WO2014159591A1 - Substituted 7-azabicycles and their use as orexin receptor modulators - Google Patents

Substituted 7-azabicycles and their use as orexin receptor modulators Download PDF

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Publication number
WO2014159591A1
WO2014159591A1 PCT/US2014/024322 US2014024322W WO2014159591A1 WO 2014159591 A1 WO2014159591 A1 WO 2014159591A1 US 2014024322 W US2014024322 W US 2014024322W WO 2014159591 A1 WO2014159591 A1 WO 2014159591A1
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Prior art keywords
compound
methyl
azabicyclo
alkyl
halo
Prior art date
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PCT/US2014/024322
Other languages
French (fr)
Inventor
Heather R. COATE
Curt A. Dvorak
Anne E. Fitzgerald
Terry P. LEBOLD
Cathy PREVILLE
Brock T. Shireman
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Janssen Pharmaceutica Nv
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Publication date
Priority to AU2014240388A priority Critical patent/AU2014240388B2/en
Priority to UAA201510021A priority patent/UA116132C2/en
Priority to KR1020157028726A priority patent/KR102209432B1/en
Priority to JP2016501497A priority patent/JP6337082B2/en
Priority to EP14717297.7A priority patent/EP2970313B1/en
Priority to EA201591675A priority patent/EA028386B1/en
Priority to US14/774,554 priority patent/US9637496B2/en
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to MX2015011816A priority patent/MX360791B/en
Priority to SG11201507431UA priority patent/SG11201507431UA/en
Priority to CN201480027442.3A priority patent/CN105209468B/en
Priority to ES14717297.7T priority patent/ES2659222T3/en
Priority to BR112015022058A priority patent/BR112015022058A2/en
Priority to CA2905012A priority patent/CA2905012C/en
Publication of WO2014159591A1 publication Critical patent/WO2014159591A1/en
Priority to CR20150434A priority patent/CR20150434A/en
Priority to IL240929A priority patent/IL240929B/en
Priority to PH12015502030A priority patent/PH12015502030A1/en
Priority to HK16107633.0A priority patent/HK1219726A1/en
Priority to AU2018253525A priority patent/AU2018253525A1/en

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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention is directed to substituted 7-azabicyclic compounds, pharmaceutical compositions comprising them, methods of making them, and methods of using them for the modulation of the orexin receptor for the treatment of disease states, disorders, and conditions mediated by orexin receptor activity.
  • Qrexin/hypocretin signaling is mediated by two receptors and two peptide agonists.
  • the peptides (orexin- A and orexin-B) are cleavage products of the same gene, pre -pro orexin.
  • neurons producing pre -pro orexin are found solely in the perifomical nucleus, the dorsal hypothalamus, and the lateral hypothalamus (Peyron et al, 1998, J. Neurosci. 18: 9996-10015). Orexigenic cells in these regions project to many areas of the brain, extending rostrally to the olfactory bulbs and caudaily to the spinal cord (Van den Pol, 1999, J. Neurosci. 19: 3171-3182).
  • Orexin- 1 and orexin-2 receptors are G-protein-coupled, seven transmembrane receptors that share over 64% amino acid sequence identity with one another. Both receptors are generally excitatory, the common cellular response to orexin-induced receptor activation being increases in intracellular calcium. Homology between the species orthologs is high and there are no known pharmacological differences.
  • Orexin- A and -B are usually considered equal Iigands for orexin-2 receptor but orexin-B is thought to be 5- to 100-fold weaker ligand than orexin- A at the orexin- 1 receptor (Sakurai et al, 1998, Cell 92: 573-585; Ammoun et al., 2003, J.
  • Orexin- 1 receptors are selective for the limbic system (bed nucleus of the stria terminalis and amygdala), cingulate cortex and noradrenergic neurons in the locus coeruieus.
  • the orexin-2 receptor is almost the exclusive orexin receptor in the histaminergic neurons in the tuberomammilary nucleus which play a critical role in wake promotion; in paraventricular neurons and the parahrachial nucleus. In other brain regions like the dorsal raphe, the ventral tegmental area or the prefontal cortex both receptors are coexpressed.
  • Orexin signaling as a target for sleep-promoting therapies was further validated clinically by findings of attenuated orexin levels and loss of orexinergic neurons in human narcoleptic patients (Mignot et al., 2001 , Am. J. Hum. Genet. 68: 686-699; Minot & Thorsby, 2001, New England J. Med. 344: 692) or, in rare cases, to mutations in the orexin-2 gene (Peyron et al, 2000, Nature Med. . 6: 991-997). Disorders of the sleep-wake cycle are therefore likely targets for orexin-2 receptor modulator acti vity.
  • sleep-wake disorders that ma be treated by agonists or other modulators that up-regulate orexin-2 receptor-mediated processes include narcolepsy, jet lag (sleepiness) and sleep disorders secondary to neurological disorders such as depression.
  • disorders that may be treated by antagonists or other modulators that down-regulate orexin-2 receptor- mediated processes include insomnia, restless leg syndrome, jet lag (wakefulness) and sleep disorders secondary to neurological disorders such as mania, schizophrenia, pain syndromes and the like.
  • Orexirsergic neurons send projections to the ventral tegmental area and other brain regions involved in reward processing. Orexin ligands mediate reward behavior, and antagonizing these effects with a selective orexin- 1 receptor antagonist in various preclinical model of addiction has suggested that these actions are mediated through orexin- 1 receptor.
  • a selective orexin- 1 antagonist attenuates morphine conditioned place preference and reinstatement (Harris et al, 2005, Nature, 437, 556-5599: Narita et al, 2006, J Neurosci.,26, 398-405; Harris et al., 2007, Sehav Brain Res, 183, 43-51), stress-induced cocaine reinstatement, cocaine-induced behavioral and synaptic plasticity (Borgland et al., 2006, Neuron, 49, 589-601 ), and intake and cue and stress-induced reinstatement of ethanol (Lawrence et al, 2006, Br J Pharmacol, 148, 752-759), in addition to attenuating precipitated morphine withdrawal (Sharf et al., 2008, Biol PsychiaUy, 64, 175-183) and nicotme self-administration (Hollander et al., 2008, Proc Nail Acad Sci US A., 105, 19480-19485).
  • Lactate infusion or acute hypercapnia which causes panic in humans, and are used as an animal model of panic, acti v ates orexin neurons in the perifornical hypothalamus. This activation correlates with anxiety in the social interaction test or open field test.
  • Blocking orexin signaling with either siRNA or selective orexin- 1 receptor antagonists attenuates panic-like responses to lactate (Johnson et al., 2010, Nature Medicine, j . 6, 1 1 1-1 15; Johnson et al., 2012, Neuropsychopharmacology, 3 . 7, 191 1, 1922).
  • Cerebral spinal fluid (CSF) levels of orexin are lower in depressed or suicidal patients, and the level of orexin inversely correlates with illness severity (Brundin et al., 2007, European Neuropsychopharmacology, 17, 573-579; Salomon et al., 2003, Biol Psychiatry, 5 , 96- 104).
  • CSF Cerebral spinal fluid
  • the orexin system also interacts with brain dopamine systems. Intracerebroventricuiar injections of orexin in mice increase locomotor activity, grooming and stereotypy; these behavioral effects are reversed by administration of D2 dopamine receptor antagonists
  • orexin receptor modulators may be useful to treat various neurological disorders; e.g., agonists or up-regulators to treat catatonia, antagonists or down-regulators to treat Parkinson's disease, Tourette's syndrome, anxiety, delerium and dementias.
  • Orexms and their receptors have been found in both the myenteric and submucosal plexus of the enteric nervous system, where orexms have been shown to increase motility in viiro (Kirchgessner & Liu, 1999, Neuron 24: 941-951 ) and to stimulate gastric acid secretion in vitro (Takahashi et al., 1999, Biochem. Biophys. Res. Comm. 254: 623-627).
  • Orexin effects on the gut may be driven by a projection via the vagus nerve (van den Pol, 1999, supra)., as vagotomy or atropine prevent the effect of an intracerebroventricular injection of orexin on gastric acid secretion (T akahashi et al., 999, supra). Orexin receptor antagonists or other down-regulators of orexin receptor-mediated systems are therefore potential treatments for ulcers, irritable bowel syndrome, diarrhea and gastroesophageal reflux.
  • Body weight may also be affected by orexin-mediated regulation of appetite and metabolism.
  • Some effects of orexin on metabolism and appetite may be mediated in the gut, where, as mentioned, orexins alter gastric motility and gastric acid secretion, Orexin antagonists therefore are likely to be useful in treatment of overweight or obesity and conditions related to overweight or obesity, such as insulin resistance/type 11 diabetes, hyperiipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis.
  • orexin agonists are likely to be useful in treatment of underweight and related conditions such as hypotension, bradycardia, ammenorrhea and related infertility, and eating disorders such as anorexia and bulimia.
  • Intracerebroventricularly administered orexins have been shown to increase mean arterial pressure and heart rate in freely moving (awake) animals (Samson et al., 1999, Brain Res. 831 : 248-253; Shirasaka et al, 1999, Am. J. Physiol. 2 . 77: R1780-R1785) and in urethane-anesthetized animals (Chen et al, 2000, Am. J. Physiol.
  • Orexin receptor agonists may therefore be candidates for treatment of hypotension, bradycardia and heart failure related thereto, while orexin receptor antagonists may be useful for treatment of hypertension, tachycardia and other arrhythmias, angina pectoris and acute heart failure.
  • the present invention is directed to compounds of Formula 1:
  • ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyi, thiazolyl, isoxazolyl, pyrazolvi, imidazothiazolyl, benzimidazolyl, or indazolyl;
  • Ri is H, alkyl, alkoxy, hydroxyalkyiene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenvl, morpliolinyi, or clialkyiamino, wherein phenyl, triazolyl, oxazolyl, isoxazolyl, pyri
  • the invention also relates to pharmaceutical compositions comprising therapeutically effective amounts of compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.
  • Figure 1 depicts a Powder X-Ray Diffraction (PXRD) pattern for one embodiment of the invention.
  • FIG. 2 depicts a Powder X-Ray Diffraction (PXRD) pattern for one embodiment of the invention, Example 238, Form 2.
  • PXRD Powder X-Ray Diffraction
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • an alkyl group is a C-i-Ce alkyl group.
  • an alkyl group is a Q-Ct alkyl group.
  • alkyi groups examples include methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isoliexyl , and groups that in light of the ordinary skil l in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • Alkyl groups of the invention can be optionally substituted with, for example, one or more halogen atoms.
  • One exemplary substitutent is fluoro.
  • Certain substituted alkyi groups of the invention include trihalogenated alkyl groups such as trifluoromethyl groups.
  • Alky i groups of the invention can also refer to "cycloalkyl" moieties.
  • Cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 7 carbon atoms.
  • Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 - methylcyclopropyl, 2-methyIcyclopentyl, and the like.
  • alkoxy includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyi group to the rest of the molecule.
  • an alkoxy group is a Ci-Ce alkoxy group.
  • an alkoxy group is a Cj-Cs alkoxy group.
  • Alkoxy m cludes methoxy, etboxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
  • Alkoxy groups of the inventions can be optionally substituted with, for example, one or more halogen atoms (baloalkoxy).
  • One exemplary substitutent is fluoro.
  • Preferred substituted alkoxy groups of the invention are substituted with one, two, or three halogen atoms, for example, - OCHCF 2 .
  • dialkylamino represents the moiety wherein each H of the amino group is replaced by an alkyl group. These alkyl groups ca be the same or different. Preferred alkyl groups are the Ci-ealkyl groups. Examples of dialkyl amino groups include dimethylamino, diethylamino, diisopropylamino, and the like. Other examples include methylethylamino, methylisopropylamino, and the like.
  • aryl ring represents" a mono- or bi-cyclic aromatic, hydrocarbon ring structure.
  • Aryl rings can have 6 or 10 carbon atoms in the ring.
  • benzimidazolyf represents the following moiety: T/ 2
  • the benzimidazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, or
  • benzoxazolyl represents the following moiety:
  • the benoxazolyl moiety can be attached through any one of the 2-, 4-, 5-, 6- , or 7- position carbon atoms and is optionally substituted with alkyl or halo or alkoxy groups.
  • the furanyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-posiiion carbon atoms.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • eteroaryl ring represents a mono-or bicyclic aromoatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms.
  • hydroxyalkylene represents an alkyl group, terminally substituted with OH.
  • hydroxyalkylene moieties include -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 CH 2 CH?-OH, and the like.
  • imidazopyridyl represents the following moiety:
  • the imidazopyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7-position carbon atoms and is optionally substituted with alkyl or halo or alkoxy groups.
  • zopyrazinyl represents the following moiety:
  • the imidazopyrazinyl moiety can be attached through any one of the 2-, 5-, or 6-position carbon atoms.
  • imidazothiazolyl represents the following moiety :
  • the imidazothiazolyi moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.
  • indazolyl represents the following moiety:
  • the indazolyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, or 7-position atoms and is optionally substituted with alkyl or halo or aikoxy groups.
  • isoquinolinyl represents the following moiety:
  • the isoquinolinyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, 7-, or 8- position carbon atoms and is optionally substituted with alkyl or halo or aikoxy groups.
  • isoxazolyi represents the following moiety:
  • the isoxazoly i moiety can be attached through any one of the 3-, 4-, or 5-position carbon atoms.
  • Isoxazolyi groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.
  • naphthalenyl represents the following moiety :
  • the naphthalenyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms and is optionally substituted with alkyl or halo or aikoxy groups.
  • morpholinyl represents the following moiety:
  • the 4-position nitrogen atom may he substituted with H or alkyl, for example methyl.
  • the 4-position nitrogen can also be protected with a nitrogen protecting group such as a butyl- oxycarbonyl (-Boc).
  • the morpholinyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position atoms.
  • the morpholinyl ring is optionally substituted with halo or alkyl groups.
  • oxazolyl represents the following moiety:
  • Oxazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.
  • oxadiazoiyi represents a 1,2,3-oxadiazoie, 1 ,2,4-oxadiazoie, 1,2,5-oxadiazoie, or 1,3,
  • oxadiazoiyi moieties can be attached through any one of the carbon or nitrogen atoms.
  • "oxadiazoiyi" groups can be substituted with an alkyl group, preferably a methyl group.
  • tbiazolyl represents the following moiety:
  • the thiazolyl moiety can be attached through any one of the carbon atoms.
  • Thiazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.
  • thiadiazolyl represents a 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1 ,2,5- thiadiazole, or 1, 3, 4-thiadiazole moiety :
  • the thiadiazolyl moieties can be attached through any one of the carbon or nitrogen atoms.
  • "thiadiazolyl” groups can be substituted with an alkyl group, preferably a methyl group.
  • Phenyl groups of the inventions can be optionally substituted with, for example, one or more halogen atoms (haio-phenyl) or alkyl or alkoxy groups.
  • exemplary substifutents are fluoro, bromo, and chloro.
  • Preferred substituted phenyl groups of the invention are substituted with one, two, or three halogen atoms.
  • the pyridyl moiety can be attached through any one of the 2 -, 3-, 4-, 5 -, or 6-position carbon atoms.
  • Pyridyl groups of the invention can be optionally substituted with, for exampl one or more halo or alkyl groups, for example, one or two methyl groups.
  • the piperazinyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms. Any one of the nitrogen atoms of the piperazinyl moiety can be substituted with H or alkyl, for example, methyl.
  • pyrimidmyl represents the following moiety:
  • pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms.
  • "pyrimidinyl" groups of the invention can be substituted with halogen or alkyl, for example fluoro or methyl or trifluoromethyi.
  • pyrazinyl represents the following moiety:
  • the pyrazinyl moiety can be attached through any one of the 2 -, 3-, 5-, or 6-position carbon atoms and may be optionally substituted with alkyl, aikoxy or halo.
  • pyridazinyl represents the following moiety:
  • the pyridazinyl moiety can be attached through any one of the 3-, 4-, 5-, or 6-position carbon atoms and may be substituted with alkyl, aikoxy or halo groups.
  • pyrazoiyl represents the following moiety:
  • the pyrazoiyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5 -position carbon atoms.
  • Pyrazoiyl groups of the invention can be optionally substituted with, for exampl one or two alkyl groups, for example, one or two methyl groups.
  • the pyrrolidinyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5- position atoms.
  • the nitrogen can be substituted with H or alkyl, for example methyl.
  • quinolinyl represents the following moiety:
  • the quinolinyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, 7-, or 8 ⁇ position carbon atoms and may be optionally substituted with alkyl, halo or aikoxy groups.
  • quinoxalmyl represents the following moiety:
  • the quinoxalinyl moiety can be attached through any one of the 2-, 3 -, 5-, 6-, 7-, or 8-position carbon atoms and may be optionally substituted with alkyl, halo or alkoxy groups.
  • the quinoxalinyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, 7-, or 8-position carbon atoms and may be optionally substituted with alkyl, halo or alkoxy groups.
  • thiazolyl represents the following moiety:
  • the thiazolyl moiety can be attached through any one of the 2
  • the thiophenyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-position carbon atoms.
  • olopyrazinyl represents the following moiety:
  • the triazolopyrazinyl moiety can be attached through any one of ihe 1-, 3-, 4-, 5-, 6-, or 7-position atoms.
  • triazoiyi represents a 1,2,3-triazole or a 1,2,4-triazole moiety:
  • the triazolyl moieties can be attached through any one of their atoms.
  • “Pharmaceutically acceptable” means approved or appro vable by a regulatory agency of the Federal or a state go vernment or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention thai is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, in particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • 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 formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, giycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hyciroxybenzoyi)benzoic acid, cinnamic acid, mandeiic acid, methanesulfonic acid,
  • ethanesulfonic acid 1,2-ethane-disulfonic 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-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapbthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • hydrochloride hydrobromide, tartrate, mesylate, acetate, maieate, oxalate and the like.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • Subject includes humans. The terms “human,” “patient,” and “subject” are used interchangeably herein.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodinient, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • a therapeutically effective amountof a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • a "therapeutically effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • Effective amounts or doses of the compounds of the present inv ention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., 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 subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, T1D, Q1D).
  • a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/ ' day.
  • “Compounds of the present invention,” and equivalent expressions are meant to embrace compounds of the Formula (I) as described herein, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed is meant to embrace their salts, and solvates, where the context so permits.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more nonradioactive or radioactive isotopes, such as for example, deuterium ( ⁇ or D), carbon- 13 ( l3 C), nitrogen- 15 ( l5 N), or the like.
  • the following atoms, where present, may vary , so thai for example, any hydrogen may be Z H/D, any carbon may be 1 C, or any nitrogen may be ] N, and that the presence and placement of such atoms may be determined wi thin the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • Radiol abeled compounds of the invention can be used in diagnostic methods such as Single-photon emission computed tomography (SPECT).
  • SPECT Single-photon emission computed tomography
  • ⁇ , and carbon- 14, i.e. l4 C are particularly useful for their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as "C, ;8 F, i5 0 and iJ N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • deuterated analogs of compounds of Formula T as described in the Examples section.
  • deuterated analogs of compounds of Fonnula I comprise deuterium atoms attached to one or more positions on the 7-azabicyclic ring, such as bridgehead carbons, or
  • non-bridgehead carbons of the 7-azabicyclic ring and preferably comprise one or more deuterium atoms attached to non-bridgehead carbons of the 7-azabicyclic ring.
  • Deuteration of a compound of Formula I may also be effected on one or more substituents (such as e.g., ring A, R 1 , R " , or R J ) present on the
  • enantiomers Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposabie mirror images of each other are termed “enantiomers.”
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-seq encing rides of Calm and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively), A.
  • chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture.”
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological acti vity of a compound of interest.
  • Compounds of the invention may also exist as "rotamers,” that is, conformational isomers that occur when the rotation leading to different conformations is hindered, resulting a rotational energy barrier to be overcome to convert from one conformational isomer to another.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (j )-or ( ⁇ -stereoisomers or as mixtures thereof.
  • ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyl, thiazoiyi, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl;
  • Ri is H, alkyl, alkoxy, hydroxya!kyfene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino, wherein pheny l, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, or morpholinyl is optionally substituted with up to two substituents selected from halo and alkyl:
  • R 2 is H, alkyl, alkoxy, hydroxyalkylene, or halo
  • Z is H, N-alkyl, or O
  • 3 ⁇ 4 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyi, quinoxalinyl, pyrazolyl, thiazoiyi, thiadiazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cyano, alkyl carboxylate, alkoxy, and halo; and n is 0 or 1.
  • ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl,
  • Ri is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino;
  • R? is H, alkyl, alkoxy, hydroxyalkylene, or halo
  • Z is NH, N-alkyl, or O
  • 5 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyi, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo; and
  • Enantiomers and diastereomers of the compounds of Formula I are also within the scope of the invention. Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of Formula 1, as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula I. Also contemplated within the scope of the embodiments provided herein are isotopic variants of compounds of Formula 1, such as, by way of example, deuterated compounds of Formula 1.
  • Z is NFL in other embodiments, Z is N-alkyl, preferably N-Ci-ealkyl, preferably N-CH 3 .
  • Z is O
  • ring A is a heteroaryl ring.
  • ring A is furanyl, which can be attached to the compounds of Formula I through any available atom, preferably the 2-position carbon atom.
  • ring A is thiazoly i, which can be attached to the compounds of Formula I through any available atom, preferably the 4-position carbon atom.
  • ring A is isoxazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-position carbon atom.
  • ring A is pyrazo!yi, which can be attached to the compounds of Formula I through any through any available atom, preferably the 3- or 4-position carbon atoms.
  • ring A is imidazotbiazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 5-position carbon atom.
  • ring A is benzimidazolyl, which can be attached to the compounds of Formula I through any available atom, prefera bly the 2-position carbon atom.
  • ring A is indazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 3 -position carbon atom.
  • ring A is imidazopyridyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-, or 7-position carbon atom
  • ring A is quinolinyl, which can be attached to the compounds of Formula I through any av ailable carbon atom, preferably the 5- or 8-position carbon atom.
  • ring A is isoquinolinyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 4-position carbon atom.
  • ring A is pyridyl, which can be attached to the compounds of
  • Formula I through any available carbon atom, preferably the 2-, 3-, or 4-position carbon atom.
  • ring A can be an aryl ring.
  • ring A is phenyl.
  • ring A is naphthalenyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 1 -position carbon atom.
  • Rj is H, in other embodiments, R] is alkyi, preferably a C h lky!, for example, methyl.
  • Ri is aikoxy, preferably a Cj-ealkoxy such as methoxy or ethoxy.
  • R is a substituted aikoxy, preferably substituted with one or more halo such as F, CI, or Br.
  • haloalkoxy is difluoromethoxy.
  • Rj is hydroxyalkylene, for example, hydroxyCj-ealkylene such as -CH 2 -OH or -CH2CH2-OH.
  • 3 ⁇ 4 is OH.
  • Ri is halo, that is, any one of F, CI, Br, or I, with F, CI, or Br being particularly preferred.
  • Ri is phenyl.
  • j is phenyl optionally substituted with up to two substituents selected from halo and alkyl.
  • the phenyl can be substituted with at least one halo, for example, phenyl substituted with at least one of F, CI, or Br.
  • Rj is triazolyi, with 1 ,2,3-triazolyl being preferred.
  • the triazolyi can be attached through any available atom.
  • the 1 ,2,3-triazolyl is attached through the 2-position nitrogen atom.
  • the 1,2,3-triazolyl is attached through the 1 -position nitrogen atom.
  • Ri is triazolyi optionally substituted with up to two substituents selected from halo and alkyi.
  • Rj is oxazoiyl, which can be attached through any available atom, preferably attached through the 2-position carbon.
  • j is oxazoiyl optionally substituted with up to two substituents selected from halo and alkyi.
  • the oxazoiyl can be substituted with alkyl, for example, a Cs ⁇ aikyl such as methyl.
  • Rj is isoxazolyl, which can be attached through any available atom.
  • Rj is isoxazolyl optionally substituted with up to two substituents selected from halo and alkyL
  • the isoxazolyl can be substituted with alkyL for example, a Cj -galkyl such as methyl.
  • R is pyridyl, which can be attached through any available carbon atom
  • Ri is pyridyl optionaiiy substituted with up to two substituents selected from halo and alkyL
  • the pyridyl can be substituted with withat least one alkyl, for example, C h alky! such as methyl.
  • Ri is pyrimidiny!, which can be attached through any available carbon atom.
  • Ri is pyrazinyi, which can be attached through any available carbon atom.
  • Rj is pyridazinyl, which can be attached through any available carbon atom.
  • Rj is pyrimidinyl, or pyrazinyi, or pyridazinyl, each optionally substituted with up to two substituents selected from halo and alkyl.
  • Ri is piperazinyl which can be attached through any available atom.
  • Ri is piperazinyl optionally substituted with up to two substituents selected from halo and alkyl.
  • one or both nitrogen atoms of the piperazinyl may be substituted with H or alkyl, for example, Ci-ealkyl such as methyl.
  • R is morpholinyl, which can be attached through any available atom.
  • Ri is morpholinyl optionally substituted with up to two substituents selected from halo and alkyL
  • the nitrogen of the morpholinyl may be substituted with H or alkyl, for example, C h alky! such as methyl.
  • Ri is pyrrolidinyl, which can be attached through any available atom.
  • Rj is pyrrolidinyl optionally substituted with up to two substituents selected from halo and alkyl.
  • the nitrogen of the pyrrolidinyl ma be substituted with H or alkyl, for example, Cj -ealkyl such as methyl.
  • R is dialkylamino, for example, dimethylamino, diethylamino, or methylethylamino.
  • Ri is pyrazoiyl, which can be attached through any available atom.
  • i is pyrazoiyl optionally substituted with up to two substituents selected from halo and alkyl.
  • the pyrazoiyl can be substituted with with one or two alkyl, for example, C h alky 1 such as methyl.
  • Ri is oxa liazoiyl, which can be a 1,2,3 -oxadiazolyl,
  • the oxadiazolyl is 1,2,4- oxadiazolyl.
  • the oxadiazolyl can be attached through any available atom.
  • j is oxadiazolyl optionally substituted with up to two substituents selected from halo and alkyl.
  • the oxadiazolyl can be substituted with with alkyl, for example, such as methyl.
  • R is thiophenyl, which can be attached through any available carbon atom
  • Ri is thiophenyl optionally substituted with up to two substituents selected from halo and alkyl.
  • R2 is H.
  • R 2 is alkyl, for example, Ci-ealkyl such as methyl or ethyl.
  • R 2 is alkoxy, for example, Cj ⁇ alkoxy such as methoxy or ethoxy.
  • R 2 is hydroxylalkene, for example, ⁇ CH 2 -OH or CH 2 CH 2 -OH.
  • R? is halo, preferably, any one of F, CI, or Br.
  • ring A is aryl, preferably phenyl, R; is a ring selected from phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pvrazinyl, pyridazinyl, piperazinyi, pyrazoiyl, oxadiazolyl, pyrrolidinyl, thiophenyl, and morpholinyl: preierably triazolyl, pyridyl or pyrimidinyl; R 2 is H, alkyl, alkoxy, hydroxy alkylene, or halo; preferably halo; Z is NH or O, preferably NH, R5 is a heteroaryi, preferably pyridyl or pvrazinyl; and n is 0.
  • Ri is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and I1 ⁇ 2 is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula I, preferably R 2 is at the meta position adjacent to Rj .
  • Rj is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and 2 is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula 1, preferably R 2 is at the meta position not adjacent to R i .
  • R i and R may be optionally substituted as described above.
  • ring A is heteroaryi, preferably pyridinyl
  • Rj is a ring selected from phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyi, pyrazoiyl, oxadiazolyl, pyrrolidinyl, thiophenyl, and morpholinyl; preferably triazolyl, pyridyl or pyrimidinyl; R 2 is H, alkyl, alkoxy, hydroxyalkylene, or halo; preferably halo; Z is NH or O, preferably NH, R 5 is a heteroaryi, preferably pyridyl or pyrazinyl; and n is 0.
  • Rj is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and R 2 is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula I, preferably R 2 is at the meta position adjacent to Ri .
  • Ri is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and R? is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula I, preferably R 2 is at the meta position not adjacent to Ri .
  • Ri and R5 may be optionally substituted as described above, In one aspec t, the invention is directed to compounds of Formula IA:
  • X is C3 ⁇ 4, N, or NR 6 ;
  • Y is CR 7 ,N, or NR 7 ;
  • R ⁇ 5 is H, alkyi, aUkoxy, OH, halo, triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, or thiophenyl, wherein triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl pyridazinyl, pvrazolyl, or thiophenyl is optionally substituted with up to two substituents selected from halo and alkyi;
  • R 7 is H, alkyi, alkoxy, or halo
  • R is H, alkyi, alkoxy, hydroxyalkyiene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morphoiinyi, or dialkylamino, wherein phenyl, triazolyl, oxazolyl, isoxazolyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, or morphoiinyi is optionally substituted with up to two substituents selected from halo and alkyi;
  • R4 is H, alkyi, alkoxy, or halo
  • Re and R 7 together with the atoms to which they are attached, form a 5- or 6- membered heteroaryl ring optionally substituted with alkyi; or 3 and R4, together with the atoms to which they are attached, form a 6- membered aryl or 6-membered heteroaryl ring; or
  • R7 and R4 together with the atoms to which they are attached, form a 6- membered aryl or 6-membered heteroaryl ring;
  • Z is Nil, N-alkyl, or ():
  • s is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyi, quinazolinyl, quinoxalinyl, pyrazolyl, thiazolyl, thiadiazolyl, benzoxazoly!, imidazopyraziny], or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyi, cyano, aikyl carboxylate, alkoxy, or halo; and n is 0 or 1 ,
  • Enantiomers and diastereomers of the compounds of Formula 1A are also within the scope of the invention. Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of Formula IA, as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula IA. Also contemplated within the scope of the embodiments provided herein are isotopic variants of compounds of Formula IA, such as, by way of example, deuterated compounds of Formula IA.
  • X is CRe and Y is CR7.
  • X is CRe and Y is N.
  • X is N and Y is CR7.
  • R ⁇ is H.
  • R is alky]
  • Ci-ealkyl such as methyl or ethyl.
  • 3 ⁇ 4 is alkoxy, for example, Ci ⁇ alkoxy such as methoxy or ethoxy.
  • Re is OH
  • Re is halo, preferably , any one of F, CI, or Br.
  • R is triazolyl with 1 ,2,3-triazoiyf being preferred.
  • the triazolyl can be attached through any available atom.
  • the 1,2,3- triazolyl is attached through the 2-position nitrogen atom.
  • the 1,2,3- triazolyl is attached through the 1 -position nitrogen atom.
  • Re is oxazolyl, which can be attached through any- available atom.
  • the oxazolyl can be substituted with with alkyi, for example, C;-ealkyl such as methyl.
  • oxadiazolyl which can be a 1,2,3-oxadiazo!yl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl.
  • the oxadiazolyl is 1 ,2,4- oxadiazolyl.
  • the oxadiazolyl can be attached through any available atom.
  • the oxadiazolyl can be substituted with with alkyi, for example, Ci-ealkyi such as methyl.
  • CRe and Y is CR? or X is CRe and Y is ,
  • Re is pyrazolyl, which can be attached through any available atom.
  • the pyrazolyl can be substituted with one or two alkyi, for example, C h lky! such as methyl.
  • Re is thioplienyi, which can be attached through any available atom.
  • R 6 is pyridyi, which can be attached through any available atom.
  • the pyridyi can be substituted with one or more alkyi, for example, Cj-eafkyl such as methyl.
  • One exemplary substituted pyridyi is methyl-pyridyl.
  • Re is pyrimidinyl, which can be attached through any available atom.
  • e is pyraz nyl, which can be attached through any available atom.
  • e is pyridazinyl, which can be attached through any available atom.
  • R 7 is H.
  • R? is alkyi, for example, Cj-ealkyl such as methyl or ethyl.
  • R 7 is alkoxy, for example, Cj-ealkoxy such as methoxy or ethoxy.
  • the alkoxy is substituted with, for example, one or more halo.
  • One preferred substituted alkoxy is difluoromethoxy.
  • R is halo, preferably one of F, CI, or Br.
  • X is Re and Y is CR ? .
  • X is CRe and Y is NR?.
  • X is CRe and Y is CR?.
  • R? together with the atoms to which they are attached, form a 5-membered heteroaryl ring.
  • These 5-membered rings can optionally substituted with alkyl, for example C h alky! such as methyl.
  • X is N3 ⁇ 4 and Y is CR ? or X is CR f , and Y is MI;
  • R ⁇ 3 ⁇ 4 and RT together with the atoms to which they are attached, form a 6-membered heteroaryl ring.
  • These 5-membered rings can optionally substituted with alkyl, for example d-ealkyl such as methyl.
  • R? and R together with the atoms to which they are attached, form a 6-membered aryl ring.
  • R 7 and R4 together with the atoms to which they are attached, form a 6-membered heteroaryl ring.
  • R 3 is H. In other embodiments, R 3 is alkyl, for example,
  • Cj-ealkyl such as methyl or ethyl.
  • R 3 is alkoxy, for example, Ci-galkoxy such as methoxy or ethoxy.
  • ihe alkoxy is substituted with, for example, one or more halo.
  • One preferred substituted alkoxy is difiuoromethoxy.
  • R 3 is hydroxyalkylene, for example, hydroxyC i-galkylene such as
  • R 3 is OH.
  • R 3 is halo, preferably any one of F, CI, or Br.
  • R 3 is phenyl.
  • the phenyl can be substituted with one or more halo, for example, phenyl substituted with at least one of F, CI, or Br.
  • R 3 is triazolyl, with 1,2,3-triazoly! being preferred.
  • the triazolyl can be attached through any available atom.
  • the 1, 2,3 -triazolyl is attached through the 2-position nitrogen atom.
  • the 1,2,3-triazoiyl is attached through the 1 -position nitrogen atom.
  • R. is oxazolyi, which can be attached through any available atom, preferably attached through the 2-position carbon.
  • the oxazolyi can be substituted with alkyl, for example, a C h lky! such as methyl.
  • R. 3 is isoxazolyl, which can be attached through any available atom.
  • the isoxazolyl can be substituted with alkyl, for example, a Ci_ 6 alkyl such as methyl.
  • R 3 is oxadiazolyl, which can be a 1,2,3-oxacliazoiyL
  • the oxadiazolyl is 1 ,2,4- oxadiazolyl
  • the oxadiazolyl can be attached through any available atom.
  • the oxadiazoiyi can be substituted with with alkyl, for example, Cj-e lkyl such as methyl.
  • R3 is pyridyl, which can be attached through any available carbon atom, in some embodiments, the pyridyl can be substituted with with one or more alkyl, for example, Ci-ealkyl such as methyl.
  • R3 is pyrazolyl, which can be attached through any available atom.
  • the pyrazolyl can be substituted with with one or two alkyl, for example, Ci_ 6 alkyl such as methyl.
  • 3 is pyrimidinyl, which can be attached through any available carbon atom.
  • R. 3 is pyrazinyi, which can be attached through any available carbon atom, in yet other embodiments, R3 is pyridazinyl, which can be attached through any available carbon atom.
  • R3 is piperazinyl which can be attached through any available atom.
  • one or both nitrogen atoms of the piperazinyl may be substituted with H or alkyl, for example, Ci -ealkyi such as methyl.
  • R3 is morpholinyl, which can be attached through any- available atom.
  • the nitrogen atom of the morpholinyl may be substituted with H or alkyl, for example, C h lky 1 such as methyl.
  • R3 is pyrrolidinyl, which can be attached through any available atom.
  • the nitrogen atom of the pyrrolidinyl may be substituted with H or alkyl, for example, Ci-salkyl such as methyl.
  • R.3 is dialkylamino, for example, dimethylamino, diethylamino, or methyl ethylamino .
  • R3 is pyrazolyl, which can be attached through any available atom,
  • the pyrazolyl can be substituted with one or two alkyl, for example, Ci-ealkyl such as methyl.
  • R3 is thiophenyl, which can be attached through any available carbon atom.
  • R4 is H.
  • R is alkyl, for example, Cj-ealkyl such as methyl or ethyl.
  • R4 is alkoxy, for example, Ci-ealkoxy such as methoxy or ethoxy.
  • R4 is halo, preferably, any one of F, CI, or Br.
  • R3 ⁇ 4 and R4 together with the atoms to which they are attached, form a 6-membered aryi ring. In other embodiments, R3 ⁇ 4 and R , together with the atoms to which they are attached, form a 6-membered heteroarylaryl ring.
  • R5 is a heteroary] ring.
  • R5 is a heteroaryi optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, cyano, alkyl carboxylate, aikoxy, and halo.
  • R5 is pyridyl, which can be attached through any available atom, optionally substituted with a one or two subsiituenis independently selected from the group consisting of alkyl, aikoxy, or halo.
  • alkyl is trihaloalkyl, for example trifluoromethyl.
  • R 5 is pyrimidinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, aikoxy, or halo.
  • alkyl is trihaloalkyl, for example trifluoromethyl.
  • alkyl is dilialoalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
  • R$ is pyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo.
  • alkyl is trihaloalkyl, for example trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is pyridazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo.
  • alkyl is trihaloalkyl, for example trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is qumazolmyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo.
  • alkyl is trihaloalkyl, for example trifluoromethyl.
  • aikyl is dihaloalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
  • 5 is qumoxaiinyi, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo.
  • aikyl is irihaloaikyl, for example trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is pyrazolyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo.
  • alkyi is irihaloaikyl, for example trifluoromethyl.
  • the pyrazolyl is methyl- pyrazolyl substituted with trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is benzoxazolyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo.
  • alkyl is irihaloaikyl, for example trifluoromethyl.
  • alkyi is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is imidazopyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo.
  • alkyl is irihaloaikyl, for example trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is triazolopyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, alkoxy, or halo.
  • aikyl is Irihaloaikyl, for example trifluoromethyl.
  • aikyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is thiazolyl which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo.
  • alkyl is irihaloaikyl, for example trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • R 5 is thiadiazolyl which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, alkoxy, or halo.
  • alkyl is irihaloaikyl, for example trifluoromethyl.
  • alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
  • n is 0, In other embodiments, n is 1.
  • the 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 to the subject a compound of the invention.
  • the compounds described herein are selective for orexin- 1 receptor activity. In some embodiments, the compounds described herein are selective for orexin- 1 receptor activity over orexin-2 receptor activity.
  • Diseases, disorders, and conditions mediated by orexin receptor activity include disorders of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, sleep disorders secondary to neurological disorders, mania, depression, manic depression, schizophrenia, pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity, or conditions related to overweight or obesity, insulin resistance, type II diabetes, hyperiipiclemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea gastroesophageal reflux, mood disorders, posttraumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.
  • Compounds of the in vention are particularly suited for the treatment of mood disorders, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.
  • compounds of the invention are particularly suited for the treatment of mood disorders.
  • mood disorders include anxiety-related mood disorders, depression, panic-related mood disorders, stress related mood disorders and the like.
  • compounds of the invention are suitable for the treatment of post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse (e.g., morphine abuse, cocaine abuse, alcohol abuse and the like).
  • substance abuse e.g., morphine abuse, cocaine abuse, alcohol abuse and the like.
  • certain disorders such as, for example, depression and/or schizophrenia and/or substance abuse and/or cognitive impairments also have elements of anxiety and/or panic and/or stress associated with them and the treatment of such conditions and/or combinations of conditions are also contemplated within the scope of embodiments presented herein.
  • compounds of the invention treat a mood disorder (e.g., anxiety) with reduced concomitant sedation and/or with reduced effect on sleep (e.g. attenuated arousal effects).
  • a mood disorder e.g., anxiety
  • compounds of the invention are particularly suited for the treatment of anxious depression.
  • compounds of the invention are particularly suited for the treatment of panic, schizophrenia, and substance abuse.
  • Sleep disorders include, but are not limited to, sleep-wake transition disorders, insomnia, restless legs syndrome, jet-lag, disturbed sleep, and sleep disorders secondary to neurological disorders (e.g., manias, depressions, manic depression, schizophrenia, and pain syndromes (e.g., fibromyalgia, neuropathic) .
  • neurological disorders e.g., manias, depressions, manic depression, schizophrenia, and pain syndromes (e.g., fibromyalgia, neuropathic) .
  • Metabolic disorders include, but are not limited to, overweight or obesity and conditions related to overweight or obesity, such as insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, 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, catatonia, anxiety, delirium and dementias.
  • a therapeutically effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • a “therapeutically effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., 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 subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID).
  • an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a le vel at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
  • additional active ingredients may be coadministered separately with a compound of the invention or included with such an agent in a pharmaceutical composition according to the invention
  • additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
  • a pharmaceutical composition of the invention comprises: (a) an effective amount of at least one compound in accordance with the invention; and (b) a pharmaceutically acceptable excipieni.
  • compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art.
  • the compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the compounds may be formulated to yield a dosage of, e.g., from about 0,05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
  • Oral tablets may include a compound according to the invention mixed with
  • inert diluents such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative 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, poiyviny!-pyrrolidone (PVP), sodium starch giycolate, microerystalline cellulose, and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • compounds of the invention may be mixed with a solid, semi- solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides 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 before use.
  • Such liquid compositions may optionally contain:
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyleeiJuiose, earhoxymethylceliulose, aluminum stearate gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • presereatives for example, methyl or propyl p-hydroxybenzoate or sorbic acid
  • wetting agents such as lecithin
  • flavoring or coloring agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyleeiJuiose, earhoxymethylceliulose, aluminum stearate gel and the like
  • wetting agents such as lecithin
  • flavoring or coloring agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyleeiJuio
  • compositions may be formulated for rectal administration as a suppository.
  • 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 parenteral! ⁇ ' acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minuie of compound, admixed with a pharmaceutical carrier o ver a period ranging from several minutes to several days.
  • the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.
  • Compounds of the invention may al ternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • R 3 and R4 together with the atoms to which they are attached form a 6- membered and or 6 membered heteroaryl ring, or R3 is H, R4 is analogous to R2 in Formula I as above, and X and Y are independently selected from C and N, with commercially available 1,2,3-triazole, in the presence of, for example, copper(I)iodide, C82CO 3 and trans- ,N'- dimethyl-l,2-cyclohexanediamine in, for example, DMF or dioxane, at temperatures ranging from about 60 °C to about 120 °C.
  • Compounds of formula (IVc) can be converted to the corresponding esters (Vb) by treatment with, for example, alkyl iodide in the presence of a. base such as K 2 CO 3 in a solvent such as DMF.
  • a. base such as K 2 CO 3
  • a solvent such as DMF.
  • Compounds of formula (III) are obtained by reacting a compound of formula (Va) and (Vb) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from about 80 °C to about 100 °C.
