 1H), 6.82 (d, J =8.7Hz, 1H), 6.76-6.68 (m, 1H), 5.06 (dt, J =10.1,3.3Hz, 1H), 4.14-4.08 (m, 1H), 3.77 (dt, J =11.0,3.2hz, 1h), 3.44 (dd, J =10.9,1.5hz, 1h), 2.76-2.71 (m, 1H), 2.45 (s, 3H), 2.35-2.22 (m, 1H), 1.73-1.66 (m, 1H), 1.59-1.55 (m, 1H), 1.46 (dt, J =13.6,3.6hz, 1h).
Example 292: (2-fluoro-6-, (Oxazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-50. MS (ESI): c 22 H 17 F 4 N 3 O 3 The calculated mass of (a) is 447.1; the measured value of m/z is 448.5[ m ] +H] + . Analytical HPLC was obtained on an Agilent 1100 line using an Xbridge C18 column (5 μm,100x4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =45 ℃). R at 254nm t =7.18 min (main optical isomer).
Example 293: (5-fluoro-2-, (Oxazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-49. MS (ESI): c 22 H 17 F 4 N 3 O 3 The calculated mass of (a) is 447.1; the measured value of m/z is 448.5[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) delta 8.05-8.02 (m, 1H), 7.92 (dd, J =8.7,5.3Hz, 1H), 7.80 (dd, J =8.6,2.5Hz, 1H), 7.69 (d, J =0.8Hz, 1H), 7.21 (d, J =0.8Hz, 1H), 6.99-6.92 (m, 1H), 6.81 (d, J =8.7Hz, 1H), 6.69 (dd, J =8.4,2.7Hz, 1H), 5.03 (dt, J =10.2,3.3hz, 1h), 4.16-4.08 (m, 1H), 3.74 (dt, J =11.0,3.2hz, 1h), 3.44 (dd, J =10.9,1.5hz, 1h), 2.74-2.63 (m, 1H), 2.30-2.21 (m, 1H), 1.63-1.56 (m, 1H), 1.55-1.49 (m, 1H), 1.45 (dt, J =13.5,3.6hz, 1h).
Example 294: (5-methyl-3- (1H-1,2,3-triazol-1-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with the N-1 isomer (5-methyl-3- (1H-1,2,3-triazol-1-yl) picolinonitrile from intermediate A-19). MS (ESI): c 21 H 19 F 3 N 6 O 2 The calculated mass of (a) is 444.2; the measured value of m/z is 445.6[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d) Δ 8.12 (d, J =1.1Hz, 1H), 8.02-7.98 (m, 1H), 7.97-7.94 (m, 1H), 7.81 (d, J =1.1Hz, 1H), 7.78-7.76 (m, 1H), 7.72 (dd, J =8.8,2.5Hz, 1H), 6.74-6.69 (m, 1H), 4.99 (dt, J =10.2,3.3Hz, 1H), 4.43-4.34 (m, 1H), 3.48 (dt, J =11.2,3.1hz, 1h), 3.41 (dd, J =11.2,1.5hz, 1h), 2.66-2.60 (m, 1H), 2.34 (s, 3H), 2.25-2.17 (m, 1H), 1.60-1.53 (m, 1H), 1.40 (dt, J =13.6,3.6hz, 1h), 1.34-1.27 (m, 1H).
Example 295: (4-methoxy-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-15. MS (ESI): c 24 H 21 F 3 N 4 O 3 The calculated mass value of (A) is 470.2; the measured value of m/z is 471.4[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers (0.88: 6.85-6.83 (m, 1H), 6.45 (dd, J =8.4,2.6hz, 1h), 5.04 (dt, J =10.1,3.4hz, 1h), 4.19-4.09 (m, 1H), 3.81 (s, 3H), 3.62 (dt, J =10.9,3.2hz, 1h), 3.40 (dd, J =10.8,1.5hz, 1h), 2.65-2.59 (m, 1H), 2.27-2.15 (m, 1H), 1.44-1.35 (m, 2H), 1.29-1.17 (m, 1H).