  • VLIl Compounds of formula (VLIl) are obtained by reacting a compound of formula (VI) with commercially available (VTI) in the presence of a catalyst such as 1 , 1 '-Bis(di-tert-but lphosphino)ferrocene palladium dichioride and a base such as Na 2 COs in a solvent such as 2-MeTHF or THF at temperatures ranging from about 60°C to about 90°C.
  • a catalyst such as 1 , 1 '-Bis(di-tert-but lphosphino)ferrocene palladium dichioride and a base such as Na 2 COs
  • a solvent such as 2-MeTHF or THF
  • Intermediate compound (XIV) is prepared as outlined in Scheme 4 from commercially available compound (X).
  • Compounds (XI) is obtained by reacting compound (X) with commercially available acrolem in a solvent such as 1,4 dtoxane at temperatures of about 200"C in a microwave reactor.
  • Compound (XII) can be prepared from compound (XI) by treatment with an acid such as HBr in a solvent such as toluene at a temperature of about 90°C.
  • Compound (XIII) can be obtained by treatment of compound (XII) with commercially available iodoethane and a base such as K 2 COj in a solvent such as DMF at temperatures ranging from about 45°C to about 65°C.
  • Compound (XIV) is obtained by treating compound (XIII) with a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80°C to about 100°C.
  • Compounds of formula (XXIV) can be obtained from compounds of formula (XXIII) by treatment with reducing agents such as Dibai-H, L1AIH4 or L1BH4 in solvents such as THF or diethyl ether at temperatures ranging from about 0 °C to about 70 °C, Compounds of formula (XXVI) can be obtained from compounds of formula (XXIII) by treatment with bases such as aqueous sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such as water, methanol or THF.
  • bases such as aqueous sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such as water, methanol or THF.
  • (XXVIII) are prepared compounds of formula ⁇ : ⁇ : XX iX i.
  • Compounds of formula (XXVIII) are readily prepared from compounds of formula ⁇ ⁇ by treatment with metal catalyst such as Pt0 2 , Pd/C, or Pd(OH) 2 in solvents such as AcOH, MeOH or EtOH under an atmosphere of hydrogen.
  • Compounds of formula (XXIX) are readily prepared from compounds of formula (XXVIII) by reaction with DPPA and TEA in a solvent such as toluene at temperatures ranging from about 0 °C to about 100 °C, preferably about 65 °C for a period of about 1 to 8 hours. BnOH is then added to afford a compound of formula (XXIX).
  • (XXXI) is obtained from compound (XXXI) by reaction with trimethylphenyl ammonium tribromide at temperatures ranging from about 0 °C to about 23 °C, preferably about 0 °C for a period of from 2 to 6 hours, preferably about 4 hours.
  • Compound ( ⁇ ) is obtained from compound (XXXII) by treatment with a base, preferably NaH in a solvent such as DMF.
  • Compound (XXXIV) is obtained from compound (XXXIII) by elimination of HBr with tBuOK in a solvent such as THF for a period ranging from 2 to 24 hours.
  • Compound (XXXV) is obtained from compound (XXXIV) by hydroboration oxidation by treating the compound (XXXIV) with borane in a solvent such as THF at temperatures ranging from about 0 °C to about 2.3 °C, preferably at about 23 °C, for 2. to 12. hours, preferably about 2 hours followed by reaction with, for example, hydrogen peroxide in the presence of a base such as sodium hydroxide.
  • a solvent such as THF
  • Compound (XXIII) is obtained from compound (XXXII) by treatment with a base, such as NaH or preferably K2CO3 is a solvent such as DMF or preferably toluene at temperatures ranging from about 0 °C to about 100 °C with or without a protecting group present.
  • a base such as NaH or preferably K2CO3
  • a solvent such as DMF or preferably toluene at temperatures ranging from about 0 °C to about 100 °C with or without a protecting group present.
  • the choice of the protecting group and/or base and or solvents and/or reaction temperatures will vary depending on the reaction substrate and ail such variations are contemplated within the scope of embodiments provided herein.
  • a compound of formula (XXXVII) is obtained by treating a compound of formula (XXXVI) with R 5 C1, where R "1 is optionally substituted pyridyl, pyrimidyi, pyrazinyi, pyridazinyl, quinazolinyi, qumoxalinyl, pyrazolyl, benzoxazolyJ, imidazopyrazmyl, triazolopyrazinyl.
  • suitably substituted heteroaryl compounds of formula R 5 C1 are reacted with compounds of formula (XXXVI), in the presence of a suitably selected tertiary organic or inorganic base such as NaH, CS2CO3, K2CO3, TEA, iPr 2 NEt and the like; in a solvent such as DMF, diehlorom.eth.ane, THF, and the like; at a temperature between room temperature and the reflux temperature of the solvent.
  • a suitably selected tertiary organic or inorganic base such as NaH, CS2CO3, K2CO3, TEA, iPr 2 NEt and the like
  • a solvent such as DMF, diehlorom.eth.ane, THF, and the like
  • the base is NaH and the sol v ent is DMF
  • Remo v al of the feri-butyicarbamate (Boc) in compounds of formula (XXXVH) is accomplished by using methods known to one skilled in the art, such as, HQ, TFA, or /j-toluenesulfonic acid, in a solvent such as CFI 3 OH, dioxane, or CH?C1 2 .
  • a compound of formula (XXXVII) is treated with TFA in DCM or HC1 to afford a compound of formula (XXXVIII).
  • a compound of formula (XLI) is obtained by treating a compound of formula (XXXVIII) with (R !
  • R 2 A)C0 2 H where R 1 is H, alky], alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazoiyl, pyridyl, pyrimidyi, pyrazinyi, pyridazinyl, piperazinyl, pyrazolyl, oxadiazoiyl, pyrrolidinyl, thiophenvi, morpholinyi, or dialkylamino and R2 is H, alk l, alkoxy, or halo.
  • Removal of the ieri-butylearharnate (Boc) in compounds of formula (XXXVI) is accomplished by using methods known to one skilled in the art, such as, HC1, TFA, or p- toluenesulfonic acid, in a solvent such as CH 3 OH, dioxane, or CH2CI2.
  • a compound of formula (XXX 1) is treated with TFA in DCM or HCI to afford a compound of formula (XXXIX).
  • a compound of formula (XL) is obtained by treating a compound of formula (XXXIX) with (R 1 i A)C0 2 H.
  • a compound of formula (XXXIX) and (R R ' A)C0 2 H are treated with EDCI in the presence of HOBT in DMF at ambient temperature to afford a compound of formula (XL).
  • a compound of formula (XLI) is obtained by treating a compound of formula (XL) with R ' Cl.
  • n 0
  • Compound of formula (XLV) were obtained from compounds of formula (XLIV) when treated with an acid such as HC1 in a suitabie solvent such as EiQAc or DCM at room temperature.
  • Compound of formula (XLVI) were obtained from compounds of formula (XLV) using compounds of formula (XLVTT) in a suitable solvent such as DMF or DCM in the presence of a peptide coupling reagent such as HATU or T3P, a base such as DIPEA at a temperature ranging from room temperature to about 45 U C.
  • pro vided herein is a compound of Formula I of Examples 1-482. with structures and names as set forth in the Examples section below.
  • a compound of Formula I having structures and names as set forth in Table 2 below.
  • DIPEA Diisopropylethylamine DIPEA
  • reaction mixtures were magnetically stirred at room temperature
  • Melting point determinations were performed in open capillary tubes on a FP62 or MP50 apparaiits (Mettler-Toledo). Melting points were measured with a temperature gradient of 10 °C/minute. Maximum temperature was 300 °C. The melting point was read from a digital display.
  • Preparative reverse-phase high performance liquid chromatography was performed on a Gilson HPLC with an Xterra Prep RPi g (5 ⁇ , 30 x 100 mm, or 50 X 150 mm) column, and a gradient of 10 to 99% acetonitner/water (20 rnM NH4QH) over 12 to 18 min, and a flow rate of 30 mL/min.
  • HPLC reverse-phase high performance liquid chromatography
  • HPLC reverse-phase high performance liquid chromatography
  • HPLC reverse-phase high performance liquid chromatography
  • HPLC reverse-phase high performance liquid chromatography
  • HPLC reverse-phase high performance liquid chromatography
  • Analytical chromatography data was acquired using an Agilent 1 100 HPLC, with an inertsil ODS-3 3mm 4.6 x 50mm column, purchased from GL Sciences (Part # 1010L050W046). Samples were run using a gradient profile of 10 - 99% acetonitrile (ACN) in water, each containing 0.05% trifiuoroaeetic acid (TFA) over 1.6 minutes, then holding at 99% acetonitrile for 0.3 minutes. Flow rate was 5 mL/min and column temperature was set to 50 °C (Method A), Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (eaicd.) mass corresponds to the exact mass.
  • ACN acetonitrile
  • TFA trifiuoroaeetic acid
  • Nuclear magnetic resonance (MR) spectra were obtained on Broker model DRX spectrometers.
  • the ratio is represented so that the total is 1, e.g. 0.80:0.20.
  • 1H NMR data may be reported for only the major rotamer as indicated, or the data may be reported for one or more rotamers such that the total is less than 1. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.
  • Examples 301 , 307, 313, 31 9, 321 -367, 396, 464-482, and 483-495 are suitable for preparation using methods analogous to the methods described in the synthetic schemes and in the Examples section.
  • Step A 5 ⁇ methyl-3-(2H-i,2,3-triazo1 ⁇ 2 ⁇ yl)picolinonitrile.
  • 3-bromo-5- methylpicofinonitrile 1.5 g, 7.6 mmol
  • DMF dimethyl methoxymethyl
  • K2CO3 1 .2 g, 8.4 mmol
  • 2H- l,2,3-triazole 440 ⁇ , 7.6 mmol.
  • the mixture was heated to 100 °C for 16 h, cooled to rt and extracted with EtO c (2X). The combined organics were dried (Na 2 S0 4 ) and
  • Step B 5-methyl-3-(2H-l ,2,3-triazol-2-yl)picolinate.
  • EtOH 7 mL
  • 4 N NaOH 660 ⁇ _, 2.6 mmol
  • the reaction mixture was heated at 100°C for 24 h.
  • the reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.
  • MS (ESI) mass calcd. for C 9 H 3 N4O ? ., 204.1; m/z found 205.0 [M+H . 0: 5-methyl-3-( 1 H- 1 ,2,3-triazol- 1 -yl)picolinic acid.
  • Step A 5-methyl-3-(lH- l ,2,3-triazol- l -yl)picolinonitriie.
  • the title compound was prepared in Intermediate A- 19 Step A.
  • Step B 5-methyl-3-(lH- l ,2,3-triazo]- l -yi)picolinic acid.
  • Step A 6-methyl-3-(2H- I ,2,3-triazol-2-yl)picolinomtrile.
  • 3-bromo-6- methylpicoiinomtriie 2.2. g, 1 1 mmol
  • DMF 28 mL
  • K2CO 3 1.7 g, 12 mmol
  • 2H-l ,2,3-triazole 650 ⁇ ,, 1 1 mmol
  • the mixture was heated to 100 °C for 36 h, cooled to rt and extracted with EtOAc. The combined organics were dried (Na 2 S04) and concentrated.
  • Step B 6-methy ⁇ -3-(2H ⁇ l ,2,3 riazol-2.-yl)picoiimc acid.
  • EtOH 10 mL
  • 4 N NaOH 1 ml, 4 mmol
  • the reaction mixture was heated at 100°C for 24 h.
  • the reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. 22 : 3-ethoxyisoquinoline-4-carboxylic acid.
  • Step A ethyl 3-hydroxyisoquinoline-4-carboxyiate.
  • a suspension of ethyl 3- aminoisoquinoHne-4-carboxylate (583 mg, 2.70 mmol) in 6.8 mL of H2SO4 5N cooled to 0 °C was added sodium nitrite (223 mg, 3.24 mmol, dissolved in I mL of water).
  • Step B ethyl 3-ethoxyisoquinoline-4-carboxylate.
  • THF 13 mL
  • triphenylphosphine 1.06 g, 4.03 mmol
  • ethanol 0.24 mL, 4.03 mmol
  • DIAD 0.79 mL, 4.03 mmol
  • the reaction mixture was stirred at room temperature for 16h and then the solvent was evaporated.
  • the crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound of Step B (498 mg, 76%).
  • Step C 3-ethoxyisoquinoline-4--carboxyiic acid.
  • the title compound of Step B (492 mg, 2 mmol) dissolved in MeOH (15 mL) was added NaOH( aq ) 2M (2.5 mL). The reaction mixture was stirred at 60 °C for I6h and then NaOH ⁇ 4M. (2 mL) was added and the mixture was stirred at 70 °C for 4h. MeOH was evaporated and the aqueous phase was cooled to 0 °C and acidified with the addition of HCl (aq) 6N. The solid was filtered, washed with cold water and dried to afford the tilte compound (285 mg, 65%). MS (ESI) mass calcd.
  • Step A methyl 3-methyl-2-(pyrimidin-2-yl)benzoate.
  • methyl 3-methyl-2-(4,4,5,5-tetramethyi- l,3,2-dioxaboroian-2-yi)benzoate (619 mg, 2.24 mmoi) and 2-chloropyrimidine (314 mg, 2.69 mmol) in 2-MeTHF (10 mL).
  • Na 2 COs (713 mg, 6.73 ramol) was then added followed by water (3.4 ml.,) and the reaction mixture was degassed with N 2 for 45 minutes.
  • Pd(dppf)Cl 2 (66 mg, 0.09 mmoi) and the reaction mixture was heated at 75 °C for 28h.
  • Step B 3-methyl-2-(pyrimidin-2-yl)benzoic acid. Prepared analogous to intermediate A- 31 step B to give title compound. MS (ESI) mass calcd. for Ci 2 HioN 2 0 2 , 214.1 ; m/z found 215.1 i ⁇ ) H I
  • Step A Methyl 2 ⁇ methoxy-6-(pyrimidin-2-yl)benzoa.te.
  • methyl 2-methoxy-6-(4,4,5,5-tetramet yl-l,3,2-dioxaborolan-2-yl)benzoate 500 sng, 1.71 mmol
  • 2- bromopyrimidine 344 mg, 2.05 mmol
  • THF 8.5 mL
  • Na 2 C0 544 mg, 5.14 mmol
  • water 4 mL
  • Step B 2 ⁇ metlioxy ⁇ 6-(pyrimidin ⁇ 2-yl)benzoic acid.
  • Step A (265 mg, 1.09 mmol) in THF (4 mL) was added 2 N NaOH (2 mL). The mixture was heated at 50°C for 72 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.
  • MS (ESI) mass calcd. for C12H10 2O3, 230.1 ; m/z found 231.1 i ⁇ ) H i .
  • Step A 7-methoxyquinoiine-8-carboxylic acid.
  • 2- amino-6methoxybenzoic acid i lg, 66 mmol
  • acrolein 4.8 mL, 72 mmol
  • 1,4-dioxane 66 mL
  • MS (ESI) mass calcd. for C11H19NQ3, 203.1 ; m/z found 204.0 I U ; .
  • Step B 7-hydroxyquinoline-8-carboxyiic acid.
  • the title compound of Step A (2.9 g, 14.1 mmol) in HBr (14 mL) was heated at 90 °C for I h. The mixture was then concentrated washed with PhCH3 and used without further purificaition in subsequent steps.
  • Step C ethyl 7-ethoxyquinoline-8-carboxylate.
  • iodoethane 560 jiL, 6.9 mmol.
  • MS (ESI) mass calcd. for C,4H, 5 N0 3 , 245.1 ; m z found 246.0 [M+H] "1" .
  • Step D 7-ethoxyquinoline-8-carboxylic acid.
  • Li OH hydrate (675 mg, 16.5 mmol) and MeOH.
  • the mixture was heated at 67 C C for I2h. Additional LiOH hydrate (675 mg, 16.5 mmol) was added and the heating was continued at 70 °C for 1 day. Additional LiOH hydrate (1.4 g, 33 mmol) was added and the heating was continued at 75 °C for 1 day.
  • Step A Ethyl 2-(l ,4-dimethyl- lH-pyrazol-5-yl)-6-methoxybenzoate.
  • ethyl 2-bromo-6-methoxybenzoate 500 mg, 1.54 mmol
  • 1 ,4-dimethyl-5- (4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2 ⁇ yl)- lH-pyrazole 377 mg, 1.70 mmol
  • Step B 2-(l ,4-dimethyl-lH-pyrazol-5-yi)-6-methoxybenzo c acid. Prepared analogous to intermediate A-28 step B to give title compound.
  • A-31 3-methyl-2-(oxazol-2-yf)benzoic
  • Step A ethyl 3-methyl-2-(oxazol-2-yl)benzoate.
  • ethyl 2-iodo-3-methyibenzoate 627 mg, 2.16 mmol
  • 2-(tributylstannyl)oxazoIe 0.54 mL, 0.07 mmol
  • DME 2.59 mL
  • Cul 21 mg, 0.11 mmol
  • PdfJPPh ⁇ 125 mg, 0.11 mmol
  • Step B 3-methyf-2 ⁇ (oxazol ⁇ 2 ⁇ yl)benzoic acid.
  • MeOH 7.2 mL
  • 1M NaOH 7.2 mL
  • MeOH was evaporated and then 1 M HCT (aqj was added.
  • DCM was added to the solution was added DCM and the aqueous was extracted with DCM (3X). The combined organic layers were dried over MgS0 4 , filtered and evaporated to give the title compound (145 mg).
  • Step A 4-methyl-3-(2H-l ,2,3-lTiazol-2-yl)picolinonitrile.
  • 2H- l ,2,3-triazole (0.22 mL, 3.8 mmol) and Cu (26 mg) in DMF (4 mL).
  • the reaction mixture was degassed with N 2 and 3-bromo-4-methylpicolonitrile (300 mg, 1.5 mmol) was added followed by trans-N,N'-dimethyl- l ,2-cyclohexanediamine (41 ⁇ , 0.3 mmol) and Cs ⁇ CCh (844 mg, 2.6 mmol).
  • the reaction mixture was heated at 120 °C for lh in a microwave reactor.
  • Step A ethyl 3 -(2H- l ,2,3-triazol-2-yl)quinoline-2-carboxylate. Prepared analogous to Intermediate A-40 Step A substituting 2-brom.o-4-methylbenzoic acid with ethyl 3- iodoquinoline-2-carboxylate (WO 201 1093365) in ⁇ 10% yield. MS (ESI) mass calcd. for C,4H 12 4 0 2 , 268.3; m/z found 269.0 [M+H] ".
  • Step B 3-(2H- i,2,3 riazol ⁇ 2-yJ)quinoline-2-carboxylic acid.
  • aqueous 2M NaOH 1 mL
  • MS (ESI) mass caled. for C12HSN4O2, 240.2; m/z found 241.0 ⁇ ⁇ ;
  • Step A 4-methyI-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid and 4-methyl-2-(lH-l,2,3-triazol- l-yl)benzoic acid.
  • 2H-l,2,3-triazole 0.34 mL, 5.81 mmol
  • Cui 40 mg, 0.21 mmol
  • Step B methyl 4-methy3-2-(2H- l ,2,3-triazol-2-yl)benzoate.
  • K2C03 1.3 g, 9.3 mmol
  • iodomethane 0.3 mL, 4.7 mmol
  • the reaction mixture was stirred at room temperature for 16h under N2.
  • the solvent was evaporated and the residue was dissolved with a saturated solution of NaHC03.
  • the aqueous phase was extracted with DCM and the organic layer was dried over MgS04, filtered and evaporated.
  • the crude material was purified via silica gel chromatography (0% to 30% EtO Ac/heptane) to afford the title compound (470 mg, 47%).
  • Step C Prepared analogous to intermediate A-31 step B substituting ethyl 3-methyi-2-(oxazo3-2- yl)benzoate with the title compound of Step B and used without further purification in subsequent steps.
  • Step B Methyl 3-bromo-6-methylpicolinate.
  • thionyl chloride 4.4 mL, 60 mmol.
  • the reaction was heated at reflux overnight, cooled to rt and concentrated. Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.9g, 40%).
  • Step C 3-methyl-2-(tributy ⁇ stannyl)pyridine.
  • 2-bromo-3-methylpyridine 1.3 mL, 1 1.7 mmol
  • THF 35 ml.
  • ⁇ -BuLi 2.5 M in liexanes, 5.6 mL, 14 mmol
  • tri- «-butyltm chloride 3.8 mL, 14 mmol
  • Ih at - 78 °C the reaction was allowed to warm to rt.
  • EtOAc was added and the reaction mixture was washed with 10% aq KF.
  • the organic layer was dried (MgS04).
  • Step D methyl 3,6'-dimethy ⁇ -[2,3'-bipyridine]-2'-carboxy ⁇ ate.
  • Pd(PPh3)4 225 mg, 0.2 mmol.
  • the reaction was degassed with ? and heated at 150 °C for 1.5 h using microwave reactor.
  • the reaction was cooled to rt, diluted with H20 and extracted with EtOAc.
  • the organic layer was dried (MgS04). Purification via silica gel chromatography (0- 100% EtOAc in heptane) gave the title compound (101 mg, 18%).
  • Step E 3,6'-dimethyi-[2,3 , -bipyridine]-2'-carboxylic acid.
  • Step E 3,6'-dimethyi-[2,3 , -bipyridine]-2'-carboxylic acid.
  • Step A 5-fluoro-2-iodopyrimidine.
  • 2-chloro-5-fluoropyrimidine (4 mL, 32 mmol) in propionitrile (33 mL) was added chlorotrimethylsilane (12 mL, 97 mmoi) and sodium iodide (15 g, 97 mmol), and the reaction mixture was heated to 150 °C for 1 h.
  • the reaction mixture was cooled to room temperature and the solvent removed.
  • the residue was taken up in EtQAc and a solution of saturated aHCO ⁇ .
  • the organic layer was dried over MgS0 4 , filtered and evaporated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (2.82. g, 39%).
  • Step B 2-(5-fluoropyrirmdin-2-yl)benzonitrile.
  • cyanophenylboronic acid 500 mg, 3,40 mmol
  • THF 15 mL
  • the reaction mixture was degassed with N .
  • the title compound of step A 915 mg, 4.08 mmol
  • M 2 COs (1.08 g, 10.2 mmol
  • water 5 mL
  • PdCl 2 CAS 95408-45-0
  • Step C 2-(5-fluoropyrimidm-2-yl)benzoic acid.
  • a solution of the title compound of step B (1.24 g, 6.22 mmol) in H 2 S0 4 (6 mL) and water (6 mL) was stirred at 80 °C for 1 h. Then, the reaction mixture was cooled to 0 °C and the aqueous phase extracted with DCM (2X). A solution of 20 M NaOH (1 1 niL) 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 dried over MgS0 4 , filtered and concentrated to afford the title compound (672 mg, 50%).
  • Step A Methyl 2-(5-fluoropyr midm-2-yr)-3-methylbenzoate.
  • Step B 2-(5-fluoropyrimidm-2-yl)-3-methylbenzoic acid.
  • MeOH MeOH
  • 1 M NaOH 12 mL
  • the aqueous layer was extracted with EtOAc.
  • the combined organic layers were dried over MgS0 4 , filtered and concentrated to afford the title compound (1.19 g, 83%).
  • Step A Methyl 2-(pyrimidin-2-yl)benzoate. Prepared analogous to Example 260 step B substituting 2-(iributylsiannyl)oxazoie with 2-(tributylstannyl)pyrimidine. MS (ESI) mass calcd. for C12H10N7O2, 214.1 ; m/z found 215.1 i vi - l i i .
  • Step B Methyl 3-chloro-2-(pyrimidin-2-yl)benzoate.
  • compound of step A (314 mg, 1.47 mmol), Pd(OAc) 2 (49 mg, 0.07 mmol), copper (II) trifiuoroacetate (425 mg, 1.47 mmol) and calcium chloride (651 mg, 5.87 mmol).
  • the vial was capped and acetic acid (21 mL) was added.
  • the reaction mixture was stirred at 1 10 °C for 24h and solvent was evaporated.
  • Step C Sodium 3-chloro-2-(pyriinidin ⁇ 2-yl)berizoa.te. To a solution of compound of step
  • Step A Methyl 5-methyl-2-(pyrimidin-2-yi)nicotinate.
  • methyl 2-chloro-5-nietliylmcotmate (CAS 65169-43-9) (745 mg, 4.01 mmol), Cul (38 mg, 0.2 mmol), LiCl (169 mg, 4.01 mmol), and P ⁇ 3 ⁇ 4PPh.3) 4 (231 mg, 0.2 mmol) in toluene (15 mL) was added 2-(tributylstannyl)pyrimidine ( 1.5 mL, 4.4 mmol), and the reaction mixture was heated at 120 °C overnight. The reaction mixture was diluted with water and extracted with DCM.
  • Step B 5-methyl-2-(pyrimidin-2-y])mcotimc acid.
  • MeOH MeOH
  • 10 M aOH 1 mL
  • the aqueous layer was saturated with solid Nad and extracted with 20% e " PrOH in CHCI3 (3X).
  • the combined organic layers were dried over MgS0 4 , filtered and concentrated to afford the title compound (432 mg, 99%).
  • Step A Methyl 5-methy]-3-(pyrimidm-2-yl)picolmate. Prepared analogous to intermediate A-66, step A substituting methyl 2-cbloro-5-methylmcotinate with methyl 3-bromo- 5-methylpicolinate. MS (ESI) mass calcd. for & 2 ⁇ ; ⁇ ⁇ 3 ⁇ 2, 229.1 ; m/z found 230.0 [ ⁇ i ⁇ H
  • Step B Lithium 5-methyl-3-(pyrimidin-2-yl)picolinate.
  • THF THF
  • 4 M LiOH 0.8 mL
  • water 1.5 mL
  • MS (ESI) mass calcd. for C ⁇ , ; ⁇ ⁇ 215.1; m/z found 216.1 M+H] ; . : H NMR (500 MHz, Methanol-cU) ⁇ 8.83 i d.
  • Step A 2-bromo-N-(2,2-dimethoxyethyl)-6-f!uorobenzamide.
  • Step B 2-(2-bromo-6-fiuorophenyl)oxazole.
  • methanesulfonic acid 52 mL, 801 mmol
  • the title compound of step A 2.3 g, 7.54 mmol
  • DCM was added and the mixture was slowly poured into a saturated solution of aqueous NaHC(3 ⁇ 4 on ice. The mixture was extracted with DCM. The combined organic layers were dried over MgS0 4 , filtered and concentrated.
  • Step C Methyl 3-fluoro-2-(oxazol-2-yl)benzoate.
  • Step D 3-fluoro-2-(oxazol-2-yl)benzoic acid.
  • MeOH 22 niL
  • 2 M NaOH 7.5 mL
  • the reaction mixture was acidified with 1 M HCl(aq) and the solvents evaporated in vacuo.
  • the mixture was diluted with water and extracted with DCM. The combined organic were dried over MgS0 4 , filtered and concentrated to afford the title compound (905 mg, 58%).
  • Step A Methyl 5-fluoro-2-(oxazol-2-yl)benzoate.
  • methyl 2-bromo-5- fiuorobenzoate 1.1 g, 4.8 mmol
  • 2-(tri-n-butylstannyl)oxazoie 1.3 mL, 6.2 mmol
  • Pd(PPh 3 ) 4 550 mg, 0.476 mmol
  • the reaction mixture was heated via microwave heating to 150 °C for 30 min.
  • the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgS0 , filtered and concentrated.
  • Step B 5-fluoro-2-(oxazol-2-yl)benzoic acid. Prepared analogous to intermediate 68, step D, to give the title compound (858 mg, 99%). MS (ESI) mass calcd. for CjoH 6 FNQ 3 , 207.0; m/z found 208.1 ; M ⁇ ⁇ ;
  • Step A 5-(2-bromo-5-fluorophenyi)-3-methyl-l ,2,4-oxadiazofe.
  • 2- bromo-5-fluorobenzoyl chloride (2.17 g, 9.13 mmol) in TPIF (18 mL) was added DIPEA (1.7 mL, 10 mmol).
  • acetamide oxime (676 mg, 9.13 mmol) was added portionwise, and the reaction mixture was stirred at 70 °C for 16 h.
  • the reaction mixture was diluted with EtOAc and washed with a saturated solution of NaHC0 3 .
  • the combined organic layers were dried over
  • Step B 4-f1uoro-2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)benzoic acid. Prepared analogous to intermediate 68, steps C and D, to give the title compound. MS (ESI) mass calcd. for CJ0H7F 2O3, 222.0; m/z found 223.0 [M+H .
  • (+)-B-2 and (-)-B-2 (1 S,2R,4R)-2-benzyl 7-tert-butyl 7-azabicyclo[2.2.1 jheptane- 2,7-dicarboxylate.
  • H NMR (CDCI 3 ): 7.39 - 7.30 (m, SB), 5.19 - 5.08 (m, 2H), 4.55 (s, I H), 4.30 (s, IH), 2.59 (dd, J 8.9, 5.0 Hz, I TT), 2.36 - 2.24 (m, 1 H), 1.90 - 1.70 (m, 21 0. 1.68 - 1.57 fm, IH), 1.52 - 1.34 (m, 1 I I I ; ⁇ .
  • Example 1 (5-fluoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4 )-2-((pyridin-2-yloxy)methyl)-7- l)methanone.
  • Step A (l S,2R,4R)-tert-butyl 2-(( yridin-2-yloxy)methyl)-7-azabicyclo[2.2.1 ]heptane-7- carboxylate.
  • To intermediate B-9 (170 mg, 0.75 mmol) in DMF (3 mL) at 0 °C was added NaH (36 mg, 60 wt% in mineral oil, 0.9 mmol).
  • 2-fluoropyridine 102 mg, 1.0 mmol
  • DMF 0.5 mL
  • the flask was then heated to 90 °C in an oil bath.
  • 1/2 saturated NH 4 Ci was added and the reaction extracted with EtOAc (2.X). The combined organics were washed with brine and dried
  • Step B (lS,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7- carboxylate.
  • MS (ESI) mass mass calcd. for Ci ? Hi 6 N 2 O,204.1 ; m/z found 205.1 [M+H] ⁇
  • Step C (5-fluoro-2-(pyrimidin-2-yl)phenyi)((l S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • DIPEA 0.078 mL, 0.45 mmol
  • intermediate A-7 43 mg, 0.2 mmol
  • HATU 75 mg, 0.2 mmol
  • Example 3B (6-methyi-3-(pyrimidin-2-yl)pyridm-2-yl)((lR*,2S*,4S*)-2-((pyridin ⁇ 2- icyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 3 A >98% single enantiomer, 4.00 min retention time;
  • Example 3B >98% single enantiomer, 5.12 min retention time).
  • Example 3B MS (ESI) mass calcd. for C23H23N5O2, 401.2; mz found 402.1 j ⁇ 1 i i j
  • Example 5A (6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridm-2-yl)((lS,2R,4R)-2-((pyridm-2- [2,2.1 ]heptan-7-yl)methanone.
  • Example 5B (6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)(( lR,2S,4S)-2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]hepian-7-yl)methanone.
  • the title compounds were obtained by chirai SFC (CHIRALPAK AD-H 5 ⁇ 250 X 20mm) resolution of Example 4 (555 mg) using 70% C 0 2 /30% EtOH as the mobile phase to give enantiomer A (264 mg, 1 st eluting enantiomer) and enantiomer B (248 mg, 2*° eluting enantiomer).
  • the enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD (250x4.6mm) and a mobile phase of 70% C0 2 , 30% EtOH containing 0.3 % iPr H 2 over 7 minutes.
  • Example 5 A >98% single enantiomer, 2.80 min retention time; Example 5B >98% single enantiomer, 3,90 min retention time).
  • Example 5A MS (ESI) mass calcd. for C21H22 6O2, 390.2; m/z found 391.2 [M+Hf.
  • Example 5B MS (ESI) mass calcd. for
  • Example 6 (6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)((l S,2R,4R)-2 ⁇ ((pyridm ⁇ 2 ⁇
  • Example 7 ( ⁇ )-(2-(((5-fluoropyridin-2-yl)oxy)methyl) ⁇ 7-azabicyclo[2.2.1]heptan-7-yl)(6- metbyl-3-(2H-l ,2,3 riazol ⁇ 2-yl)pyridin-2-yl)methanone.
  • Step A ⁇ ⁇ i-!er!-busyl 2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicy clo[2.2.1 ]heptane-7-carboxylate.
  • Tri-n-butylphosphine (1.8 mL, 7.8 mmol) was added to intermediate B-10 (830 mg, 3.7 mmol) and 5-fluoropyridin-2( lH)-one (500 mg, 4.4 mmol) in THF (1 1 mL) under nitrogen bubbling at rt. After 5 min of stirring, DEAD (1.4 mL, 7.1 mmol) was added and the mixture was stirred at 50°C for 18 hours. The mixture was concentrated and purified silica gel chromatography (0- 15% EtOAc in Heptane) to give the title compound of step A. (590 mg, 45%) as a white solid.
  • Step A ( ⁇ )-tert-butyl 2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate.
  • MS (ESI) mass calcd. for C 17 H 23 FN 2 0 3 , 322.2; m/z found 323.0 [M+H] _ . ⁇ NMR (CDC1 3 ): 8.02 - 7.87 (m, I H), 7.41 - 7.27 (m, i l l ). 6.70 uki. ./ 9.1, 3.6 Hz, Hi), 4.39 - 4.10 (m, 2H), 4.09 - 3.89 (m, 2H), 2.25 - 2.09 (m, IH), 1.91 - 1.26 (m, 15H).
  • Step B ( ⁇ )-2-(((5-fluoropyridin-2-yl)oxy)metb.yl)-7-azabicyclo[2.2.1]heptaiie.
  • ( ⁇ )-tert-butyl-2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate with the title compound from Step A.
  • Step C ( ⁇ )-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)methanone.
  • Example 1 substituting 5-fluoro-2-(pyrimidin-2-yI)benzoic acid with 6-methyl-3-(2H ⁇ I,2,3-triazol ⁇ 2- yDpicolinic acid.
  • MS (ESI) mass mass calcd. for C 21 H 2 iFN 6 0 3 ⁇ 4 408.2; m/z found 409.2.
  • Example 8A ((lS,2R,4R)-2-(((5-fluoropyridin-2-yl)oxy)methy ⁇ )-7-azabicyclo[2.2.1 ]heptan-7- y3)(6-Tnetbyl-3-(2H- l,2,3-triazol-2-yl)pyridm-2-yr)methanone.
  • Example 8B ((lR,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)Tne hyr)- 1 ,2,3-triazol-2-yl)pyridin-2-yl)methaaone.
  • Example 7 The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 ⁇ 250 X 20mm) resolution of Example 7 (259 mg) using 70% CO 2 /30% mixture of EtOH/i -PrOH (50/50 v/v) the mobile phase to give enantiomer A. (72 mg, 1 st eluting enantiomer) and enantiomer B (84 mg, 2 nd eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a
  • Example 8A 100% single enantiomer, 3.10 min retention time;
  • Example 8B 100% single enantiomer, 4,58 min retention time).
  • Example 8A MS (ESI) mass calcd. for ( ' . , I L X.-.C 408.2; m/z found 409.2 i ⁇ ) H I
  • Example 8B MS (ESI) mass calcd.
  • Example 1 OA ((1 S,2R,4R)-2-(((5-fiuoropyridin-2-yl)oxy)methyl)-7-azabicycfo[2.2.1 jheptan-7- ol-2-yl)phenyl)methanone.
  • Example 10B ((lR,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yi)(5-methyl-2-(2H- 1 ,2,3-triazol ⁇ 2-y])phenyl)methanone.
  • Example 10A >98% single enantiomer, 2.42 min retention time; Example iOB >98% single enantiomer, 3.20 min retention time).
  • Example 1 1 ( ⁇ )-(2-(((5-f1uoropyridjii-2-yl)oxy)methyl)-7-azabicyclo[2.2J ]heptan-7-y1)(2- one.
  • Example 12B (( 1 R*,2S*,4S*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- 7-yl)(2-(thiophen-2-yi)phenyi)methanone.
  • Example 1 The title compounds were obtained by chiral SFC (CHIRALPAK AS-H 5 ⁇ 250 X 20mm at 40 °C) resolution of Example 1 1 using 4.2 mL/min MeOH with 0.2% TEA, 37 mL/n CO2 as the mobile phase to give enantsoraer A. ( 1 st eluting enantsoraer) and enantiomer B (2 ! ' ⁇ eluting enantiomer).
  • Example 12A MS (ESI) mass calcd. for C . ⁇ ⁇ > i ; N >i> >S. 408.2; m/z found 409.2 ⁇ ⁇ ⁇ ⁇
  • Step A ( ⁇ )-7-azabicyclo[2.2.1 ]heptan-2-ylmethanol hydrochloride.
  • Step B (( ⁇ )-2-(hydroxymethyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5-methyl-2-(2H- 1 ,2,3- triazol-2-yl)phenyi)methanone.
  • TEA 5- methyl-2-(2H-l ,2,3-triazol-2-yl)benzoic acid and HA ' T ' U.
  • H 2 0 was added and the mix extracted with EtOAc (2X). The combined organics were washed with brine and dried (Na 2 S04).
  • Silica gel chromatography (1-7% 2M NHyMeOH in DCM) gave the title compound (371 mg, 46%).
  • Step C ( ⁇ )-(5-methyl-2-(2H- 1 ,2,3-triazol-2-y1)phenyl)(2-(((4- (trifjuoroTnethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicycio[2.2.1 ]heptan-7-yl)mefhanone.
  • To the title compound of step B (33 mg, 0.1 mmol) in THF (2 mL) was added NaO Bu (16 mg, 0.16 mmol). The reaction was then heated at reflux for 15 min and 2-chioro-4- trifluoromethylpyrimidme (19 mg, 0.16 mmol) was added. The reaction was heated at reflux temperature for Ih, cooled to rt, diluted with H 2 0 and extracted with DCM (2X). The combined organics were dried a2S04). Purification via silica gel chromatography (0.5-4% 2M
  • Example 16 ( ⁇ )-(5-rriethyl-2-(2H- 1 5 2,3-triazol-2-y3)phenyl)(2-(((6-(trifluoTomethyI)pj'ridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
  • Example 17 ( ⁇ )-(5-methyl-2-(2H-l,2,3-triazoi-2-yr)phenyl)(2-(((4-methylpyridii-2- o[2.2.1]heptan ⁇ 7-yl)methanone.
  • Example 18 ( ⁇ )-(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyI)(2-(((6-ineihyIpyridin ⁇ 2- .2.1]heptan-7-yl)methanone.
  • Example 19 ( ⁇ )-(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2- .2.1]heptan ⁇ 7-yl)methanone.
  • Example 21 ( ⁇ )-(5-methyl-2-(2H- l ,2,3-iriazol-2-yl)phenyi)(2-(((3-(trifluoromeihyi)quinoxalin- -yl)oxy)met y])-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 22 ( ⁇ )-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)meth.yl)-7- methanone.
  • Example 23 (i)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- yl)(quinolin-8-yl)methanone.
  • Example 24 ( ⁇ )-2-(((5-fluoropyridin-2-yl)oxy)met yl)-7-azabicyclo[2.2.1]heptan-7- .
  • Example 25 (i)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(2- ne.
  • Example 28 ( ⁇ )-(2-ethoxynaphthalen- 1 -yi)(2-(((5-fluoropyridin-2-yl)oxy)methyl)- azabicyelo[2.2, 1 ]heptan-7-yl)methanone.
  • Example 32 ( ⁇ )-(5-fluoro-2-(pyr rddin-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- ethanone.
  • Example 33 ( ⁇ )-(2-(((5-fluoropyridk-2-yl)oxy)memyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5- ])methanone.
  • Example 34 ( ⁇ )-(2-(2H- 1 > 2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyi)-7- thanone.
  • Step A ( ⁇ )-2-(-7-azab " icyclo[2.2.1]heptan-2-ylmethoxy)quinoxaline.
  • To intermediate B- 10 (2.40 mg, 1.1 mmol) in THF (4 mL) was added NaOtBu (130 mg, 1.4 mmol). The reaction was heated at reflux for 15 min and 2-ch.loroquinoxaline (207 mg, 1.3 mmol) was added. After 45 min, the reaction was cooled to rt and 1 ⁇ 2 saturated NH4CI (aq) was added. The solution was made slightly basic with 5% Na2C03 (aq) and extracted with DCM (3X). The combined organics were dried (Na 2 S0 4 ). The resulting compound was treated with TFA in DCM.
  • Step B ( ⁇ )-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone.
  • Step B ( ⁇ )-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone.
  • Example 35 ( ⁇ )-(2-fluoro-6-(2H- i,2,3-triazol-2-y3)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- one.
  • Example 36 ( ⁇ )-(5-methyl-2-(2H-l J 2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 37 ( ⁇ )-(5-fluoro-2-(2H-l ,2,3-triazol-2-yl)pheny1)(2-((quinoxalin-2-y1oxy)inethyl)-7- ne.
  • Example 39 ( ⁇ )-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptaii-7- -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
  • Step A ( ⁇ )-2-(((4,6-dimethyipyrimidin-2-yl)oxy)metliyl)-7-azabi
  • Step B ( ⁇ )-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 jlieptan-7- yl)(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone.
  • Example 40 ( ⁇ )-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -methyl-5-phenylisoxazol-4-yl)methanone.
  • Example 41 ( ⁇ )-(2-(((4,6-dimethylpyritnidin-2-yi)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -ethoxynaphthalen- 1 -yl)methan.one.
  • Example 43 (i)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -fluoro-6-(pyrimidin-2 ⁇ yI)phenyl)methanone.
  • Example 44 ( ⁇ )-(2-(((4,6-dimethylpyrmiidin-2-yI)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7 -fluoro-2-(pyrimidin-2-yl)phenyI)methanone.
  • Example 45 ( ⁇ )-(2-(((4,6-dimethylpyritnidin-2-yI)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -methyl-2-(pyri.midm-2-yl)phenyj.)methanone.
  • Example 46 ( ⁇ )-(2-(((4,6-dimethylpyrimid " in-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan- -ifhiophen-2 -yl)phenyl)methanone.
  • Step A ( ⁇ )-2-(((5-(trifiuoroniethyl)
  • Example 49 ( ⁇ )-(2-(((5-bromopyridin-2-yl)oxy)nieth.yl)-7-azabicyclo[2.2.1]heptan-7-yl)(6- 1)pyridin-2-yl)methanone.
  • Step A ( ⁇ )-2-(((5-bromopyrid n-2-y])oxy)methyi)-7-azabicyclo[2.2.1 Jheptane.
  • To intermediate B-10 (175 mg, 0.8 mmol) in DMF (3.5 mL) at 0 °C was added NaH (60 wt% in mineral oil, 37 mg, 0.9 mmol).
  • 5-bromo-2-fluoropyridine 190 mg, 1.1 mmol
  • DMF 0.5 mL
  • brine was added and the reaction extracted with EtOAc (2.X).
  • Step B Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-l,2,3-triazo]-2-yl)picolinic acid and (lS,2R,4R)-tert-butyl-2-((pyri.din- 2-yloxy)methyl)-7-azabicycfo[2.2.1 jheptane-7-carboxylate with the title compound of Step A.
  • Example 50 ( ⁇ )-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2JJheptan-7-yl)(3- fluoro -2-methoxypheny l)methan one .
  • Example 52 ( ⁇ )-(3-fluoro-2-(pyrimicUn-2-yl)phenyi)(2-((pyridin-2 ⁇ yioxy)methyl)-7- azabicyelo[2.2, 1 ]heptan-7-yl)raethanone.
  • Step A ( ⁇ )-ieri-butyl 2-((pyridazin-3-yioxy)methyl)-7-azabicyclo[2.2.1 ]heptane-7- carboxylate.
  • To intermediate B- 10 (266 mg, 1 .2 mmol) in THF (4 ml.,) at 0 °C was added NaH (60 wt% in mineral oil, 70 mg, 1.8 mmol). After 15 min, 3-chforopyridazine (.160 mg, 1 .4 mmol) was added. The reaction allowed to warm to rt. After 18h, H?0 was added and the mixture extracted with EtOAc. The organic layer was dried.
  • Step B ( ⁇ )-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1 ]heptaiie hydrochloride.
  • To the title compound from step A 300 mg, 1 mmol) in 1 ,4-dioxane (3 mL) was added 6N HCl in iPrOH (1 mL).
  • Step C ( ⁇ )-(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)(2-((pyridazin-3- yioxy)methyl)-7-azabicyc1o[2.2.1 ]beptan-7-yl)methanone.
  • DIPEA 630 ⁇ , 3.6 mmol
  • HBTU HBTU
  • Example 54 ( ⁇ )-(6-methyl-3-(2H-l 9 2 -triazol-2-yl)pyridin-2-yl)(2-(((2-methylpyTidin-3- yl)oxy)met yl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Step A ( ⁇ )-tert-butyl-2-(((methylsulfonyl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7- carboxylate.
  • To intermediate B-10 (545 mg, 2,4 mmol) in DCM (12 mL) at 0 °C was added TEA (333 ⁇ ,, 2.4 mmol) followed by MsCl ( 190 ⁇ , 2.4 mmol). After 2h, brine was added and the mixture was extracted with DCM (2X). The combined organics were dried (Na 2 S0 4 ) to give the title compound (650 mg, 89%) that was used without further purification.
  • MS (EST) mass mass calcd. for C ] 2 H 23 0 5 S, 305.1 ; m z found 249.9 [ M - 55 1
  • Step B ( ⁇ )-tert-butyl 2-(((2-metb.ylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane- 7-carboxylate.
  • KOH 2-methylpyridin-3-ol in DMF
  • the solution was stirred for 30 min at ri, then the title compound from step A was added and the reaction was heated at 80 °C. After 5h, 3 ⁇ 40 was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgS04), Purification via silica gel chromatography (0-7% MeOH in DCM) gave the title compound (201 mg, 90%).
  • Step C ( ⁇ )-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.
  • Step C ( ⁇ )-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.
  • Step C substituting ( ⁇ )-tert-buty1 2-((pyridazin-3-yloxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate with ( ⁇ )-tert-butyl 2-(((2-methylpyridin-3- yl)oxy)methyl)-7-azabieyclo[2.2.1 Jheptane-7-carboxylate.
  • MS (ESI) mass mass calcd. for C13H18 2O, 218.1 ; m/z found 219.1 [M+l ] + .
  • Step D ( ⁇ )-(6-methyl-3-(2H- 1 ,2,3-triazol-2-yI)pyridin-2-yl)(2-(((2-methylpyridin-3- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
  • Step A (i-)-tert-butyl 2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2. ljheptane- 7-carboxylate. Prepared analogous to Example 7 Step A Method A substituting PBu3 with PPh3, DEAD with DIAD, 5-fluoropyridin-2(lH)-one with 3-methylpyridin-2-ol and performing the reaction at ri MS (EST) mass calcd. for 318.2; m/z found 319.0 [M+Hj + .
  • Step B ( ⁇ )-2-(((2-methylpyrid " in-3-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane.
  • Prepared analogous to Example 53 Step B substituting ( ⁇ )-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7- azabicyclo[2.2.1 jheptane-7-carboxylate with ( ⁇ )-tert ⁇ butyl 2-(((2-methylpyridin-3- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.
  • Step C ( ⁇ )-(6-methyl-3-(2H-l,2,3-triazol-2-y])p ⁇
  • Example 56 ( ⁇ )-(2-(((l -methyl- 1 H-pyrazol-5-yl)oxy)methy ⁇ )-7-azabicyclo[2.2.1 jheptan-7-yl)(6- 2-y3)pyridm-2-yl)methanone.
  • Step A ( ⁇ )-tert-butyl 2-((( I -methyl- 1 H-pyrazol-5-yl)oxy)methyl)-7- azabicycJo[2.2.1]heptane-7-carboxylate.
  • Example 7 Step A Method A substituting THF with PhC3 ⁇ 4 and 5-fluoropyridin-2(l H)-one with 1 -methyl- lH-pyrazol-5-ol.
  • MS (ESI) mass mass calcd. for C16H25 3O3, 307.2; m/z found 308.0 [M+H] ⁇ .
  • Step B ( ⁇ )-2-((( 1 -methyl- 1 H-pyrazol-5-yl)oxy)niethyl)-7-azabicyelo[2.2.1 jheptane.
  • Step B substituting ( ⁇ )-tert-butyl 2-((pyridazin-3- yloxy)methyl)-7-azabicyclo[2.2.1 jheptane-7-carboxylate the title compound of Step A.
  • Step C ( ⁇ )-(2-(((l-methyl-lH-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptan-7- yl)(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)methanone.
  • Step C substituting ( ⁇ )-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1 jheptane hydrochloride with the title compound of Step B, MS (ESI) mass calcd. for C20H23N7O2, 393.2; m/z found 394.2 [M+H] .
  • Example 58 ( ⁇ )-(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridm-2-yl)(2-((pyridm-3-yloxy)meth l)methanone.
  • Example 60 ( ⁇ )-(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrazm-2-yloxy)methy -azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 63 ( ⁇ )-(2-(((5-fluoropyridin-2-yi)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- 2-yr)methanone.
  • Example 64 (i)-(2-(((5-fluoropyridin-2-yl)oxy)metb.yl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
  • Example 66 ( ⁇ )-(2-(((5-fluoropyridm-2-yi)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6- methyl-3-(3-methyl- ⁇ ,2,4-oxadiazol-5-yl)pyridm-2-yf)methanone.
  • Example 68 ( ⁇ )-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- din-2-yl)niethanone.
  • Step A 6-methyl-3-(pyrrolidin-l -yl)picolinonitrile.
  • 2-bromo-6-methyl-3-(2H- 1 ,2,3- triazol-2 ⁇ yi)pyridine (720 nig, 3,7 mmol), pyrollidine (450 ⁇ 3_,, 5.5 mmol), Pd(OAc) 2 (25 mg, 11 mol%), XPhos (122 mg, 25 mol%) and Cs 2 C0 3 (2.4 g, 7.3 mmol) in a sealed tube was added PhCH3.
  • the vessel was sealed and heated at 100 °C overnight. After cooling to rt, the reaction was diluted with EtOAc and H 2 0. The organic layer was dried (MgS04) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in DCM) gave the title compound ( 186
  • Step B 6-methyi-3-(pyiToiidin- l-yi)picolinic acid.
  • 4M KOH 650 ⁇ , 2.6 mmol
  • the reaction was then heated at 90 °C for 18h. Additional 4M KOH (1.5 mL,6 mmol) was added and heating continued overnight.
  • the reaction was then cooled to rt, acidified with IN HQ (aq), concentrated and used without further purification in the next step.
  • Step C ( ⁇ )-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6- methyl-3-(pyrrolidin-l-yl)pyridin-2-y])methanone
  • MS (ESI) mass calcd. for C23H27FN4O2, 410.2; m/z found 41 1.2 ; ⁇ ) H i . ⁇ NMR (DMSO-D 6 ): 8.14 i d. ./ 3.0 Hz, 0.5H), 8.10 i d.
  • Example 69 # ( ⁇ )-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- l)pyridin-2-yl)methanone.
  • Example 70 (i)-(2-(((5-fluoropyridin-2-yl)oxy)meth.yl)-7-azabicyc1o[2.2.1 ]heptan-7 ⁇ yl)(6- inethyl-3-( IIi-pyrazol-l-yl)pyrM ⁇ ⁇
  • Example 71 ( ⁇ )-(5-methyl-3-(2H- 1 ,2,3-triazoI-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyI)-7- methanone.
  • Example 72 (d_)-(4-methyl-3-(2H-l,2,3-n'iazoI-2-yl)pyridin ⁇ 2-yl)(2-((pyridin ⁇ 2- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 73 ( ⁇ )-(3-(dimethylamino)-6-methylpyridm-2-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Step A 3-(dimethylamino)-6-methylpicolinamide.
  • a mixture of 3-bromo-6- metbylpicolinonitriie (lg, 5 mmof) and dimethylamine (2 mL) were heated in a microwave reactor for 2h at 140 °C. The mixture was then concentrated and purified via silica gel chromatography (0-5% MeOH in DCM) to give the title compound (2.49 mg, 27%).
  • Step B 3-(dimethylamino)-6-methylpicolinic acid.
  • EiOH 1 mL
  • 4M KOH 0.5 ⁇
  • the reaction was then heated at 90 °C for 18h.
  • Step C Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step B.
  • Example 74 ( ⁇ )-(3-(2H- 1 ,2,3-triazol-2-yl)quinolin-2-yl)(2-((pyridin-2-ylox )methyl)-7- ethanone.
  • Example 75 ( ⁇ )-(7-etboxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 76 ( ⁇ )-(3,6-dimethylimidazo [ 1 , 2-a]pyridin-5 -yl)(2-((pyridm-2-yloxy)methyl)- 7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Step A 3,6-dimethylimidazo[l,2-a]pyridine-5-carboxylic acid. Prepared analogous to Example 82 substituting chloroacetaldehyde with 2-bromopropanal, MS (ESI) mass calcd. for CioHio 2 0 2 , 190.1 ; m/z found 191.0 ; U j
  • Step B ( ⁇ )-(3,6-dimethylimidazo[ l
  • Example 78 ( ⁇ )-( 1 -methyl-3-phenyl- 1 H-pyrazol-4-yl)(2-((pyridin-2-yloxy)methyl)-7- l)methanone.
  • Step A Prepared analogous to Example 76 substituting 6-ammo-3-methylpicolinic acid with 2-ammo-4-methylmcotimc acid.
  • Step B ( ⁇ )-((3,7-dimethylimidazo[ 1 ,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone.
  • Step A 7-methylimidazo[l,2-a]pyridine-8-carboxylic acid. Prepared analogous to Example 82 substituting 6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.
  • Step B ( ⁇ )-(7-methylimidazo[l ,2-a]pyridm-8-yl)(2-((pyTidm-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Step B ( ⁇ )-(7-methylimidazo[l ,2-a]pyridm-8-yl)(2-((pyTidm-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Example 81 ( ⁇ )-(l-methyl-4 ⁇ henyl- lH-pyTazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
  • Step A 6-amino-3-metkylpicolinic acid.
  • tetramethyistannane 900 jiL, 6.5 mmol
  • LiCl 354 mg, 8.7 mmol
  • Pd(PPh 3 )4 76 mg, 10 mol%)
  • the reaction mixture was heated at 110 °C for 3k. Additional tetramethyistannane, LiCi and Pd(PPks) 4 were added and heating continued for 6k. Purification via silica gel chromatography (0-20% MeOH in DCM) gave the title compound.
  • Step B 6-metkylimidazo[l,2-a]pyridine-5-carboxylic acid.
  • Step C ( ⁇ )-((6-methylimidazo[l ,2-ajpyridin-5-y])(2-((pyTidin-2-y]oxy)methyf)-7- azabicyclo[2.2.1 ]keptan-7-yl)metkanone.
  • Step C ( ⁇ )-((6-methylimidazo[l ,2-ajpyridin-5-y])(2-((pyTidin-2-y]oxy)methyf)-7- azabicyclo[2.2.1 ]keptan-7-yl)metkanone.
  • Example 2 substituting intermediate A-9 with 6-metkylimidazo[l ,2-a]pyridine-5-earboxy].ic acid.
  • the product is present as a mixture of conformers (ratio ca.
  • Example 83 ( ⁇ )-(3-ethoxyisoquinolin-4-yl)(2-((pyTidin-2-yloxy)metkyl)-7- l)metkanone.
  • Example 84 ( ⁇ )-( 1 -metbyl-5-phenyl- 1 H-pyrazol-4-yl)(-2-((pyridm-2-yloxy)methy3)-7- -yl)methanone.
  • Example 85 ( ⁇ )-(6-methyl-3-(4-methyipiperazin- 1 -yl)pyridin-2-y])(2-( ' (pyridin-2- [2.2.1 ]heptan-7-yl)methanone.
  • Step A 6-methyl-3-(4-methylpiperazin- l -yI)picolmonitrile. Prepared analogous to Example 68 substituting pyrollidine with 1 -methylpiperazine. MS (ESI) mass calcd. for C12H16N4, 21 6.1 ; m/z found 217.0 ⁇ vi - ! ! j
  • Step B 6-metliyl-3-(4-methy]piperazin- l-yi)picolinic acid. Prepared analogous to Example 68 substituting 6-methyl-3-(pyrrolidin- l -yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for C12H17N3O2, 235.1 ; m/z found 236.0 [M+H] + .
  • Step C Prepared analogous to Example 2. substituting intermediate A-9 with the title compound of Step B. MS (ESI) mass calcd. for C24H 3 iN 5 0 2 , 421.2; m/z found 422.2
  • Example 86 ( ⁇ )-(6-methyl-3-(piperazin- 1 -yl)pyridin-2-yl)(2-((pyridin-2-yloxy)ixiethyl)-7- l)methanone.

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Abstract

The present invention is directed to compounds of Formula I: wherein ring A is phenyl, naphihalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyi, tlisazolyl, isoxazolvl, pyrazolyl, imidazothiazolyi, benzimidazolyl, or indazolyi; R1 is H, alky], aikoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazofyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazmyl, piperazinyl, pyrazolyl, oxadiazolvl, pyrrolidinyl, thiophenyi, morpholinyl, or dialkyiamino; R2 is H, alkyl, aikoxy, hydroxyalkylene, or halo; Z is NH, N- alkyl, or O; R5 is pyridyl, pyrimidinyl, pyrazinyl, pyridazmyl, qumazolinyi, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, triazolopyrazinyl, optionally substituted with a one or two substiiuents independently selected from the group consisting of alkyl, aikoxy, or halo; and n is 0 or 1, Methods of making the compounds of Formula 1 are also described. The invention also relates to pharmaceutical compositions comprising compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

Description

SUBSTITUTED 7-AZABICYCLES AND THEIR USE AS QREXIN RECEPTOR
MODULATORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/780,428, filed March 13, 2013, which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
The present invention is directed to substituted 7-azabicyclic compounds, pharmaceutical compositions comprising them, methods of making them, and methods of using them for the modulation of the orexin receptor for the treatment of disease states, disorders, and conditions mediated by orexin receptor activity.
BACKGROUND
Qrexin/hypocretin signaling is mediated by two receptors and two peptide agonists. The peptides (orexin- A and orexin-B) are cleavage products of the same gene, pre -pro orexin. In the central nervous system, neurons producing pre -pro orexin are found solely in the perifomical nucleus, the dorsal hypothalamus, and the lateral hypothalamus (Peyron et al, 1998, J. Neurosci. 18: 9996-10015). Orexigenic cells in these regions project to many areas of the brain, extending rostrally to the olfactory bulbs and caudaily to the spinal cord (Van den Pol, 1999, J. Neurosci. 19: 3171-3182).
The orexins bind to two high affinity receptors, referred to as orexin- 1 and orexin-2 receptors. Orexin- 1 and orexin-2 receptors are G-protein-coupled, seven transmembrane receptors that share over 64% amino acid sequence identity with one another. Both receptors are generally excitatory, the common cellular response to orexin-induced receptor activation being increases in intracellular calcium. Homology between the species orthologs is high and there are no known pharmacological differences. Orexin- A and -B are usually considered equal Iigands for orexin-2 receptor but orexin-B is thought to be 5- to 100-fold weaker ligand than orexin- A at the orexin- 1 receptor (Sakurai et al, 1998, Cell 92: 573-585; Ammoun et al., 2003, J.
Pharmacol. Exp. Ther. 305: 507-514).
Many regions of the brain have fairly selective expression of the orexin- 1 or orexin-2. receptors (Marcus et al., 2001 , J Comp Neurology 435, 6-25; Trivedi et al., 1998, FEES Letters, 438, 71-75). Orexin- 1 receptors are selective for the limbic system (bed nucleus of the stria terminalis and amygdala), cingulate cortex and noradrenergic neurons in the locus coeruieus.
- i - Conversely, the orexin-2 receptor is almost the exclusive orexin receptor in the histaminergic neurons in the tuberomammilary nucleus which play a critical role in wake promotion; in paraventricular neurons and the parahrachial nucleus. In other brain regions like the dorsal raphe, the ventral tegmental area or the prefontal cortex both receptors are coexpressed.
The broad CNS distribution of cells producing orexin, as well as ceils expressing the orexin receptors, suggests involvement of orexin in a number of 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. Physio!. Ceil Physio!,, 304, C2-C32). Orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse (Mahler et a!., 2012, Progress in Brain Research, 198, 79-121).
Several lines of evidence indicate that the orexin system is an important modulator of arousal. Rodents administered orexin intracerebroventricularly spend more time awake (Piper et a!,, 2000, J. Neurosci. 12: 726-730. Orexin-mediated effects on arousal have been linked to orexin neuronal projections to histaminergic neurons in the tuberomammillary nucleus
(Yamanaka et al., 2002, Biochem. Biophys. Res. Comm. 290: 1237-1245). Rodents whose pre- pro orexin gene has been knocked out, or whose orexigenic neurons have been killed, display altered sleep/wake cycles similar to narcolepsy (Chemelli et al., 1999, Cell 98: 437-451 ; Hara et aL, 2001, Neuron 30: 345-354). Dog models of narcolepsy have been shown to have mutant or non- functional orexin-2 receptors (Lin et al, 1999, Cell 98: 365-376). Orexin signaling as a target for sleep-promoting therapies was further validated clinically by findings of attenuated orexin levels and loss of orexinergic neurons in human narcoleptic patients (Mignot et al., 2001 , Am. J. Hum. Genet. 68: 686-699; Minot & Thorsby, 2001, New England J. Med. 344: 692) or, in rare cases, to mutations in the orexin-2 gene (Peyron et al, 2000, Nature Med. .6: 991-997). Disorders of the sleep-wake cycle are therefore likely targets for orexin-2 receptor modulator acti vity. Examples of sleep-wake disorders that ma be treated by agonists or other modulators that up-regulate orexin-2 receptor-mediated processes include narcolepsy, jet lag (sleepiness) 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 leg syndrome, jet lag (wakefulness) and sleep disorders secondary to neurological disorders such as mania, schizophrenia, pain syndromes and the like.
Evidence has accumulated to demonstrate a clear involvement of orexin signaling in reward pathways associated with drug dependence (Mahler et al, 2012, Progress in Brai Research, 198, 79-121). Orexirsergic neurons send projections to the ventral tegmental area and other brain regions involved in reward processing. Orexin ligands mediate reward behavior, and antagonizing these effects with a selective orexin- 1 receptor antagonist in various preclinical model of addiction has suggested that these actions are mediated through orexin- 1 receptor. Specifically, a selective orexin- 1 antagonist attenuates morphine conditioned place preference and reinstatement (Harris et al, 2005, Nature, 437, 556-5599: Narita et al, 2006, J Neurosci.,26, 398-405; Harris et al., 2007, Sehav Brain Res, 183, 43-51), stress-induced cocaine reinstatement, cocaine-induced behavioral and synaptic plasticity (Borgland et al., 2006, Neuron, 49, 589-601 ), and intake and cue and stress-induced reinstatement of ethanol (Lawrence et al, 2006, Br J Pharmacol, 148, 752-759), in addition to attenuating precipitated morphine withdrawal (Sharf et al., 2008, Biol PsychiaUy, 64, 175-183) and nicotme self-administration (Hollander et al., 2008, Proc Nail Acad Sci US A., 105, 19480-19485). Another recent study has also suggested a role for OX2R (Shoblock et al, 201 1, Psychopharmacology, 215, 191 -203).
Orexin' s role in more complex emotional behavior is also emerging (Johnson et al., 2012, Progress in. Brain Research, 198, 133-161). Changes in orexin levels in patients with panic and posttraumatic stress disorders have been noted as have changes in the prevalence of anxiety behaviors in narcoleptic patients (Johnson et al., 2010, Nature Medicine, _1__6_, 1 1 1- 1 15; Fortuyn et al., 2010, General Hospital Psychiatry, 32, 49-56; Strawn et al., 2010,
Psychoneuroendocrinology, 35, 1001-1007). Lactate infusion or acute hypercapnia , which causes panic in humans, and are used as an animal model of panic, acti v ates orexin neurons in the perifornical hypothalamus. This activation correlates with anxiety in the social interaction test or open field test. Blocking orexin signaling with either siRNA or selective orexin- 1 receptor antagonists attenuates panic-like responses to lactate (Johnson et al., 2010, Nature Medicine, j.6, 1 1 1-1 15; Johnson et al., 2012, Neuropsychopharmacology, 3.7, 191 1, 1922).
Cerebral spinal fluid (CSF) levels of orexin are lower in depressed or suicidal patients, and the level of orexin inversely correlates with illness severity (Brundin et al., 2007, European Neuropsychopharmacology, 17, 573-579; Salomon et al., 2003, Biol Psychiatry, 5 , 96- 104). A positive correlation between orexin- 1 receptor mRIslA in the amygdala and depressive behavior in the forced swim test in mice has been reported (Arendt, 2013, Behavioral Neuroscience, 127, 86-94).
The orexin system also interacts with brain dopamine systems. Intracerebroventricuiar injections of orexin in mice increase locomotor activity, grooming and stereotypy; these behavioral effects are reversed by administration of D2 dopamine receptor antagonists
(Nakamura et al., 2000, Brain Res, 873: 181 - 187). Therefore, orexin receptor modulators may be useful to treat various neurological disorders; e.g., agonists or up-regulators to treat catatonia, antagonists or down-regulators to treat Parkinson's disease, Tourette's syndrome, anxiety, delerium and dementias.
Orexms and their receptors have been found in both the myenteric and submucosal plexus of the enteric nervous system, where orexms have been shown to increase motility in viiro (Kirchgessner & Liu, 1999, Neuron 24: 941-951 ) and to stimulate gastric acid secretion in vitro (Takahashi et al., 1999, Biochem. Biophys. Res. Comm. 254: 623-627). Orexin effects on the gut may be driven by a projection via the vagus nerve (van den Pol, 1999, supra)., as vagotomy or atropine prevent the effect of an intracerebroventricular injection of orexin on gastric acid secretion (T akahashi et al., 999, supra). Orexin receptor antagonists or other down-regulators of orexin receptor-mediated systems are therefore potential treatments for ulcers, irritable bowel syndrome, diarrhea and gastroesophageal reflux.
Body weight may also be affected by orexin-mediated regulation of appetite and metabolism. Some effects of orexin on metabolism and appetite may be mediated in the gut, where, as mentioned, orexins alter gastric motility and gastric acid secretion, Orexin antagonists therefore are likely to be useful in treatment of overweight or obesity and conditions related to overweight or obesity, such as insulin resistance/type 11 diabetes, hyperiipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis. Conversely, orexin agonists are likely to be useful in treatment of underweight and related conditions such as hypotension, bradycardia, ammenorrhea and related infertility, and eating disorders such as anorexia and bulimia.
Intracerebroventricularly administered orexins have been shown to increase mean arterial pressure and heart rate in freely moving (awake) animals (Samson et al., 1999, Brain Res. 831 : 248-253; Shirasaka et al, 1999, Am. J. Physiol. 2.77: R1780-R1785) and in urethane-anesthetized animals (Chen et al, 2000, Am. J. Physiol. 278: R692-R697), with similar results, Orexin receptor agonists may therefore be candidates for treatment of hypotension, bradycardia and heart failure related thereto, while orexin receptor antagonists may be useful for treatment of hypertension, tachycardia and other arrhythmias, angina pectoris and acute heart failure.
From the foregoing discussion, it can be seen that the identification of orexin receptor modulators, will be of great advantage in the development of therapeutic agents for the treatment of a wide variety of disorders that are mediated through these receptor systems.
SUMMARY
The present invention is directed to compounds of Formula 1:
Figure imgf000006_0001
wherein ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyi, thiazolyl, isoxazolyl, pyrazolvi, imidazothiazolyl, benzimidazolyl, or indazolyl; Ri is H, alkyl, alkoxy, hydroxyalkyiene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenvl, morpliolinyi, or clialkyiamino, wherein phenyl, triazolyl, oxazolyl, isoxazolyl, pyridy l, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, or morpholinyl is optionally substituted with up to two substituents selected from halo and alkyl; P 2 is H, alkyl, alkoxy, hydroxyalkyiene, or halo; Z is NF1, N-alkyl, or O; R is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, thiazolyl, thiadiazoiyi, benzoxazoiyl, imidazopyrazinyl, triazolopyrazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cyano, alkyl carboxylate, alkoxy , and halo: and n is 0 or 1. Enantiomers and diastereomers of the compounds of Formula I are also described, as well as the pharmaceutically acceptable salts.
Methods of making the compounds of Formula I are also described. The invention also relates to pharmaceutical compositions comprising therapeutically effective amounts of compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 depicts a Powder X-Ray Diffraction (PXRD) pattern for one embodiment of the invention. Example 238, Form 1.
Figure 2 depicts a Powder X-Ray Diffraction (PXRD) pattern for one embodiment of the invention, Example 238, Form 2.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The invention may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples.
The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. In some embodiments, an alkyl group is a C-i-Ce alkyl group. In some embodiments, an alkyl group is a Q-Ct alkyl group. Examples of alkyi groups include methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isoliexyl , and groups that in light of the ordinary skil l in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Alkyl groups of the invention can be optionally substituted with, for example, one or more halogen atoms. One exemplary substitutent is fluoro. Certain substituted alkyi groups of the invention include trihalogenated alkyl groups such as trifluoromethyl groups.
Alky i groups of the invention can also refer to "cycloalkyl" moieties. Cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 7 carbon atoms. Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 - methylcyclopropyl, 2-methyIcyclopentyl, and the like.
The term "alkoxy" includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyi group to the rest of the molecule. In some embodiments, an alkoxy group is a Ci-Ce alkoxy group. In some embodiments, an alkoxy group is a Cj-Cs alkoxy group. Alkoxy mcludes methoxy, etboxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. Alkoxy groups of the inventions can be optionally substituted with, for example, one or more halogen atoms (baloalkoxy). One exemplary substitutent is fluoro. Preferred substituted alkoxy groups of the invention are substituted with one, two, or three halogen atoms, for example, - OCHCF2.
The term "alkyl carboxylate" refers to the group -(C=Q)Q- alkyi, where alkyl is as defined above.
The term "amino" represents NH?. The term "dialkylamino" represents the moiety wherein each H of the amino group is replaced by an alkyl group. These alkyl groups ca be the same or different. Preferred alkyl groups are the Ci-ealkyl groups. Examples of dialkyl amino groups include dimethylamino, diethylamino, diisopropylamino, and the like. Other examples include methylethylamino, methylisopropylamino, and the like.
The term "aryl ring" represents" a mono- or bi-cyclic aromatic, hydrocarbon ring structure. Aryl rings can have 6 or 10 carbon atoms in the ring.
The term "benzimidazolyf" represents the following moiety: T/2
' N .
The benzimidazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, or
-position atoms and is optionally substituted with alkyl or halo or alkoxy groups. The term "benzoxazolyl" represents the following moiety:
Figure imgf000008_0001
The benoxazolyl moiety can be attached through any one of the 2-, 4-, 5-, 6- , or 7- position carbon atoms and is optionally substituted with alkyl or halo or alkoxy groups.
The term ''furanyl" represents the following moiety:
Figure imgf000008_0002
The furanyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-posiiion carbon atoms.
The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.
The term " eteroaryl ring" represents a mono-or bicyclic aromoatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms.
The term "hydroxyalkylene" represents an alkyl group, terminally substituted with OH. Examples of hydroxyalkylene moieties include -CH2-OH, -CH2CH2-OH, -CH2CH2CH?-OH, and the like.
The term "imidazopyridyl" represents the following moiety:
Figure imgf000008_0003
The imidazopyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7-position carbon atoms and is optionally substituted with alkyl or halo or alkoxy groups.
zopyrazinyl" represents the following moiety:
Figure imgf000008_0004
The imidazopyrazinyl moiety can be attached through any one of the 2-, 5-, or 6-position carbon atoms.
The term "imidazothiazolyl" represents the following moiety :
Figure imgf000009_0001
The imidazothiazolyi moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.
The term "indazolyl" represents the following moiety:
Figure imgf000009_0002
The indazolyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, or 7-position atoms and is optionally substituted with alkyl or halo or aikoxy groups.
The term "isoquinolinyl" represents the following moiety:
Figure imgf000009_0003
8
The isoquinolinyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, 7-, or 8- position carbon atoms and is optionally substituted with alkyl or halo or aikoxy groups.
The term "isoxazolyi" represents the following moiety:
Figure imgf000009_0004
The isoxazoly i moiety can be attached through any one of the 3-, 4-, or 5-position carbon atoms. Isoxazolyi groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.
The term "naphthalenyl" represents the following moiety :
Figure imgf000009_0005
8 1
The naphthalenyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms and is optionally substituted with alkyl or halo or aikoxy groups.
The term "morpholinyl" represents the following moiety:
Figure imgf000010_0001
4
The 4-position nitrogen atom may he substituted with H or alkyl, for example methyl. The 4-position nitrogen can also be protected with a nitrogen protecting group such as a butyl- oxycarbonyl (-Boc). The morpholinyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position atoms. The morpholinyl ring is optionally substituted with halo or alkyl groups.
The term "oxazolyl" represents the following moiety:
Figure imgf000010_0002
The oxazolyl moiety can be attached through any one of the carbon atoms. Oxazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.
The term "oxadiazoiyi" represents a 1,2,3-oxadiazoie, 1 ,2,4-oxadiazoie, 1,2,5-oxadiazoie, or 1,3,
Figure imgf000010_0003
The oxadiazoiyi moieties can be attached through any one of the carbon or nitrogen atoms. Within the scope of the invention, "oxadiazoiyi" groups can be substituted with an alkyl group, preferably a methyl group.
rm "tbiazolyl" represents the following moiety:
Figure imgf000010_0004
The thiazolyl moiety can be attached through any one of the carbon atoms. Thiazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.
The term "thiadiazolyl" represents a 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1 ,2,5- thiadiazole, or 1, 3, 4-thiadiazole moiety :
Figure imgf000010_0005
The thiadiazolyl moieties can be attached through any one of the carbon or nitrogen atoms. Within the scope of the invention, "thiadiazolyl" groups can be substituted with an alkyl group, preferably a methyl group.
"phenyl" represents the following moiety:
Figure imgf000011_0001
Phenyl groups of the inventions can be optionally substituted with, for example, one or more halogen atoms (haio-phenyl) or alkyl or alkoxy groups. Exemplary substifutents are fluoro, bromo, and chloro. Preferred substituted phenyl groups of the invention are substituted with one, two, or three halogen atoms.
"pyridyl" represents the following moiety:
Figure imgf000011_0002
The pyridyl moiety can be attached through any one of the 2 -, 3-, 4-, 5 -, or 6-position carbon atoms. Pyridyl groups of the invention can be optionally substituted with, for exampl one or more halo or alkyl groups, for example, one or two methyl groups.
The term "piperazinyl" represents the following moiety:
Figure imgf000011_0003
The piperazinyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms. Any one of the nitrogen atoms of the piperazinyl moiety can be substituted with H or alkyl, for example, methyl.
The term "pyrimidmyl" represents the following moiety:
Figure imgf000011_0004
The pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms. Within the scope of the invention, "pyrimidinyl" groups of the invention can be substituted with halogen or alkyl, for example fluoro or methyl or trifluoromethyi.
The term "pyrazinyl" represents the following moiety:
Figure imgf000012_0001
4
The pyrazinyl moiety can be attached through any one of the 2 -, 3-, 5-, or 6-position carbon atoms and may be optionally substituted with alkyl, aikoxy or halo.
pyridazinyl" represents the following moiety:
Figure imgf000012_0002
The pyridazinyl moiety can be attached through any one of the 3-, 4-, 5-, or 6-position carbon atoms and may be substituted with alkyl, aikoxy or halo groups.
The term "pyrazoiyl" represents the following moiety:
1
4 3
The pyrazoiyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5 -position carbon atoms. Pyrazoiyl groups of the invention can be optionally substituted with, for exampl one or two alkyl groups, for example, one or two methyl groups.
The term "pyrrolidinyl" represents the following moiety:
1
. N .
The pyrrolidinyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5- position atoms. When the pyrrolidinyl moiety is not attached through the 1 -position nitrogen, the nitrogen can be substituted with H or alkyl, for example methyl.
The term "quinolinyl" represents the following moiety:
Figure imgf000012_0003
The quinolinyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, 7-, or 8· position carbon atoms and may be optionally substituted with alkyl, halo or aikoxy groups.
The term "quinoxalmyl" represents the following moiety:
Figure imgf000013_0001
The quinoxalinyl moiety can be attached through any one of the 2-, 3 -, 5-, 6-, 7-, or 8-position carbon atoms and may be optionally substituted with alkyl, halo or alkoxy groups.
The term "quinazolinyl" represents the following moiety:
Figure imgf000013_0002
The quinoxalinyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, 7-, or 8-position carbon atoms and may be optionally substituted with alkyl, halo or alkoxy groups.
The term "thiazolyl" represents the following moiety:
Figure imgf000013_0003
The thiazolyl moiety can be attached through any one of the 2
The term "thiophenyl" represents the following moiety
Figure imgf000013_0004
The thiophenyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-position carbon atoms.
olopyrazinyl" represents the following moiety:
Figure imgf000013_0005
The triazolopyrazinyl moiety can be attached through any one of ihe 1-, 3-, 4-, 5-, 6-, or 7-position atoms.
The term "triazoiyi" represents a 1,2,3-triazole or a 1,2,4-triazole moiety:
N 1 .X
·€> nor
The triazolyl moieties can be attached through any one of their atoms. "Pharmaceutically acceptable" means approved or appro vable by a regulatory agency of the Federal or a state go vernment or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention thai is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, in particular, such salts are non-toxic may 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 formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, giycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hyciroxybenzoyi)benzoic acid, cinnamic acid, mandeiic acid, methanesulfonic acid,
ethanesulfonic acid, 1,2-ethane-disulfonic 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-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapbthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanoiamine, diethanolamine, Methanol amine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maieate, oxalate and the like.
"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.
"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodinient, "treating" or "treatment" refers to delaying the onset of the disease or disorder.
In treatment methods according to the invention, a therapeutically effective amountof a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. A "therapeutically effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present inv ention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., 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 subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, T1D, Q1D). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/'day. "Compounds of the present invention," and equivalent expressions, are meant to embrace compounds of the Formula (I) as described herein, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more nonradioactive or radioactive isotopes, such as for example, deuterium (Ή or D), carbon- 13 ( l3C), nitrogen- 15 (l5N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary , so thai for example, any hydrogen may be ZH/D, any carbon may be 1 C, or any nitrogen may be ] N, and that the presence and placement of such atoms may be determined wi thin the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. Radiol abeled compounds of the invention can be used in diagnostic methods such as Single-photon emission computed tomography (SPECT). The radioactive isotopes tritium, i.e. "Ή, and carbon- 14, i.e. l4C, are particularly useful for their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as "C, ;8F, i50 and iJN, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
All isotopic variants of the compounds of the invention, radioactive or not, are intended to be encompassed within the scope of the invention. In one aspect, provided herein are deuterated analogs of compounds of Formula T as described in the Examples section. In one embodiment, deuterated analogs of compounds of Fonnula I comprise deuterium atoms attached to one or more positions on the 7-azabicyclic ring, such as bridgehead carbons, or
non-bridgehead carbons of the 7-azabicyclic ring, and preferably comprise one or more deuterium atoms attached to non-bridgehead carbons of the 7-azabicyclic ring. Also contemplated within the scope of embodiments described herein are compounds in which a single proton in compounds of Formula I is replaced with a deuterium, or 2 protons in compounds of Formula I are replaced with deuterium, or more than 2 protons in compounds of Formula I are replaced with deuterium. Deuteration of a compound of Formula I may also be effected on one or more substituents (such as e.g., ring A, R1, R", or RJ) present on the
7-azabicyclic ring. Deuterated analogs of compounds of Formula TA are also contemplated within the scope of embodiments provided herein.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."
Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposabie mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-seq encing rides of Calm and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively), A. chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture."
"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological acti vity of a compound of interest.
Compounds of the invention may also exist as "rotamers," that is, conformational isomers that occur when the rotation leading to different conformations is hindered, resulting a rotational energy barrier to be overcome to convert from one conformational isomer to another.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (j )-or (^-stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. The present inventi :
Figure imgf000017_0001
wherein ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyl, thiazoiyi, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl;
Ri is H, alkyl, alkoxy, hydroxya!kyfene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino, wherein pheny l, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, or morpholinyl is optionally substituted with up to two substituents selected from halo and alkyl:
R2 is H, alkyl, alkoxy, hydroxyalkylene, or halo;
Z is H, N-alkyl, or O;
¾ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyi, quinoxalinyl, pyrazolyl, thiazoiyi, thiadiazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cyano, alkyl carboxylate, alkoxy, and halo; and n is 0 or 1.
In one aspect the inv la 1:
Figure imgf000018_0001
wherein
ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl,
furanyl, thiazoiyi, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl;
Ri is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino;
R? is H, alkyl, alkoxy, hydroxyalkylene, or halo;
Z is NH, N-alkyl, or O;
5 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyi, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo; and
or 1. Enantiomers and diastereomers of the compounds of Formula I are also within the scope of the invention. Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of Formula 1, as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula I. Also contemplated within the scope of the embodiments provided herein are isotopic variants of compounds of Formula 1, such as, by way of example, deuterated compounds of Formula 1.
In preferred embodiments of the invention, Z is NFL in other embodiments, Z is N-alkyl, preferably N-Ci-ealkyl, preferably N-CH3.
In alternative embodiments, Z is O.
In preferred embodiments of the invention, ring A is a heteroaryl ring. Preferably, ring A is furanyl, which can be attached to the compounds of Formula I through any available atom, preferably the 2-position carbon atom. In other embodiments, ring A is thiazoly i, which can be attached to the compounds of Formula I through any available atom, preferably the 4-position carbon atom.
In still other embodiments, ring A is isoxazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-position carbon atom.
In yet other embodiments, ring A is pyrazo!yi, which can be attached to the compounds of Formula I through any through any available atom, preferably the 3- or 4-position carbon atoms.
Also preferred are embodiments wherein ring A is imidazotbiazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 5-position carbon atom.
In certain embodiments of the invention, ring A is benzimidazolyl, which can be attached to the compounds of Formula I through any available atom, prefera bly the 2-position carbon atom.
In other embodiments of the invention, ring A is indazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 3 -position carbon atom.
In yet other embodiments, ring A is imidazopyridyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-, or 7-position carbon atom In still other embodiments, ring A is quinolinyl, which can be attached to the compounds of Formula I through any av ailable carbon atom, preferably the 5- or 8-position carbon atom.
In other embodiments, ring A is isoquinolinyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 4-position carbon atom.
In certain embodiments, ring A is pyridyl, which can be attached to the compounds of
Formula I through any available carbon atom, preferably the 2-, 3-, or 4-position carbon atom.
In some preferred embodiments, ring A can be an aryl ring. In certain embodiments, ring A is phenyl. In other embodiments, ring A is naphthalenyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 1 -position carbon atom.
In preferred embodiments of the inven tion, Rj is H, in other embodiments, R] is alkyi, preferably a Ch lky!, for example, methyl.
In still other embodiments, Ri is aikoxy, preferably a Cj-ealkoxy such as methoxy or ethoxy. Alternatively, R; is a substituted aikoxy, preferably substituted with one or more halo such as F, CI, or Br. One preferred haloalkoxy is difluoromethoxy.
In other embodiments, Rj is hydroxyalkylene, for example, hydroxyCj-ealkylene such as -CH2-OH or -CH2CH2-OH. In yet other embodiments, ¾ is OH.
In other preferred embodiments, Ri is halo, that is, any one of F, CI, Br, or I, with F, CI, or Br being particularly preferred.
In still other embodiments, Ri is phenyl. In some embodiments, j is phenyl optionally substituted with up to two substituents selected from halo and alkyl. In some embodiments, the phenyl can be substituted with at least one halo, for example, phenyl substituted with at least one of F, CI, or Br.
In certain embodiments, Rj is triazolyi, with 1 ,2,3-triazolyl being preferred. The triazolyi can be attached through any available atom. In preferred embodiments, the 1 ,2,3-triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl is attached through the 1 -position nitrogen atom. In some embodiments, Ri is triazolyi optionally substituted with up to two substituents selected from halo and alkyi.
In yet other embodiments, Rj is oxazoiyl, which can be attached through any available atom, preferably attached through the 2-position carbon. In some embodiments, j is oxazoiyl optionally substituted with up to two substituents selected from halo and alkyi. In some embdoiments, the oxazoiyl can be substituted with alkyl, for example, a Cs ^aikyl such as methyl.
In other embodiments, Rj is isoxazolyl, which can be attached through any available atom. In some embodiments, Rj is isoxazolyl optionally substituted with up to two substituents selected from halo and alkyL In some embodiments, the isoxazolyl can be substituted with alkyL for example, a Cj -galkyl such as methyl.
In still other embodiments, R; is pyridyl, which can be attached through any available carbon atom, in some embodiments, Ri is pyridyl optionaiiy substituted with up to two substituents selected from halo and alkyL In some embodiments, the pyridyl can be substituted with withat least one alkyl, for example, Chalky! such as methyl.
In certain embodiments, Ri is pyrimidiny!, which can be attached through any available carbon atom. In other embodiments, Ri is pyrazinyi, which can be attached through any available carbon atom. In yet other embodiments, Rj is pyridazinyl, which can be attached through any available carbon atom. In some of such embodiments, Rj is pyrimidinyl, or pyrazinyi, or pyridazinyl, each optionally substituted with up to two substituents selected from halo and alkyl.