Example 296: (3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-42. MS (ESI): c 22 H 18 F 3 N 5 O 2 The calculated mass value of (a) is 441.1; the measured value of m/z is 442.4[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound present as a mixture of optical isomers (0.81: 7.22 (t, J =4.9hz, 1h), 7.15 (dd, J =8.0,4.7hz, 1h), 6.91 (d, J =8.7hz, 1h), 5.04 (dt, J =10.2,3.4hz, 1h), 4.35-4.20 (m, 1H), 3.73 (dt, J =10.8,3.2hz, 1h), 3.47 (d, J =10.9hz, 1h), 2.72-2.65 (m, 1H), 2.30-2.13 (m, 1H), 1.60-1.44 (m, 3H).
Example 297: (2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-37. MS (ESI): c 23 H 19 F 3 N 4 O 2 The calculated mass value of (A) is 440.1; the measured value of m/z is 441.4[ M ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.88: J =7.6,1.3hz, 1H), 6.88 (td, J =7.5,1.3hz, 1H), 6.83 (d, J =8.7hz, 1H), 5.01 (dt, J =10.2,3.4hz, 1H), 4.24-4.10 (m, 1H), 3.64 (dt, J =10.9,3.2hz, 1H), 3.41 (dd, J =10.8,1.5hz, 1H), 2.66-2.61 (m, 1H), 2.27-2.12 (m, 1H), 1.47-1.37 (m, 2H), 1.34-1.19 (m, 1H).
Example 298: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 25, intermediate A-20 was replaced with intermediate A-47. MS (ESI): c 23 H 20 F 3 N 5 O 2 The calculated mass of (a) is 455.2; the measured value of m/z is 456.4[ m ] +H] + 。 1 H NMR (500 MHz, chloroform-d, compound presented as a mixture of optical isomers (0.87.
Example 299: ((1S, 4R, 6R) -6- ((5-chloropyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Preparation analogous to example 284, intermediate a-2 was replaced with intermediate a-40. MS (ESI): c 19 H 18 ClN 7 O 2 The calculated mass value of (A) is 411.1; measured value of m/z is 412.3[ 2 ], [ M ] +H] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =45 ℃). R at 254nm t =5.23 min (main optical isomer).
Example 300: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-chloropyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Preparation analogous to example 284, intermediate a-2 was replaced with intermediate a-1. MS (ESI): c 19 H 17 ClN 6 O 2 The calculated mass of (a) is 396.1; the measured value of m/z is 397.1[ M ] +H] + 。 1 H NMR (400 MHz, chloroform-d, compound presented as a mixture of optical isomers, reporting the major isomer) δ 8.22 (s, 2H), 7.88-7.85 (m, 1H), 7.81 (s, 2H), 7.40-7.31 (m, 1H), 7.17 (dd, J =7.7,1.5hz, 1h), 6.90 (t, J =7.5hz, 1h), 4.87 (dt, J =10.2,3.3hz, 1h), 4.10-3.98 (m, 1H), 3.63 (dt, J =10.9,3.2hz, 1h), 3.42 (dd, J =10.9,1.4hz, 1h), 2.66-2.60 (m, 1H), 2.29-2.12 (m, 1H), 1.54 (J =13.6, 3.6, 1.42 hz, 1.33H), 1.33-2.33H).
Example 301: ((1S,4R,6R) -6- ((1,8-naphthyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Preparation was analogous to example 287, substituting intermediate A-1 with intermediate A-2. MS (ESI): c 25 H 20 FN 5 O 2 The calculated mass of (a) is 441.2; measured value of m/z is 442.2[ 2 ], [ M ] +H ] + . Analytical HPLC was obtained on an Agilent 1100 series using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 In OH, 8 minutes, then 3 minutes at 100% acn, at a flow rate of 1mL/min (temperature =45 ℃). R at 254nm t =4.68 minutes.
Example 302: ((1S, 4R, 6R) -6- ((1,8-naphthyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
The preparation is similar to that of example 287,intermediate A-1 was replaced with intermediate A-41. MS (ESI): c 25 H 22 N 6 O 2 The calculated mass of (a) is 438.2; the measured value of m/z is 439.2[ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =45 ℃). R at 254nm t =4.33 min (main optical isomer).
Example 303: (2- (pyridazin-3-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 304: (2- (pyridazin-4-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 305: (2- (pyridin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 306: (2- (pyridin-3-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 307: (2- (pyridin-4-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 308: (2- (pyrazin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 309: (2- (3-methylpyridin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 310: (2- (5-methyliso-yl) benzeneOxazol-3-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 311: (2- (3,5-dimethylisoOxazol-4-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 312: ((1S,4R,6R) -6- ((4,6-dimethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 313: ((1S, 4R, 6R) -6- ((4,6-dimethylpyrimidin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 314: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 315: ((1S, 4R, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 316: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (hydroxymethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 317: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (fluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 318: ((1S,4R,6R) -6- ((5- (hydroxymethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 319: ((1S, 4R, 6R) -6- ((5- (fluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 320: (3- (5-fluoropyrimidin-2-yl) -5-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 321: (2- (5-Fluoropyrimidin-2-yl) -6-methylpyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 322: (3- (5-fluoropyrimidin-2-yl) -6-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 323: (2- (5-fluoropyrimidin-2-yl) -5-methylpyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 324: (3- (5-fluoropyrimidin-2-yl) -4-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 325: (3- (5-fluoropyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 326: (2- (5-fluoropyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 327: (5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 328: (6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 329: (6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 330: (5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 331: (4 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 332: [2,3 '-bipyridine ] -2' -yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 333: [2,2' -bipyridin ] -3-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 334: (3,5 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 335: (3 ', 6-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 336: (3,6 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 337: (3 ', 5-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 338: (3,4 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 339: (3-methyl- [2,3 '-bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 340: (3 '-methyl- [2,2' -bipyridine ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 341: (3-fluoro-5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 342: (3 '-fluoro-6-methyl- [2,2' -bipyridine ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 343: (3-fluoro-6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 344: (3 '-fluoro-5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 345: (3-fluoro-4 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 346: (3-fluoro- [2,3 '-bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 347: (3 '-fluoro- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 348: (5-methyl-3-, (Oxazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 349: (6-methyl-2-, (Oxazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 350: (6-methyl-3-, (Azol-2-yl) pyridin-2-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridine)-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 351: (5-methyl-2-, (Oxazol-2-yl) pyridin-3-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 352: (4-methyl-3-, (Oxazol-2-yl) pyridin-2-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1 ]Hept-2-yl) methanone.
Example 353: (3- (Oxazol-2-yl) pyridin-2-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 354: (2- (Oxazol-2-yl) pyridin-3-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 355: (5-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 356: (6-methyl-2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 357: (6-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 358: (5-methyl-2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 359: (4-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 360: (3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 361: (2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 362: (2- (pyridazin-3-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 363: (2- (pyridazin-4-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 364: (2- (pyridin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 365: (2- (pyridin-3-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 366: (2- (pyridin-4-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 367: (2- (pyrazin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 368: (2- (3-methylpyridin-2-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 369: (2- (5-methyliso-yl) benzeneOxazol-3-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 370: (2- (3,5-dimethylisoOxazol-4-yl) phenyl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 371: (3- (5-fluoropyrimidin-2-yl) -5-methylpyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 372: (2- (5-Fluoropyrimidin-2-yl) -6-methylpyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 373: (3- (5-fluoropyrimidin-2-yl) -6-methylpyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 374: (2- (5-Fluoropyrimidin-2-yl) -5-methylpyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 375: (3- (5-fluoropyrimidin-2-yl) -4-methylpyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 376: (3- (5-fluoropyrimidin-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 377: (2- (5-fluoropyrimidin-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 378: (5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 379: (6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 380: (6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 381: (5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 382: (4 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 383 [2,3 '-bipyridin ] -2' -yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 384 [2,2' -bipyridin ] -3-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 385: (3,5 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 386: (3 ', 6-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 387: (3,6 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 388: (3 ', 5-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 389: (3,4 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 390: (3-methyl- [2,3 '-bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 391: (3 '-methyl- [2,2' -bipyridine ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 392: (3-fluoro-5 ' -methyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 393: (3 '-fluoro-6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 394: (3-fluoro-6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 395: (3 '-fluoro-5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 396: (3-fluoro-4 ' -methyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 397: (3-fluoro- [2,3 '-bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 398: (3 '-fluoro- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 399: (5-methyl-3-, ( Oxazol-2-yl) pyridin-2-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 400: (6-methyl-2-, (Oxazol-2-yl) pyridin-3-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 401: (6-methyl-3-, (Oxazol-2-yl) pyridin-2-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 402: (5-methyl-2-, (Oxazol-2-yl) pyridin-3-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 403: (4-methyl-3-, (Oxazol-2-yl) pyridin-2-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 404: (3- (Oxazol-2-yl) pyridin-2-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 405: (2- (Oxazol-2-yl) pyridin-3-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1]Hept-2-yl) methanone.