In other embodiments, Ri is piperazinyl which can be attached through any available atom. In some embodiments, Ri is piperazinyl optionally substituted with up to two substituents selected from halo and alkyl. In some embodiments, one or both nitrogen atoms of the piperazinyl may be substituted with H or alkyl, for example, Ci-ealkyl such as methyl.
In still other embodiments, R; is morpholinyl, which can be attached through any available atom. In some embodiments, Ri is morpholinyl optionally substituted with up to two substituents selected from halo and alkyL In some embodiments, the nitrogen of the morpholinyl may be substituted with H or alkyl, for example, Chalky! such as methyl.
In yet other embodiments, Ri is pyrrolidinyl, which can be attached through any available atom. In some embodiments, Rj is pyrrolidinyl optionally substituted with up to two substituents selected from halo and alkyl. In some embodiments, the nitrogen of the pyrrolidinyl ma be substituted with H or alkyl, for example, Cj -ealkyl such as methyl.
In other embodiments, R; is dialkylamino, for example, dimethylamino, diethylamino, or methylethylamino.
In other embodiments, Ri is pyrazoiyl, which can be attached through any available atom. In some embodiments, i is pyrazoiyl optionally substituted with up to two substituents selected from halo and alkyl. In some embodiments, the pyrazoiyl can be substituted with with one or two alkyl, for example, Chalky 1 such as methyl.
In yet other embodiments, Ri is oxa liazoiyl, which can be a 1,2,3 -oxadiazolyl,
1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, or 1 ,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4- oxadiazolyl. The oxadiazolyl can be attached through any available atom. In some
embodiments, j is oxadiazolyl optionally substituted with up to two substituents selected from halo and alkyl. In some embodiments, the oxadiazolyl can be substituted with with alkyl, for example, such as methyl.
In still other embodiments, R; is thiophenyl, which can be attached through any available carbon atom, in some embodiments, Ri is thiophenyl optionally substituted with up to two substituents selected from halo and alkyl.
In preferred embodiments of the invention, R2 is H. In other embodiments, R2 is alkyl, for example, Ci-ealkyl such as methyl or ethyl. In yet other embodiments, R2 is alkoxy, for example, Cj ^alkoxy such as methoxy or ethoxy. In other embodiments, R2 is hydroxylalkene, for example, ~CH2-OH or CH2CH2-OH. In stiil other embodiments, R? is halo, preferably, any one of F, CI, or Br.
In some embodiments of Formula I, ring A is aryl, preferably phenyl, R; is a ring selected from phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pvrazinyl, pyridazinyl, piperazinyi, pyrazoiyl, oxadiazolyl, pyrrolidinyl, thiophenyl, and morpholinyl: preierably triazolyl, pyridyl or pyrimidinyl; R2 is H, alkyl, alkoxy, hydroxy alkylene, or halo; preferably halo; Z is NH or O, preferably NH, R5 is a heteroaryi, preferably pyridyl or pvrazinyl; and n is 0. In some of such embodiments, Ri is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and I½ is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula I, preferably R2 is at the meta position adjacent to Rj . In some other such embodiments, Rj is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and 2 is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula 1, preferably R2 is at the meta position not adjacent to R i . R i and R; may be optionally substituted as described above.
In some embodiments of Formula I, ring A is heteroaryi, preferably pyridinyl, Rj is a ring selected from phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyi, pyrazoiyl, oxadiazolyl, pyrrolidinyl, thiophenyl, and morpholinyl; preferably triazolyl, pyridyl or pyrimidinyl; R2 is H, alkyl, alkoxy, hydroxyalkylene, or halo; preferably halo; Z is NH or O, preferably NH, R5 is a heteroaryi, preferably pyridyl or pyrazinyl; and n is 0. In some of such embodiments, Rj is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and R2 is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula I, preferably R2 is at the meta position adjacent to Ri . In some other such embodiments, Ri is a ring at the ortho position on ring A relative to the carbonyl group in Formula I, and R? is at the ortho, meta or para position on ring A relative to the carbonyl group in Formula I, preferably R2 is at the meta position not adjacent to Ri . Ri and R5 may be optionally substituted as described above, In one aspec t, the invention is directed to compounds of Formula IA:
Figure imgf000023_0001
wherein
Figure imgf000023_0002
wherein
X is C¾, N, or NR6;
Y is CR7,N, or NR7;
R<5 is H, alkyi, aUkoxy, OH, halo, triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, or thiophenyl, wherein triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl pyridazinyl, pvrazolyl, or thiophenyl is optionally substituted with up to two substituents selected from halo and alkyi;
R7 is H, alkyi, alkoxy, or halo;
R;, is H, alkyi, alkoxy, hydroxyalkyiene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morphoiinyi, or dialkylamino, wherein phenyl, triazolyl, oxazolyl, isoxazolyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, or morphoiinyi is optionally substituted with up to two substituents selected from halo and alkyi;
R4 is H, alkyi, alkoxy, or halo;
or
Re and R7) together with the atoms to which they are attached, form a 5- or 6- membered heteroaryl ring optionally substituted with alkyi; or 3 and R4, together with the atoms to which they are attached, form a 6- membered aryl or 6-membered heteroaryl ring; or
R7 and R4, together with the atoms to which they are attached, form a 6- membered aryl or 6-membered heteroaryl ring; Z is Nil, N-alkyl, or ():
s is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyi, quinazolinyl, quinoxalinyl, pyrazolyl, thiazolyl, thiadiazolyl, benzoxazoly!, imidazopyraziny], or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyi, cyano, aikyl carboxylate, alkoxy, or halo; and n is 0 or 1 ,
Enantiomers and diastereomers of the compounds of Formula 1A are also within the scope of the invention. Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of Formula IA, as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula IA. Also contemplated within the scope of the embodiments provided herein are isotopic variants of compounds of Formula IA, such as, by way of example, deuterated compounds of Formula IA.
In certain of these embodiments, X is CRe and Y is CR7.
In other of these embodiments, X is CRe and Y is N.
In still other of these embodiments, X is N and Y is CR7.
In those embodiments wherein X is CRe, for example those embodiments wherein X is C -6 and Y is CR? or X is CRe and Y is N, R^ is H. Alternatively, R is alky], for example, Ci-ealkyl such as methyl or ethyl.
In other of these embodiments, ¾ is alkoxy, for example, Ci^alkoxy such as methoxy or ethoxy.
In still other of these embodiments, Re is OH.
In yet other of these embodiments, Re is halo, preferably , any one of F, CI, or Br.
In those embodiments wherein X is CRe, for example those embodiments wherein X is CR-6 and Y is CR? or X is CRe and Y is N, R is triazolyl with 1 ,2,3-triazoiyf being preferred. The triazolyl can be attached through any available atom. In preferred embodiments, the 1,2,3- triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3- triazolyl is attached through the 1 -position nitrogen atom.
In those embodiments wherein X is CRe, for example those embodiments wherein X is C e and Y is CR7 or X is CR and Y is N, Re is oxazolyl, which can be attached through any- available atom. In some embodiments, the oxazolyl can be substituted with with alkyi, for example, C;-ealkyl such as methyl.
In those embodiments wherein X is CRg, for example those embodiments wherein X is C e and Y is CR? or X is CRe and Y is N, is oxadiazolyl, which can be a 1,2,3-oxadiazo!yl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1 ,2,4- oxadiazolyl. The oxadiazolyl can be attached through any available atom. In some
embodiments, the oxadiazolyl can be substituted with with alkyi, for example, Ci-ealkyi such as methyl.
In those embodiments wherein X is CRe, for example those embodiments wherein X is
CRe and Y is CR? or X is CRe and Y is , Re is pyrazolyl, which can be attached through any available atom. In some embodiments, the pyrazolyl can be substituted with one or two alkyi, for example, Ch lky! such as methyl.
In those embodiments wherein X is CRe, for example those embodiments wherein X is CRe and Y is CR? or X is CRe and Y is , Re is thioplienyi, which can be attached through any available atom.
In those embodiments wherein X is CRf,, for example those embodiments wherein X is CRe and Y is CR? or X is CRe and Y is , R6 is pyridyi, which can be attached through any available atom. In some embodiments, the pyridyi. can be substituted with one or more alkyi, for example, Cj-eafkyl such as methyl. One exemplary substituted pyridyi is methyl-pyridyl.
In those embodiments wherein X is CRe, for example those embodiments wherein X is CRe and Y is CR? or X is CRe and Y is , Re is pyrimidinyl, which can be attached through any available atom. In other embodiments, e is pyraz nyl, which can be attached through any available atom. In still other embodiments, e is pyridazinyl, which can be attached through any available atom.
In preferred embodiments wherein Y is CR?, for example, those embodiments wherein X is CRe and Y is CR? or X is N and Y is CR?, R7 is H. In other embodiments, R? is alkyi, for example, Cj-ealkyl such as methyl or ethyl.
In those embodiments wherein Y is CR?, for example, those embodiments wherein X is CRe and Y is CR? or X is N and Y is CR?, R7 is alkoxy, for example, Cj-ealkoxy such as methoxy or ethoxy. In other embodiments, the alkoxy is substituted with, for example, one or more halo. One preferred substituted alkoxy is difluoromethoxy.
In those embodiments wherein Y is CR?, for example, those embodiments wherein X is CRe and Y is CR? or X is N and Y is CR.?, R is halo, preferably one of F, CI, or Br.
In some embodiments, X is Re and Y is CR?.
In other embodiments, X is CRe and Y is NR?.
In other embodiments, X is CRe and Y is CR?.
In those embodiments wherein X is NRe and Y is CR? or X is CRe and Y is NR?, Re and
R?, together with the atoms to which they are attached, form a 5-membered heteroaryl ring. These 5-membered rings can optionally substituted with alkyl, for example Chalky! such as methyl.
In those embodiments wherein X is N¾ and Y is CR? or X is CRf, and Y is MI;, R<¾ and RT, together with the atoms to which they are attached, form a 6-membered heteroaryl ring. These 5-membered rings can optionally substituted with alkyl, for example d-ealkyl such as methyl.
In those embodiments wherein Y is CR? or NR7, R? and R , together with the atoms to which they are attached, form a 6-membered aryl ring. Alternatively, R7 and R4, together with the atoms to which they are attached, form a 6-membered heteroaryl ring.
In preferred embodiments, R3 is H. In other embodiments, R3 is alkyl, for example,
Cj-ealkyl such as methyl or ethyl.
In other embodiments, R3 is alkoxy, for example, Ci-galkoxy such as methoxy or ethoxy. In some embodiments, ihe alkoxy is substituted with, for example, one or more halo. One preferred substituted alkoxy is difiuoromethoxy.
In some embodiments, R3 is hydroxyalkylene, for example, hydroxyC i-galkylenesuch as
-CH2-OI-I and -CH2CH2-OH. In yet other embodiments, R3 is OH.
In other preferred embodiments, R3 is halo, preferably any one of F, CI, or Br.
In still other embodiments, R3 is phenyl. In some embodiments, the phenyl can be substituted with one or more halo, for example, phenyl substituted with at least one of F, CI, or Br.
In certain embodiments, R3 is triazolyl, with 1,2,3-triazoly! being preferred. The triazolyl can be attached through any available atom. In preferred embodiments, the 1, 2,3 -triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3-triazoiyl is attached through the 1 -position nitrogen atom.
In yet other embodiments, R. is oxazolyi, which can be attached through any available atom, preferably attached through the 2-position carbon. In some embdoiments, the oxazolyi can be substituted with alkyl, for example, a Ch lky! such as methyl.
In other embodiments, R.3 is isoxazolyl, which can be attached through any available atom. In some embodiments, the isoxazolyl can be substituted with alkyl, for example, a Ci_6alkyl such as methyl.
In other embodiments, R3 is oxadiazolyl, which can be a 1,2,3-oxacliazoiyL
1 ,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, or 1 ,3,4- oxadiazolyl. Preferably, the oxadiazolyl is 1 ,2,4- oxadiazolyl The oxadiazolyl can be attached through any available atom. In some embodiments, the oxadiazoiyi can be substituted with with alkyl, for example, Cj-e lkyl such as methyl.
In still other embodiments, R3 is pyridyl, which can be attached through any available carbon atom, in some embodiments, the pyridyl can be substituted with with one or more alkyl, for example, Ci-ealkyl such as methyl.
In other embodiments, R3 is pyrazolyl, which can be attached through any available atom. In some embodiments, the pyrazolyl can be substituted with with one or two alkyl, for example, Ci_6alkyl such as methyl.
In certain embodiments, 3 is pyrimidinyl, which can be attached through any available carbon atom. In other embodiments, R.3 is pyrazinyi, which can be attached through any available carbon atom, in yet other embodiments, R3 is pyridazinyl, which can be attached through any available carbon atom.
In other embodiments, R3 is piperazinyl which can be attached through any available atom. In some embodiments, one or both nitrogen atoms of the piperazinyl may be substituted with H or alkyl, for example, Ci -ealkyi such as methyl.
In still other embodiments, R3 is morpholinyl, which can be attached through any- available atom. In some embodiments, the nitrogen atom of the morpholinyl may be substituted with H or alkyl, for example, Ch lky 1 such as methyl.
In yet other embodiments, R3 is pyrrolidinyl, which can be attached through any available atom. In some embodiments, the nitrogen atom of the pyrrolidinyl may be substituted with H or alkyl, for example, Ci-salkyl such as methyl.
In other embodiments, R.3 is dialkylamino, for example, dimethylamino, diethylamino, or methyl ethylamino .
In other embodiments, R3 is pyrazolyl, which can be attached through any available atom, In some embodiments, the pyrazolyl can be substituted with with one or two alkyl, for example, Ci-ealkyl such as methyl.
In still other embodiments, R3 is thiophenyl, which can be attached through any available carbon atom.
In preferred embodiments of the invention, R4 is H. In other embodments, R is alkyl, for example, Cj-ealkyl such as methyl or ethyl. In still other embodiments, R4 is alkoxy, for example, Ci-ealkoxy such as methoxy or ethoxy. In yet other embodiments, R4 is halo, preferably, any one of F, CI, or Br.
In some embodiments, R¾ and R4, together with the atoms to which they are attached, form a 6-membered aryi ring. In other embodiments, R¾ and R , together with the atoms to which they are attached, form a 6-membered heteroarylaryl ring.
In preferred embodiments of the invention, R5 is a heteroary] ring. In some of such embodiments, R5 is a heteroaryi optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, cyano, alkyl carboxylate, aikoxy, and halo. A ccording to some embodiments of the invention, R5 is pyridyl, which can be attached through any available atom, optionally substituted with a one or two subsiituenis independently selected from the group consisting of alkyl, aikoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.
According to some embodiments of the invention, R5 is pyrimidinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, aikoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl. In other embodiments, alkyl is dilialoalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R$ is pyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is pyridazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is qumazolmyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl. In other embodiments, aikyl is dihaloalkyi, e.g., difluoromethyi or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, 5 is qumoxaiinyi, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo. In some
T7 embodiments, aikyl is irihaloaikyl, for example trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is pyrazolyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyi is irihaloaikyl, for example trifluoromethyl. In some embodiments, the pyrazolyl is methyl- pyrazolyl substituted with trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is benzoxazolyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is irihaloaikyl, for example trifluoromethyl. In other embodiments, alkyi is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is imidazopyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is irihaloaikyl, for example trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is triazolopyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, alkoxy, or halo. In some embodiments, aikyl is Irihaloaikyl, for example trifluoromethyl. In other embodiments, aikyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is thiazolyl which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is irihaloaikyl, for example trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
According to some embodiments of the invention, R5 is thiadiazolyl which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of aikyl, alkoxy, or halo. In some embodiments, alkyl is irihaloaikyl, for example trifluoromethyl. In other embodiments, alkyl is dihaloalkyi, e.g., difluoromethyl or monohaloalkyl, e.g., monofluoromethyl.
In some embodiments of the invention n is 0, In other embodiments, n is 1. The 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 to the subject a compound of the invention. In some embodiments, the compounds described herein are selective for orexin- 1 receptor activity. In some embodiments, the compounds described herein are selective for orexin- 1 receptor activity over orexin-2 receptor activity.
Diseases, disorders, and conditions mediated by orexin receptor activity include disorders of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, sleep disorders secondary to neurological disorders, mania, depression, manic depression, schizophrenia, pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity, or conditions related to overweight or obesity, insulin resistance, type II diabetes, hyperiipiclemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea gastroesophageal reflux, mood disorders, posttraumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.
Compounds of the in vention are particularly suited for the treatment of mood disorders, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.
In one aspect, compounds of the invention are particularly suited 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, compounds of the invention are suitable for the treatment of post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse (e.g., morphine abuse, cocaine abuse, alcohol abuse and the like). It will be understood that certain disorders such as, for example, depression and/or schizophrenia and/or substance abuse and/or cognitive impairments also have elements of anxiety and/or panic and/or stress associated with them and the treatment of such conditions and/or combinations of conditions are also contemplated within the scope of embodiments presented herein. In some embodiments, advantageously, compounds of the invention treat a mood disorder (e.g., anxiety) with reduced concomitant sedation and/or with reduced effect on sleep (e.g. attenuated arousal effects). In one embodiment, compounds of the invention are particularly suited for the treatment of anxious depression. In another embodiment, compounds of the invention are particularly suited for the treatment of panic, schizophrenia, and substance abuse.
Sleep disorders include, but are not limited to, sleep-wake transition disorders, insomnia, restless legs syndrome, jet-lag, disturbed sleep, and sleep disorders secondary to neurological disorders (e.g., manias, depressions, manic depression, schizophrenia, and pain syndromes (e.g., fibromyalgia, neuropathic) .
Metabolic disorders include, but are not limited to, overweight or obesity and conditions related to overweight or obesity, such as insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, 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, catatonia, anxiety, delirium and dementias.
In treatment methods according to the invention, a therapeutically effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. A "therapeutically effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., 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 subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a le vel at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate ievel, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. In addition, the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with a compound of the invention or included with such an agent in a pharmaceutical composition according to the invention, in an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
The compounds of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one compound in accordance with the invention; and (b) a pharmaceutically acceptable excipieni.
Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.
For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0,05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
Oral tablets may include a compound according to the invention mixed with
pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative 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, poiyviny!-pyrrolidone (PVP), sodium starch giycolate, microerystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi- solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides 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 before use. Such liquid compositions may optionally contain:
pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyleeiJuiose, earhoxymethylceliulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; presereatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid): wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
The active agents of this invention may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. 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 parenteral!}' acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minuie of compound, admixed with a pharmaceutical carrier o ver a period ranging from several minutes to several days. For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.
Compounds of the invention may al ternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.
The synthesis of exemplary intermediates
Figure imgf000034_0001
formula
(R1R2A)C02H, is show n in Schemes 1-6 below, and also in the Examples section
(Intermediates A- l to A- 1 ).
Scheme 1
Figure imgf000034_0002
Intermediate compounds of formula (Ilia) and (Illb) can be prepared as outlined in
Scheme 1 from commercially available or synthetically accessible compounds of formula (A) where R¾, R , are defined in formula (IA) as above, or Rj is H, Rj is analogous to R2 in Formula I as above, and X and Y are independently selected from C and N. Compounds of formula (Ila) and (lib), are obtained by reacting a compound of formula (A), with commercially available 1,2,3-triazole, in the presence K. C 'Q ; in DMF or dioxane, at temperatures ranging from about 60 °C to about 100 °C, Compounds of formula (Ilia) and (Illb) are obtained by reacting compounds of formula (II) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from 80 °C to 100 "C. One skilled in the art will recognize that 1 ,2,3-triazole can exist in two tautomeric forms defined as 2.H-[L2,3]triazole and lH-[l,2,3jtriazole thus accounting for the formation of (ilia) and (nib).
Scheme 2
Figure imgf000035_0001
(iVa) W is CN (Va) W is CM
[iVb) W is C02Alkyi (Vb) W is C02Alkyl
(iVc) W is C02H (II !) W is C02H
Intermediate compounds of formula (III) can be prepared as outlined in Scheme 2 from commercially available or synthetically accessible compounds of formula (IVa_j. Compounds of formula (III), (Va.) and (Vb) are obtained by reacting compounds of formula (IVa), (IVb) and (IVc) where Hal is -Br, or -I; W is C02H, C02Alkyl, or CN and R3 and R4 are ~H,
halo,
Figure imgf000035_0002
and R3 and R4 together with the atoms to which they are attached form a 6- membered and or 6 membered heteroaryl ring, or R3 is H, R4 is analogous to R2 in Formula I as above, and X and Y are independently selected from C and N, with commercially available 1,2,3-triazole, in the presence of, for example, copper(I)iodide, C82CO3 and trans- ,N'- dimethyl-l,2-cyclohexanediamine in, for example, DMF or dioxane, at temperatures ranging from about 60 °C to about 120 °C. Compounds of formula (IVc) can be converted to the corresponding esters (Vb) by treatment with, for example, alkyl iodide in the presence of a. base such as K2CO3 in a solvent such as DMF. Compounds of formula (III) are obtained by reacting a compound of formula (Va) and (Vb) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from about 80 °C to about 100 °C. One skilled in the art will recognize that 1 ,2,3-triazole can exist in two tautomeric forms defined as 2H-[l,2,3]triazofe and iiI- L2,3]triazole thus compounds of formula (Va), (Vb), and (III) can also exist as the Nl linked variant (structure not shown). It will be understood that the heterocycle in (Va) and (Vb) is not limited to triazole and may be any other suitable heterocycle. Scheme 3
Figure imgf000036_0001
Intermediate compounds of formula (IX) are prepared as outlined in Scheme 3 from commercially available or synthetically accessible compounds of formula (VI) where R , ¾, are detmed as in formula IA above, or R3 is H, R4 is analogous to R2 in Formula I as above, and X and Y are independently selected from C and , G is SnBuj or 4,4,5,5 tetramethyl- l,dioxaboralane and Hal is C , or Br, preferably Br in this case. Compounds of formula (VLIl) are obtained by reacting a compound of formula (VI) with commercially available (VTI) in the presence of a catalyst such as 1 , 1 '-Bis(di-tert-but lphosphino)ferrocene palladium dichioride and a base such as Na2COs in a solvent such as 2-MeTHF or THF at temperatures ranging from about 60°C to about 90°C. Compounds of formula (IX) are obtained by reacting a compound of formula (VIII) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80°C to about 100°C or acids such as H2S0 in solvents such as H20 at temparatures ranging from about 80 to about 100 °C. It will be understood that the heterocycle in (VII) is not limited to pyrimidine and may be any other suitable heterocycle.
Scheme 4
Figure imgf000036_0002
Intermediate compound (XIV) is prepared as outlined in Scheme 4 from commercially available compound (X). Compounds (XI) is obtained by reacting compound (X) with commercially available acrolem in a solvent such as 1,4 dtoxane at temperatures of about 200"C in a microwave reactor. Compound (XII) can be prepared from compound (XI) by treatment with an acid such as HBr in a solvent such as toluene at a temperature of about 90°C. Compound (XIII) can be obtained by treatment of compound (XII) with commercially available iodoethane and a base such as K2COj in a solvent such as DMF at temperatures ranging from about 45°C to about 65°C. Compound (XIV) is obtained by treating compound (XIII) with a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80°C to about 100°C.
Scheme 5
Figure imgf000037_0001
Intermediate compounds of formula (XVI) are prepared as outlined in Scheme 5 from ornmercially available or synthetically accessible compounds of formula (XIV) where 2 is -H, - Ci-4alkyl,or
Figure imgf000037_0002
Compounds of formula (XV) are obtained by reacting a compound of formula (XIV) with commercially available (VII) in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as Na2C0 in a solvent such as 2-MeTHF at temperatures ranging from 75°C to 150°C. Compounds of formula (XVI) are obtained by reacting a compound of formula (XV) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80°C to about 100°C.
Scheme 6
Figure imgf000037_0003
(XX) (XXI) Intermediate compounds of formula (XXI) can be prepared as outlined in Scheme 6 from commercially available or synthetically accessible compounds of formula (XVII) where Hal is Br or I; and where R3 is H, R is analogous to R2 in Formula I as above, and X and Y are independently selected from C and N. Compounds of formula (XVIIIa) can be converted to the corresponding ester (XVIIIb) by treatment with thionyl chloride in a solvent such as MeOH. Compounds of the formula (XX) are obtained by reacting compounds of formula (XVL!lb) with commercially available compounds of the formula XIX where L is a heterocyle such as pyrazole, pyridyl, or oxazole; G is SnBun or 4,4,5,5 tetramethyl- l,dioxaboralane and RJ A and R2A are -H,■■ alkyJ.or -alkoxy; or R!A and R2A are -H, halo, -C j alkyl,or
Figure imgf000038_0001
in the presence of a catalyst such as Pd(Prt3P)4 and a base such as Na2COs in a mixture of solvents such as DME and H20 at temperatures ranging from 100°C to 150"C. Compounds of formula (XXI) are obtained by reacting a compound of formula (XX) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 8(f C to about 10Q°C,
Scheme
Figure imgf000038_0002
Intermediate compounds of formula (XXIV) and (XXVII) are readily prepared as outlined in Scheme 7 from commercially available or synthetically accessible compounds of formula (XXII) or (XXV). Compounds of formula (ΧΧΠί) can be obtained from compounds of formula (XXII) as described in the references listed in Scheme 7. Compounds of formula (XXIV) can be obtained from compounds of formula (XXIII) by treatment with reducing agents such as Dibai-H, L1AIH4 or L1BH4 in solvents such as THF or diethyl ether at temperatures ranging from about 0 °C to about 70 °C, Compounds of formula (XXVI) can be obtained from compounds of formula (XXIII) by treatment with bases such as aqueous sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such as water, methanol or THF.
Compounds of formula (XXVI) can also be obtained from compounds of formula (XXV) using procedures described in WO 2004074292.
Scheme 8
Figure imgf000039_0001
{±)■ (-)-(XXVII)
Referring to Scheme 8, where PGi is a Boe protecting group, compounds of formula ( (XXV11) were resolved into individual enantiomers of formula (+)-(XXVII) and (-)-(XXVII) using SFC chromatography on a chirai SFC (CHIRALPAK IC 5 μΜ 250 X 20mm) column using 80% CO2/20% PrOH as the mobile phase.
Scheme 9
Figure imgf000039_0002
'xxviin Referring to Scheme 9, where PGj is a Boc protecting group, compounds of formula
(XXVIII) are prepared compounds of formula · :····: XX iX i. Compounds of formula (XXVIII) are readily prepared from compounds of formula ΧΧΥΙ Π by treatment with metal catalyst such as Pt02, Pd/C, or Pd(OH)2 in solvents such as AcOH, MeOH or EtOH under an atmosphere of hydrogen. Compounds of formula (XXIX) are readily prepared from compounds of formula (XXVIII) by reaction with DPPA and TEA in a solvent such as toluene at temperatures ranging from about 0 °C to about 100 °C, preferably about 65 °C for a period of about 1 to 8 hours. BnOH is then added to afford a compound of formula (XXIX). Scheme 10
Figure imgf000040_0001
(XXXV) According to Scheme 10, compound (XXXI) is obtained by reaction of compound
(XXX) with, for example, DPPA and TEA in a sol vent such as toluene at temperatures ranging from about 0 °C to about 100 °C, preferably about 65 °C for a period of about 1 to 8 hours, preferably about 4 h. Benzyl alcohol (BnOH) is then added to afford a compound of formula
(XXXI) . Compound (XXXII) is obtained from compound (XXXI) by reaction with trimethylphenyl ammonium tribromide at temperatures ranging from about 0 °C to about 23 °C, preferably about 0 °C for a period of from 2 to 6 hours, preferably about 4 hours. Compound (ΧΧΐΐΙ) is obtained from compound (XXXII) by treatment with a base, preferably NaH in a solvent such as DMF. Compound (XXXIV) is obtained from compound (XXXIII) by elimination of HBr with tBuOK in a solvent such as THF for a period ranging from 2 to 24 hours. Compound (XXXV) is obtained from compound (XXXIV) by hydroboration oxidation by treating the compound (XXXIV) with borane in a solvent such as THF at temperatures ranging from about 0 °C to about 2.3 °C, preferably at about 23 °C, for 2. to 12. hours, preferably about 2 hours followed by reaction with, for example, hydrogen peroxide in the presence of a base such as sodium hydroxide. Also contemplated within the scope of embodiments presented here are other nitrogen protecting groups which are known to one skilled in the art. Scheme 10-A
Figure imgf000041_0001
(XXXSV) (XXXV) Certain variations of Scheme 10 are described in Scheme 10-A above. It will be understood that the protecting group in compound (XXXI) may be varied as shown in Scheme 10-A, for example, by adding any other suitable alcohol. An alcohol such as BnOH or preferably tBuOH is added to afford a compound of formula (XXXI). Additionally, the protecting group in a compound of formula (XXXI) can be exchanged utilizing standard methods, for example, from BOC to TFA. It will be further understood that the base utilized for the conversion of compound (XXXII) to (XXXIII) may be varied as sho wn in Scheme 10-A. Compound (XXIII) is obtained from compound (XXXII) by treatment with a base, such as NaH or preferably K2CO3 is a solvent such as DMF or preferably toluene at temperatures ranging from about 0 °C to about 100 °C with or without a protecting group present. Further, the choice of the protecting group and/or base and or solvents and/or reaction temperatures will vary depending on the reaction substrate and ail such variations are contemplated within the scope of embodiments provided herein.
Scheme 1 1
Figure imgf000042_0001
(XL) (XLi)
Referring to Scheme 1 1, one skilled in the art would recognize that compounds of formula (XLI) may be obtained from compounds of formula (XXXVI) by converging pathways. In one sequence, a compound of formula (XXXVII) is obtained by treating a compound of formula (XXXVI) with R5C1, where R"1 is optionally substituted pyridyl, pyrimidyi, pyrazinyi, pyridazinyl, quinazolinyi, qumoxalinyl, pyrazolyl, benzoxazolyJ, imidazopyrazmyl, triazolopyrazinyl. Commercially available or synthetically accessible suitably substituted heteroaryl compounds of formula R5C1 are reacted with compounds of formula (XXXVI), in the presence of a suitably selected tertiary organic or inorganic base such as NaH, CS2CO3, K2CO3, TEA, iPr2NEt and the like; in a solvent such as DMF, diehlorom.eth.ane, THF, and the like; at a temperature between room temperature and the reflux temperature of the solvent. In a preferred embodiment the base is NaH and the sol v ent is DMF, Remo v al of the feri-butyicarbamate (Boc) in compounds of formula (XXXVH) is accomplished by using methods known to one skilled in the art, such as, HQ, TFA, or /j-toluenesulfonic acid, in a solvent such as CFI3OH, dioxane, or CH?C12. In a preferred embodiment, a compound of formula (XXXVII) is treated with TFA in DCM or HC1 to afford a compound of formula (XXXVIII). A compound of formula (XLI) is obtained by treating a compound of formula (XXXVIII) with (R!R2A)C02H, where R1 is H, alky], alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazoiyl, pyridyl, pyrimidyi, pyrazinyi, pyridazinyl, piperazinyl, pyrazolyl, oxadiazoiyl, pyrrolidinyl, thiophenvi, morpholinyi, or dialkylamino and R2 is H, alk l, alkoxy, or halo. Commercially available or synthetically accessible suitably substituted carboxcylic acid compounds of formula (R^AiCChH are combined with compounds of formula (XXXVIII) using under amide coupling methods known to one skilled in the art, such as, CDl, EDCI, HATU, or T3P in a solvent such as THF, DCM, or DMF In a preferred embodiment, a compound of formula (XXXVIII) and (R'R^CCbH are treated with EDCI in the presence of HOST in DMF at ambient temperature to afford a compound of formula (XLI). One skilled in the art would recognize that compounds of formula (XLI) may also be obtained from compounds of formula (XL). Removal of the ieri-butylearharnate (Boc) in compounds of formula (XXXVI) is accomplished by using methods known to one skilled in the art, such as, HC1, TFA, or p- toluenesulfonic acid, in a solvent such as CH3OH, dioxane, or CH2CI2. In a preferred embodiment, a compound of formula (XXX 1) is treated with TFA in DCM or HCI to afford a compound of formula (XXXIX). A compound of formula (XL) is obtained by treating a compound of formula (XXXIX) with (R1 iA)C02H. Commercially available or synthetically accessible suitably substituted carboxcylic acid compounds of formula (R:R2A)CO?H are combined with compounds of formula (XXXIX) under amide coupling methods known to one skilled in the art, such as, CDl, EDCI, HATU, or T3P in a solvent such as THF, DCM, or DMF
1 7
In a preferred embodiment, a compound of formula (XXXIX) and (R R'A)C02H are treated with EDCI in the presence of HOBT in DMF at ambient temperature to afford a compound of formula (XL). A compound of formula (XLI) is obtained by treating a compound of formula (XL) with R'Cl. Commercially available or synthetically accessible suitably substituted heteroaryl compounds of formula RSC1 are reacted with compounds of formula (XL), in the presence of a suitably selected tertiary organic or inorganic base such as NaH, C82CO3, K2CO3, TEA, iPr2N£t and the like; in a solvent such as DMF, dichloromethane, THF, and the like; at a temperature between room temperature and the reflux temperature of the solvent. In a preferred embodiment the base is NaH and the solvent is DMF to provide compounds of formula (XLI).
Scheme 12
Figure imgf000044_0001
(XL!I) (XLIII) (XL!V)
- PGi
Figure imgf000044_0002
Where n is 0
(XLVI)
and Z is NH
Referring to Scheme 12, compounds of formula (XLVI) were synthesized from compounds of formula (XLII) where PGi is Boc, PG? is Cbz, Z is O or IslH and n is 0 or 1 . PG? was removed when compound of formula (XLII) was treated with, for example, a Pd catalyst such as 10 wt% Pd/C wet Degussa under an atmosphere of H? in a solvent such as EiQH to give compound of formula (XLIII). Compounds of formula (XLIV) were obtained from compounds of formula (XLIII) using compounds of formula (XLVIII) in a suitable solvent such as DMSO or DMF in the presence of a base such as K2CQ3 at a temperature of about 70 °C. Compounds of formula (XLIV) could also be obtained when compounds of formula (XLIII) and (XLVIII) were treated with a Pel catalyst such as Pd(OAc)2, a ligand such as racemic BINAP, a base such as sodium tert-butoxide in a solvent such as toluene at a temperature of about 70 °C. Compound of formula (XLV) were obtained from compounds of formula (XLIV) when treated with an acid such as HC1 in a suitabie solvent such as EiQAc or DCM at room temperature. Compound of formula (XLVI) were obtained from compounds of formula (XLV) using compounds of formula (XLVTT) in a suitable solvent such as DMF or DCM in the presence of a peptide coupling reagent such as HATU or T3P, a base such as DIPEA at a temperature ranging from room temperature to about 45 UC.
Scheme 13
Figure imgf000044_0003
Referring to Scheme 13, compounds of formula (L), where R4 is analogous to R2 of Formuia I above, were obtained from compound of formula (XLIX) using compounds of formula (LI) in a solvent such as DME in the presence of a Pd catalyst such as Pd(PPh3)4, an additive or catalyst such as copper iodide at a temperature ranging from about 120 °C to about 150 °C.
In one group of embodiments, pro vided herein is a compound of Formula I of Examples 1-482. with structures and names as set forth in the Examples section below. In another group of embodiments, provided herein is a compound of Formula I of Examples 1 -367 with structures and names as set forth in the Examples section below. In yet another embodiment, provided herein is a compound of Formula I of Examples 368-482 with structures and names as set forth in the Examples section below. In an additional embodiment, provided herein is a compound of Formula IA of Examples 483-495 with structures and names as set forth in the Examples section below. In one group of embodiments, provided herein is a compound of Formula I having structures and names as set forth in Table 2 below.
EXAMPLES
Abbreviations
Term Acronym
Acetic Acid HOAc
Acetonitrile ACN
Apparent app
Aqueous „aq
Atmosphere aim
2~(lH-9-Azobenzotriazole-l-yl)- l, l,3,3-tetrameihyIaminium
HATU
hexafluorophosphaie
0-(Benzotriazol- 1 -y\)~N,N,N', N'-tetramethyluroniura
HBTU
nhexafluorophosphate
I-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDCI
Hydroxybenzotriazole HOBt
Benzyl Bn
2,2'-bis(diphenylphosphino)-l , i '-binaphthalene BINAP
[l, -Bis(di-ieri-butylphosphino)ferrocene]dichloropalladium(II) PdCl2(dtbpf)
Broad br
teri-B utylcarbamoy 1 Boc/Boc
Dichloromethane DCM
Diisopropylethylamine DIPEA
1 ,2-Dimethoxy ethane DME
N,iV-Dimethylformamide DMF
Dimethylsulfoxide DMSO Term Acronym
Doublet d
Electrospray ionization ESI
Enantiomeric excess ee
Ethanoi EtOH
Ethyl Acetate EtO Ac, or EA
Grams _£
Hertz Hz
High-pressure liquid chromatography HPLC
Hours h
Liquid chromatography and mass spectrometry LCMS
Mass spectrometry MS
Mass to charge ratio mix
Methanol MeOH
Microliter μΕ
Milligrams mg
Milliliter mL
Millimofes mmol
Minute min
Molar M
Multipiet m
Normal N
Nuclear magnetic resonance NMR
Palladium on carbon Pd/C
Palladium hydroxide on carbon Pd(OH)2/C
Parts per million ppm
Phenyl Ph
Propylphosphonic anhydride T3P
Retention time Rt
Room temperature rt
Quartet q
Singlet s
Supercritical Fluid Chromatography SFC
Temperature T
Thin layer chromatography TLC
Times X
Triethylamine TEA
Trifluoroacetic acid TFA
Triplet t
Diphenylphosphoryl azide DPPA
Diisopropyl azodicarboxylate DIAD Chemistry:
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 stated, reaction mixtures were magnetically stirred at room temperature
(it) under a nitrogen atmosphere. Where solutions were "dried," they were generally dried over a drying agent such as Na2S04 or MgS04> filtered and concentrated. Where mixtures, solutions, and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage nitiator or CEM Discover instrument.
Melting point determinations were performed in open capillary tubes on a FP62 or MP50 apparaiits (Mettler-Toledo). Melting points were measured with a temperature gradient of 10 °C/minute. Maximum temperature was 300 °C. The melting point was read from a digital display.
Normal-phase flash column chromatography (FCC) was performed on silica gel (Si02) using prepackaged cartridges, eluting with the indicated solvents.
Where compounds were purified by "Prep HPLC" the method employed was either: Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Gilson HPLC with an Xterra Prep RPi g (5 μιη, 30 x 100 mm, or 50 X 150 mm) column, and a gradient of 10 to 99% acetonitiile/water (20 rnM NH4QH) over 12 to 18 min, and a flow rate of 30 mL/min.
or
Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1 00 Series HPLC with an XBridge C I 8 column (5 urn, 30 x 1 00mm), mobile phase of 5%ACN in 20mM NH40H (hold for 2min) then ramp 5-99% ACN over 15 min, hold at 99% ACN for 5 min. and a flow rate of 40 mL/min.
or
Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1 1 00 Series HPLC with an XBridge C I 8 column (5 μχα, 50 x 100mm), mobile phase of 5%ACN in 20mM NH40H (hold for 2min) then ramp 5-99%ACN over 15 min, hold at 99% ACN for 5 min. and a flow rate of 80 mL/min.
or
Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Gilson HPLC with an Xterra Prep RP] g (5 μηι, 30 x 100 mm, or 50 X 150 mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH4OH) over 12 to 18 niin, and a flow rate of 30 mL/min.
Where compounds were purified by "Agilent Prep Method X" the method employed was either:
Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1 100 Series HPLC with an XBridge C18 OBD column (5 urn, 30 x 100mm), mobile phase of 5% ACN in 20mM NH4OH was held for 2 min, then a gradient of 5- 99% ACN over 15 min, then held at 99% ACN for 5 min, with a flow rate of 40 mL/min.
or
Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1 100 Series HPLC with an XBridge C18 OBD column (5 μτη, 50 x 100mm), mobile phase of 5% ACN in 20mM NH OH was held for 2min, then a gradient of 5- 99% ACN over 15 min, then held at 99% ACN for 5 min, with a flow rate of 80 mL/min.
Analytical chromatography data was acquired using an Agilent 1 100 HPLC, with an inertsil ODS-3 3mm 4.6 x 50mm column, purchased from GL Sciences (Part # 1010L050W046). Samples were run using a gradient profile of 10 - 99% acetonitrile (ACN) in water, each containing 0.05% trifiuoroaeetic acid (TFA) over 1.6 minutes, then holding at 99% acetonitrile for 0.3 minutes. Flow rate was 5 mL/min and column temperature was set to 50 °C (Method A), Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (eaicd.) mass corresponds to the exact mass.
Nuclear magnetic resonance ( MR) spectra were obtained on Broker model DRX spectrometers. The format of the 1H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration). Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, m = multiplet, br = broad. For compounds that are present as a mixture of rotamers the ratio is represented so that the total is 1, e.g. 0.80:0.20. Alternatively, 1H NMR data may be reported for only the major rotamer as indicated, or the data may be reported for one or more rotamers such that the total is less than 1. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.
Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp., Cambridge, MA) or ACD Name Version 10.01 (Advanced Chemistry). Where compounds were purified by "SFC Chromatography" the method employed was either:
on preparative APS 1010 syste with autoprep otion from Berger instrument, consisted of two varian SD- 1 pumps (walnut creek, CA, USA), one of which was extensively modified to pump CO?, a special pump head heat exchanger, a julabo FT 401 chiller (iabortechnik GmbH, Sellback, Germany), a model SCM 2500 phase separator (berger instruments) with selection valve and set of collection vessels in a Bodan robot. A model Knauer 2500 UV detector with high pressure flo cell (berlin, germany). Samples were applied using a six-port injection valve (Valco, Houston, TX, USA)) with a 5 mi sample loop and a model YP-300 syringue pump (cavro, san Jose, CA).
or
On a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Modifier was pump with a model K1800 Knauer (Berlin, germany), with 100ml Pump Head. The CO?, was pump with 2. iewa pumps (Leonberg Germany). Cooling of the pump head and the C02 line was achieved by a coil alimented by a Huber chiller (Offenburg / Germany). Sample injections were made using 6 switching valves (Valco, Houston, TX, USA) and a 5 ml sample loop. The system is managed by a PLC automation system.
Examples 301 , 307, 313, 31 9, 321 -367, 396, 464-482, and 483-495 are suitable for preparation using methods analogous to the methods described in the synthetic schemes and in the Examples section.