Example 406: (5-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 407: (6-methyl-2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 408: (6-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 409: (5-methyl-2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 410: (4-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 411: (3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 412: (2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 413: ((1S,4S,6R) -6- ((4,6-dimethylpyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 414: ((1S,4S,6R) -6- ((4,6-dimethylpyrimidin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 415: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 416: ((1S, 4S, 6R) -6- ((5- (difluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 417: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 418: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 419: (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 420: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Preparation analogous to example 77, intermediate A-40 was replaced with intermediate A-6. MS (ESI): c 23 H 19 F 4 N 5 O 2 The calculated mass of (a) is 473.2; the actual measurement value of m/z is 474.2[ M ] +H] + . On the Agilent 1100 line, analytical HPLC was obtained using an Xbridge C18 column (5 μm, 100X 4.6 mM), mobile phase 10-100% ACN in 20mM NH 4 OH, 8 minutes, then 3 minutes under 100% ACN, at a flow rate of 1mL/min (temperature =45 ℃). R at 254nm t =6.79 min (main optical isomer).
Example 421: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 422: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 423: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 424: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 425: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 426: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 427: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 428: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 429: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 430: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 431: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 432: (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 433: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 434: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 435: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 436: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 437: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 438: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 439: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 440: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 441: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 442: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 443: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 444: ((1S,4R,6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 445: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 446: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 447: ((1S,4R,6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 448: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 449: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 450: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 451: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 452: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 453: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Example 454: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 455: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 456: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 457: (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 458: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 459: (2- (5-fluoropyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 460: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 461: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 462: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 463: (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 464: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 465: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 466: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 467: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 468: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 469: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 470: ((1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 471: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 472: ((1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 473: ((1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 474: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 475: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 476: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 477: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 478: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Example 479: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 480: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 481: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 482: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 483: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2- (5-fluoropyrimidin-2-yl) phenyl) methanone.
Example 484: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 485: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 486: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 487: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 488: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 489: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 490: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Example 491: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 492: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 493: (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 494: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 495: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 496: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 497: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 498: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 499: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 500: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 501: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 502: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 503: (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 504: (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 505: (2-fluoro-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 506: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 507: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 508: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 509: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 510: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 511: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 512: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 513: ((1S,4R,6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 514: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 515: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 516: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 517: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 518: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 519: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 520: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 521: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 522: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Example 523: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 524: ((1S,4R,6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 525: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 526: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 527: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 528: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 529: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 530: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 531: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 532: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 533: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Example 534: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 535: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 536: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 537: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 538: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 539: (5-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 540: (4-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 541: ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 542: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 543: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 544: (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 545: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 546: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 547: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl) methanone.
Example 548: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) methanone.
Example 549: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) methanone.
Example 550: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 551: ((1S,4R,6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 552: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 553: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 554: (2- (2H-1,2,3-triazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 555: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone.
Example 556: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (3-fluoro-2- (pyrimidin-2-yl) phenyl) methanone.
Example 557: ((1S, 4R, 6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 558: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 559: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 560: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 561: ((1S, 4R, 6R) -6- ((5-chloropyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) methanone.
Example 562: ((1S, 4R, 6R) -6- ((5-bromopyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) methanone.
Example 563: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 564: (5-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 565: (6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 566: (6-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 567: (5-methyl-2- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 568: (5-methyl-2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 569: (2-methoxy-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 570: ((1S,4R,6R) -6- ((5-chloropyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-methoxy-6- (pyrimidin-2-yl) phenyl) methanone.
Example 571: (2-methoxy-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 572: ((1S,4R,6R) -6- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-methoxy-6- (pyrimidin-2-yl) phenyl) methanone.
Example 573: ((1S,4R,6R) -6- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2-methoxy-6- (pyrimidin-2-yl) phenyl) methanone.
Example 574: (2-methoxy-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 575: (2-methoxy-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 576: (2-methoxy-6- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 577: (3-fluoro-2- (pyrimidin-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5-methylpyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 578: ((1S,4R,6R) -6- ((5-methylpyrazin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) (2- (pyrimidin-2-yl) phenyl) methanone.
Example 579: (3- (5-fluoropyrimidin-2-yl) -5-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 580: (2- (5-fluoropyrimidin-2-yl) -6-methylpyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 581: (3- (5-fluoropyrimidin-2-yl) -6-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 582: (2- (5-fluoropyrimidin-2-yl) -5-methylpyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 583: (3- (5-fluoropyrimidin-2-yl) -4-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 584: (3- (5-fluoropyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 585: (2- (5-fluoropyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 586: (5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 587: (6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 588: (6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 589: (5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 590: (4 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 591: [2,3 '-bipyridine ] -2' -yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 592 is: [2,2' -bipyridin ] -3-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 593: (3,5 ' -dimethyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 594: (3 ', 6-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 595: (3,6 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 596: (3 ', 5-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 597: (3,4 ' -dimethyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 598: (3-methyl- [2,3 '-bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 599: (3 '-methyl- [2,2' -bipyridine ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 600: (3-fluoro-5 ' -methyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 601: (3 '-fluoro-6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 602: (3-fluoro-6 ' -methyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 603: (3 '-fluoro-5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 604: (3-fluoro-4 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 605: (3-fluoro- [2,3 '-bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 606: (3 '-fluoro- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 607: (5-methyl-3-, ( Oxazol-2-yl) pyridin-2-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 608: (6-methyl-2-, (Oxazol-2-yl) pyridin-3-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 609: (6-methyl-3-, (Oxazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 610: (5-methyl-2-, (Oxazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 611: (4-methyl-3-, (Azol-2-yl) pyridine-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 612:3- (Oxazol-2-yl) pyridin-2-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 613: (2- (Oxazol-2-yl) pyridin-3-yl ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2]Oct-2-yl) methanone.
Example 614: 5-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 615: (6-methyl-2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 616: (6-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 617: (5-methyl-2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 618: (4-methyl-3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 619: (3- (thiazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 620: (2- (thiazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 621: (2- (1-methyl-1H-imidazol-2-yl) phenyl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 622: (2- (1-methyl-1H-imidazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 623: (3- (1-methyl-1H-imidazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 624: (5-methyl-3- (1-methyl-1H-imidazol-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 625: (6-methyl-2- (1-methyl-1H-imidazol-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 626: (6-methyl-4- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 627: (2-methyl-4- (pyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) oxy) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 628: (2- (5-fluoropyrimidin-2-yl) -6-methylpyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 629: (2- (5-fluoropyrimidin-2-yl) -5-methylpyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 630: (2- (5-fluoropyrimidin-2-yl) pyridin-3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 631: (5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 632: (6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 633: (5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 634: [2,2' -bipyridin ] -3-yl ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 635: (3,5 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 636: (3 ', 6-dimethyl- [2,2' -bipyridine ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 637: (3 ', 5-dimethyl- [2,2' -bipyridine ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 638: (3 '-methyl- [2,2' -bipyridine ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 639: (3-fluoro-5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 640: (3 '-fluoro-6-methyl- [2,2' -bipyridine ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 641: (3 '-fluoro-5-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 642: (3 '-fluoro- [2,2' -bipyridine ] -3-yl) ((1S, 4S, 6R) -6- ((5- (trifluoromethyl) pyrazin-2-yl) amino) -2-azabicyclo [2.2.1] hept-2-yl) methanone.
Example 643: (3- (5-fluoropyrimidin-2-yl) -5-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 644: (2- (5-fluoropyrimidin-2-yl) -6-methylpyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 645: (3- (5-fluoropyrimidin-2-yl) -6-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 646: (2- (5-fluoropyrimidin-2-yl) -5-methylpyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 647: (3- (5-fluoropyrimidin-2-yl) -4-methylpyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 648: (5 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 649: (6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 650: (6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 651: (3- (5-fluoropyrimidin-2-yl) pyridin-2-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 652: (2- (5-fluoropyrimidin-2-yl) pyridin-3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 653: (3,5 ' -dimethyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 654: (3 ', 6-dimethyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 655: (3,6 ' -dimethyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 656: (3-fluoro- [2,3 '-bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 657: (3 '-fluoro- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 658: (3-fluoro-5 ' -methyl- [2,3' -bipyridin ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 659: (3 '-fluoro-6-methyl- [2,2' -bipyridin ] -3-yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Example 660: (3-fluoro-6 ' -methyl- [2,3' -bipyridine ] -2' -yl) ((1S, 4R, 6R) -6- ((5- (trifluoromethyl) pyridin-2-yl) amino) -2-azabicyclo [2.2.2] oct-2-yl) methanone.