Intermediates
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Synthesis of 3-fluoro-2-(pyrimidin-2-y!)benzoni1xile (Intermediate in the synthesis of interme
Figure imgf000051_0002
To a solution of 3-fluoro-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile (4.98 g, 19.1 mmol) and 2-bromopyrimidine (3.85 g, 23 mmol) in THF (96 mL) was added a2C03 (6 g, 57.4 mmol) followed by water (43 mL). The reaction mixture was degassed with N2 for 10 minutes. PdCkCdtbpf) (374 mg, 0,57 mmol) was added and the reaction mixture was stirred at 80 °C for 5h. The solution was cooled to room temperature and a mixture of EtOAc and water was added. The aqueous was extracted twice with EtOAc and the combined organic layers were dried over MgS04, filtered and evaporated. The title compound was precipitated by dissolving the residue in a minimum amount of EtOAc and then adding hexanes. The solid was filtered, washed with hexanes and dried to afford the title compound (2.46 g, 64%). MS (ESI) mass calcd, for Ci iH6F 3, 199.1; m/z found 200.1 [ M H I TI NMR (400 MHz, Chloroform-d) δ 9.02 - 8.91 (m, 2H), 7.65 (dt, J= 7.7, 1.0 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.51 - 7.43 (m, 1H), 7.41 (t, J = 4.9 Hz, 1H). 19: 5-methyI-3-(2H~ 1 ,2,3-triazol-2-yl)picolinic acid.
Figure imgf000052_0001
Step A: 5~methyl-3-(2H-i,2,3-triazo1~2~yl)picolinonitrile. To 3-bromo-5- methylpicofinonitrile (1.5 g, 7.6 mmol) in DMF (19 niL) was added K2CO3 (1 .2 g, 8.4 mmol) and 2H- l,2,3-triazole (440 μΕ, 7.6 mmol). The mixture was heated to 100 °C for 16 h, cooled to rt and extracted with EtO c (2X). The combined organics were dried (Na2S04) and
concentrated. Purification via silica gel chromatography (5-60% EtOAc in hexanes) gave the title compound (490 mg, 35%) ¾ NMR (500 MHz, CDC13) 8.58 - 8.53 (m, 1 H), 8.29 - 8.24 (m, IH), 7.98 (s, 2H), 2.54 (s, 3H) and 5-methyl-3-(lH-l,2,3-triazol-l-yl)picolinonitrile (387 mg, 27%).
Step B: 5-methyl-3-(2H-l ,2,3-triazol-2-yl)picolinate. To a solution of the the title compound of Step A (489 mg, 2.6 mmol) in EtOH (7 mL) was added 4 N NaOH (660 μΙ_, 2.6 mmol). The mixture was heated at 100°C for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C9H3N4O?., 204.1; m/z found 205.0 [M+H . 0: 5-methyl-3-( 1 H- 1 ,2,3-triazol- 1 -yl)picolinic acid.
Figure imgf000052_0002
Step A: 5-methyl-3-(lH- l ,2,3-triazol- l -yl)picolinonitriie. The title compound was prepared in Intermediate A- 19 Step A. Ή NMR (500 MHz, CDC13) 8.65 (dd, J= 1.8, 0.9 Hz, 1H), 8.41 (d, J = 1.2 Hz, IH), 8.18 - 8.1 5 (m, 1H), 7.95 (d, J = 1.2 Hz, I H), 2.58 (s, 3H).
Step B: 5-methyl-3-(lH- l ,2,3-triazo]- l -yi)picolinic acid. Prepared analogous to
Intermediate A- 19 substituting 5-methyl-3-(2H- l ,2,3-triazol-2-yl)picolinonitrile with the title compound of Step A. MS (ESI) mass eaicd. for C9HSN4O2, 204.1 ; m/z found 205.0 j \ 1 · i 11
Intermediate A-21 : 6-methyl-3-(2H- l ,2,3-triazol-2-yl)picolinic acid.
Figure imgf000053_0001
Step A: 6-methyl-3-(2H- I ,2,3-triazol-2-yl)picolinomtrile. To 3-bromo-6- methylpicoiinomtriie (2.2. g, 1 1 mmol) in DMF (28 mL) was added K2CO3 (1.7 g, 12 mmol) and 2H-l ,2,3-triazole (650 ΐ,, 1 1 mmol). The mixture was heated to 100 °C for 36 h, cooled to rt and extracted with EtOAc. The combined organics were dried (Na2S04) and concentrated.
Purification via silica gel chromatography (10- 100% EtOAc in hexanes) gave the title compound (Ig, 48%).
Step B: 6-methy{-3-(2H~ l ,2,3 riazol-2.-yl)picoiimc acid. To a solution of the the title compound of Step A (730 mg, 4 mmol) in EtOH (10 mL) was added 4 N NaOH (1 ml,, 4 mmol). The mixture was heated at 100°C for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. 22 : 3-ethoxyisoquinoline-4-carboxylic acid.
Figure imgf000053_0002
Step A: ethyl 3-hydroxyisoquinoline-4-carboxyiate. To a suspension of ethyl 3- aminoisoquinoHne-4-carboxylate (583 mg, 2.70 mmol) in 6.8 mL of H2SO4 5N cooled to 0 °C was added sodium nitrite (223 mg, 3.24 mmol, dissolved in I mL of water). The reaction mixture was stirred at 0 °C for 2.5 h and then NaOH(aq, IN was added until pH=7. The aqueous phase was extracted twice with DCM and the combined organic phases were dried over MgS0 , filtered and evaporated to give the title compound of Step A which was used without further purification in the next step (583 nig, 99%). MS (ESI.) mass calcd. for
Figure imgf000054_0001
217.1; m/z found 218.1 [M÷H]+.
Step B: ethyl 3-ethoxyisoquinoline-4-carboxylate. To the title compound of Step A (583 mg, 2,68 mmol) in THF (13 mL) was added triphenylphosphine (1.06 g, 4.03 mmol), ethanol (0.24 mL, 4.03 mmol) and DIAD (0.79 mL, 4.03 mmol). The reaction mixture was stirred at room temperature for 16h and then the solvent was evaporated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound of Step B (498 mg, 76%). MS (ESI) mass calcd. for C14H15NO3, 245.1 ; m/z found 246.1 [M+Hf . Ή N.M.R (500 MHz, Chloroform-d) δ 8.97 (s, I H), 7.91 - 7.82 (m, 2H), 7.65 - 7.60 (m, IH), 7.42 - 7.36 (m, IH), 4.59 - 4.48 (m, 4H), 1.48 - 1.39 (m, 6H).
Step C: 3-ethoxyisoquinoline-4--carboxyiic acid. The title compound of Step B (492 mg, 2 mmol) dissolved in MeOH (15 mL) was added NaOH(aq) 2M (2.5 mL). The reaction mixture was stirred at 60 °C for I6h and then NaOH^ 4M. (2 mL) was added and the mixture was stirred at 70 °C for 4h. MeOH was evaporated and the aqueous phase was cooled to 0 °C and acidified with the addition of HCl(aq) 6N. The solid was filtered, washed with cold water and dried to afford the tilte compound (285 mg, 65%). MS (ESI) mass calcd. for C12H11NO3, 2.17.1 ; m/z found 218.1 j VI · Π ; Ti NMR (400 MHz, DMSO-d6) δ 13.36 (s, IH), 9.15 (s, Hi), 8.13 - 8.06 (m, IH), 7.82 - 7.70 (m, 2H), 7.54 - 7.47 (m, IH), 4.50 (q, J - 7.0 Hz, 2H), 1.35 (t, J= 7.0 Hz, 3H). (difluoromethoxy)-2-(2H- 1 ,2,3-iriazol-2-yl)benzoic acid
Figure imgf000054_0002
Prepared analogous to Intermediate A- 19 substituting 2-bromo-6-methyl-3-(2H- 1,2,3- triazol-2-yl)pyridine with 4-(difluoromethoxy)-2-fluorobenzonitrile.
Intermediate Name Structure Reference
Prepared according
3-methyl-2-(2H- to WO
A-24 l ,2,3-triazol-2- 201 1/050198 yJ)benzoic acid
Intermediate 82
O Prepared according
4-fiuoro-2- to WO
A-25 (pyrimidin-2- 201 1/050198 yl)benzoic acid
Intermediate 87
O -26: 3-methyf-2~(pyrimidin-2~yl)benzoic acid
Figure imgf000055_0001
Step A: methyl 3-methyl-2-(pyrimidin-2-yl)benzoate. In a microwave vial was dissolved methyl 3-methyl-2-(4,4,5,5-tetramethyi- l,3,2-dioxaboroian-2-yi)benzoate (619 mg, 2.24 mmoi) and 2-chloropyrimidine (314 mg, 2.69 mmol) in 2-MeTHF (10 mL). Na2COs (713 mg, 6.73 ramol) was then added followed by water (3.4 ml.,) and the reaction mixture was degassed with N2 for 45 minutes. Pd(dppf)Cl2 (66 mg, 0.09 mmoi) and the reaction mixture was heated at 75 °C for 28h. More Pd(dppf)Cl2 (33 mg, 0.045 mmol) was added and the reaction mixture was heated at 150 °C for 3.5h. The mixture was fsitered through a pad of celite and rinsed with EtOAc and water. The layers were separated and the aqueous was extracted once with EtOAc. The combined organic layers were dried over MgS04, filtered and evaporated. The crude was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (1 16 mg, 23%). MS (ESI) mass calcd. for &3Ηι2Ν202, 228.1 ; m/z found 229.1 [M+H]+. Ή NMR (500 MHz, CDC13) 8.95 - 8.76 (m, 2H), 7.99 - 7.75 (m, III), 7.50 - 7.44 (m, ill), 7.43 - 7.37 (m, H ), 7.32 - 7.24 (m, IH), 3.64 (s, 3H), 2.15 (s, 3H).
Step B: 3-methyl-2-(pyrimidin-2-yl)benzoic acid. Prepared analogous to intermediate A- 31 step B to give title compound. MS (ESI) mass calcd. for Ci2HioN202, 214.1 ; m/z found 215.1 i \) H I
Figure imgf000055_0002
Intermediate A-28: 2-methoxy-6-(pyrimidin-2-yl)benzoic acic
Figure imgf000056_0001
Step A: Methyl 2~methoxy-6-(pyrimidin-2-yl)benzoa.te. In a microwave vial was dissolved methyl 2-methoxy-6-(4,4,5,5-tetramet yl-l,3,2-dioxaborolan-2-yl)benzoate (500 sng, 1.71 mmol), commercially available from Combi-Blocks (CAS # 1 146214-77-8), and 2- bromopyrimidine (344 mg, 2.05 mmol) in THF (8.5 mL). Na2C0 (544 mg, 5.14 mmol) was then added followed by water (4 mL) and the reaction mixture was degassed with >½ for 10 minutes. PdCl2(dtbpf) (45 mg, 0.069 mmol) was then added and the reaction mixture was heated at 80 °C for 4h. The mixture was cooled to room temperature and water and EtOAc added. The reaction mixture was extracted with EtOAc (3*). The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude was purified via silica gel chromatography (0-70% EtOAc in hexanes) to afford the title compound (265 mg, 63%). MS (ESI) mass calcd. for CI JH12N20J, 244.1 ; m/z found 245.1 j V! · Π j I I I NMR (400 MHz, Chloroform-d) 8.78 (d, J 4.9 Hz, 2H), 7.99 (dd, J - 7.9, 0.9 Hz, 1H), 7.49 (t, j - 8.1 Hz, 1H), 7.19 (t, j - 4.8 Hz, 1H), 7.09 (dd, J = 8.3, 0.9 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H).
Step B: 2~metlioxy~6-(pyrimidin~2-yl)benzoic acid. To a solution of the title compound of
Step A (265 mg, 1.09 mmol) in THF (4 mL) was added 2 N NaOH (2 mL). The mixture was heated at 50°C for 72 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C12H10 2O3, 230.1 ; m/z found 231.1 i \) H i . 1 H NMR (500 MHz, DMSO-de) 12.63 (s, Hi), 8.86 (d, J = 4.9 Hz, 2H), 7.77 (dd, J = 7.9, 1.0 Hz, I I I ) . 7.51 (t, J = 8.1 Hz, IH), 7.45 (t, J - 4.9 Hz, IH), 7.25 (dd, J = 8.4, 1.0 Hz, IH), 3.83 (s, 3H). 7-eihoxyqumoline-8-carboxylic acid
Figure imgf000056_0002
Step A: 7-methoxyquinoiine-8-carboxylic acid. In lg separate batches a mixture of 2- amino-6methoxybenzoic acid (i lg, 66 mmol) and acrolein (4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor for 20 min at 200 °C. After combining the reactions, the mixture was concentrated and purified via silica gel chromatography (0-10% MeOH in DCM) to give the title compound (2.8g, 20%). MS (ESI) mass calcd. for C11H19NQ3, 203.1 ; m/z found 204.0 I U ; .
Step B: 7-hydroxyquinoline-8-carboxyiic acid. The title compound of Step A (2.9 g, 14.1 mmol) in HBr (14 mL) was heated at 90 °C for I h. The mixture was then concentrated washed with PhCH3 and used without further purificaition in subsequent steps.
Step C: ethyl 7-ethoxyquinoline-8-carboxylate. To the title compound of Step B (800 mg, 3.9 mmol) and K2C03 (1.4 g, 10.4 mmol) in DMF (15 mL) was added iodoethane (560 jiL, 6.9 mmol). After stimng overnight at rt, the reaction was concentrated and purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound. MS (ESI) mass calcd. for C,4H,5N03, 245.1 ; m z found 246.0 [M+H]"1".
Step D: 7-ethoxyquinoline-8-carboxylic acid. To the title compound of Step C (1.3 g, 5.4 mmol) in THF (22 mL) and H20 (1 1 ml.) wras added Li OH hydrate (675 mg, 16.5 mmol) and MeOH. The mixture was heated at 67 CC for I2h. Additional LiOH hydrate (675 mg, 16.5 mmol) was added and the heating was continued at 70 °C for 1 day. Additional LiOH hydrate (1.4 g, 33 mmol) was added and the heating was continued at 75 °C for 1 day. The reaction was allowed to cool to rt, acidified to pH=3 with IN HQ (aq) and concentrated. Purification via prep HPLC gave the title compound (1 g, 84%). MS (ESI) mass calcd. for C] 2HnN03, 217.1 ; m/z found 21 8.0 [M+H]+. -30: 2-( l ,4-dimethyl- iH-pyrazol-5-yl)-6-methoxybenzoic acid
Figure imgf000057_0001
Step A: Ethyl 2-(l ,4-dimethyl- lH-pyrazol-5-yl)-6-methoxybenzoate. In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 1 ,4-dimethyl-5- (4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2~yl)- lH-pyrazole (377 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2C03 (259 mg, 3.09 mmol) was then added followed by Pd{ P h - (89 mg, 0,077 mmol) and the reaction mixture was degassed with N2 for 1 0 minutes. The reaction mixture was then heated at 100 °C for Ih in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (402 mg, 95%). MS (ESI) mass calcd. for C15H18 2O3, 274.1 ; m/z found 275.2 [M+Hf. 1H NMR (400 MHz, Chloroform-d) 7.45 (dd, J = 8.4, 7.6 Hz, IH), 7.29 (s, IH), 7.04 (dd, J - 8.5, 0.9 Hz, 1H), 6.84 (dd, J - 7.6, 0.9 Hz, IH), 4.07 (qd, J - 7.2, 1.5 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, .·■! ! ). 1 .01 (t, J = 7.1 Hz, 3H).
Step B: 2-(l ,4-dimethyl-lH-pyrazol-5-yi)-6-methoxybenzo c acid. Prepared analogous to intermediate A-28 step B to give title compound. MS (ESI) mass calcd. for C13H14N2O3, 246.1; m/z found 247.2 [M+Hf. ]H NMR (500 MHz, DMSO-de) 7.50 (dd, J - 8.5, 7.6 Hz, IH), 7.25 (s, IH), 7.21 (dd, J = 8.5, 0.9 Hz, IH), 6.85 (dd, J = 7.6, 0.9 Hz, IH), 3.84 (s, 3H), 3.49 (s, 3H), 1.79 (s, 3H). A-31 : 3-methyl-2-(oxazol-2-yf)benzoic
Figure imgf000058_0001
Step A: ethyl 3-methyl-2-(oxazol-2-yl)benzoate. In a microwave vial was dissolved ethyl 2-iodo-3-methyibenzoate (627 mg, 2.16 mmol) and 2-(tributylstannyl)oxazoIe (0.54 mL, 0.07 mmol) in DME (2.59 mL). The solution was degassed with N2 for 5 minutes then Cul (21 mg, 0.11 mmol) and PdfJPPh^ (125 mg, 0.11 mmol) were added. The reaction was purged with N? and heated at 150 °C for Hi. The reaction was cooled to rt, filtered through a pad of eeliie and purified via silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound of step A (333 mg, 67%). MS (ESI) mass calcd. for C ;i l .NO ;. 231.1 ; m/z found 232.1 j \1 H i . U NMR (500 MHz, Chloroform-d) 7.89 - 7.82 (m, IH), 7.79 i d. ./ 0.8 Hz, i l l s. 7.48 - 7.43 (ni, 2H), 7.30 (d, J = 0.9 Hz, 1 H), 4.17 (q, /= 7.1 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).
Step B: 3-methyf-2~(oxazol~2~yl)benzoic acid. To the title compound of step A (166 mg, 0.72 mmol) was added MeOH (7.2 mL) and 1M NaOH(a ) (7.2 mL). MeOH was evaporated and then 1 M HCT(aqj was added. To the solution was added DCM and the aqueous was extracted with DCM (3X). The combined organic layers were dried over MgS04, filtered and evaporated to give the title compound (145 mg). MS (ESI) mass calcd. for C11H9NO3, 203.1; m/z found
204.1 [M+H] r. H NMR (400 MHz, DMSO-de) δ 8.20 fs, IH), 7.79 - 7.68 fm, IH), 7.65 - 7.49 (m, 2H), 7.35 (s, IH), 4.34 (s, IH), 2.20 (s, 3H).
Intermediate A-32: 4-methyl-3-(2H-l,2,3-triazol-2-yl)picolinic acid.
Figure imgf000059_0001
Step A: 4-methyl-3-(2H-l ,2,3-lTiazol-2-yl)picolinonitrile. In a microwave vial was dissolved 2H- l ,2,3-triazole (0.22 mL, 3.8 mmol) and Cu (26 mg) in DMF (4 mL). The reaction mixture was degassed with N2 and 3-bromo-4-methylpicolonitrile (300 mg, 1.5 mmol) was added followed by trans-N,N'-dimethyl- l ,2-cyclohexanediamine (41 μΕ, 0.3 mmol) and Cs^CCh (844 mg, 2.6 mmol). The reaction mixture was heated at 120 °C for lh in a microwave reactor. Then H20 was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSCXs). Purification via silica gel chromatography (0-50% EtOAc in heptane) gave the title compound (1 12 mg, 27%). MS (ESI) mass calcd. for C9H7N5, 1 85.2; m/z found 186
Step B: 4-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picoiinic acid. Prepared analogous to Intermediate A- 19 substituting 5-methyf-3-(2tI- l ,2,3-triazol-2-yl)picolinonitrile with the title compound of Step A. The reaction mixture was acidified to pH=4 before concentrating. MS (ESI) mass calcd. for C11H9NO3, 203.1 ; m/z found 204.1 [M+H] ÷. : 3-(2H- l ,2,3-triazol-2-yl)quinol"ine-2-carboxylic acid
Figure imgf000059_0002
Step A: ethyl 3 -(2H- l ,2,3-triazol-2-yl)quinoline-2-carboxylate. Prepared analogous to Intermediate A-40 Step A substituting 2-brom.o-4-methylbenzoic acid with ethyl 3- iodoquinoline-2-carboxylate (WO 201 1093365) in <10% yield. MS (ESI) mass calcd. for C,4H12 402, 268.3; m/z found 269.0 [M+H] ".
Step B: 3-(2H- i,2,3 riazol~2-yJ)quinoline-2-carboxylic acid. To the title compound of Step A (134 mg, 0.5 mmol) in MeOH (1 mL) was added aqueous 2M NaOH (1 mL). After l h at rt, the reaction was heated to 50 °C for lh, cooled to rt, acidified with IN HC1, concentrated and used in subsequent steps without further purification. MS (ESI) mass caled. for C12HSN4O2, 240.2; m/z found 241.0 ί Π ;
Figure imgf000060_0001
Intermediate A-40: 4-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid.
Figure imgf000060_0002
Step A: 4-methyI-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid and 4-methyl-2-(lH-l,2,3-triazol- l-yl)benzoic acid. In a mscrowave vial was dissolved 2H-l,2,3-triazole (0.34 mL, 5.81 mmol) and Cui (40 mg, 0.21 mmol) in DMF (5 mL). The reaction mixture was degassed with N? for 10 minutes and 2--bromo-4-methylbenzoic acid (500 mg, 2,33 mmol) was added followed by trans- N,N'-dimethy!- l,2-cyc1ohexanediamine (62 L, 0.40 mmol) and CS2CO3 (1.29 g, 3.95 mmol). The reaction mixture was stirred at 100 °C for 20 minutes using a microwave oven before being partitioned between water, HCi(a i (pH=3) and EtOAc. The organic layer was dried over MgSO/i, filtered and evaporated to give the crude product mixture which was used in the next step without any further purification.
Step B: methyl 4-methy3-2-(2H- l ,2,3-triazol-2-yl)benzoate. To the title compound of step A (945 mg, 4.65 mmol) in DMF (28 mL) was added K2C03 ( 1.3 g, 9.3 mmol) and iodomethane (0.3 mL, 4.7 mmol). The reaction mixture was stirred at room temperature for 16h under N2. The solvent was evaporated and the residue was dissolved with a saturated solution of NaHC03. The aqueous phase was extracted with DCM and the organic layer was dried over MgS04, filtered and evaporated. The crude material was purified via silica gel chromatography (0% to 30% EtO Ac/heptane) to afford the title compound (470 mg, 47%).
Step C: Prepared analogous to intermediate A-31 step B substituting ethyl 3-methyi-2-(oxazo3-2- yl)benzoate with the title compound of Step B and used without further purification in subsequent steps.
Figure imgf000061_0002
: 3,6,~dimethy1-[2,3'~bipyridinej-2'-earboxy1ic acid.
Figure imgf000061_0001
Step A: 3-bromo-6-methylpicolmic acid. 'TO 3-bromo~6-methyipicolinonitrile (4g, 20.3 mmol) in EtOH (40 mL) in a sealed tube was added aqueous 4M NaOH ( 15 mL). The reaction was heated at 90 °C for 24h. Additional aqueous 4M NaOH was added and heating continued at 90 °C for 24h. The reaction was cooled to rt, acidified to pH=3 with IN HC1 (aq), concentrated and used without further purification in subsequent steps. MS (ESI) mass calcd. for C7H6Br 02, 216.0; m/z found 218 [ M H I
Step B: Methyl 3-bromo-6-methylpicolinate. To the title compound of step A (10.3 g, 20 mmol) in MeOH (50 mL) was added thionyl chloride (4.4 mL, 60 mmol). The reaction was heated at reflux overnight, cooled to rt and concentrated. Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.9g, 40%). MS (ESI) mass caled. for CsHgBrN02, 230.1 ; m/z found 232 [M+Hf
Step C: 3-methyl-2-(tributy{stannyl)pyridine. To 2-bromo-3-methylpyridine (1.3 mL, 1 1.7 mmol) in THF (35 ml.) at -78 °C was added κ-BuLi (2.5 M in liexanes, 5.6 mL, 14 mmol). After 30 min, tri-«-butyltm chloride (3.8 mL, 14 mmol) was added. After Ih at - 78 °C, the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10% aq KF. The organic layer was dried (MgS04). Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.2g, 27%). MS (ESI) mass calcd. for C] g¾3N8n, 382.2: m/z found 384.0 [ XI I ί 1
Step D: methyl 3,6'-dimethy{-[2,3'-bipyridine]-2'-carboxy{ate. To the title compound of step B (509 mg, 2.2 mmol) and the title compound of step C (1. lg, 2.9 mmol) in PhCH3 (6.6 mL) was added Pd(PPh3)4 (225 mg, 0.2 mmol). The reaction was degassed with ? and heated at 150 °C for 1.5 h using microwave reactor. The reaction was cooled to rt, diluted with H20 and extracted with EtOAc. The organic layer was dried (MgS04). Purification via silica gel chromatography (0- 100% EtOAc in heptane) gave the title compound (101 mg, 18%). MS (EST) mass calcd. for 0|4Η,4 2θ2, 242.3; m/z found 243 [M+Hf.
Step E: 3,6'-dimethyi-[2,3,-bipyridine]-2'-carboxylic acid. Prepared analogous to intermediate A-33 step B substituting ethyl 3-(2H- 1 ,2,3-triazo1-2-yl)quinoline-2-carboxylate with the title compound of step D. MS (ESI) mass calcd. for C13H12N2O2, 228.2; m/z found 229 i v! - ! H 43: 6-metliyl-3-(oxazol-2-yl)p coHn c acid
Figure imgf000062_0001
Prepared analogous to Intermediate A-31 substituting ethyl 2-iodo-3-methylbenzoate with methyl 3-iodo-6-methylpicoimate. MS (EST) mass calcd. for
Figure imgf000062_0002
204.2; m/z found 161
\ Intermediate | Name [ Structure ] Reference ]
Figure imgf000063_0001
intermediate Name Structure Reference
5-methoxy-3-(2H-
WO 2012/145581
A-53 l,2,3-triazol-2-
Intermediate 105 yi)picolinic acid if
0
6-methyl-3-(4-
A-54 methyloxazol-2- yl)picolinic acid
OH
Intermediate A-55: 2-(5-fluoropyrimidin-2-yl)benzoic acic
Figure imgf000064_0001
Step A: 5-fluoro-2-iodopyrimidine. To a solution of 2-chloro-5-fluoropyrimidine (4 mL, 32 mmol) in propionitrile (33 mL) was added chlorotrimethylsilane (12 mL, 97 mmoi) and sodium iodide (15 g, 97 mmol), and the reaction mixture was heated to 150 °C for 1 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature and the solvent removed. The residue was taken up in EtQAc and a solution of saturated aHCO^. The organic layer was dried over MgS04, filtered and evaporated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (2.82. g, 39%).
Step B: 2-(5-fluoropyrirmdin-2-yl)benzonitrile. In a microwave vial was dissolved cyanophenylboronic acid (500 mg, 3,40 mmol) in THF ( 15 mL), and the reaction mixture was degassed with N . Then, the title compound of step A (915 mg, 4.08 mmol), M 2COs (1.08 g, 10.2 mmol), water (5 mL), and PdCl2(dtbpf) (CAS 95408-45-0) (89 mg, 0.14 mmol) were added, and the reaction mixture was stirred at room temperature for I h and then heated via microwave heating to 75 °C for 2 h. The mixture was cooled to room temperature and water and EtQAc added. The reaction mixture was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound (280 mg, 41%). MS (ESI) mass calcd. for C;jH6FN3, 199.1 ; m/z found 200.0 [M+H]+.
Step C : 2-(5-fluoropyrimidm-2-yl)benzoic acid. A solution of the title compound of step B (1.24 g, 6.22 mmol) in H2S04 (6 mL) and water (6 mL) was stirred at 80 °C for 1 h. Then, the reaction mixture was cooled to 0 °C and the aqueous phase extracted with DCM (2X). A solution of 20 M NaOH (1 1 niL) 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 dried over MgS04, filtered and concentrated to afford the title compound (672 mg, 50%). MS (ESI) mass calcd, for Ci 1H7F 2O2, 218.1 ; m/z found 219.1 [M+H] +. intermediate A-56: 2~(5-f!uoropyrimidin~2-yi)-3~methylbenzoic acid.
Figure imgf000065_0001
Step A: Methyl 2-(5-fluoropyr midm-2-yr)-3-methylbenzoate. A solution of methyl 3- methyl-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate (CAS 887234-98-2) (3 g, 1 1 mmoi) in THF (30 niL) was degassed with N2. Then, 2-chloro-5-fluoropyrimidine (1.6 mL, 13.04 mmol), Na2C03 (3.45 g, 32.6 mmol), water (TO mL), and Pd(dppf)CT2 (354 mg, 0.434 mmol) were added, and the reaction mixture was stirred at 100 °C overnight. 'The mixture was cooled to room temperature and water and EtOAc added. The reaction mixture was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated. 'The crude was purified via silica gel chromatography (0-40% EtOAc in hexanes) to afford the title compound (1.07 g, 40%).
Step B: 2-(5-fluoropyrimidm-2-yl)-3-methylbenzoic acid. To a solution of the title compound of Step A (1 .46 g, 5.93 mmol) in MeOH (20 mL) was added 1 M NaOH (12 mL), and the reaction mixiure was stirred at room temperature overnight. The solvent was removed and the crude was diluted with water until pFI = 10. The aqueous layer was extracted with EtOAc. The aqueous layer was further acidified with 12 M HCl(aq) until pH = 2 and extracted writh EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated to afford the title compound (1.19 g, 83%). MS (ESI) mass calcd. for C12H9FN202, 232.1; m/z found 233.1 [M+Hf. Intermediate A-57: 3-fluoro-2-(5-fluoropyrimidin-2-yl)benzoic acid.
Figure imgf000066_0001
Prepared analogous to Intermediate A-55, substituting cyanophenylboronic acid with (2-cyano-6- fluorophenyl)boronic acid (CAS 656235-44-8). MS (ESI) mass calcd. for CnH6F2N202, 236.0; m/z found 237.1 [M÷Hj+. odium 3-chloro-2-(pyriniidin-2-yl)benzoate.
Figure imgf000066_0002
Step A: Methyl 2-(pyrimidin-2-yl)benzoate. Prepared analogous to Example 260 step B substituting 2-(iributylsiannyl)oxazoie with 2-(tributylstannyl)pyrimidine. MS (ESI) mass calcd. for C12H10N7O2, 214.1 ; m/z found 215.1 i vi - l i i . Π N M (500 MHz, CDCI3) δ 8.84■■ 8.78 (m, 2H), 8.06 - 7.99 (m, I H), 7.76 - 7.71 (m, 1 H), 7.60 (td, J = 7.6, 1.4 Hz, 1H), 7.52 (td, J = 7.5, 1.3 Hz, 1H), 7.24 (t, J= 4.9 Hz, 1H), 3.75 (s, 3H).
Step B: Methyl 3-chloro-2-(pyrimidin-2-yl)benzoate. In a microwave vial was combined compound of step A (314 mg, 1.47 mmol), Pd(OAc)2 (49 mg, 0.07 mmol), copper (II) trifiuoroacetate (425 mg, 1.47 mmol) and calcium chloride (651 mg, 5.87 mmol). The vial was capped and acetic acid (21 mL) was added. The reaction mixture was stirred at 1 10 °C for 24h and solvent was evaporated. The residue was taken up in EtOAc and a solution of saturated NaHCOj, The aqueous phase was extracted 3 times with EtOAc and the combined organic layers were dried over MgS04, filtered and evaporated. Purification via silica gel chromatography (0- 40% EtOAc in hexanes) gave the title compound (77 mg, 21%). MS (ESI) mass calcd. for C12H9CTN2O2, 248.0; m/z found 249.1. !H NMR (500 MHz, CDCI3) 5 8.86 (d, J = 4.9 Hz, 2H), 8.00 (dd, J = 7.9, 1.2 Hz, I H), 7.68 (dd, J = 8.1, 1.2 Hz, lH), 7.46 (t, J= 8.0 Hz, 1H), 7.33 (t, J = 4.9 Hz, HI), 3.65 (s, 3H).
Step C: Sodium 3-chloro-2-(pyriinidin~2-yl)berizoa.te. To a solution of compound of step
B (103 mg, 0.42 mmol) in THF (2 mL) was added 3.75M MaOH in water (0.44 mL, 1.66 mmol). The reaction mixture was stirred at 50 °C for 48h and solvent was evaporated. The residue was taken up in water and lyophilized to give the title compound (106 mg, 100%). MS (ESI) mass calcd. for Cj iHyCl yO?., 234.0; m/z found 235.0. Ή NMR (500 MHz, CD30D) δ 8.80 (d, J= 5.0 Hz, 2H), 7.88 (dd, J = 7.7, 1.2 Hz, IH), 7.52 (dd, J= 8.0, 1.2 Hz, IH), 7.48 - 7.38 (m, 2H).
Figure imgf000067_0001
-66: 5-methyi-2-(pyrimidin-2-yl)nicotinic acid.
Figure imgf000068_0001
Step A: Methyl 5-methyl-2-(pyrimidin-2-yi)nicotinate. To a sealed tube containing methyl 2-chloro-5-nietliylmcotmate (CAS 65169-43-9) (745 mg, 4.01 mmol), Cul (38 mg, 0.2 mmol), LiCl (169 mg, 4.01 mmol), and P<¾PPh.3)4 (231 mg, 0.2 mmol) in toluene (15 mL) was added 2-(tributylstannyl)pyrimidine ( 1.5 mL, 4.4 mmol), and the reaction mixture was heated at 120 °C overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over MgS0 , filtered and evaporated. Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (494 mg, 52%). MS (ESI) mass calcd. for α12Η, , 302, 229.1 ; nv'z found 229.99.
Step B: 5-methyl-2-(pyrimidin-2-y])mcotimc acid. To a solution of the title compound of step A (466 mg, 2.03 mmol) in MeOH (10 mL) was added 10 M aOH (1 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude residue was diluted with water and acidified with 6 M HCl(aq) until pH = 3. The aqueous layer was saturated with solid Nad and extracted with 20% e"PrOH in CHCI3 (3X). The combined organic layers were dried over MgS04, filtered and concentrated to afford the title compound (432 mg, 99%). MS (ESI) mass calcd. for C11H9 3O2, 215.1 ; m/z found 216.1 [ M H I H NMR (500 MHz, Methanol^) δ 8.90 (br. s, 2H), 8.64 (br. s, IH), 8.17 (s, I l l s. 7.55 (br. s, IH), 2.51 (s, 3H). : Lithium 5-methyl-3-(pyrimidin-2-yl)picolinate.
Figure imgf000068_0002
Step A: Methyl 5-methy]-3-(pyrimidm-2-yl)picolmate. Prepared analogous to intermediate A-66, step A substituting methyl 2-cbloro-5-methylmcotinate with methyl 3-bromo- 5-methylpicolinate. MS (ESI) mass calcd. for &2Η; ιΝ3θ2, 229.1 ; m/z found 230.0 [ \i · H |
Step B: Lithium 5-methyl-3-(pyrimidin-2-yl)picolinate. To a solution of the title compound of step A (592 mg, 2.58 mmol) in THF (5 mL) was added 4 M LiOH (0.8 mL) and water (1.5 mL), and the reaction mixture was stirred at room temperature for 2.5 h. The solvent was removed and the crude reaction mixture placed under vacuum overnight to give the title compound (591 mg), which was used in the next step without further purification. MS (ESI) mass calcd. for C Η, ;ί Κ 215.1; m/z found 216.1 M+H] ;. :H NMR (500 MHz, Methanol-cU) δ 8.83 i d. ./ 4.9 Hz, 2H), 8.39 (br. s, 1H), 8.23 - 8.18 fm, 1H), 7.38 (t, ./ 4.9 Hz, 1H), 2.44 (s, 3H). 8: 3-fluoro-2-(oxazol-2-yI)benzoic acid.
Figure imgf000069_0001
Step A: 2-bromo-N-(2,2-dimethoxyethyl)-6-f!uorobenzamide. To a solution of 2-bromo-
6-fluorobenzoic acid (2 g, 9.1 mmol) in DMF (27 mL) was added HBTU (5.20 g, 13.7 mmol) and DIPEA (4.7 mL, 27 mnioi), and the reaction mixture was stirred for 10 min. Then, 2,2- dimethoxyethylamine (1.3 mL, 1 1.9 mmol) was added and the reaction mixture stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCC . The combined organic layers were dried over MgSO/i, filtered and concentrated. Purification via silica gel chromatography (0-25% EtOAc in hexanes) gave the title compound (2.3 g, 82%).
Step B: 2-(2-bromo-6-fiuorophenyl)oxazole. To P2Os (6.4 g, 22.6 mmol) was added methanesulfonic acid (52 mL, 801 mmol), and the reaction mixture was stirred at room temperature for 1 h. Then, the title compound of step A (2.3 g, 7.54 mmol) was added to the reaction mixture, and the mixture heated to 140 °C for 2 h. DCM was added and the mixture was slowly poured into a saturated solution of aqueous NaHC(¾ on ice. The mixture was extracted with DCM. The combined organic layers were dried over MgS04, filtered and concentrated. Purification via silica gel chromatography (0-10% EtOAc in hexanes) gave the title compound (1.5 g, 82%). MS (ESI) mass calcd. for C9H5BrFNO, 240.95; m/z found 242.0 [M+H]+.
Step C: Methyl 3-fluoro-2-(oxazol-2-yl)benzoate. A solution of the title compound of step B (2.18 g, 8.99 mmol), Pd(QAc)2 (40 mg, 0.18 mmol), 1,1 '- bis(diphenylphosphino)ferrocene (199 mg, 0.36 mmol), and Et3N (3.7 mL, 27 mmol) in 1 : 1 MeOH/1 ,4-dioxane (36 mL) was degassed with 2 for 15 min. Then, the mixture was stirred at 95 °C under an atmosphere of carbon monoxide overnight. The reaction mixture was diluted with EtOAc and washed with a solution of aHCOs. The organic layer was separated, dried over MgSC>4, filtered, and concentrated. Purification via silica gel chromatography (0-12% EtOAc in hexanes) gave the title compound (1.7 g, 83%). MS (ESI) mass calcd. for Cj jHgF 03, 221.1; m/z found 222.0 [M+H]+.
Step D: 3-fluoro-2-(oxazol-2-yl)benzoic acid. To a solution of the title compound of step C (1.65 g, 7.46 mmol) in MeOH (22 niL) was added 2 M NaOH (7.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1 M HCl(aq) and the solvents evaporated in vacuo. The mixture was diluted with water and extracted with DCM. The combined organic were dried over MgS04, filtered and concentrated to afford the title compound (905 mg, 58%). MS (ESI) mass calcd. for Ci0H6FNO3, 207.0; m/z found 208.0 i V! · ! i I MP = 182 °C.
Intermediate A-69: 5-fluoro-2-(oxazol-2-yl)benzoic acid.
Figure imgf000070_0001
Step A: Methyl 5-fluoro-2-(oxazol-2-yl)benzoate. To a solution of methyl 2-bromo-5- fiuorobenzoate (1.1 g, 4.8 mmol) and 2-(tri-n-butylstannyl)oxazoie (1.3 mL, 6.2 mmol) in toluene (14 mL) was added Pd(PPh3)4 (550 mg, 0.476 mmol), and the reaction mixture was heated via microwave heating to 150 °C for 30 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgS0 , filtered and concentrated. Purification via silica gel chromatography (0-40% EtOAc in hexanes, followed by a second column 0-10% EtOAc in hexanes) gave the title compound (553 mg, 52%). MS (ESI) mass calcd. for C; ;H6FN03, 221.1 ; m/z found 222.1 [M+H .
Step B: 5-fluoro-2-(oxazol-2-yl)benzoic acid. Prepared analogous to intermediate 68, step D, to give the title compound (858 mg, 99%). MS (ESI) mass calcd. for CjoH6FNQ3, 207.0; m/z found 208.1 ; M · Π ;
Intermediate A-70: 2-fluoro-6-(oxazol-2-yl)benzoie acid. o
""V A^OH Prepared analogous to intermediate 68, substituting 2-bromo-6-fluorobenzoic acid with 2-bromo- 3-fluorobenzoic acid. MS (ESI) mass calcd. for CioHeFNOj, 207.0; m/z found 208.0 [M+H]+. 1 : 4-fluoro-2-(3-methyl-l ,2,4-oxadiazo]-5-yl)bei zoic acid.
Figure imgf000071_0001
Step A: 5-(2-bromo-5-fluorophenyi)-3-methyl-l ,2,4-oxadiazofe. To a solution of 2- bromo-5-fluorobenzoyl chloride (2.17 g, 9.13 mmol) in TPIF (18 mL) was added DIPEA (1.7 mL, 10 mmol). Then, acetamide oxime (676 mg, 9.13 mmol) was added portionwise, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with EtOAc and washed with a saturated solution of NaHC03. The combined organic layers were dried over
MgS0 , filtered and concentrated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (2.35 g, 57%). MS (ESI) mass calcd. for CgHeBrFNjO, 255.96; m/z found 257.0 i \I I f !
Step B: 4-f1uoro-2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)benzoic acid. Prepared analogous to intermediate 68, steps C and D, to give the title compound. MS (ESI) mass calcd. for CJ0H7F 2O3, 222.0; m/z found 223.0 [M+H .
Intermediate B-l : (±)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carbox lic acid.
Figure imgf000071_0002
Prepared as described in in WO 2004/074 292 Al . ¾ NMR (CDC13): 4.54 (d, J- ----- 4.6 Hz,
IFF), 4.33 - 4.24 (m, 1H), 2.61 - 2.18 (m, 4H), 1.90 - 1.71 (m, 2ΡΪ), 1.68 - 1.57 (m, IH), 1.56 -- 1.35 (m, 10H).
Intermediates (+)-B-2 and (-)-B-2: (1 S,2R,4R)-2-benzyl 7-tert-butyl 7-azabicyclo[2.2.1 jheptane- 2,7-dicarboxylate.
Figure imgf000072_0001
and (lR,28,4S)-2-benzyl 7-tert-butyl-7-azabicyclo[2.2.1 ]heptane-2,7-dicarboxylate
Figure imgf000072_0002
The title compounds were obtained by chirai SFC (CHIRALPAK IC 5 μΜ 250 X 20mm) resolut ion of Intermediate B-3 (17 g) using 80% CO?/20% ?'PrOH as the mobile phase to
Figure imgf000072_0003
B-3 enantiomer A (7.5 g, 1 st eluting enantiomer) and enantiomer (+)-B3 (7.3 g, 2na eluting enantiomer).
Intermediate (■) -B-2: (-)-2-benzyl 7-ieri-butyl-7-azabicyclo[2.2.1 ]heptane-2,7-dicarboxylate. Enantiomer A, [<x]D 25 -25.2 (c 2.8, CHC13).
Intermediate (+)-B-2: (+)-2 -benzyl 7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. Enantiomer B, [a]D 25 +25.0 (c 2.8, CHCI3). !H NMR (CDCI3): 7.39 - 7.30 (m, SB), 5.19 - 5.08 (m, 2H), 4.55 (s, I H), 4.30 (s, IH), 2.59 (dd, J = 8.9, 5.0 Hz, I TT), 2.36 - 2.24 (m, 1 H), 1.90 - 1.70 (m, 21 0. 1.68 - 1.57 fm, IH), 1.52 - 1.34 (m, 1 I I I ;·.
Intermediate B-3 : (1 S,2R,4R)-7-(tert-butoxycarbonyl)-7-azabicycio[2.2.1 ]heptane-2-carboxylic acid
Figure imgf000072_0004
To intermediate (+)-B-2 (3.5g, 10.6 mmol) in EtOH (1 00 mL) was added 10 wt% Pd/C wet Degussa (750 mg). The reaction was purged with N? followed by H¾ then allowed to proceed under an atmosphere of H2 (balioon). Upon completion, the reaction was filtered and concentrated to give the title compound (2.4g, 94%) that was used without further purification. !H NMR (CDCI3): 4.62 - 4.52 (m, IH), 4.35 - 4.26 (m, I TT), 2.59 (ddd, J= 8.9, 5.0, 1 .5 Hz, I H), 2.29 - 2.19 (m, Hi), 1.91 - 1.71 (m, 2H), 1.68 - 1.58 (m, I H), 1.54 - 1.35 (m, 1 I H). Intermediate B-4: ( 1 S,2R,4R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate.
Figure imgf000073_0001
To intermediate B-3 (2.4g, 9.9 mmol) in PhC¾ (32 mL) was added TEA ( 1.5 mL, 10.9 mmol). After heating in an oil bath to 70 °C, DPPA (2.4 mL, 10.9 mmol) in PhCEb (3 mL) was added. After 1 h, BnOH ( 1 .0 g, 9,5 mmol) was added and the oil bath temperature increased to 90 °C. After an additional 1 8h, the reaction was cooled to rt, diluted with EtOAc and washed with saturated NaHCOs (aq). The aqueous layer was extracted with EtOAc (IX). The combined organics were washed with brine and dried (Na2SQ4). Purification via silica gel chromatography (10-50% EtOAc in hexanes) gave gave the title compound (2.8g, 78%). Ή NMR (CDC13): 7.39 - 7.28 (m, 5H), 5.20 - 4.84 (m, 3H), 4.30 - 4.06 (m, 3H), 3.86 - 3.68 (m, I I I ). 1.93 (dd, ./ 13.4, 8.1 Hz, l i b. 1.85 - 1.63 (m, 2H), 1.54 - 1.29 (m, 1 I I I ).
Intermediate B-5: (+)-(! S,2R,4R)-tert-butyl 2-amino-7-azabicyclo[2.2. l ]heptane-7-carboxylate.
Figure imgf000073_0002
To intermediate B-4 (400 mg, 1.2 mmol) in EtOH (5 mL) was added 10 wt% Pd/C wet Degussa (85 mg). The reaction was purged with N2 followed by ¾, then allowed to proceed under an atmosphere of lb (balloon). Upon completion, the reaction was filtered and concentrated to give the title compound (244 mg, 99%) that was used without further purification. MS (ESI) mass ealcd. for C11H20 2O2, 212.1 ; m/z found 213.1 [M+H]+. [ct]D 25 +9.8 (c 4.9, CHCI3) !H NMR (CDC13): 4.25 - 4.13 (m, I TT), 3.94 - 3.82 (m, I I I ). 2.96 (dd, J = 7.8, 3.0 Hz, i l l }. 1 .85 - 1.25 (m, 15H).
Intermediate B-6: (±)-tert- butyl 2-amino-7-azabicycIo[2.2.1 jheptane-7-carboxylate.
Figure imgf000073_0003
Prepared analogous to intermediate B-5 substituting intermediate B-4 with (±)-7-(tert- butoxycarbonyl)-7-azabicyclo[2.2. l ]heptane-2-carboxylic acid (intermediate B- l). B-7: (±)-tert-but l 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate.
Figure imgf000074_0001
Intermediate B-8: (-)-(lR,2S,4S)-tert-butyl 2-amino-7-azabicyclo[2.2.1 ]heptane-7-carboxylate.
Boc
N
Prepared analogous to intermediate B-5 substituting enaniionier (1 S,2R,4R)-2-benz l 7- tert-butyi 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (intermediate (+)-B-2) with enantiomer (lR,2S,4S)-2-benzyl 7-tert-butyl-7-azabicyclo[2.2.1 ]heptane-2,7-dicarboxylate (intermediate (-)-
B-2 i.
Intermediate B-9: (1 S,2R,4R)-tert-butyl 2-(hydroxymethyl)-7-azabicyclo[2.2. l]heptane-7- carboxylate.
Figure imgf000074_0002
To intermediate (+)-B-2 (504 mg, 1.5 mmol) in THF (12 mL) at 0 °C was added Dibal-H ( 1M in THF, 4.6 mL). After ih, additional Dibal-H was added. The reaction allowed to warm to it and quenched with Rochelle's Salt (20 wt%). EtOAc was added and the mixture allowed to stir until 2 clear layers had formed. The aqueous layer was extracted with EtOAc (2X). The combined organics were washed with brine and dried (N 2S04). Purification via silica gel chromatography (10-50% EtOAc in hexanes) gave the title compound (171 mg, 49%). MS (ESI) mass calcd. for Ci2H2u C>3, 227.2; m/z found 228.2 [M+H]+, 172.2 [M-55]+. Ή NMR (CDC13): 4.26 - 4.12 (m, 2H), 3.45 - 3.32 (m, 3.00 - 2.04 (m, I I I ). 1.95 - 1.90 (m, 1 H), 1.83 - 1.73 · η·. 2H), 1.53 - 1.37 (m, 12H), 1.32 - 1.28 (m, I I I ;·.
Intermediate B-10: (±)-tert-butyl 2-(hydroxymethyl)-7-azabicyclo[2.2.1 ]heptane-7-carboxylate.
Figure imgf000074_0003
As in Org. Syn., 1997, 74, 212, Tet. Lett. 1997, 38, 6829 and Biorg. Med. Chem. Lett. 2006, 14, 8219. Ή NMR (CDCL): 4.25 -■ 4.13 (m, 2H), 3.47 - 3.32 (m, 11 1 ). 1.98 - 1.68 (m, 4H), 1.56 - 1.26 (m, 13H). Intermediate B- 1 1 : (±)-ter/-Butyl 2-hydroxy-7-azabicyclo[2.2.1 jheptane-7-carboxylate.
Figure imgf000075_0001
To a solution of (±)-ieri -butyl 7-azabicyclo[2.2.1]hept-5-ene-7-carboxylate (3.4g, 17.4 mmol; Helvetica Chimica Acta, 2Θ04, 87, 2764) in THF (50 mL) was added borane THF complex (27 mL, ~1M in THF). The solution was stirred at room temperature for ~2h and then the excess borane was quenched by slow addition of water (7 mL, bubbling observed). 6M NaOH (25 mL) was then added followed by slow dropwise addition of H?0? (15 mL, 30%;). The resulting solution was stirred at room temperature overnight. The excess H2O2 was then quenched by slow addition of solid sodium meta-bisulfite. This mixture was diluted with water (200 mL) and extracted with DCM (3x75 mL). The combined organics were dried over Na2S04, filtered and the solvent removed. Purification via silica gel chromatography (0-100 % EtOAc in hexanes) gave the title compound (2.74 g) as a clear colorless oil that slowly solidified. MS (ESI): mass calcd. for C1 1H19NO3, 213.2; m/z found, 158.1 [M+2H-iBu] : . Tl NMR (400 MHz, CDCI3) δ 4.28 - 4.20 (†, J = 4.9 Hz, IH), 4.16 - 4.06 (d, J = 5.2 Hz, IH), 3.91 - 3.80 (td, J = 7.4, 6.4, 1.9 Hz, IH), 2.00■■ 1.88 (s, IH), 1.88■■ 1.80 (m, IH), 1.78■■ 1.69 (m, i l l s. 1.69 - 1.55 (m, 2H), 1.50 - 1.40 (s, 9H), 1.31 - 1.20 (m, 2H).
Example 1 : (5-fluoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4 )-2-((pyridin-2-yloxy)methyl)-7- l)methanone.
Figure imgf000075_0002
Step A: (l S,2R,4R)-tert-butyl 2-(( yridin-2-yloxy)methyl)-7-azabicyclo[2.2.1 ]heptane-7- carboxylate. To intermediate B-9 (170 mg, 0.75 mmol) in DMF (3 mL) at 0 °C was added NaH (36 mg, 60 wt% in mineral oil, 0.9 mmol). After 30 min, 2-fluoropyridine ( 102 mg, 1.0 mmol) in DMF (0.5 mL) was added dropwise and the 0 °C ice bath was removed. The flask was then heated to 90 °C in an oil bath. After 2h, 1/2 saturated NH4Ci was added and the reaction extracted with EtOAc (2.X). The combined organics were washed with brine and dried
(Na?S04). Purification via silica gel chromatography (5-30% EtOAc in hexanes) gave the title compound ( 172 mg, 76%) as a white solid. MS (ESI) mass calcd. for
Figure imgf000076_0001
304.2; m/z found 305.1 [M+H]+. 'H MR (CDCI3): 8.13 (dd, J = 5.1 , 2.0 Hz, 1H), 7.55 (ddd, J= 8.7, 7.1 , 2.0 Hz, IH), 6.84 (dd, J= 7.0, 5.0 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 4.35 - 4.1 5 (ni, 2H), 4.15 - 3.99 (m, 2H), 2.26 - 2.14 (m, 1H), 1.90 - 1.68 (m, 2H), 1 .64 - 1.55 (m, IH), 1.54 - 1.31 (m, 12H).
Step B: (lS,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7- carboxylate. To the title compound from Step A (130 mg, 0.4 mmol) in EtOAc was added 4M HC1 in dioxane. After 3h, the reaction was concentrated, neutralized with 5% a?C03 and extracted with DCM, The combined organics were dried
Figure imgf000076_0002
to give the title compound from step B as a white solid that was used without further purification. MS (ESI) mass calcd. for Ci ?Hi6N2O,204.1 ; m/z found 205.1 [M+H] ~
Step C: (5-fluoro-2-(pyrimidin-2-yl)phenyi)((l S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of Step B (50 mg, 0.18 mmol) in DMF (1 ,4 mL) was added DIPEA (0.078 mL, 0.45 mmol), intermediate A-7 (43 mg, 0.2 mmol) and HATU (75 mg, 0.2 mmol). Upon completion of the reaction, purification was performed using Agilent prep method A to give the title compound. MS (ESI) mass calcd. for C23H2iF 4O2,404.2; m z found 405.2 [M+H . Ή NMR (CDCI3): 8.78 (d, J = 4.9 Hz, 1H), 8.71 (d, J - 4.8 Hz, IH), 8.26 - 8.21 (m, 2H), 7.60 - 7.50 (m, 1H), 7.23 - 7.00 (m, 3H), 6.90 - 6.82 (m, i l l !. 6.78 - 6.71 (m, 0.5H), 6.59 - 6.51 (m, 0.5H), 4.88 - 4.78 (m, IH), 4.26 - 4.09 ·: m. I I I ;·. 4.09 - 3.95 (m, l i b. 3.92 - 3.79 (m, IH), 2.39 - 2.18 (m, IH), 2.04 - 1.86 (m, IH), 1.81 - 1.31 (m, 5H).
Example 2: (±)-(6-methyl-3-(pyrimidin-2-yI)pyridm-2-yl)(2-((pyridin~2-yl^
)methanone.
Figure imgf000076_0003
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-1G, 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-9 and HATU with HBTU to give the title compound. MS (ESI) mass calcd. for C23H23N5O2, 401 .2; m/z found 402.2 [M+H]+. Ή NMR (DMSO-D6): 8.92 {■:!. J - 4.9 Hz, I H), 8.84 i d. J - 4.9 Hz, i l l }. 8.32 (t, J - 8.3 Hz, 1 H), 8.24 (dd, J = 5.0, 1.4 Hz, 0.5H), 8.15 (dd, J = 5.0, 1.5 Hz, 0.5H), 7.76 - 7.69 (m, 0.5H), 7.69 - 7.62 (m,0.5H), 7.52. - 7.42 (m, 1.5H), 7.34 (d, J = 8.1 Hz, 0.5H), 7.05 - 6.92 (m, IH), 6.87 (d, J = 8.3 Hz, 0.5H), 6.68 (d, J = 8.3 Hz, 0.5H), 4.60 - 4.56 (m, I H), 4.19 (id, J = 10.3, 3.7 Hz, IH), 4.06 (dt, J = 10.4, 5.3 Hz, IH), 3.86 (t, J = 4.0 Hz, 0.5H), 3.77 (d, J - 4.1 Hz, 0.5H), 2.56 (s, 1.5H), 2.39 - 2.15 (m, IH), 2.06 (s, 1.5H), 1.88 - 1.33 (m, 6H).
Example 3A: (6-methyl-3-^yrimidin-2-yl)pyridin-2-yl)((lS*,2R*,4R*)-2-((pyr!din-2^
[2.2.1]heptan-7-yl)methanone.
Figure imgf000077_0001
and Example 3B: (6-methyi-3-(pyrimidin-2-yl)pyridm-2-yl)((lR*,2S*,4S*)-2-((pyridin~2- icyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000077_0002
The title compounds were obtamed by chiral SFC (CHTRALPAK AD-H 5 μΜ 250 X 20mm) resolution of Example 2 (538 mg) using 70% CO2/30% EtOH as the mobile phase to give enantiomer A (230 mg, 1st eluting enantiomer) and enantiomer B (226 mg, 2n" eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD (250x4.6 mm) and a mobile phase of 70% C02, 30% EtOH containing 0.3 % iPrNH2 over 7 minutes. (Example 3 A: >98% single enantiomer, 4.00 min retention time; Example 3B >98% single enantiomer, 5.12 min retention time). Example 3 A: MS (ESI) mass calcd. for
C23H23N5O2, 401.2; m/z found 402.1 [M+Hf , i i NMR (CDCI3): 8.83 (d, J - 4.8 Hz, 0.8H), 8.72 fd, J = 4.8 Hz, 1.2H), 8.43 - 8.37 (m, IH), 8.19 - 8.09 (m, IH), 7.59 - 7.48 (m, I H), 7.28 i d. J 8.0 Hz, 0.4H), 7.19 - 7.16 On.1.6H), 6.88 - 6.81 (m, lis}.6.76 (dt, J = 8.4, 1.0 Hz, 0.4H), 6.57 (dt, J = 8.3, 0.9 Hz, 0.6H), 4.92 - 4.84 (m, 1H), 4.38 - 4.23 (m, 1H), 4.17 (ddd, J - 15.4, 10.3, 5.7 Hz, 1H), 3.97-3.87 (m, 1H), 2.62 (s, lH), 2.39 - 2.18 (m, 2.5H), 2.11 - 1.81 (m, 2H), 1.74 (dd, J - 12.3, 8.6 Hz, 0.5H), 1.68 - 1.36 (m, 4H).
Example 3B: MS (ESI) mass calcd. for C23H23N5O2, 401.2; mz found 402.1 j \1 i i j
Example 4: (-i-)-(6-meihyl-3-(2H-I,2,3-triazol-2-yl)pyridm-2-yl)
l)methanone.
Figure imgf000078_0001
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10, intermediate A-7 with intermediate A-21 and HATU with HBTU to give the title compound. MS (ESI) mass calcd. for C2iH22N602, 390.2; mz found 391.2 [M+H . 'HNMR (500 MHz, CDCI3): 8.20 - 8.07 (m, 2H), 7.84 - 7.75 (m, 2H), 7.61 - 7.49 (m, 1H), 7.31 (d,J = 8.4 Hz, 0.4H), 7.19 (d, J= 8.4 Hz, 0.6H), 6.87 - 6.83 (m, 1H), 6.76 (dt, J= 8.4, 0.9 Hz, 0,4! i ).6.57 (dt, J= 8.3, 0.9 Hz, 0.6H),4.9! - 4.81 (m, 1H), 4.32 - 4.07 (m, 2H), 3.96 - 3.84 (m, IE), 2.62 (s, 1.2H), 2.40 - 2,17 (m, 2.8H), 2.13 - 1.94 (m, ill).1.94 - 1.68 (m, I.8H), 1.68 - 1.37 (m, 3.2H).
Example 5A: (6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridm-2-yl)((lS,2R,4R)-2-((pyridm-2- [2,2.1 ]heptan-7-yl)methanone.
Figure imgf000078_0002
and Example 5B: (6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)(( lR,2S,4S)-2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]hepian-7-yl)methanone.
Figure imgf000079_0001
The title compounds were obtained by chirai SFC (CHIRALPAK AD-H 5 μΜ 250 X 20mm) resolution of Example 4 (555 mg) using 70% C 02/30% EtOH as the mobile phase to give enantiomer A (264 mg, 1 st eluting enantiomer) and enantiomer B (248 mg, 2*° eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD (250x4.6mm) and a mobile phase of 70% C02, 30% EtOH containing 0.3 % iPr H2 over 7 minutes. (Example 5 A: >98% single enantiomer, 2.80 min retention time; Example 5B >98% single enantiomer, 3,90 min retention time). Example 5A: MS (ESI) mass calcd. for C21H22 6O2, 390.2; m/z found 391.2 [M+Hf. Example 5B: MS (ESI) mass calcd. for
C21H22N602, 390.2; m/z found 391.2 j .YJ i l l .
Example 6: (6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)((l S,2R,4R)-2~((pyridm~2~
[2.2.1Jheptan~7-yl)methanone.
Figure imgf000079_0002
Prepared analogous to Example 1 substituting intermediate A- 7 with intermediate A-21.
MS (ESI) mass calcd. for C2iH22N602, 390.2; m/z found 391 .2 [M+H]+. [a]D 20 +1 1.4° (c 0.88, CHC ). Ή NMR (CDCI3): 8.19 - 8.06 (m, 2H), 7.83 - 7.73 (m, 2H), 7.61 - 7.48 (m, IH), 7.30 (d, J = 8.4 Hz, 0.4H), 7.19 fd, J = 8.4 Hz, 0.6H), 6.89 - 6.81 (m, IH), 6.78 - 6.73 (m, 0.4H), 6.61 - 6.52 (m, 0.6H), 4.91 - 4.81 (m, IH), 4.32 - 4.08 (m, 2H), 3.96 - 3.84 (m, IH), 2.62 (s, 1.2H), 2.39 - 2.18 (m, 2.8H), 2.1 1 - 1.94 (m, 1 .5H), 1 .94 - 1.37 (ni, 4.5H).
Example 7: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)~7-azabicyclo[2.2.1]heptan-7-yl)(6- metbyl-3-(2H-l ,2,3 riazol~2-yl)pyridin-2-yl)methanone.
Figure imgf000080_0001
Step A Method A: { · i-!er!-busyl 2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicy clo[2.2.1 ]heptane-7-carboxylate. Tri-n-butylphosphine (1.8 mL, 7.8 mmol) was added to intermediate B-10 (830 mg, 3.7 mmol) and 5-fluoropyridin-2( lH)-one (500 mg, 4.4 mmol) in THF (1 1 mL) under nitrogen bubbling at rt. After 5 min of stirring, DEAD (1.4 mL, 7.1 mmol) was added and the mixture was stirred at 50°C for 18 hours. The mixture was concentrated and purified silica gel chromatography (0- 15% EtOAc in Heptane) to give the title compound of step A. (590 mg, 45%) as a white solid.
Step A Method B: (±)-tert-butyl 2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example B-6 substituting intermediate B-9 with (±)-B-9 and 2-fluoropyridine with 2,5-difluoropyridine. MS (ESI) mass calcd. for C17H23FN203, 322.2; m/z found 323.0 [M+H] _. Ή NMR (CDC13): 8.02 - 7.87 (m, I H), 7.41 - 7.27 (m, i l l ). 6.70 uki. ./ 9.1, 3.6 Hz, Hi), 4.39 - 4.10 (m, 2H), 4.09 - 3.89 (m, 2H), 2.25 - 2.09 (m, IH), 1.91 - 1.26 (m, 15H).
Step B: (±)-2-(((5-fluoropyridin-2-yl)oxy)metb.yl)-7-azabicyclo[2.2.1]heptaiie. Prepared analogous to Example 1 substituting (±)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate with the title compound from Step A. Ή NMR
(CDCI3): 7.96 (d, J= 3.1 Hz, IH), 7.33 (ddd, J= 9.0, 7.6, 3.1 Hz, IH), 6.70 (dd, J - 9.0, 3.6 Hz, IH), 4.09 - 3.98 (m, 2H), 3.72 - 3.56 (m, 2H), 2.22 - 1.99 (m, 3H), 1.72 - 1.53 (m, 3H), 1.49 - 1.34 (m, IH).
Step C: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)methanone. Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yI)benzoic acid with 6-methyl-3-(2H~I,2,3-triazol~2- yDpicolinic acid. MS (ESI) mass calcd. for C21H2iFN60¾ 408.2; m/z found 409.2.
Example 8A: ((lS,2R,4R)-2-(((5-fluoropyridin-2-yl)oxy)methy{)-7-azabicyclo[2.2.1 ]heptan-7- y3)(6-Tnetbyl-3-(2H- l,2,3-triazol-2-yl)pyridm-2-yr)methanone.
Figure imgf000081_0001
and Example 8B: ((lR,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)Tne hyr)- 1 ,2,3-triazol-2-yl)pyridin-2-yl)methaaone.
Figure imgf000081_0002
The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μΜ 250 X 20mm) resolution of Example 7 (259 mg) using 70% CO2/30% mixture of EtOH/i -PrOH (50/50 v/v) the mobile phase to give enantiomer A. (72 mg, 1 st eluting enantiomer) and enantiomer B (84 mg, 2nd eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a
CHIRALPAK AD-H (250x4.6mm) and a mobile phase of 70% C02, 15% EtQH, 15% iPrOH containing 0.3 % iPrNH2 over 7 minutes. (Example 8A: 100% single enantiomer, 3.10 min retention time; Example 8B 100% single enantiomer, 4,58 min retention time). Example 8A: MS (ESI) mass calcd. for (' ., I L X.-.C 408.2; m/z found 409.2 i \) H I Example 8B: MS (ESI) mass calcd. for C2iH2,FN602, 408.2; m z found 409.2 j \ 1 · i 11 Example 9: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5- l)phenyl)methanone.
Figure imgf000081_0003
Prepared analogous to Example 7 substituting intermediate A-21 with intermediate A-37. MS (EST.) mass calcd. for C22H22FN5O2, 407.2; m/z found 408.3 i \l - H i . ]H NMR (CDCI3): 8.03 - 7.95 (m, 1H), 7.81 - 7.70 (m, 3H), 7.38 - 7.1 1 (m, 3H), 6.72 (dd, J - 9.0, 3.6 Hz, 0.5H), 6.52 (dd, J = 9.0, 3.5 Hz, 0.5H), 4.86 - 4.74 (m, i l l ). 4.15 - 3.68 (m, 3H), 2.46 - 2.37 (s, 1.611), 2.32 - 1.78 (m, 4.4H), 1.72 - 1.22 (m, 4H).
Example 1 OA: ((1 S,2R,4R)-2-(((5-fiuoropyridin-2-yl)oxy)methyl)-7-azabicycfo[2.2.1 jheptan-7- ol-2-yl)phenyl)methanone.
Figure imgf000082_0001
and Example 10B: ((lR,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yi)(5-methyl-2-(2H- 1 ,2,3-triazol~2-y])phenyl)methanone.
Figure imgf000082_0002
The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μ'Μ 250 X 20mm) resolution of Example 9 (290 mg) using 60% CO?/40% r'-PrOH as the mobile phase to give enantiomer A (140 mg, 1st eluting enantiomer) and enantiomer B (134 mg, 2 " eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD-H (250x4.6mm) and a mobile phase of 60% C02, 40% iPrOH containing 0.3 % iPr L over 7 minutes. (Example 10A: >98% single enantiomer, 2.42 min retention time; Example iOB >98% single enantiomer, 3.20 min retention time).
Example 1 1 : (±)-(2-(((5-f1uoropyridjii-2-yl)oxy)methyl)-7-azabicyclo[2.2J ]heptan-7-y1)(2- one.
Figure imgf000082_0003
To (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane (35 mg, 0.2 mmol) in DCM (2.5 mL) was added TEA (25 μΕ, 0.2 mmol)) followed by 2-(thiophen-2- yljbenzoyl chloride (40 mg, 0.2 mmol) in DCM (2.5 mL). After 18b, the reaction was diluted with DCM and washed with ¾0. The aqueous layer was extracted DCM (IX), The combined organics were dried (Na2S04). Purification via silica gel chromatography (50- 100% EtOAc in hexanes) gave the title compound (37mg, 57%). MS (ESI) mass calcd. for C23H2JFN2O2S, 408.1 ; m/z found 409.1 [M÷Hf.
Example 12A: ((1 S*,2R*,4R*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- (2-(thiophen-2~y{)phenyl)methanon
Figure imgf000083_0001
and Example 12B: (( 1 R*,2S*,4S*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- 7-yl)(2-(thiophen-2-yi)phenyi)methanone.
Figure imgf000083_0002
The title compounds were obtained by chiral SFC (CHIRALPAK AS-H 5 μΜ 250 X 20mm at 40 °C) resolution of Example 1 1 using 4.2 mL/min MeOH with 0.2% TEA, 37 mL/n CO2 as the mobile phase to give enantsoraer A. ( 1 st eluting enantsoraer) and enantiomer B (2!'β eluting enantiomer).
Example 12A : MS (ESI) mass calcd. for C .\ \ > i;N >i> >S. 408.2; m/z found 409.2 Ι Μ · Η | Ή NMR (CDCI3): 7.97 (dd, J - 1 1.0, 3.0 Hz, lH), 7.54 - 7.20 (m, 6.5H), 7.01 (dd, J - 5.0, 3.7 Hz, l .SH), 6.71 ukl. J 9.1 , 3.5 Hz, 0.5H), 6.45 (dd, J - 9.0, 3.6 Hz, 0.5H), 4.83 - 4.63 (m, 1 H), 4.1 8 --- 3.38 (m, 3H), 2.70-0.40 (m, 7H). Example J 2B: MS (ESI) mass calcd. for C23H21FN2O2S, 408.2; m/z found 409.2 ί Λ ΐ - 1 1 j 1 1 NMR (CDCI3): 7.97 (dd, J = 1 1.0, 3.0 Hz, 1H), 7.54 - 7.20 (m, 6.5H), 7.01 (dd, J = 5.0, 3.7 Hz, 1.5H), 6.71 (dd, J = 9.1 , 3.5 Hz, 0.5.H), 6.45 (dd, J = 9.0, 3.6 Hz, 0.5H), 4.83 - 4.63 (m, 1H), 4.1 8 - 3.38 (m, 3H), 2.70-0.40 (m, 7H).
Example 13 : (±)-(5-methyl-2-(2H- l ,2,3-triazoi-2-yl)ph^
o[2.2.1 ]heptan-7-yl)methan.one.
Figure imgf000084_0001
Step A: (±)-7-azabicyclo[2.2.1 ]heptan-2-ylmethanol hydrochloride. To intermediate B- 10
( l . lg, 4.9 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (3 mL). After 6h, the reaction was concentrated to give the title compound that was used without further purification.
Step B: ((±)-2-(hydroxymethyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5-methyl-2-(2H- 1 ,2,3- triazol-2-yl)phenyi)methanone. To the title compound of Step A in DMF was added TEA, 5- methyl-2-(2H-l ,2,3-triazol-2-yl)benzoic acid and HA'T'U. After 1 8h, H20 was added and the mix extracted with EtOAc (2X). The combined organics were washed with brine and dried (Na2S04). Silica gel chromatography (1-7% 2M NHyMeOH in DCM) gave the title compound (371 mg, 46%). MS (ESI) mass calcd. for &7Η2οΝ4θ2,312.2; m z found 313.2 [M+H]+.
Step C: (±)-(5-methyl-2-(2H- 1 ,2,3-triazol-2-y1)phenyl)(2-(((4- (trifjuoroTnethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicycio[2.2.1 ]heptan-7-yl)mefhanone. To the title compound of step B (33 mg, 0.1 mmol) in THF (2 mL) was added NaO Bu (16 mg, 0.16 mmol). The reaction was then heated at reflux for 15 min and 2-chioro-4- trifluoromethylpyrimidme (19 mg, 0.16 mmol) was added. The reaction was heated at reflux temperature for Ih, cooled to rt, diluted with H20 and extracted with DCM (2X). The combined organics were dried a2S04). Purification via silica gel chromatography (0.5-4% 2M
NHVMeOH in DCM gave the title compound (28 mg, 57%). MS (EST.) mass calcd. for
C22H21F3N602, 457.2; m/z found 458.2 [M+H] 1". !H NMR (CDCI3): 8.82 - 8.72 (m, I H), 7.86 - 7.69 (m, 31 1 ;·. 7.36 - 7.10 (m, 3H), 4.85 (m, I H), 4.47 (t, J = 10.1 Hz, 0.5H), 4.20 - 3.98 (m, 1.5H), 3.90 (d. J - 4.7 Hz, O.SH), 3.78 ((, J = 4.5 Hz, 0.5H), 2,51 - 2.20 (m, 3H), 2.14 - 1.82 · η·. 2H), 1.78 - 1.17 (m, 5H).
Example 14: (±)-(5-methyl-2-(2H-
Figure imgf000085_0001
.1 ]heptan-7-yl)methanone.
Figure imgf000085_0002
Prepared analogous to Example 13 substituting 2-c oro-4-(trifluoroineihyl)pyriinidine with 2-chloro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C23H22F3 5Q2, 457.2; m/'z found 458.2 i \I I f !
Example 15: (±)-(5-methyl-2-(2H-l,2,3-triazol-2-yl)phen^
o[2,2.1 ]heptan-7-yl)methanone.
Figure imgf000085_0003
Prepared analogous to Example 13 substitutin ■chloTO-4-(trifluoromethyl)pyrimidine with 2-chloro-3-(trifluoromethyl)pyridiae. MS (ESI) mass calcd. for C23H22F3Ns02, 457.2; m/z found 458.2 i vi - l i i !H NMR (CDCI3): 8.36 - 8.26 (m, 1H), 7.91 - 7.69 (m, 4H), 7.36 - 7.29 (m, O.SH), 7.25 - 7.16 (m, 1H), 7.13 - 7.07 (m, 0.5H), 6.97 (dd, J = 7.5, 5.1 Hz, 1H), 4.87 - 4.70 (m, IH), 4.53 - 4.34 (m, 0.5H), 4.25 - 4.06 (m, 1 H), 3.92 (t, J - 10.9 Hz, 0.5! U. 3.85 - 3.71 (m, 1H), 2.46 - 2.40 (m, 1.5H), 2.39 - 2.19 (m, 1.5H), 2.04 - 1.79 (m, 3H), 1.72 - 1.19 (m, 4H).
Example 16: (±)-(5-rriethyl-2-(2H- 152,3-triazol-2-y3)phenyl)(2-(((6-(trifluoTomethyI)pj'ridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000086_0001
Prepared analogous to Example 13 substituting 2~chloro-4-(trifluoroniethyl)pyriniidine with 2-chloro-6-(trifluoromethy{)pyridine. MS (ESI) mass calcd. for C23H22F3N5O2, 457.2; m/z found 458.2 j M · Π ; ]H NMR fCTXl.}: 7.87 - 7.63 (m, 4H), 7.37 - 7.11 (m, 3H), 6.92 (d, J - 8.4 Hz, 0.51 n.6.73 (d, J = 8.4 Hz, 0.5H), 4.88 - 4.75 On. His.4.20 - 3.84 (m, 2H), 3.81 - 3.67 (m, 1H), 2.49 - 2.36 (s, 2H), 2.34 - 2.13 (m, 1H), 2.08 - 1.77 (m, 3ΙΠ.1.76 - 1.10 (m, 4H).
Example 17: (±)-(5-methyl-2-(2H-l,2,3-triazoi-2-yr)phenyl)(2-(((4-methylpyridii-2- o[2.2.1]heptan~7-yl)methanone.
Figure imgf000086_0002
Prepared analogous to Example 13 substituting 2~chloro-4-(trifluoroniethyl)pyriniidine with 2-chloro-4-(methy1)pyridine. MS (ESI) mass calcd. for C23H25N5O2, 403.2; m/z found 404.2 [M+Hf. ii NMR i( IX 1;}: 8.10 - 7.91 (m, 1H), 7.87 (d, J - 3.7 Hz, 2H), 7.82 - 7.70 (m, Hi!.7.50■-- 7.42 (m, I I I).7.34 - 7.24 (m, 0.5Ή), 7.16 - 7.08 mi.0.5H), 6.90■-- 6.80 (m, I I I ). 6.7 - 6.66 (m, 0.4H), 6.59 - 6.45 (m, 0.6H), 4.68 (q, J - 4.0, 3.3 Hz, lH), 4.16 - 3.71 (m, 3H), 2.49 -2.18 (m, 5H), 1.94 - 1.17 (m, 8H).
Example 18: (±)-(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyI)(2-(((6-ineihyIpyridin~2- .2.1]heptan-7-yl)methanone.
Figure imgf000086_0003
Prepared analogous to Example 13 substitutmg 2-chloro-4-(trifluoromethyl)pyrimidine wiih 2-chloro-6-(methyl)pyridine. MS (ESI) mass caicd, for C23H25N5O2, 403,2; m/z found 404.2 ; H i . ]H NMR (CDCI3): 7.89 (d, J = 1.3 Hz, 2H), 7.82 - 7.66 (m, 1.5H), 7.61 (dd, J = 8.3, 7.3 Hz, 0.5H), 7.43 (ddd, J - 8.3, 1.9, 0.9 Hz, 0.5H), 7.35 - 7.26 (m, I H), 7.16 - 7.09 (m, 0.5H), 6.88 (dd, J 16. 1 , 7.3 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 0. H i. 6.53 (d, J - 8.3 Hz, 0. H i. 4.74 - 4.64 (m, 1H), 4.24 - 4.04 (m, 1H), 4.02 - 3.76 (m, 2H), 2,55 - 2.21 (m, 5H), 2,05 - 1.23 (m, 8H).
Example 19: (±)-(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2- .2.1]heptan~7-yl)methanone.
Figure imgf000087_0001
Prepared analogous to Example 13 substituting 2~chloro-4-(trifluoroniethyl)pyriniidine with 2-chloro-5-(methyl)pyridiiie. MS (ESI) mass caicd. for C23H25N5O2, 403.2; m/z found 404.2 i V! · 1 Π 1 1 NMR (CDCI3): 8. i 0 - 7.58 (m, 4H), 7.43 - 7.29 (m, 1.5H), 7.26 - 7.1 1 (m, 1.5H), 6.66 i d. J = 8.4 Hz, 0.5H), 6.45 (d, J - 8.4 Hz, 0.5H), 4.86 - 4.71 (m, 1H), 4, 17 - 3.66 (m, 3H), 2.46 - 2.38 (s, 1.2H), 2.31 - 2.14 (m, 3.8H), 2.01 - 1.79 (m, 2H), 1.71 - 1.18 (m, 6H).
Example 20: (i)-(2-(((3,6-dimethylp_v 'azin-2-yl)oxy)methyl)-7-azab
l)phenyl)meihanone.
Figure imgf000087_0002
Prepared analogous to Example 13 substituting 2-cliloro-4-(trifluoromethyl)pyrimidme with 3-chloro-2,5-dimeth.ylpyrazine. MS (ESI) mass caicd. for C23H26 6O2, 418.2; m/z found 419.2 [M+H] r . 'H MR (400 MHz, CDCI3) 7.88 - 7.84 (m, IH), 7.81 - 7.72 (m, 2.5H), 7.36 - 7.12 (m, 2H), 7.1 1 - 7,06 (m, 0.5H), 4.86 - 4.75 (m, IH), 4.26 - 4.15 (m, 0.5H), 4.08 (dd, ./ 11 .0, 5.5 Hz, IH), 3.86 - 3.71 (m, 1.5H), 2.48 - 2.34 (m, 6H), 2.34 - 2.13 (m, 3H), 1.96 - 1.25 (m, 7H). Example 21 : (±)-(5-methyl-2-(2H- l ,2,3-iriazol-2-yl)phenyi)(2-(((3-(trifluoromeihyi)quinoxalin- -yl)oxy)met y])-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000088_0001
Prepared analogous to Example 13 substituting 2-chloTO-4-(trifluoromethyl)pyrimidine with 2-chloro-3-(trifluoromethyl)qtiinoxalme. MS (ESI) mass calcd. for C26H23F3N6O2, 508.2; m/z found 509.2 [M+H]+. !H NMR (CDCI3): 8.16 - 8.09 (m, IH), 7.97 - 7.62 (m, 6H), 7.37 - 7.23 (m, I H), 7.19 - 7.06 (m, I H), 4.87 (t, J = 4.7 Hz, 0.5H), 4.80 (d, J = 4.8 Hz, 0.5H), 4.71 - 4.56 (m, 0.5H), 4.38 - 4.22 (m, IH), 4.16 - 4.01 (m, 0.5H), 3.87 - 3.73 (m, I I I ). 2.49 - 2.23 (m, 4H), 2,05 1 .24 un. 6H).
Example 22: (±)-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)meth.yl)-7- methanone.
Figure imgf000088_0002
Prepared analogous to Example 7 substituting intermediate A-21 with intermediate A-l . MS (ESI) mass calcd. for C21H20FN5O2, 393.2; m/z found 394.2 i v! - ! i ] I I N M (400 MHz, MeOD) 8.02 - 7.78 (m, 4H), 7.62 - 7.53 (m, 0.5H), 7.49 - 7.28 (m, 3H), 7.13 - 7.01 (m, 0.5H), 6.75 (dd, J = 9.0, 3.6 Hz, 0.5H), 6.51 (dd, J = 9.0, 3.6 Hz, 0.5H), 4.85 - 4.71 (m, I H), 4.21 - 4.03 (m, IH), 4.02 - 3.72 (m, 2.39 - 2.09 (m, IH), 2.04 - 1.16 (m, 6H).
Example 23: (i)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- yl)(quinolin-8-yl)methanone.
Figure imgf000088_0003
Prepared analogous to Example 22 substituting intermediate A- 1 with quinoline-8- carboxylic acid. MS (ESI) mass calcd. for C22H20FN3O2, 377,2; m/z found 378.2 [M+Hff. Ή NMR (400 MHz, CDCI3): 8.95 - 8.69 (m, IH), 8.16 (dd, J = 8.3, 1.8 Hz, 0.4H), 8.1 1 - 7.81 (m, 2H), 7.81 - 7.67 (m, I I I ). 7.64 - 7.51 (m, 1 H), 7.47 - 7.09 (m, 2.6H), 6.79 (dd, J = 9.0, 3.6 Hz, 0.5H), 6.25 (s, 0.5H), 5.08 - 4.96 (m, Hi), 4.29 (s, 0.7H), 4.13 - 3.94 (m, 1.3H), 3.65 - 3.45 (m, l i b. 2.47 - 2.02 (m, 2H), 2.02 - 1.30 (m, 5H).
Example 24: (±)-2-(((5-fluoropyridin-2-yl)oxy)met yl)-7-azabicyclo[2.2.1]heptan-7- .
Figure imgf000089_0001
Prepared analogous to Example 22 substituting intermediate A-1 with 1 -naphthoic acid. MS (ESI) mass calcd. for C23H21FN2O2, 376.2; m/z found 377.2 j V! · Π j JH NMR (400 MHz, CDCI3): 8.10 - 7.95 (m, 1.5H), 7.92 - 7.83 (m, 1.5H), 7.81 - 7.71 (m, IH), 7.58 - 7.31 (m, 4H), 7.25 - 7.13 (m, IH), 6.77 (dd, .7 = 9.0, 3.6 Hz, 0.5H), 6.36 - 6.24 (m, 0.5H), 5.04 - 4.92 (m, I H), 4.30 - 4.13 (m, IH), 4.07 - 3.84 (m, I H), 3.81 - 3.64 (m, I H), 2.44 - 2.30 (m, 0.5H), 2.27 - 2.00 (m, 1.5H), 1.89 - 1.37 (m, 5H).
Example 25: (i)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(2- ne.
Figure imgf000089_0002
Prepared analogous to Example 22 substituting intermediate A- 1 with 2-methy3- l - naphthoic acid. Π N M R (CDCI3): 8.06 - 7.86 (m, I H), 7.85 - 7.62 (m, 2.6H), 7.60 - 7.54 (m, 0.2H), 7.49 - 7.21 (m, 3.4H), 7.13 (m, 0.8H), 6.77 (ddd, J - 12.7, 9.0, 3.6 Hz, 0.6H), 6.43 (dd, J = 9.0, 3.6 Hz, 0.2H), 6.03 (dd, J = 9.0, 3.6 Hz, 0.2H), 5.1 1 - 4.99 (m, 0.9H), 4.38 - 4.09 (m, 1 .2H), 4.08 - 3.82 (m, 0.7H), 3.69 - 3.43 (m, 1 ,2H), 2.58 - 2.27 (m, 3.5H), 2.23 - 1.97 (m, 1.5H), 1.92 - 1.28 (m, 5H). Example 26: (±)-2-( IH-pyrazol- 1 -yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- methanone.
Figure imgf000090_0001
Prepared analogous to Example 22 substituting intermediate A- l with 2~( lH-pyrazol-1 - yl)benzoic acid. MS (ESI) mass calcd. for C22H21F 4O2, 392.2; m/z found 393.2 [M+H]+. Ή NMR (CDCI3): 7.98 (dd, J = 8.3, 3.1 Hz, S i n. 7.91 - 7.83 (m, 1H), 7.69 (d, J = 1.9 Hz, 1 H), 7.64 - 7.23 (m, 4.5H), 6.99 (i, J = 7.4 Hz, 0.5H), 6.71 (dd, J - 9.0, 3.6 Hz, 0.5H), 6.47 - 6.34 (m, 1.5H), 4.79 - 4.63 (m, 1H), 4.03 - 3.65 (m, 2H), 3.66 - 3.54 (m, IH), 2.27 - 2.03 (m, I H), 1.86 - 0.74 (m, 6H).
Example 27: (±)-2-(((5-fluo"ropyrid"in-2-yl)oxy)methyl)-7-azabicyclo[2.
e.
Figure imgf000090_0002
Prepared analogous to Example 22 substituting intermediate A- l with 3~phenyifuran-2- carboxylic acid. MS (ESI) mass calcd. for C22H2iF 2i¾, 392.2; m/z found 393.2 [M+Hf. Ή NMR (CDCI3): 8.05 - 7.82 (m, 1H), 7.59 - 7.44 (m, 7H), 6.77 - 6.40 (m, 2H), 4.85 - 4.61 (m, i l l ). 4.45 - 4.29 (m, 0.5H), 4.24 - 4.08 (m, 0.5H), 4.06 - 3.76 (m, 2H), 2.32 -- 2.1 1 (m, IH), 2.01 - 0.83 (m, 6H).
Example 28 : (±)-(2-ethoxynaphthalen- 1 -yi)(2-(((5-fluoropyridin-2-yl)oxy)methyl)- azabicyelo[2.2, 1 ]heptan-7-yl)methanone.