Measurement of：
By competitive radioligand binding, using [ 2], [ respectively ] 3 H](1- (5- (2-fluoro-phenyl) -2-methyl-thiazol-4-yl) -1- ((S) -2- (5-phenyl- (1,3,4)Oxadiazol-2-ylmethyl) -pyrrolidin-1-yl-methanone (Langmead et al, 2004) and [ 2 ], [ 3 H]EMPA (n-ethyl-2 [ 96-methoxy-pyridin-3-yl) - (toluene-2-sulfonyl) -amino]-N-pyridin-3-ylmethyl acetamide) (Langmead et al, 2004, british Journal of Pharmacology 141; malherbe et al, 2004, british Journal of Pharmacology 156, 1326-41), to determine the in vitro affinity of the compounds of the invention for the rat/human orexin 1 and human orexin 2 receptors.
In vitro functional antagonism of compounds at the human orexin 1 and orexin 2 receptors was determined using a calcium assay based on a fluorescence imaging plate reader (FLIPR).
Data were analyzed using a pc-Sandy macro and plotted on Graphpad Prism 5. For analysis, each concentration point was averaged over three replicates and the average was plotted on Graphpad Prism. One site-competitive IC50 was determined by using the following formula (GraphPad Prism 5.0, san diego), where X = log (concentration) and Y = specific binding. Top represents total [3H ]]- (1- (5- (2-fluoro-phenyl) -2-methyl-thiazol-4-yl) -1- ((S) -2- (5-phenyl- (1,3,4) Oxadiazol-2-ylmethyl) -pyrrolidin-1-yl) -methanone) and the bottom indicates non-specificity [3H]- (1- (5- (2-fluoro-phenyl) -2-methyl-thiazol-4-yl) -1- ((S) -2- (5-phenyl- (1,3,4)Oxadiazol-2-ylmethyl) -pyrrolesAlk-1-yl) -methanone). Ki values calculated by Graphpad Prism via IC50, and [3H]- (1- (5- (2-fluoro-phenyl) -2-methyl-thiazol-4-yl) -1- ((S) -2- (5-phenyl- (1,3,4)Oxadiazol-2-ylmethyl) -pyrrolidin-1-yl) -methanone) and [3H]-a predetermined Kd value for EMPA. The Ki for each compound was then uploaded into 3 DX. Each run included triplicate of each compound. The data in tables 1 and 2 represent the average between 2-20 runs.
Rat and human orexin 1 receptor radioligand binding studies
Human embryonic kidney 293 cells (HEK 293) stably expressing the rat orexin 1 receptor (Genebank accession NM-001525) or Chinese ovarian Cells (CHO) stably expressing the human orexin 1 receptor (Genebank accession NM-001526) were grown at 150cm 2 Tissue culture plates were grown to confluence in DMEM (Hyclone, cat. No. SH 30022), 10% FBS, 1X penicillin/streptomycin, 1X sodium pyruvate, 10mM HEPES, 600. Mu.g/mL G418 and DMEM/F12 (Gibco, cat. No. 11039), 10% FBS, 1X Pen/Strep, 600. Mu.g/mL G418 media, washed with 5mM EDTA in PBS (Hyclone Dulbecco's phosphate buffered saline 1X with calcium and magnesium, cat. No. SH30264.01, hereinafter PBS for short), and scraped into 50mL tubes. After centrifugation (2K XG, 5 min at 4 ℃), the supernatant was aspirated and the pellet was frozen and stored at-80 ℃. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, cat # 11836145001) per 50 mL. Each cell pellet from a 15cm plate was resuspended in 10mL, stored on ice, and homogenized for 45 seconds before being added to the reaction. A competitive binding assay was performed in a 96-well polypropylene plate using the expression [ 2 ] 3 H]- (1- (5- (2-fluoro-phenyl) -2-methyl-thiazol-4-yl) -1- ((S) -2- (5-phenyl- (1,3,4)Oxadiazol-2-ylmethyl) -pyrrolidin-1-yl) -methanone) (Moraveck Corporation, specific activity =35.3 Ci/mmol) diluted to 10nM concentration in PBS solution (final 4 nM).Compounds were dissolved in 100% DMSO (Acros Organics, cat. No. 61042-1000) and tested in 7 concentration ranges (from 0.1nM to 10. Mu.M). The final concentration of DMSO in the reaction was equal to or less than 0.1%. Both total and non-specific binding were determined in the absence and presence of 10 μ M amoxicillin. The total volume of each reaction was 200. Mu.L (20. Mu.L of the diluted compound, 80. Mu.L of the solution in PBS [ ] [, ] 3 H]- (1- (5- (2-fluoro-phenyl) -2-methyl-thiazol-4-yl) -1- ((S) -2- (5-phenyl- (1,3,4)Oxadiazol-2-ylmethyl) -pyrrolidin-1-yl) -methanone), and 100 μ L of the cell suspension). The reaction was allowed to run at room temperature for 60 minutes and stopped by filtering through GF/C filter plates (PerkinElmer, cat # 6005174) pre-soaked in 0.3% polyethyleneimine using a cell harvester (PerkinElmer Filtermate). The filter plates were washed 3 times by aspirating 30mL of PBS through the filter plates. The filter plates were dried in an oven at 55 ℃ for 60 minutes, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