Figure imgf000091_0001
Prepared analogous to Example 22 substituiiRg intermediate A-I with 2-ethoxy-i- naphthoic acid. MS (ESI) mass calcd. for C25H25FN2O3, 420.2; m/z found 421.2 [M+H]+. Ή NMR (CDCI3): 8.03 (d, J = 3.0 Hz, Q.2H), 7.95 (dd, J = 8.1 , 3.1 Hz, 0.5H), 7.86 - 7.70 (m, 2.6H), 7.69 - 7.63 (m, 0.3H), 7.60 - 7.55 (m, 0.3H), 7.50 - 7.00 (m, 4.2! n. 6.76 (ddd, J - 9.3, 6.1, 3.6 Hz, 0.5H), 6.44 (dd, J = 9.0, 3.5 Hz, 0.2H), 6.03 (dd, J = 9.0, 3.6 Hz, 0.2H), 5.08 - 4.97 (m, 1H), 4.35 - 3.92 (m, 3.3H), 3.91 - 3.76 (m, 0.5H), 3.68 - 3.52 (m, I .2H), 2.44 - 2.27 (m, 0.8H), 2.20 - 1.93 (m, 2H), 1.85 - 1.18 (m, 7.2H). Exampie 29: (±)-(5-(2-fluorophenyi)-2-meth^
yl)oxy)methyl)-7-azabicyelo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000091_0002
Prepared analogous to Example 22 substituiiRg intermediate A-1 with 5-(2- fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) mass calcd. for C23H21F2 3O2S, 441.2; m/z found 442.2 [M+Hf. ;H NMR (CDCI3): 7.99 - 7.93 (m, 1H), 7.53 - 7.44 (m, 1 H), 7.36 - 7.09 (m, 3.5H), 7.04 (ddd, J - 9.8, 8.5, 1.2 Hz, 0.5Ή), 6.66 (ddd, J - 15.9, 9.0, 3.6 Hz, 1H), 4.79 - 4.68 (m, 1H), 4.27 - 4.21 (m, 0.5H), 4.07 (t, J - 4.6 Hz, 0.5H), 3.96 - 3.73 (m, 2H). 2.74 (s, 1.5H), 2.42 (s, 1.5H), 2.23 - 2.11 (m, 1 H), 1.89 - 1.57 (m, 2H), 1.54 - 1.24 (m, 3.5H), 0.92 - 0.81 (m, 0.5H).
Exampie 30: (±)■·( 5 -fluoro-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridm-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methan.one.
Figure imgf000092_0001
Prepared analogous to Example 22 substituting intermediate A-1 with intermediate A- 10.
MS (ESI) mass calcd. for II .;lvN.?<).>.411.2; m/z found 412.2 ;\l Hi . Ή NMR ·:< IK hi: 7.98 (dd, J= 7.4, 3.0 Hz, 1H), 7.86 (did, J= 21.7, 8.9, 4.7 Hz, 1H), 7.81 - 7.75 (m, 1.5H), 7.38 - 7.03 (m, 3.5H), 6.72 (dd, J= 9.0, 3.6 Hz, 0.5H), 6.52 (dd, J = 9.0, 3.6 Hz, 0.5H), 4.85 - 4.75 (m, ill).4.17 - 4.02 (m, ill).4.02 - 3.83 (m, ill).3.83 - 3.75 (m, 1H), 2,34 - 2.15 (m, 1H), 2.03 - 1.80 (m, 1H), 1.74 - 1.20 (m, 5H).
Example 31 : (rt)-(2~fiuoro~6-(pyrimidin~2~yl)pheny
methanone.
Figure imgf000092_0002
Prepared analogous to Example 22 substituting intermediate A-1 with intermediate A-6. MS (EST) mass calcd. for C23H20F2N4O2, 422.2; m/z found 423.2 [M+Hf . lH NMR (CDCI3): 8.93 - 8.61 (m, 1.8H), 8.15- 7.92 (m, 1.6H), 7.56 - 7.05 (m, 4.3H), 6.94 (t, J= 8.6 Hz, 0.3H), 6.73 (ddd, ./ === 8.9, 5.2, 3.5 Hz, 0.6H), 6.59 - 6.35 (m, 0. Hi.4.99 - 4.79 fm, 1H), 4.31 (t, ./ === 9.9 Hz, 0.3H), 4.25 - 3.63 (m, 2.7H), 2.47 -1.11 (ra, 7H).
Example 32: (±)-(5-fluoro-2-(pyr rddin-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- ethanone.
Figure imgf000092_0003
Prepared analogous to Example 22 substituting intermediate A-1 with 5-†luoro-2-
(pyrimidin-2-yl)beiizoic acid. MS (ESI) mass calcd. for C23H20F2N4O2, 422.2; m/z found 423.2 I ]H NMR (500 MHz, CDCI3) 8.78 (d, J= 4.9 Hz, 1H), 8.72 (d, J= 4.8 Hz, 1H), 8.22 (ddd, J= 20.6, 8.7, 5.5 Hz, 1H), 8.01 - 7.93 (m, I H), 7.37 - 7.27 (m, H), 7.23 - 7.13 (m, 1 .5H), 7.13 - 6.99 (m, 1.5H), 6.72 (dd, J 9.0, 3.5 Hz, 0.5H), 6.52 fdd, J= 9.0, 3.5 Hz, 0.5H), 4.90 - 4.75 (m, IH), 4.25 - 3.91 (m, 2H), 3.91 - 3.78 (m, IH), 2.39 - 2.15 (m, IH), 2.08 - 1.13 (m. 61 ! )
Example 33: (±)-(2-(((5-fluoropyridk-2-yl)oxy)memyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5- ])methanone.
Figure imgf000093_0001
Prepared analogous to Example 22 substituting intermediate A-1 with 5-methyl-2- (pyrimidm-2-yl)benzoic acid. MS (ESI) mass calcd. for C24H23FN4O2, 418.2; m/z found 419.2 I i i ; . ]H NM (CDCI3): 8.81 - 8.68 (m, 2H), 8.09 (dd, J- 9.9, 8.0 Hz, IH), 7.98 (dd, J - 8.6, 3.1 Hz, IH), 7.41 - 7.24 (m, 1.5H), 7.22 - 7.16 (m, IH), 7.16 - 7.09 (m, 1.5H), 6.73 (dd, J = 9.1, 3.6 Hz, 0.5H), 6.52 (dd, J= 9.0, 3.6 Hz, 0.5H), 4.88 - 4.77 (m, I H), 4.21 - 4.01 (m, I H), 4.01 - 3.89 (m, IH), 3.88 - 3.76 fm, IH), 2.42 (s, 1.6H), 2.35 - 2.10 (m, i l l ). 2.07 - 1.81 (m, 2.4H), 1.81 - 1.16 (m, 5H). Example 34: (±)-(2-(2H- 1 >2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyi)-7- thanone.
Figure imgf000093_0002
Step A: (±)-2-(-7-azab"icyclo[2.2.1]heptan-2-ylmethoxy)quinoxaline. To intermediate B- 10 (2.40 mg, 1.1 mmol) in THF (4 mL) was added NaOtBu (130 mg, 1.4 mmol). The reaction was heated at reflux for 15 min and 2-ch.loroquinoxaline (207 mg, 1.3 mmol) was added. After 45 min, the reaction was cooled to rt and ½ saturated NH4CI (aq) was added. The solution was made slightly basic with 5% Na2C03 (aq) and extracted with DCM (3X). The combined organics were dried (Na2S04). The resulting compound was treated with TFA in DCM. After the reaction was complete, the reaction was concentrated, neutralized with 5% Na^COs and extracted with DCM. The combined organics were dried (Na^S L). Purification via silica gel chromatography (1-7% (2M NH3 in MeOH)/DCM) gave the title compound (208 mg, 78%). MS (ESI) mass calcd. for C15H17N3O, 255.1 ; m/'z found 256.2 [M+H] ~.
Step B: (±)-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 7 substituting 6- methyl-3-(2H-l ,2,3-triazol-2-yl)picolinic acid with intermediate A-1 and (±)-2-(((5- fJuoropyridin-2-yl)oxy)methyi)-7-azabicyclo[2,2.1 Jheptane with the title compound of Step A. MS (ESI) mass calcd. for C24H22N6O2, 426.2; m/z found 427.2 j \M 1 1 Ή NMR (CDClj): 8.49 (s, 0.5H), 8.31 - 8.21 (s, 0.5H), 8.08 - 7.98 (m, 1H), 7.95 - 7.75 (m, 3.4H), 7.75 - 7.66 (m, 1.1H), 7.65 - 7.50 (m, 1.7H), 7.50 - 7.39 (m, 1.1H), 7.36 - 7.28 (m, 1H), 7.24 - 7.13 (m, 0.7H), 4.92 - 4.80 (m, 1H), 4.47 - 4.28 (m, 1H), 4.22 - 4.07 (m, I H), 3.87 - 3.77 (m, H), 2.46 - 2.23 fm, 1.7H), 2.07 - 1.83 (m, 1.3H), 1.82 - 1.29 (m, 4H).
Example 35: (±)-(2-fluoro-6-(2H- i,2,3-triazol-2-y3)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- one.
Figure imgf000094_0001
Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A- 1 1. MS (EST) mass calcd. for (" ,:! ! l;N;,().:. 444.2; m/z found 445.2 j \! H i .Ή NMR (CDCI3): 8.52 - 8.47 (m, 0.5H), 8.27 - 8.21 (m, 0.4H), 8.07 - 7.95 (m, H), 7.91 - 7.09 (m, 7.8H), 6.72 - 6.63 fm, 0.3H), 4.98 - 4.87 (m, IH), 4.63 - 4.54 (dd, J - 10.7, 9.1 Hz, 0.5H), 4.46 - 4.29 (m, I H), 4.20 - 4.04 (m, 0.5H), 3.96 - 3.76 (m, IH), 2.51 - 2.23 (m, IH), 2.17 - 1.88 (m, IH), 1.84 - 1.19 (m, 1 ! :·.
Example 36: (±)-(5-methyl-2-(2H-lJ2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000095_0001
Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A-37, MS (ESI) mass calcd. for C b :\,..( 440.2; m/z found 441.2 ; M H | . I I MR ·: < I K h i: 8.49 (s, 0.5H), 8.26 (s, 0.5H), 8.03 (ddd, J = 8.3, 4.4, 1.4 Hz, 1H), 7.90 - 7.74 (m, 3H), 7.74 - 7.65 (m, H), 7.59 (dddd, J - 8.3, 7.0, 4.8, 1.4 Hz, 1H), 7.33 (ddd, J - 8.3, 1.9, 0.9 Hz, 0.6H), 7.29 - 7.22 (m, IH), 7.21 - 7.10 fm, 1.4H), 4.90 - 4.79 (m, 1 H), 4.46 - 3.98 (m, 2H), 3.91 - 3.72 (m, l i b. 2.47 - 2.20 (m, 4H), 2.05 - 1.22 (m, 6H).
Example 37: (±)-(5-fluoro-2-(2H-l ,2,3-triazol-2-yl)pheny1)(2-((quinoxalin-2-y1oxy)inethyl)-7- ne.
Prepared analogous to Example 34 substituting intermediate A- 1 with intermediate A- 10. MS (ESI) mass calcd. for C^^FNgC , 444.2; m/z found 445.2 [M+H]+. !H NMR (CDC13): 8.55 - 8.44 (m, 0.5H), 8.36 - 8.23 (m, 0.5H), 8.08 - 8.00 (m, 1H), 7.90 - 7.55 (m, 5H), 7.49 - 7.09 (m, 3H), 4.91 - 4.82 (m, 1H), 4.50 - 4.29 (m, IH), 4.23 - 4.07 (m, IH), 3.82 (dd, J = 10.0, 5.0 Hz, IH), 2.48 - 2.25 (m, IH), 2.09 - 1.88 (m, IH), 1.82 - 1.31 (m, 5H).
Example 38 : (±)-(5-methyl-2-(pyrimidin-2-y1)^^
thanone.
Figure imgf000095_0003
Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A-34. MS (ESI) mass caicd. for C27H25N5O2, 451.2; m/z found 452.2 [M+H]+. !H NMR (CDCI3): 8.87 - 8.79 (m, IH), 8.75 - 8.68 (m, IH), 8.49 (s, 0.5H), 8.27 (s, 0.5H), 8.14 - 7.98 (m, 2H), 7.85 (ddd, J - 16.5, 8.3, 1.5 Hz, IH), 7.74 - 7.66 (m, IH), 7.64 - 7.54 (m, IH), 7.35 - 7.29 (m, 0.5H), 7.24 - 7.19 (m, 0.5H), 7.18 - 7.07 ·: m. 2H), 4.94 - 4.83 (m, IH), 4.52 - 4.07 (m, 2H), 3.93 - 3.82 (m, IH), 2.51 - 2.20 (m, 2.6H), 2.08 - 1.83 (m, 1. U s. 1.81 - 1.12 (m, 6H).
Example 39: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptaii-7- -methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000096_0001
Step A: (±)-2-(((4,6-dimethyipyrimidin-2-yl)oxy)metliyl)-7-azabi
Prepared analogous to Example 34 substituting 2-cbloroquinoxaline with 2-chloro-4,6- dimethylpyrimidme. 1 1 NMR (CDCI3): 6.65 (s, IH), 4.21 - 3.99 ·: m. 2H), 3.74 - 3.56 (m, 2H), 2.39 (s, 6H), 2.14 (ddd, J= 9.0, 5.1, 3.7 Hz, IH), 1.86 (s, 2H), 1.67 - 1.49 (m, 2H), 1.47 - 1.30 (m, 2H).
Step B: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 jlieptan-7- yl)(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone. Prepared analogous to Example 7 substituting 6-meihyi-3-(2H~l,2,3-triazol-2-yl)picolinic acid with 5-inethyl-2-(2H- 1,2,3 -triazol- 2-yl)benzoic acid and (±)-2-(((5-fluoropyridin-2-yj.)oxy)methyl)-7-azabicyclo[2.2.1] heptane with the title compound of Step A. MS (ESI) mass calcd. for CaHzeNeOz, 418.2; m/z found 419.2 I I - 1 1 ] 1 1 NMR (CDCU): 7.83 - 7.70 (m, 2.5H), 7.35 - 7.10 (m, 2.5H), 6.71 - 6.65 (m, IH), 4.87 - 4.72 (m, IH), 4.34 (dd, J = 10.5, 8.8 Hz, 0.5H), 4.14 - 3.89 (m, 2H), 3.79 - 3.70 (m, 0.5H), 2.48 - 2.18 (m, 7.5H), 2.07 - 1.83 (m, 2.5H), 1 .79 - 1.1 8 (m, 6H). Example 40: (±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -methyl-5-phenylisoxazol-4-yl)methanone.
Figure imgf000097_0001
Prepared analogous to Example 39 substituting 5-methyl-2-(2H- l ,2,3-triazol-2- yl)benzoic acid with 3-methyl-5-phenylisoxazole-4-carboxylic acid. MS (ESI) mass calcd. for C24H26N4O3, 418.2; m/z found 419.2 [M+Hf . ;H NMR (CDCI3): 7.67 (m, 2H), 7.50 - 7.31 (m, M l ). 6.69 {·:!. J - 6.7 Hz, i l l ). 4.74 (dd, J - 10.8, 5.1 Hz, i l l ). 4.17 (dd, J - 10.8, 9.2 Hz, 0.5H), 3.85 - 3.78 (m, 1H), 3.70 id, J = 4.9 Hz, 0.5 ! h. 3.64 - 3.42 (m, 1H), 2.55 (s, 1 .4H), 2.49 (s, 1.6H), 2.43 (s, 3H), 2.39 (s, 3H), 2.29 - 2.07 (m, 1H), 1.90 - 1.55 (m, 2H), 1.53 -■ 1.06 (m, 3H), 0.76 - 0.53 (m, 1H).
Example 41 : (±)-(2-(((4,6-dimethylpyritnidin-2-yi)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -ethoxynaphthalen- 1 -yl)methan.one.
Figure imgf000097_0002
Prepared analogous to Example 39 substituting 5-methyl-2-(2H- l ,2,3-triazol-2- yl)benzoic acid with 2-ethoxy- 1 -naphthoic acid. 1 H NMR (CDCI3): 7.91 - 7.70 (m, 2.5H), 7.67 - 7.54 (m, 0.5H), 7.49 - 7.38 (m, 0.8H), 7.37 - 7.28 (m, 0.8H), 7.27 - 7.16 (m, 0.9H), 7.10 - 7.02 (m, 0.5H), 6.70 (s, 0.2H), 6.65 (s, 0.5H), 6.53 (s, 0.3H), 5.09 - 4.95 (m, 1H), 4.56 - 4.47 (m, 0.5H), 4.28 - 3.87 (m, 3.3H), 3.79 - 3.55 (m, 1.2H), 2.46 - 2.35 (m, 4.5H), 2.28 (s, 1.5H), 2.21 - 1.95 (m, 2H), 1.85 - 1 .5 f m, 3.5H), 1.51 - i .24 (m, 4.5H).
Example 42: (±)-(2-(((4,6-dimerthyipyrimidm^
yl) (2- ethoxyphenyl)methan one) ,
Figure imgf000098_0001
Prepared analogous to Example 39 substituting 5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)benzoic acid wiih 2-ethoxybenzoic acid, MS (ESI) mass caled. for C22H27N3O3, 381.2; m/z found 382.2 [M+H]+. 'H NMR (CDCI3): 7.34 - 7.27 (m, I H), 7.21 - 7.12 (m, I H), 6.98 - 6.92 (m, 0.5H), 6.89 (d, J - 8.2 Hz, 0.5H), 6.78 (d, J - 8.3 Hz, 0.5H), 6.72 - 6.63 (m, 1 .5H), 4.89 - 4.78 (in, I H), 4.36 (dd, J = 10.6, 8.7 Hz, O.SH), 4.14 - 3.71 (m, 4.5H), 2.45 - 2.16 (m, 6.5H), 2.06 - 1.82 (m, 1.5H), 1.82 - 1.28 (m, 8H).
Example 43 : (i)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -fluoro-6-(pyrimidin-2~yI)phenyl)methanone.
Figure imgf000098_0002
Prepared analogous to Example 39 substituting 5-methyl-2-(2H- l ,2,3-tria.zol nzoic acid with 2-fluoro-6-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass caled
C24H24F 5O2, 433.2; m/z found 434.2 [M+Hf . Ή NMR (CDCI3): 9.02 - 8.90 (m, 0.7! I ). 8.82 - 8.65 (m, 1.3H), 8.14 -■ 7.95 (m, IH), 7.58■- 7.31 (m, 1H), 7.31■- 7.07 (m, 1.7H), 6.97 - 6.86 (m, 0.3H), 6.75 - 6.51 (m, IH), 4.96 - 4.83 (m, IH), 4.55 (dd, J = 10.3, 9.0 Hz, 0.25H), 4.36 (dd, I = 10.6, 8.9 Hz, 0.25H), 4.21 - 3.78 (m, 2.5H), 2.48 - 1.17 (m, 1 3H).
Example 44: (±)-(2-(((4,6-dimethylpyrmiidin-2-yI)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7 -fluoro-2-(pyrimidin-2-yl)phenyI)methanone.
Figure imgf000098_0003
Prepared analogous to Example 39 substituting 5-methyl-2-(2H- l ,2,3-triazol-2- yl)benzoic acid with 5-fluoro-2-(pyritnidin-2-yl)benzoic acid. MS (ESI) mass calcd, for Q24H24FN5O2, 433.2; m/z found 434.2 [M+H]+. Ή NMR (CDCI3): 8.88 - 8.78 (m, 1 H), 8.72 (d, J - 4.8 Hz, IE), 8.26 (dd, J - 8.7, 5.5 Hz, 0.5H), 8.22 - 8.16 (m, 0.5H), 7.29 - 7.09 (m, 2H), 7.06 - 6.97 ( in. I l . 6.68 (s, 1 H), 4.88 - 4.81 (m, i l l ). 4.40 (t, J = 9.7 Hz, 0.51 0. 4.25 (t, J = 10.8 Hz, 0.5H), 4.05 (dd, J = 10.2, 6.2 Hz, 0.5H), 3.99 - 3.91 (m, 1H), 3.89 - 3.80 (m, 0.5H), 2.45 - 2.21 (m, 7H), 2.05 - 1 .87 (m, 1H), 1.81 - 1 .30 (m, 5H).
Example 45: (±)-(2-(((4,6-dimethylpyritnidin-2-yI)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -methyl-2-(pyri.midm-2-yl)phenyj.)methanone.
Figure imgf000099_0001
Prepared analogous to Example 39 substituting 5-methyl~2~(2H- l ,2,3~triazol-2- ylibenzoic acid with 5-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C25H27N502, 429.2: m/z found 430.2 [M+Hf . ¾ NMR (CDCI3): 8.83 (d, J - 5.0 Hz, 1H), 8.71 (d, J = 4.8 Hz, 1 H), 8.09 (dd, J = 13.6, 8.0 Hz, 1 H), 7.33 - 7.10 (m, 3H), 6.68 (d, J = 1 .4 Hz, 1 H), 4.90 - 4.79 (m, 1 H), 4.41 (dd, J - 1 0.4, 8.8 Hz, 0.5H), 4.20 (t, J - 10.6 Hz, 0.5H), 4.07 - 3.94 (m, 1 .5H), 3.80 (t, J === 4.7 Hz, 0.51 1 ;·. 2.49 - 2.19 (m, 7H), 2.04 - 1.89 (m, 3H), 1.87 - 1.47 (m, 4.5H), 1.45 - 1.29 (m, 1.5H).
Example 46: (±)-(2-(((4,6-dimethylpyrimid"in-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan- -ifhiophen-2 -yl)phenyl)methanone.
Figure imgf000099_0002
Prepared analogous to Example 1 1 substituting (±)~2-(((5-iluoropyridin-2- yl)oxy)methy{)-7~azabicyclo[2.2.1 Jheptane with (±)-2-(((4,6-dimethy]pyrimidm-2- yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane. MS (ESI) mass calcd. for C24H25N3O2S, 419.2; m/z found 420.2 i \) 1 1 1 H NMR (400 MHz, CDC13): 7.55 - 6.83 (m, 71 i ·. 6.75 - 6.62 (m, 1H), 4.87 - 4.62 (m, l i b. 4.09 - 3.38 (m, 3H), 2.54 - 2.32 (m, U s. 2.32 - 2.03 (m, 1H), 1.97 - 0.87 (m, 6H). Example 47: (±)-(6-methyl-3-(2H- 1
Figure imgf000100_0001
)methyl)-7-azabicyclo[2.2.1 ]hepian-7-yi)meihanone.
Figure imgf000100_0002
Step A: (±)-2-(((5-(trifiuoroniethy
Prepared analogous to Example 49 substituting 5-bromo-2-fluoropyridine with 2-fluoro-5- (trifluoromethyl)pyridine. MS (ESI) mass calcd. for C13H15F3N2O, 272.1 ; m/z found 273.1 , I f 1 j
Step B: (±)-(6-methyl-3-(2H- l ,2,3-triazol-2-y3)p rridin-2-yl)(2-(((5- (trifluoromemyl)pyridin^ Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3- (2H- 1 ,2,3-rriazol-2-yl)picolinic acid and (1 S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2. I ]heptane-7-carboxylate with the title compound of Step A, MS (EST) mass calcd. for C ^! h F : \ 458.2; m/z found 459.2 [ M i s ] !H NMR (CDCI3): 8.47 - 8.37 (m, 1 H), 8.12 (dd, J = 13.2, 8.4 Hz, H I ). 7.85 - 7.69 (m, 3H), 7.32 (dd, J = 8.4, 0.6 Hz, 0.51 1 }. 7.22 (dd, J - 8.4, 0.6 Hz, 0.5H), 6.88 - 6.82 (m, 0.5H), 6.69 - 6.59 (m, 0.5H), 4.93 - 4.81 (m, 1 H), 4.39 - 4.18 (m, 2H), 3.94 - 3.87 (m, 1 H), 2.65 - 2.60 (s, 1 .2H), 2.39 - 2.22 (m, 2.8H), 2.1 1 - 1 .33 (m, 6H).
Example 48: (±)-(3-ethoxy-6-methyjpyridm-2-yl)(2-(((5-('trifluoromethyl)pyri
yl)oxy)methyl)-7-azabicyclo[2.2.1 ]beptan-7-yr)methanone.
Figure imgf000100_0003
Prepared analogous to Example 47 substituting 6-methyl-3-(2H-l ,2,3-triazol-2- yl)picolinic acid with 3-ethoxy-6-niet ylpicolinic acid. MS (ESI) mass calcd. for C22H24F3 3Q3. 435.2; mix found 436.2 [M+Hf . lH NMR (CDCI3): 8.43 - 8.35 (m, 1H), 7.79 - 7.68 (m, 1 H), 7.1 8 - 7.07 (m, I H), 7.07 - 6.96 (m, 1H), 6.86 (d, J - 8.7 Hz, 0.5H), 6.64 (d, J - 8.7 Hz, 0.5H), 4.92 - 4.86 (m, i l l ). 4.29 - 4.20 (m, Hi), 4.19 - 4. 0 (m, i i ! ). 4.10 - 3.83 · η·. 2H), 3.74 (t, J = 3.9 Hz, IH), 2.52 - 2.47 (s, 1.5H), 2.41 - 2.32 (m, 0.5H), 2.28 - 2.18 (m, 2H), 2.07 - 1.84 (m, 2H), 1.78 - 1.63 (m, IH), 1.62 - 1.41 (m, 3H), 1.37 (dt, J = 1 1 .8, 7.0 Hz, 3H).
Example 49: (±)-(2-(((5-bromopyridin-2-yl)oxy)nieth.yl)-7-azabicyclo[2.2.1]heptan-7-yl)(6- 1)pyridin-2-yl)methanone.
Figure imgf000101_0001
Step A: (±)-2-(((5-bromopyrid n-2-y])oxy)methyi)-7-azabicyclo[2.2.1 Jheptane. To intermediate B-10 (175 mg, 0.8 mmol) in DMF (3.5 mL) at 0 °C was added NaH (60 wt% in mineral oil, 37 mg, 0.9 mmol). After 30 niin, 5-bromo-2-fluoropyridine ( 190 mg, 1.1 mmol) in DMF (0.5 mL) was added dropwise and the 0 °C ice bath was removed. After 2h, brine was added and the reaction extracted with EtOAc (2.X). The combined organics were washed with brine and dried (Na2S04) to give a clear oil which was treated with TFA and DCM (1 : 1, 10 mL). After 2h, the reaction was concentrated, dissolved in DCM and neutralized with 5% Na2C03 (aq). The combined organics were extracted with DCM (3X) and dried (Na2S04) to give the title compound that was used in subsequent reactions without further purification. MS (ESI) mass calcd. for C i 3 rN .( ). 282.0; m/z found 283.1, 285.1 i VI I ! ] NMR (500 MHz, CDCI3): 8.17 (d, J= 2.5 Hz, H), 7.63 (dd, J = 8.8, 2.5 Hz, I H), 6.65 (d, J = 8.8 Hz, H), 4.08 - 3.99 (m, 2H), 3.65 (t, J= 4.5 Hz, I H), 3.59 (d, ./ 4.1 Hz, IH), 2.12 - 2.06 (m, I H), 1.87 (s, I H), 1.68 - 1.52 (m, 21 1 ;·. 1.45 - 1.13 (m, 3H), 0.95 - 0.76 (m, IH).
Step B: Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-l,2,3-triazo]-2-yl)picolinic acid and (lS,2R,4R)-tert-butyl-2-((pyri.din- 2-yloxy)methyl)-7-azabicycfo[2.2.1 jheptane-7-carboxylate with the title compound of Step A. MS (ESI) mass calcd. for ( > \ \ > Μΐ\ί ) 468.1 ; m/z found 469.1 , 471.1 [M+H] r. 'H MR (CDC13): 8.20 (d, J - 2.6 Hz, 0.4H), 8.16 (d, J = 2.6 Hz, 0.6H), 8.13 (d, J = 8.3 Hz, 0.4H), 8.10 id, J = 8.4 Hz, 0.6! ! ·. 7.82 - 7.77 (m, 11 1 ). 7.64 (dd, J = 8.8, 2.6 Hz, 0.4H), 7.60 fdd, J = 8.8, 2,6 Hz, 0.6H), 7.33 - 7.29 (m, 0.4H), 7.22 (d, J - 8.4 Hz, 0.6H), 6.69 (d, J = 8.8 Hz, 0.4H), 6.50 (d, J = 8.8 Hz, 0.6H), 4.84 (dd, J = 1 1.1 , 5.2 Hz, 1H), 4.30 - 4.04 (m, 2H), 3.93 - 3.85 (m, H), 2.62 (s, 1 .3H), 2.38 - 2.1 7 (m, 2.7H), 2.1 1 - 1 .95 (m, 1H), 1.94 - 1 .77 (m, 1H), 1.77 - 1 .40 (m, 4H).
Example 50: (±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2JJheptan-7-yl)(3- fluoro -2-methoxypheny l)methan one .
Figure imgf000102_0001
Prepared analogous to Example 49 substituting 6-methyl-3-(2H- l ,2,3-triazol-2- yl)picoiinic acid with 3 -fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for
C2oH2oBrf?N2i¾, 434.1 ; m/z found 435.1 , 437.1 [M+H]+. !H NMR (CDC13): 8.19 - 8.12 (m, IH), 7.61 (ddd, J - 26.6, 8.8, 2.5 Hz, IH), 7.16 - 6.98 (m, 2H), 6.96 (dt, J - 7.6, 1 .3 Hz, 0.5H), 6.85 - 6.81 (m, 0.5H), 6.69 fdd, J = 8.8, 0.8 Hz, 0.5H), 6.46 (d, J - 8.7 Hz, 0.SH), 4.88 - 4.77 (m, i l l ). 4.17 - 4.06 (m, IH), 4.03 - 3.86 (m, 4H), 3.81 - 3.75 (m, IH), 2.37 - 2.22 (m, IH), 2.04 - 1.40 ( m, 61
Example 51 : (±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2
ethoxy-6-methyipyridin-2-yl)methanone.
Figure imgf000102_0002
Prepared analogous to Example 49 substituting 6-methyl-3-(2H- 1 ,2,3-triazol-2- yl)picofinic acid with 3-ethoxy-6-methylpicolinic acid. MS (EST) mass calcd, for
Figure imgf000102_0003
445.1 : m/z found 446.1 , 448.1 [M+H]+. Ή NMR (CDCI3): 8.17 - 8.1 1 (m, IH), 7.61 (ddd, - 19.5, 8.8, 2.6 Hz, IH), 7.16 - 7.06 (m, IH), 7.05 - 6.96 (m, IH), 6.69 (dd, J = 8.8, 0.7 Hz, 0.5H), 6.47 (dd, J - 8.8, 0.7 Hz, 0.5H), 4.90 - 4.84 (m, I H), 4.20 - 4.10 (m, I H), 4.09 - 3.82 (m, 3H), 3.78 - 3.72 (m, Hi), 2.50 (s, 1.4H), 2.38 - 2.25 (m, 2.61 1 ·. 2.04 - 1.84 (m, 2H), 1.75 - 1.40 (m,
4H), 1.60 - 1.40 (m, 3H), 1.36 (dt, J = 7.8, 7.0 Hz, 3H). Example 52: (±)-(3-fluoro-2-(pyrimicUn-2-yl)phenyi)(2-((pyridin-2~yioxy)methyl)-7- azabicyelo[2.2, 1 ]heptan-7-yl)raethanone.
Figure imgf000103_0001
Prepared analogous to Example 1 substituting 5-fiuoro-2~(pyrim din-2-yl)benzoic acid with 3-fluoro-2-(pyrimidm-2-yl)benzoic acid and intermediate B-9 with intermediate B- 10. MS (ESI) mass calcd. for C23H21FN402) 404.2; m/z found 405.2 j \ 1 · i 1 1 Ή NMR (CDCi3): 8.81 (dd, J = 18.0, 4.9 Hz, 2H), 8.20 - 8.12 (m, 1 H), 7.56 (ddd, J = 8.3, 7. 1, 2.0 Hz, 1 H), 7.45 (td, J = 8.0, 5.1 Hz, 0.5H), 7.28 - 7.22 (m, I .5H), 7.21 - 7.08 (m, 1.5H), 7.05 - 6.96 (m, 0.5H), 6.88 (dddd, J = 13.2, 7.1 , 5.1 , 1.0 Hz, 1H), 6.71 [d\. 8.4, 0.9 Hz, 0.51 1 ). 6.61 it. J 8.4, 0.9 Hz, 0.5H), 4.70 - 4.61 (m, 1H), 4.15 - 4.07 (m, 1H), 4.06 - 3.89 (m, 2H), 2.26 (ddt, J = 15.3, 8.3, 4.5 Hz, 1 H), 1.93 - 1.27 (m, 6H).
Example 53 : (±)-(6-methyl-3 -(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridazin-3■
y1oxy)methy{)-7~azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000103_0002
Step A: (±)-ieri-butyl 2-((pyridazin-3-yioxy)methyl)-7-azabicyclo[2.2.1 ]heptane-7- carboxylate. To intermediate B- 10 (266 mg, 1 .2 mmol) in THF (4 ml.,) at 0 °C was added NaH (60 wt% in mineral oil, 70 mg, 1.8 mmol). After 15 min, 3-chforopyridazine (.160 mg, 1 .4 mmol) was added. The reaction allowed to wann to rt. After 18h, H?0 was added and the mixture extracted with EtOAc. The organic layer was dried. Purification via silica gel chromatography (0-30% EtOAc in heptane) gave the title compound (300 mg, 90%). MS (ESI) mass calcd. for C16H73 3O3, 305.2; m/z found 306.0 ί \ I - 1 1 ] Step B: (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1 ]heptaiie hydrochloride. To the title compound from step A (300 mg, 1 mmol) in 1 ,4-dioxane (3 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70 °C for 3h, cooled to it and concentrated to give the title compound that wras used without further purification. MS (EST) mass calcd. for C11H15N3O, 205.1 ; m/z found 206.0 j V! · Π j
Step C: (±)-(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)(2-((pyridazin-3- yioxy)methyl)-7-azabicyc1o[2.2.1 ]beptan-7-yl)methanone. To 6-methyl-3-(2H- 1 ,2,3-triazol-2- ylipicoiinic acid (270 mg, 1.3 mmol) in DMF (3 mL) was added DIPEA (630 μΕ, 3.6 mmol), HBTU (590 mg, 1.5 mmol) and the title compound from step B (250 mg, 1 mmol). After stirring overnight, saturated aHCGs (aq) was added and the mixture extracted with EtOAc (3 ). The combined organics were dried (MgS04). Purification by reverse phase chromatography gave material that was triturated with Et20/pentane to give the title compound (1 15 mg, 28%) as a beige solid. MS (ESI) mass calcd. for C20H21N7O2, 391.2; m/z found 392.2 [M+H]+. Ή NMR (DMSO-De): 8.91 (dd, J = 8.5, 4.4 Hz, 1H), 8.23 - 8.04 (m, 3H), 7.69 - 7.52 (m, 1.5H), 7.41 (d, J= 8.4 Hz, 0.5H), 7.28 (d, J= 8.9 Hz, 0.5H), 7.10 (d, J= 8.9 Hz, 0.5H), 4.60 (t J - 4.8 Hz, 1H), 4.40 - 4.19 (m, 2H), 3.87 (t, J 4.3 Hz, 0.5H), 3.79 (d, ./ 4.3 Hz, 0.SH), 2.58 (s, 1 .51 1 ;. 2.46 - 2.24 (m, 1H), 2.06 (s, 1.5H), 1.81 - 1.34 (m, 6H).
Example 54: (±)-(6-methyl-3-(2H-l92 -triazol-2-yl)pyridin-2-yl)(2-(((2-methylpyTidin-3- yl)oxy)met yl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000104_0001
Step A: (±)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7- carboxylate. To intermediate B-10 (545 mg, 2,4 mmol) in DCM (12 mL) at 0 °C was added TEA (333 μΐ,, 2.4 mmol) followed by MsCl ( 190 μί, 2.4 mmol). After 2h, brine was added and the mixture was extracted with DCM (2X). The combined organics were dried (Na2S04) to give the title compound (650 mg, 89%) that was used without further purification. MS (EST) mass calcd. for C] 2H23 05S, 305.1 ; m z found 249.9 [ M - 55 1
Step B: (±)-tert-butyl 2-(((2-metb.ylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane- 7-carboxylate. To 2-methylpyridin-3-ol in DMF was added KOH. The solution was stirred for 30 min at ri, then the title compound from step A was added and the reaction was heated at 80 °C. After 5h, ¾0 was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgS04), Purification via silica gel chromatography (0-7% MeOH in DCM) gave the title compound (201 mg, 90%). MS (ESI) mass calcd. for C18H26N2O3, 318.2; m/z found 319.0 [M+i]+ .
Step C: (±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to example 53 step B substituting (±)-tert-buty1 2-((pyridazin-3-yloxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate with (±)-tert-butyl 2-(((2-methylpyridin-3- yl)oxy)methyl)-7-azabieyclo[2.2.1 Jheptane-7-carboxylate. MS (ESI) mass calcd. for C13H18 2O, 218.1 ; m/z found 219.1 [M+l ]+.
Step D: (±)-(6-methyl-3-(2H- 1 ,2,3-triazol-2-yI)pyridin-2-yl)(2-(((2-methylpyridin-3- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Prepared analogous to example 53 step C substituting (±)-2-((pyridazin-3-yloxy)methyl)-7- azabicyclo[2.2.1 jheptane hydrochloride with (±)-2-(((2-methy{pyridin-3-yl)oxy)methyl)-7- azabicyclo[2.2.1 jheptane. MS (ESI) mass calcd. for C22H24N602, 404.2; m/z found 405.2
[M- ii . !H NMR (DMSO-De): 8.22 - 7.92 (m, 4H), 7.55 (d, J- 8.4 Hz, 0.3H), 7.45 - 7.33 (m, 1H), 7.32 - 7.10 (m, 1.7H), 4. 60 - 4.57 (m, 1H), 3.92 - 3.67 (m, 3H), 2.57 (s, 0.9KQ, 2.42 - 2.18 (m, 1.9H), 2.08 (s, 2.1H), 1.95 (s, 2.1H), 1.80 - 1.31 (m, 6H). Example 55: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-y^
o[2.2.1]heptan-7-yl)methan.one.
Figure imgf000105_0001
Step A: (i-)-tert-butyl 2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2. ljheptane- 7-carboxylate. Prepared analogous to Example 7 Step A Method A substituting PBu3 with PPh3, DEAD with DIAD, 5-fluoropyridin-2(lH)-one with 3-methylpyridin-2-ol and performing the reaction at ri MS (EST) mass calcd. for
Figure imgf000105_0002
318.2; m/z found 319.0 [M+Hj+.
Step B: (±)-2-(((2-methylpyrid"in-3-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane. Prepared analogous to Example 53 Step B substituting (±)-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7- azabicyclo[2.2.1 jheptane-7-carboxylate with (±)-tert~butyl 2-(((2-methylpyridin-3- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. MS (ESI) mass calcd. for Ci3li|g ?0, 218, 1 ; m/z found 219.0 j .YJ f 11
Step C: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-y])p^
y])oxy)methyI)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanoi e.
Prepared analogous to Example 53 Step C substituting (±)-2-((pyridazin-3-yloxy)methyl)-7- azabicyclo[2.2.1]heptane hydrochloride with (±)-2~(((2-methylpyridin-3-yl)oxy)rnethyl)~7- azabicyclo[2.2.1 jheptane. MS (ESI) mass calcd. for C22H24 602, 404.2; m/z found 405.2 i \) H I Example 56: (±)-(2-(((l -methyl- 1 H-pyrazol-5-yl)oxy)methy{)-7-azabicyclo[2.2.1 jheptan-7-yl)(6- 2-y3)pyridm-2-yl)methanone.
Figure imgf000106_0001
Step A: (±)-tert-butyl 2-((( I -methyl- 1 H-pyrazol-5-yl)oxy)methyl)-7- azabicycJo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 7 Step A Method A substituting THF with PhC¾ and 5-fluoropyridin-2(l H)-one with 1 -methyl- lH-pyrazol-5-ol. MS (ESI) mass calcd. for C16H25 3O3, 307.2; m/z found 308.0 [M+H]÷.
Step B: (±)-2-((( 1 -methyl- 1 H-pyrazol-5-yl)oxy)niethyl)-7-azabicyelo[2.2.1 jheptane. Prepared analogous to Example 53 Step B substituting (±)-tert-butyl 2-((pyridazin-3- yloxy)methyl)-7-azabicyclo[2.2.1 jheptane-7-carboxylate the title compound of Step A. MS (ESI) mass calcd. for C, 1H17N3O, 207.1 ; m/z found 208.0 j \ ί · Π j
Step C: (±)-(2-(((l-methyl-lH-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptan-7- yl)(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)methanone. Prepared analogous to Example 53 Step C substituting (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1 jheptane hydrochloride with the title compound of Step B, MS (ESI) mass calcd. for C20H23N7O2, 393.2; m/z found 394.2 [M+H] . H NMR (DMSO-D6): 8.1 8 - 8.05 (m, 3H), 7.56 (d, J= 8.4 Hz, 0.4H), 7.49 (d, J = 8.4 Hz, 0.6H), 7.23 (d, J= 1.7 Hz, 0.4H), 7.19 (d, J = 1.7 Hz, 0.61 i l 5.70 (d, J= 1.8 Hz, 0.4H), 5.59 id, J= 1.8 Hz, 0.6H), 4.59 - 4.56 (m, i l l ). 3.96 - 3.76 (m, 3H), 3.57 (s, 1.2H), 3.34 (s, 1.8H), 2.58 (s, 1.2H), 2.39 - 2.17 (m, 2.8H), 1.87 -- 1.27 (m, 6H). Example 57: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-yl)py
l)methanone.
Figure imgf000107_0001
Prepared analogous to Example 54 subsituting 2-raethylpyridin-3-ol with pyridin-4-ol. MS (ESI) mass calcd. for ( . !!, ¾),.390.2; m/z found 391.2 j V! · Π j Ή NMR (DMSO-D6): 8.41 (d, J = 5,5 Hz, 0.8H), 8.36 (d, J= 5.5 Hz, 1.2H), 8.20 - 8.02 (m, 3H), 7.55 (d, J = 8.4 Hz, 0.4H), 7.40 (d, J= 8.4 Hz, 0.6H), 7.00 (d, J= 6.2 Hz, 0.8H), 6.88 (d, J= 6.2 Hz, 1.2H), 4.64 - 4.51 (m, IH), 4.02 - 3.78 (m, 2.4H), 3.75 (d, J= 4.4 Hz, 0.6H), 2.57 (s, 1.2H), 2.39 - 2.20 (m, Mb.2.04 (s, 1.8H), 1.87 - 1.30 (m, 6H).
Example 58: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridm-2-yl)(2-((pyridm-3-yloxy)meth l)methanone.