IC was calculated by fitting sigmoidal dose-response curves using GraphPad Prism Software (GraphPad Prism Software Inc., san Diego, calif.) 50 Value (i.e. the concentration of unlabelled compound required to compete for 50% specific binding to the radioligand). With K i ＝IC 50 /(1+C/K d ) Calculating the apparent value of Ki, where C is the concentration of radioligand and K is the receptor for orexin 1 in rats d =4nM and K of the human orexin 1 receptor d ＝6nM。
Human orexin 2 receptor radioligand binding studies
HEK293 stably expressing human orexin 2 receptor (GenBank accession No. NM _ 001526) was grown to confluence in DMEM (Hyclone, catalog No. SH 30022), 10% fbs, 1X penicillin/streptomycin, 1X sodium pyruvate, 10mM HEPES, 600ug/mL G418 medium on 150cm2 tissue culture plates, washed with 5mM EDTA in PBS solution (Hyclone Dulbecco phosphate buffered saline with calcium and magnesium 1X, catalog No. SH30264.01, hereinafter abbreviated as PBS) and scraped into 50mL tubes. Separation deviceAfter the heart (2K XG, 5 min at 4 ℃), the supernatant was aspirated and the spheroids were frozen and stored at-80 ℃. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, cat # 11836145001) per 50 mL. Each cell pellet from a 15cm plate was resuspended in 10mL, stored on ice, and homogenized for 45 seconds immediately before addition to the reaction. Competitive binding experiments were performed in 96-well polypropylene plates using the use [ alpha ], [ 2 ] 3 H]EMPA (Moraveck Corporation, specific activity =29.6 Ci/mmol), diluted to a 5nM concentration in PBS solution (final concentration 2 nM). Compounds were dissolved in 100% DMSO (Acros Organics, cat. No. 61042-1000) and tested in 7 concentration ranges (from 0.1nM to 10. Mu.M). The final concentration of DMSO in the reaction was equal to or less than 0.1%. Both total and non-specific binding were determined in the absence and presence of 10 μ M amoxicillin. The total volume of each reaction was 200. Mu.L (20. Mu.L of the diluted compound, 80. Mu.L of the solution in PBS [ ] [, ] 3 H]EMPA, and 100. Mu.L of cell suspension). The reaction was allowed to run at room temperature for 60 minutes and stopped by filtering through GF/C filter plates (PerkinElmer, cat # 6005174) pre-soaked in 0.3% polyethyleneimine using a cell harvester (PerkinElmer Filtermate). The filter plates were washed 3 times by aspirating 30mL of PBS through the filter plates. The filter plates were dried in an oven at 55 ℃ for 60 minutes, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
IC was calculated by fitting sigmoidal dose-response curves using GraphPad Prism Software (GraphPad Prism Software Inc., san Diego, calif.) 50 Value (i.e. the concentration of unlabelled compound required to compete for 50% specific binding to the radioligand). With K i ＝IC 50 /(1+C/K d ) Calculating the apparent value of Ki, where C is the concentration of radioligand and K d ＝2nM。
Human orexin 1 receptor Ca 2+ Mobility testing
CHO cells stably transfected with human orexin 1 receptor (Genebank accession NM-001526) were grown to confluence in DMEM/F12, 10% FBS, 1 XPicillin-streptomycin, 400. Mu.g/ml G418. Cells were seeded at a density of 10,000 cells/well in 384-well Packard in plates and incubated overnight at 37 ℃ in 5% CO2. In HBSS (Gibco, cat. No. 14025-092) with 2.5mM probenecid, cell dye was adsorbed with BD calcium assay kit (BD, cat. No. 640178) and 5% CO was determined at 37 ℃% 2 Incubate for 45 minutes. Cells were preincubated with compound (diluted in DMEM/F-12) for 15-30 minutes, followed by antagonist (orexin A,10 nM) stimulation. Ligand-induced Ca assay Using fluorescence imaging microplate reader (FLIPR, molecular Devices, sunnyvale, calif.) 2+ And (4) releasing. The functional response was determined as the peak fluorescence intensity minus the baseline value. The concentration of antagonist that produces a half maximal response is expressed as EC 50 The value is obtained. Conversion of antagonistic potency values to apparent pK Using modified Cheng-Prusoff correction B The value is obtained. Apparent pK B ＝-log IC 50 1+ [ antagonist concentration/EC 50 ]。
Human orexin 2 receptor Ca 2+ Mobility testing
PFSK-1 cells endogenously expressing the human orexin 2 receptor were grown to confluence in RPMI1640 (Hyclone, catalog number 30027.02), 10% FBS, 1 XPS-streptomycin. Cells were seeded at a density of 5,000 cells/well in 384-well Packard viewing plates and cultured overnight at 37 ℃,5% co 2. In HBSS (Gibco, cat. No. 14025-092) with 2.5mM probenecid, cell dye was adsorbed with BD calcium assay kit (BD, cat. No. 640178) and cultured at 37 ℃ for 45 minutes at 5% CO2. Cells were preincubated with compound (diluted in DMEM/F-12) for 15-30 minutes, followed by antagonist (orexin B,100 nM) stimulation. Ligand-induced Ca assay Using fluorescence imaging microplate reader (FLIPR, molecular Devices, sunnyvale, calif.) 2+ And (4) releasing. The functional response was determined as the peak fluorescence intensity minus the baseline value. The concentration of antagonist that produces a half-maximal response is expressed as EC 50 The value is obtained. Conversion of antagonistic potency values to apparent pK Using modified Cheng-Prusoff correction B The value is obtained. Apparent pK B ＝-log IC 50 1+ [ antagonist concentration/EC 50 ]。
Preferred compounds of the invention are shown in the following table. The orexin receptor activity of certain compounds of the present invention is also shown in table 1 below.
TABLE 1
Preferred compounds of the invention are shown in the following table. The orexin receptor activity of certain compounds of the present invention is also shown in table 2 below.
TABLE 2

Claims (8)

1. A pharmaceutical composition comprising:
(a) A therapeutically effective amount of a compound selected from:
and (b) at least one pharmaceutically acceptable excipient selected from inert diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents and preservatives.
2. The pharmaceutical composition of claim 1, wherein the compound is
3. Use of a pharmaceutical composition according to claim 1 or 2 in the manufacture of a medicament for treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity.
4. The use of claim 3, wherein the disease, disorder, or medical condition mediated by orexin receptor activity is sleep-wake cycle disorder, insomnia, restless leg syndrome, jet lag, disturbed sleep, sleep disorders secondary to neurological disorders, mania, depression, manic depression, schizophrenia, pain syndrome, fibromyalgia, neuropathic pain, tension, parkinson's disease, tourette's syndrome, anxiety, delusions, dementia, overweight, obesity or conditions associated with overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, cardiac arrhythmia, angina, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorder, attention deficit disorder, cognitive deficit or substance abuse.
5. The use according to claim 4, wherein the disease, disorder or medical condition is a mood disorder, a post-traumatic stress disorder, a panic disorder, an attention deficit disorder, a cognitive deficit, or substance abuse.
6. The use of claim 4, wherein the disease, disorder or medical condition is an anxiety-related mood disorder, depression, a panic-related mood disorder or a stress-related mood disorder.
7. The use of claim 4, wherein the disease, disorder or medical condition is anxiety, anxious depression, panic, schizophrenia, or substance abuse.
8. The use of claim 4, wherein the disease, disorder, or medical condition is anxious depression.
HK42020010838.9A 2013-03-13 2020-07-09 Substituted 2-azabicycles and their use as orexin receptor modulators HK40020928B (en)

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