Figure imgf000107_0002
Prepared analogous to Example 54 subsituting 2-methylpyridin-3-ol with pyridin-3-ol. MS (ESI) mass calcd. for C> il»N<.0>.390.2; m/z found 391.2 [M+H] . Ή NMR (DMSO-D6): 8.33 (d, J - 2.7 Hz, 0.4H), 8.21 - 8.05 (m, 4.6H), 7.55 (d, J= 8.4 Hz, 0.4H), 7.46 - 7.25 (m, 2.6H), 4.58 (t, J----- 4.8 Hz, IH), 3.95 - 3.80 (m, 2.4H), 3.77 (d, ./= 4.4 Hz, 0.6H), 2.57 (s, 1.2H), 2.38-2.18 (m, IH), 2.02 (s, i Hi I).1.85 -1.31 (m, 6H). Exampie59: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyriniidin-2-ylox
7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000108_0001
Prepared analogous to Example 53 substituting 2-chloropyridazine with 2- chloropyriniidine. MS (ESI) mass calcd. for C2oH2;N7G2, 391 ,2; m/z found 392.2 [M+H]+. !H NMR (DMSO-De): 8.65 (d, J= 4.8 Hz, 0.8H), 8.59 (d, J= 4.8 Hz, 1.2H), 8.22. - 8.02 (m, 3H), 7.56 (d, J = 8.4 Hz, 0.4H), 7.44 (d, J = 8.4 Hz, 0.6H), 7.19 - 7.13 (m, I H), 4.59 (t, J = 4.5 Hz, 0.6H), 4.55 (d, J= 4.4 Hz, 0.4H), 4.24 - 4.04 (m, 2H), 3.85 (t, J - 4.3 Hz, 0.4H), 3.78 (d, J = 4.0 Hz, 0 61 0. 2.58 (s, 1.2H), 2.39 - 2.21 (m, 1 H), 2.1 1 (s, 1.8H), 1.86 - 1 .29 (m, 6H).
Example 60: (±)-(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrazm-2-yloxy)methy -azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000108_0002
Prepared analogous to Example 53 substituting 2-chloropyridazine with 2-pyrazine. MS (ESI) mass calcd. for C20H21N7O2, 391.2; m/z found 392.2 [M+H . Example 61 :
Figure imgf000108_0003
(¾)yrimidin-4-yloxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000108_0004
Prepared analogous to Example 55 substituting 3-methylpyridin-2-ol with pyrimidin-4-ol. MS (EST) mass calcd. for C2OH2!NT02, 391.2; m/z found 392.2 [M+H]÷. The product is present as a mixtsire of conformers (ratio ca. 50:50) JH NMR (300 MHz, DMSO) 8.84 (s, 0.5H), 8.77 (s, 0.5H), 8.53 (d, ,/ 5.8 Hz, 0.51 0. 8.49 (d, ./ 5.8 Hz, 0.5H), 8.22 - 8.01 (m, 3H), 7.55 (d, ./ 8.4 Hz, O.SH), 7.43 id, J= 8.4 Hz, O.SH), 7.00 (d, J= 5.7 Hz, 0.5H), 6.85 (d, ,/ 5.8 Hz, 0.5H), 4.58 (t, J= 3.7 Hz, 0.5H), 4.53 (d, J= 4.2 Hz, 0.5H), 4.25 - 4.04 (m, 2H), 3.85 (t, J = 3.7 Hz, O.SH), 3.75 (d, J= 3.9 Hz, 0.5H), 2.57 (s, 1.5H), 2.40 - 2.16 (m, 1H), 2.12 (s, 1.5H), 1.85 - 1.31 (m, 6H).
Exanipie 62: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-yl)py^
yl)oxy)methyl)-7-azabicyelo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000109_0001
Prepared analogous to Example 55 substituting 3-methylpyridin-2-ol with 6- methylpyridin-2-ol. MS (ESI) mass calcd. for C22H24N0O2, 404.2; nv'z found 405.2 [M+Hf. Ή NMR (DMSO-De): 8.17 (d, J= 8.4 Hz, O.SH), 8.12 (d, J= 8.4 Hz, O.SH), 8.10 (s, I H), 8.06 (s, 1H), 7.63 - 7.49 (m, i .5Ti), 7.41 (d, J - 8.4 Hz, 0.5H), 6.85 (d, J = 7.2 Hz, O.SH), 6.81 (d, J= 7.2 Hz, O.SH), 6.64 i d. ./ 8.2 Hz, O.SH), 6.46 (d, J= 8.2 Hz, 0.5H), 4.58 (t, . 4.4 Hz, O.SH), 4.54 (d, J = 4.5 Hz, O.SH), 4.16 - 3.95 (m, 2H), 3.83 (t, J= 4.4 Hz, O.SH), 3.74 (d, J= 4.4 Hz, O.SH), 2.58 (s, 1.5H), 2.43 (s, 1 ,5H), 2.37 (s, 1 .5H), 2.33 - 2.14 (m, IH), 2.1 1 (s, 1 ,5H), 1.85 - 1.31 (m, 6H).
Example 63 : (±)-(2-(((5-fluoropyridin-2-yi)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- 2-yr)methanone.
Figure imgf000109_0002
Prepared analogous to Example 7 substituting intermediate A-21 with intermediate A-43. MS (ESI) mass calcd. for C22H2 F 4O3, 408.2; m/z found 409.2 [M+H}
Example 64: (i)-(2-(((5-fluoropyridin-2-yl)oxy)metb.yl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000110_0001
Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3- (pyrimidin-2-yl)picolinic acid. MS (ESI) mass calcd. for C23H22F 5O2, 419.2; m/z found 420,2. [M+H . ¾ NMR (DMSO-D6): 8.91 (d, J= 4.9 Hz, 0.8H), 8.84 (d, ,1= 4.9 Hz, 1.2H), 8.33 - 8.29 fni, 1H), 8.22 (d, J 3.1 Hz, 0.4H), 8.13 (d, ./ 3.1 Hz, 0.6H), 7.76 - 7.59 (m, IH), 7.53 - 7.41 (m, 1.4H), 7.35 (d, J= 8.1 Hz, 0.6H), 6.94 (dd, J= 9.1, 3.6 Hz, 0.4H), 6.75 (dd, J = 9.1, 3.6 Hz, 0.6H), 4.59 (t, J = 4.1 Hz, 0.6H), 4.56 (d,J=3.8 Hz, 0.4H), 4.16 (dd, J= 14.6, 6.2 Hz, IH), 4.08 - 3.97 (m, IH), 3.87 (br s, 0.4H), 3.76 (d, J= 3.9 Hz, 0.6H), 2.56 (s, I.2H), 2.39 - 2.15 (m, IH), 2.10 (s, I.8H), 1.91 1.32 (m, 6H).
Example 65: (±)-(3,6'-dimethyl-[2,3'-bipyrid¾
ethanone.
Figure imgf000110_0002
Prepared analogous to Example 7 substituting intermediate A-21 with 3,6'-dimethyl-[2,3'- bipyridine]-2'-carboxylic acid. MS (ESI) mass calcd. for C25H25FN4O2, 432,2; m/z found 433.2 [M+H]+. !H NMR (DMSO-De): 8.33 (t, J= 5.1 Hz, IH), 8.16 (s, IH), 7.79 - 7.60 (m, 3H), 7.40 (d, J === 7.9 Hz, 0.51!).7.32 - 7.23 (m, IH), 7.20 (dd, J= 7.6, 4.8 Hz, 0.510.6.85 (dd, ./ 9.1, 3.6 Hz, 0.5H), 6,80 (dd, J = 9.1, 3.6 Hz, 0.5H), 4.39 (brs, 0.5H), 4.35 (d, J= 4.1 Hz, 0.5H), 4.19 (f, J = 10.3 Hz, 0.5H), 4.04 (dd, J= 10.4, 5.2 Hz, 0.5H), 3.90 (d, J= 4.8 Hz, 0.5H), 3.85 (t, J =4.0 Hz, 0.5H), 3.75 - 3.53 (m, IH), 2.56 (s, 1.5H), 2.222.17 (m, 3.5H), 2.11 (s, 1.5H), 1.90 - 1.81 (m, 0.5H), 1.79 - 1.17 (m, 6H).
Example 66: (±)-(2-(((5-fluoropyridm-2-yi)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6- methyl-3-(3-methyl-{,2,4-oxadiazol-5-yl)pyridm-2-yf)methanone.
Figure imgf000111_0001
Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3-(3- methyl- 1 ,2,4- oxadiazol-5-y l)picolinic acid. MS (ESI) mass calcd. for C22H22F 503, 423.2; m/z found 424.2 [M+Hf. !H NMR (DMSO-D6): 8.33 (d, J = 8.1 Hz, 0.4H), 8.28 (d, J = 8.1 Hz, 0.6H), 8.14 (d, ,7 - 3.1 Hz, 0.4H), 8.10 (d, j = 3.1 Hz, 0.6H), 7.76 - 7.60 (m, 1H), 7.58 (d, J= 8.2 Hz, 0.41 n. 7.47 ( d. ./ 8.2 Hz, 0.6H), 6.95 (dd, 3.6, 9.2 Hz, 0.4H), 6.72 (dd, 3.6, 9.2 Hz, 0.6! I ·. 4.67 (t, ,/ 4.5 Hz, 0.6H), 4.62 (d, ./ - 4.6 Hz, 0.4H), 4.16 - 3.92 (m, 2H), 3.81 (t, . / 4.3 Hz, 0.4H), 3.73 (d, J = 4.6 Hz, 0.61 ! s. 2.60 (s, 1 .2H), 2.41 (s, 1.2H), 2.38 (s, 1.8H), 2.37 - 2.19 (m, I H), 2.1 8 (s, 1.8H), 1.90 - 1 .30 (m, 6 H i.
Example 67: (±)-(2-(((5-fluoropyridin-2-yl)oxy)met yl)-7-azabicyclo[
l- i-yi)pyridin-2-yl)methanone.
Figure imgf000111_0002
Prepared analogous to Example 7 substituting mtermediate A-21 with 6-methy3-3-(3- methyl- 1 H-pyrazol- 1 - l)picolinic acid. MS (ESI) mass calcd. for C23H24FN5O2, 421.2; m/z found 422.2 [M+H . MP=123.2°C.
Example 68 : (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- din-2-yl)niethanone.
Figure imgf000111_0003
Step A: 6-methyl-3-(pyrrolidin-l -yl)picolinonitrile. To 2-bromo-6-methyl-3-(2H- 1 ,2,3- triazol-2~yi)pyridine (720 nig, 3,7 mmol), pyrollidine (450 μ3_,, 5.5 mmol), Pd(OAc)2 (25 mg, 11 mol%), XPhos (122 mg, 25 mol%) and Cs2C03 (2.4 g, 7.3 mmol) in a sealed tube was added PhCH3. The vessel was sealed and heated at 100 °C overnight. After cooling to rt, the reaction was diluted with EtOAc and H20. The organic layer was dried (MgS04) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in DCM) gave the title compound ( 186
Step B: 6-methyi-3-(pyiToiidin- l-yi)picolinic acid. To the title compound of Step A ( 162 mg, 0.9 mmol) in EtOH (2.6 mL) was added 4M KOH (650 μΕ, 2.6 mmol). The reaction was then heated at 90 °C for 18h. Additional 4M KOH (1.5 mL,6 mmol) was added and heating continued overnight. The reaction was then cooled to rt, acidified with IN HQ (aq), concentrated and used without further purification in the next step.
Step C: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6- methyl-3-(pyrrolidin-l-yl)pyridin-2-y])methanone Prepared analogous to Example 7 substituting intermediate A-9 with the title compound from Step B. MS (ESI) mass calcd. for C23H27FN4O2, 410.2; m/z found 41 1.2 ; \) H i . Π NMR (DMSO-D6): 8.14 i d. ./ 3.0 Hz, 0.5H), 8.10 i d. ./ 3.0 Hz, 0.5H), 7.68 - 7.38 (m, 2H), 6.92 (dd, J= 9.1 , 3.6 Hz, 0.5H), 6.71 (dd, J = 9.1, 3.6 Hz, 0.5H), 4.66 (br s, 0.5H), 4.60 (br s, 0.5H), 4.08 - 3.01 (m, 7H), 2.45 (s, 1.5H), 2.40 - 2.01 (m, 2.5H), 1.94 - 1.30 (m, 10H).
Example 69: # (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- l)pyridin-2-yl)methanone.
Figure imgf000112_0001
Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3-(3- methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C23H23FN4O3, 422.2; m/z found 423.2 [M+Hf. Ή NMR (DMSO-D6): 8.11 (dt, J = 10.0, 5.4 Hz, 2H), 7.77 - 7.55 (m, 1H), 7.50 id, J 8.2 Hz, 0.4H), 7.38 (d, ./ 8.2 Hz, 0.6H), 6.94 ; dd. ./ 9.1, 3.6 Hz, 0.4H), 6.70 (dd, J = 9.1, 3.6 Hz, 0.6H), 6.62 (d, J= 1.6 Hz, 1H), 4.67 (t, J = 4.6 Hz, 0.6H), 4.61 i d. ./ 4.7 Hz, 0.4H),
- I l l - 3.98-3.88 (m, 2H), 3.60 (t, J 4.5 Hz, 0.4H), 3.54 (d, ./ 3.8 Hz, 0.6H), 2,55 (s, I .2H), 2.38 - 2.14 (m, 4H), 2.12 (s, 1.8H), 1.86 - 1.13 (m, 6H).
Example 70: (i)-(2-(((5-fluoropyridin-2-yl)oxy)meth.yl)-7-azabicyc1o[2.2.1 ]heptan-7~yl)(6- inethyl-3-( IIi-pyrazol-l-yl)pyrM^^^
Figure imgf000113_0001
Prepared analogous to Example 63 substituting 6-meihyl-3--(oxazoi--2-yl)picoiinic acid with 6-methyl-3-(1 H-pyrazol- 1 -yl)picolinic acid. MS (ESI) mass calcd. for C22H22FN5O2, 407.2; m/z found 408.2 [M+H]MH NMR (DMSO-D6): 8.17 i d. ./ 3. 1 Hz, 0.5H), 8.13 (d, 7= 3.1 Hz,
0.5H), 8.08 ( i. ./ 2.4 Hz, 1H), 7.95 i t. J 8.5 Hz, 1H), 7.74 - 7.61 (m, 2H), 7.49 UL ./ 8.3 Hz, 0.5H), 7.36 (d, J= 8.4 Hz, 0.5H), 6.91 (dd, J = 9.1, 3.6 Hz, 0.5H), 6.72 uki. J 9.1, 3.6 Hz, 0.5H), 6.52 - 6.49 (m, 0.5H), 6.49 - 6.46 (m, 0.5H), 4.55 (t, ./ 4.5 Hz, 0.5H), 4.50 i d../ 4.7 Hz, 0.5H), 3.94 (d, ,/ 7.6 Hz, 2H), 3.67 (t, ./ 4.2 Hz, 0.5H), 3.59 (d, ,/ 4.5 Hz, 0.5H), 2.54 (s, 1.5H), 2.30 - 2.1 1 (m, 1H), 2.07 (s, 1.5H), 1.76 - 1.14 (m, 6H).
Example 71 : (±)-(5-methyl-3-(2H- 1 ,2,3-triazoI-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyI)-7- methanone.
Figure imgf000113_0002
Prepared analogous to Example 2 substituting intermediate A-9 with 5-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass eaicd. for C21H22 6O2, 390.2; m/z found 391.0 i M - i i ; M P 159.7°C
Example 72: (d_)-(4-methyl-3-(2H-l,2,3-n'iazoI-2-yl)pyridin~2-yl)(2-((pyridin~2- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000114_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 4-methyl-3-(2H- l,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C21H22N6O2, 390.2; m/z found 391.0 | .YJ M j ' . U 4..v\ "
Example 73 : (±)-(3-(dimethylamino)-6-methylpyridm-2-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000114_0002
Step A: 3-(dimethylamino)-6-methylpicolinamide. A mixture of 3-bromo-6- metbylpicolinonitriie (lg, 5 mmof) and dimethylamine (2 mL) were heated in a microwave reactor for 2h at 140 °C. The mixture was then concentrated and purified via silica gel chromatography (0-5% MeOH in DCM) to give the title compound (2.49 mg, 27%). MS (ESI) mass calcd. for ( \,i l - ;S ;0. 179.1 ; m/z found 180.0 ; H i .
Step B: 3-(dimethylamino)-6-methylpicolinic acid. To the title compound of Step A (91 mg, 0.5 mmol) in EiOH ( 1 mL) was added 4M KOH (0.5 μΕ). The reaction was then heated at 90 °C for 18h. The reaction was then cooled to rt, acidified with IN HCl (aq) to pH=3, concentrated and used without further purification in the next step.
Step C: Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step B. MS (ESI) mass calcd. for C21H26 4O2, 366.2; m/z found 367 [M+H]+.
Example 74: (±)-(3-(2H- 1 ,2,3-triazol-2-yl)quinolin-2-yl)(2-((pyridin-2-ylox )methyl)-7- ethanone.
Figure imgf000115_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 3-(2H- l ,2,3-triazol- 2-yl)quinoline-2-carboxylic acid. MS (ESI) mass calcd. for€24Η22Νβ02, 426.2; m/z found 427.2 i V! · 1 Π lB NMR (DMSO-D6): 8.93 (s, 0.5H), 8.87 (s, 0.5H), 8.26 - 8.09 (m, 2H), 7.96 - 7.86 (m, 0.5H), 7.82 - 7.51 (m, 5H), 7.33 (d, J= 8.4 Hz, 0.5H), 7.00 (t, J = 6.0 Hz, 1H), 6.87 (d, J= 8.3 Hz, 0.5H), 6.52 (d, J = 8.3 Hz, 0.5H), 4.70 - 4.57 (m, 1H), 4.33 (t, J = 10.5 Hz, 0.5H), 4.24 - 4.05 (m, 1 .5H), 4.00 (br t, J= 3.8 Hz, 0.5H), 3.93 (d, J = 3.6 Hz, 0.5H), 2.44 - 2.20 (m, I I I ). 2.01 --- 1 .35 (m, 6Ii).
Example 75: (±)-(7-etboxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000115_0002
Prepared analogous to Example 2 substituting intermediate A-9 with intermediate A-29. MS (ESI) mass calcd. for C > :H >.;\ ;C> ;. 403.2; m/z found 404.2 [M+Hf. Ή NMR (DMSO-D6): 9.02 - 8.54 (m, 1 .6H), 8.42 (d, J = 7.9 Hz, 0.8H), 8.31 - 7.83 (m, 2.2H), 7.83 - 6.75 (m, 3.8H), 6.64 - 6.46 (m, 0.2H), 6.24 (m, 0.4H), 4.86 - 4.62 (m, 1.2H), 4.46 - 4.01 (m, 3.6H), 3.61 - 3.23 (m, 1.2H), 2.44 - 2.06 (m, 1H), 2.06 - 1.15 (m, 9H).
Example 76 : (±)-(3,6-dimethylimidazo [ 1 , 2-a]pyridin-5 -yl)(2-((pyridm-2-yloxy)methyl)- 7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000116_0001
Step A: 3,6-dimethylimidazo[l,2-a]pyridine-5-carboxylic acid. Prepared analogous to Example 82 substituting chloroacetaldehyde with 2-bromopropanal, MS (ESI) mass calcd. for CioHio 202, 190.1 ; m/z found 191.0 ; U j
Step B: (±)-(3,6-dimethylimidazo[ l
Figure imgf000116_0002
azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step A. MS (ESI) mass calcd. for C22H24 4O2, 376,2; m/z found 377.2 [M+HTf. The product is present as a mixture of conformers (ratio ca, 85: 15). ! i NMR (300 MHz, DMSO) 8.18 (dd, J 4.5, 1.4 Hz, 0.85H), 7.91 i d. ./ 5.1 Hz, 0.15H), 7.74 (id, J= 7.1 , 1.8 Hz, 0.85H), 7.53 (d, J - 9.1 Hz, 0.85H), 7.50 - 7.39 (m, 0.15H),
7.36 (s, 1H), 7.12 (dd, J = 6.3 Hz, I H), 7.06 - 6.95 (m, 0.85.H), 6.88 (d, J= 8.4 Hz, 0.85H), 6.72 (d, J= 8.6 Hz, 0.15H), 6.62 (d, J= 7.4 Hz, 0.15H), 6.46 (d, J= 8.5 Hz, 0.15H), 4.77 (d, J= 4.4 Hz, 0.85H), 4.72 i d. ./ 3.6 Hz, 0.15H), 4.25 - 4.10 (m, IH), 4.10 - 3.98 (m, I H), 3.78 (br s, 0.85H), 3.69 (br s, 0.15H), 2.48 - 2.38 (m, 1.85H), 2.36 (s, 2H), 2.30 (s, 2H), 2.25 - 2.21 (m, 0.85H), 2.20 - 2.16 (m, 0.3H), 1 .98 - 1.32 (m, 6.H),
Example 77: (=i-)-( l-methyl~4-phenyl- lH-pyrazol-3-yi)(2~((pyridm-2~yioxy)rnethyl)-7- J)methanone.
Figure imgf000116_0003
Prepared analogous to Example 2 substituting intermediate A-9 with 1 -methyl-4-phenyl- lH-pyrazole-3-carboxylic acid. MS (EST.) mass calcd. for C23H24N4O2, 388.2; m/z found 389.2 i \I i i ; . i i NMR (DMSO-D6): 8.1 8 (d, J = 3.8 Hz, 0.5H), 8.08 (d, J = 3.9 Hz, 0.5H), 8.03 (s, 0.5H), 7.92 (s, 0.5H), 7.76 - 7.62 (m, IH), 7.46 - 7.16 (m, 5H), 7.04 --- 6.90 (m, I H), 6.84 i d. ./ 8.3 Hz, 0.5H), 6.71 (d, J = 8.3 Hz, 0.5H), 4.60 (t, . / 4.6 Hz, 0.5H), 4.56 i d. ./ "? Hz, 0.5H), 4.15 (br s, III), 4.06 (br s, 1H), 3.98 - 3.83 (m, 2.5H), 3.55 (s, 1.5H), 2.29- 2, 15 (m, 1H), 1.79 - 1.22 (m, 6H).
Example 78: (±)-( 1 -methyl-3-phenyl- 1 H-pyrazol-4-yl)(2-((pyridin-2-yloxy)methyl)-7- l)methanone.
Figure imgf000117_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 1 -methyl-3-phenyl- 1 H-pyrazole-4-carboxy lie acid. MS (ESI) mass calcd. for C23H24N4O2, 388.2; m/z found 389.2 i v! Ι Π ! i NMR (DMSO-D6): 8.16 (br s, M l 5. 8.09 - 7.75 (m, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 7.0 Hz, 2H), 7.47 - 7.20 (m, 3H), 7.10 - 6.90 (m, 1H), 6.92 - 6.52 (br s, 1H), 4.48 (br s, 1H), 4.21 - 3.44 (m, 6H), 2.17 (br s, 1 H), 1.86 - 1.05 (m, 6H).
Example 79: (±)-((3,7-dimethylimidazo[l ,2-alpyridin-8-yl)(2-((pyridi
yl)methanone.
Figure imgf000117_0002
Step A: Prepared analogous to Example 76 substituting 6-ammo-3-methylpicolinic acid with 2-ammo-4-methylmcotimc acid.
Step B: (±)-((3,7-dimethylimidazo[ 1 ,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 2 substituting intermediate A-9 with 3,7-dimethyfimidazo[l ,2-a]pyridine-8-carboxylic acid. MS (ESi) mass calcd. for C22H24N4O2, 376.2; m/z found 377.2 ; \ I · Π ] 1 1 N ! R (DMSO-D6): 8.24 - 8.03 (m, 2H), 7.80 - 7.68 (m, 0.5H), 7.61 (br s, 0.5H), 7.30 (s, 1H), 7.06 - 6.27 (m, 3H), 4.70 (t, J = 4.3 Hz, 1H), 4.32 - 3.67 (m, 2H), 3.42 (m, 2H), 2.45 (s, 2H), 2.38 - 2.02 (m, 4H), 2.02 - 1.18 (m. Example 80: (±)-(7-methylimidazo[l ,2-a]pyTidin-8-yl)(2-((pyTidin-2-yloxy)methyi)-7- -yl)methanone.
Figure imgf000118_0001
Step A: 7-methylimidazo[l,2-a]pyridine-8-carboxylic acid. Prepared analogous to Example 82 substituting 6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.
Step B: (±)-(7-methylimidazo[l ,2-a]pyridm-8-yl)(2-((pyTidm-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 2. substituting intermediate A-9 with the title compound of Step A. MS (ESi) mass calcd. for C21H22 4O2, 362.2; m/z found 363.2 ; \ I · Π j Ή NMR (DM80-D6): 8.46 (d, J= 6.9 Hz, 0.5H), 8.38 (d, J 6.3 Hz, 0.5H), 8.17 (d, J = 3.6 Hz, 0.5H), 8.12 (d, J= 3.8 Hz, 0.5H), 7.91 (s, 1H), 7.79 - 7.39 (m, 2H), 7.14 - 6.70 (m, 2H), 6.70 - 6.33 (m, IH), 4.71 (br s, 1 H), 4.45 - 3.66 (m, 2H), 3.63 - 3.22 (m, 2H), 2.44 - 2.02 (m, 3H), 2.02 - 1 .08 (m, 6H).
Example 81 : (±)-(l-methyl-4^henyl- lH-pyTazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000118_0002
Prepared analogous to Example 2 substituting intermediate A-9 with l -methyl-4-phenyl- lH-pyrazole-5-carboxylic acid. MS (ESI) mass calcd. for C23H24N4O2, 388.2; m/z found 389.2 [ +H]+. Π NMR (DMSO-D6): 8.19 (d, J = 3.8 Hz, 0.6H), 8.09 (d, J= 4.0 Hz, 0.4H), 7.79 - 7.57 (m, 2H), 7.43 - 7.19 (m, 5H), 7.05 - 6.91 (m, 1H), 6.84 (d, ./ 8.3 Hz, 0.6H), 6.62 (d, ./ 8.3 Hz, 0.4H), 4.62 (t, J = 4.5 Hz, 0.4H), 4.57 (d, J = 4.5 Hz, 0.6H), 3.96 - 3.87 (m, 2H), 3.85 (s, I .8H), 3.79 (s, 1.2H), 3.58 (t, J - 4.3 Hz, 0.6H), 3.52 (d, J - 4.7 Hz, 0.4H), 2.28 - 2.02 (m, IH), 1.76 --- 1 .07 (m, 6H). Example 82: (±)-((6-metkylimidazo[ i ,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7- -yl)methanone.
Figure imgf000119_0001
Step A: 6-amino-3-metkylpicolinic acid. To methyl 6-amino-3-bromopicolinate (500 mg, 2,2 mmol), tetramethyistannane (900 jiL, 6.5 mmol) and LiCl (354 mg, 8.7 mmol) in DMF (6 mL) was added Pd(PPh3)4 (76 mg, 10 mol%). The reaction mixture was heated at 110 °C for 3k. Additional tetramethyistannane, LiCi and Pd(PPks)4 were added and heating continued for 6k. Purification via silica gel chromatography (0-20% MeOH in DCM) gave the title compound.
Step B: 6-metkylimidazo[l,2-a]pyridine-5-carboxylic acid. To the title compound of Step A (340 mg, 2.2 mmol) in H20 (7 mL) was added 1M aq. NaGH (2.2 mL, 2.2 mmol) and ckloroacetaldekyde (210 μί_·, 3.4 mmol) and the reaction mixture heated in a microwave reactor at 150 °C for 2b. Additional 1M aq. NaOH (2.2 mL, 2.2 mmol) and ckloroacetaldekyde (210 LiL, 3.4 mmol) were added and heating continued at 150 °C for 2h. The reaction was purified via prep HPLC to give the title compound (282 mg, 72%). MS (ESI) mass calcd. for CgHgiN Cb, 176.1 ; m/z found 177.0 [M+H]+
Step C: (±)-((6-methylimidazo[l ,2-ajpyridin-5-y])(2-((pyTidin-2-y]oxy)methyf)-7- azabicyclo[2.2.1 ]keptan-7-yl)metkanone. Prepared analogous to Example 2 substituting intermediate A-9 with 6-metkylimidazo[l ,2-a]pyridine-5-earboxy].ic acid. The product is present as a mixture of conformers (ratio ca. 80:20 ; f i N.M R (300 MHz, DMSO) 8.44 - 8.13 (m, 1 ,6H), 8.13 - 7.86 (m, 3H), 7.86 - 7.41 (m, 1.2H), 6.97 (br d, ./ 33.5 Hz, 1.6H), 6.68 (br d. J 1.0 Hz, 0.2H), 6.39 (br d, J= 1.0 Hz, 0.4H), 4.80 (d, J= 16.5 Hz, 1.6H), 4.09 - 4.06 (m, 0.2H), 3.58 (s, 2H), 3.46 - 3.30 (m, 0.2H), 2.47 - 2.07 (m, 4H), 2.07 - 1.02 (m, 6H).
Example 83: (±)-(3-ethoxyisoquinolin-4-yl)(2-((pyTidin-2-yloxy)metkyl)-7- l)metkanone.
Figure imgf000119_0002
Prepared analogous to Example 164 substituting intermediate B-9 with intermediate B- 10. MS (ESI) mass calcd. for C24H25N3O3, 403.2; m/z found 404.2 j YM I j
Example 84: (±)-( 1 -metbyl-5-phenyl- 1 H-pyrazol-4-yl)(-2-((pyridm-2-yloxy)methy3)-7- -yl)methanone.
Figure imgf000120_0001
Prepared analogous to Example 2 substituting intermediate A-9 with mtermediate A- MS (ESI) mass calcd. for C23H24N4O2, 388.2; m/z found 389.2 [M+H]÷.
Example 85 : (±)-(6-methyl-3-(4-methyipiperazin- 1 -yl)pyridin-2-y])(2-('(pyridin-2- [2.2.1 ]heptan-7-yl)methanone.
Figure imgf000120_0002
Step A: 6-methyl-3-(4-methylpiperazin- l -yI)picolmonitrile. Prepared analogous to Example 68 substituting pyrollidine with 1 -methylpiperazine. MS (ESI) mass calcd. for C12H16N4, 21 6.1 ; m/z found 217.0 ί vi - ! ! j
Step B: 6-metliyl-3-(4-methy]piperazin- l-yi)picolinic acid. Prepared analogous to Example 68 substituting 6-methyl-3-(pyrrolidin- l -yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for C12H17N3O2, 235.1 ; m/z found 236.0 [M+H]+.
Step C: Prepared analogous to Example 2. substituting intermediate A-9 with the title compound of Step B. MS (ESI) mass calcd. for C24H3iN502, 421.2; m/z found 422.2 | M - f i | I ! NMR (DMSO-D6): 8.19 - 8.14 (m, 0.5H), 8.12 (dd, J= 5.0, 1.5 Hz, 0.5H), 7.78 - 7.68 (m, 0.5H), 7.68 - 7.59 (m, 0.5H), 7.52 (d, J= 8.4 Hz, 0.5H), 7.37 (d, J= 8.4 Hz, 0.5H), 7.23 (d, J= 8.4 Hz, 0.5H), 7.07 (d, J= 8.3 Hz, 0.5H), 6.97 (ddd, J= 12.3, 6.7, 5.4 Hz, 1 H), 6.87 (d, J- 8.3 Hz, 0.5H), 6.59 (d, ,/ 8.3 Hz, 0.51 1 ;·. 4.63 ( i . ./ 4.5 Hz, 0.5H), 4.59 i d. ./ 3.9 Hz, 0.5H), 4.19 - 3.81 (m, 2H), 3.46 (t J= 3.9 Hz, 0.5H), 3.39 (d, J = 4.7 Hz, 0.5H), 3.07 - 2.92 (m, 2H), 2.92 2.78 (m, 2H), 2.46 - 2.27 (m, 6H), 2.22 - 2.05 (m, 3.5H), 1.97 (s, 1.5H), 1.94 - 1.27 (m, 6H).
Example 86: (±)-(6-methyl-3-(piperazin- 1 -yl)pyridin-2-yl)(2-((pyridin-2-yloxy)ixiethyl)-7- l)methanone.
Figure imgf000121_0001
Step A: tert- butyl 4-(2-cyano-6-niethylpyridin-3-yl)piperazine- l -carboxylate. Prepared analogous to Example 68 substituting pyrollidine with tert-butyl piperazine- 1 -carboxylate. MS (EST) mass calcd. for CJ6H22N4O2, 302.2; ro/z found 303.0 [M+H]+.
Step B: 3-(4-(tert-butoxycarbonyl)piperazin- l -yl)-6-methylpicolinic acid.
Prepared analogous to Example 68 substituting 6-methyl-3-(pyrrolidin- l-yl)picolinonilTij.e with the title compound of Step A. MS (ESI) mass calcd. for C16H23N3O , 321 .2; m/z found 322.0 i \) H I
Step C: tert-butyl 4-(6-methyl-2-((±)-2-((pyridin-2-yloxy)methyl)-7- azahicyeJo[2.2, 1 ]heptane~7-carbonyl)pyridin-3~yl)piperazine~ 1 -carboxylate. Prepared analogous to example 2 substituting intermediate A-9 with the title compound of Step B.
Step Di (±)-(6-memyl-3 -(piperazin- l -yl)pyridm^
azabieyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound from step C (1 82 nig, 0.4 mmol) in 1 ,4-dioxane (I mL) was added 6N HC1 in iPrOH (400 μΕ). The reaction was heated to 70 °C for 3h, cooled to rt, concentrated and purified via reverse phase chromatography. The mixture was dissolved with a saturated NaHC03 (aq) and extracted with DCM (x3). The organic layers were dried over MgS04 and concentrated. The crude product was triturated with diethyl ether and n-pentane to give the title compound (5 mg, 3%). MS (ESI) mass calcd. for
C23H29N5O2, 407.2; m/z found 408.2 [M+Hf. !H NMR (DMSO-D6): 8.17 (d, J= 4.0 Hz, 0.4H),
8.12 (d, J = 3.8 Hz, 0.6H), 7.72 (t, /= 7.6 Hz, 0.4H), 7.63 (t, J = 6.9 Hz, 0.6H), 7.48 (d, J = 8.3 Hz, 0.4H), 7.34 (d, J= 8.3 Hz, 0.6H), 7.22 (d, /= 8.3 Hz, 0.4H), 7.06 (d, J = 8.3 Hz, 0.6H), 7.02 - 6.90 (m, IH), 6.86 (d, ./ 8.1 Hz, 0.4H), 6.58 i d. ./ 8.3 Hz, 0.6H), 4.63 - 4.60 (m, i l l ). 4.14 - 3.92 (m, 2H), 3.86 (t, J = 10.4 Hz, 1H), 2.99 - 2.65 (m, 8H), 2.39 (s, IH), 2.34 - 2.28(m, IH), 2.1 8 - 2.1 l (m, IH), 1.96 - 1.88 (m, 2H), 1.86 - 1.20 (m, 6H). Example 87: (±)-(6-methyl-3 -moipholinopyridin-2--yl)((l S,2R,4R)- 7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000122_0001
Step A: 6-methyl-3-morpholinopicolinonitrile. Prepared analogous to Example 68 substituting pyrollidine with morpholine. MS (ESI) mass calcd. for C11H13 3O, 203.1 ; m/z found 204.0 I Λ 1 · i 1 1
Step B: 6~nietliyl~3-morpliolinopicolimc acid. Prepared analogous to Example 68 substituting 6-methyi-3-(pyrrolidin- l -yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for CJ JHJ^OS, 222.1 ; m/z found 223.0 [M+H .
Step C: Prepared analogous to Example 2 substituting intermediate A- 9 with the title compound of Step B. MS (ESI) mass calcd. for C23H28N4O3, 408.2; m/z found 409.2 [M+H]+.
Example 88: (±)-(7-methoxyqumolm-8-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicycJo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000122_0002
Step A: 7-methoxyquinoline-8-carboxylic acid. In I g separate batches a mixture of 2- amino-6-methoxybenzoic acid (1 Ig, 66 mmol) and acrolein (4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor for 20 min at 200 °C. After combining the reactions, the mixture was concentrated and purified via silica gel chromatography (0- 10% MeOH in
DCM) to give the title compound (2.8g, 20%). MS (EST) mass calcd. for C1 1H19NO3, 203.1 ; m z found 204.0 i vi - l i i
Step B: Prepared analogous to Example 2. substituting intermediate A-9 with the title compound of Step A. MS (EST) mass calcd. for QjEfeNjOj, 389.2; m/z found 390.2 [M+H]+. Example 89: (±)-(2-ethoxynaphthalen- 1 -yl)(2-((pyridin-2-yloxy)methy l)-7- l)methanone.
Figure imgf000123_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 2-ethoxy-l - naphthoic acid. MS (ESI) mass calcd. for C25H26 2O3, 402.2; m/z found 403.2 [M÷H]+ .
Example 90: (±)-(3,6,-dimethyl 2,3'-bipyridin]-2!-yl)(2-((pyridin-2-yloxy)methyl)- l)methanone.
Figure imgf000123_0002
Prepared analogous to Example 2 substituting intermediate A-9 with 3,6'-dimethyl-[2,3' bipyridme]-2'-carboxylic acid. MS (ESI) mass calcd. for C25H26 4O2, 414.2; m/z found 415.2 ! Ni M l .
Example 9 i : (±)-(3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7- -yl)methanone.
Figure imgf000123_0003
Prepared analogous to Example 2. substituting intermediate A-9 with 3-(2H- 1 ,2,3-triazol- 2-yl)picolinic acid. MS (ESI) mass calcd. for C2oH2oN602, 376.2; m/z found 377.2 [M+H]+. Ή NMR (DMSO-D6): 8.70 (d, J= 3.6 Hz, 0.5H), 8.40 - 7.99 (m, 4.5H), 7.82 - 7.47 (m, 2H), 7.02 - 6.85 (m, 1 1 1 ) 6.86 (d, ./ 8.2 Hz, 0.6H), 6.64 (d, ./ 8.1 Hz, 0.4H), 4.62 ~- 4,65 (m, 1H), 4.20 -- 3,97 (m, 3H), 2.35 - 2.24 (in, I H), 2.00 - 1.09 (m, 6H). Example 92: (±)-(2-methyl-5^henylthiazol-4-yi)(2-((pyridin-2-yloxy)niethyl)-7- azabicyeJo[2.2, 1 ]heptan-7-yl)raethanone.
Figure imgf000124_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 2-methyl-5- phenylthiazole-4-carboxylic acid. MS (ESI) mass calcd. for C23H23 3O2S, 405.2; nv'z found 406.2 [M+Hf . 'H MR (DMSO-D6) 8.18 Uid. ./ 5.0, 1.4 Hz, 0.5H), 8.10 f dd. ./ 5.0, 1.4 Hz, 0.SH), 7.77 - 7.61 (m, i l l ). 7.52 - 7.29 (m, 5H), 7.04 - 6.89 (m, 1H), 6.82 (d, J 8.3 Hz, 0.5H), 6.69 (d, J = 8.3 Hz, 0.5H), 4.57 (t, J= 4.5 Hz, 0.5H), 4.52 (d, J= 4.7 Hz, 0.5H), 3.90 - 3.79 (m, 2.5H), 3.69 (†, J= 10.6 Hz, 0.5H), 2.69 (s, 1.5H), 2.28 (s, 1.5H), 2.25 - 2.06 (m, 1 H), 1.72 - 1.04 (m, 6H).
Example 93: (±)-(6-methyl-3-(oxazoI-2-yl)pyridin-2-yl)(2-((pyridin- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000124_0002
Prepared analogous to Example 2 substituting intermediate A-9 with intermediate A-43. MS (ESI) mass calcd. for C22H22 4O3, 390.2; m/z found 391.2 [M+H]+. !H NMR (DMSO-D6): 8.22 (dt, J = 14.0, 7.8 Hz, 2.5H), 8.12 (dd, .7 - 5.0, 1.4 Hz, 0.5H), 7.78 - 7.68 (m, 0.5H), 7.68 - 7.59 (m, 0.5H), 7.49 (d, ./ 8.2 Hz, 0.5H), 7.41 - 7.29 (m, 1.5H), 6.97 (ddd, ,/ 14.7, 6.5, 5.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 0.5H), 6.63 (d, J = 8.3 Hz, 0.5H), 4.66 (t, J = 4.6 Hz, 0.5H), 4.62 (d, J= 4.8 Hz, 0.5H), 4.22 - 3.93 (m, 2H), 3.70 ( J = 4.4 Hz, 0.5H), 3.61 (d, J = 4.0 Hz, 0.5H), 2.55 (s, 1.5H), 2.40 - 2.14 (m, 1 H), 2.08 (s, 1.5H), 1.93 - 1.23 (m, 6H).
Example 94: (±)--(6- nethyl-3-(3--methylisoxazo
7-azabicyclo[2.2.1 ]heptan-7~yl)methanone.
Figure imgf000125_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3-(3- methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C23H24N4O3, 404.2; m z found 405.0 [M+Hf . !H NMR (DMSO-D6): 8.20 - 8.02 (m, 2H), 7.73 (t, J = 6.9 Hz, 0.4H), 7.65 (t, J = 7.7 Hz, 0.6H), 7.50 (d, J = 8.1 Hz, 0.4H), 7.37 (d, J = 8.2 Hz, 0.6H), 7.03 - 6.91 (m, 1H), 6.87 id, ./ = 8.3 Hz, 0.4H), 6.68 - 6.58 (m, 1.6H), 4.68 (t, ,/ = 4.6 Hz, 0.6H), 4.62 (d, J = 4.7 Hz, 0.4H), 4.01-3.93 (m, 2H), 3.60 (t, J = 4.4, 0.4H), 3.55 (d, J = 3.1, 0.6H), 2.55 (s, 1.2H), 2.36 - 2.14 (m, 4H), 2.09 (s, 1.8H), 1.88 - 1.07 (m, 6H). Exampie 95: (±)-(6-methyl-3-( IH-pyrazol- 1 -yl)pyridin-2-yl)(2-((pyridin-2-yioxy)methyl)-7- )methanone.
Figure imgf000125_0002
Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl -3 -(I H- pyrazol- l -yi)picolinic acid. H NMR (DMSO-D6): 8.19 (dd, J = 5.0, 1.4 Hz, 0.51 ! ). 8.14 (dd, ,/ 5.1, 1.5 Hz, 0.5H), 8.08 (t, J= 2.9 Hz, 1H), 7.97 (d, J= 8.3 Hz, 0.5H), 7.93 (d, J= 8.3 Hz, 0.5H), 7.76 - 7.61 (m, 2H), 7.49 (d, J= 8.4 Hz, 0.5H), 7.34 (d, J= 8.4 Hz, 0.5H), 6.97 (td, J= 7.3, 5.2 Hz, i l l ). 6.84 (d, ./ 8.3 Hz, 0.5H), 6.65 (d, ./ 8.3 Hz, 0.51 s ). 6.53 - 6.48 (m, 0.SH), 6.48 - 6.43 (m, 0.5H), 4.55 (t J = 4.5 Hz, 0.5H), 4.51 (d, J - 4.7 Hz, 0.5H), 4.02 - 3.93 (m, 2H), 3.67 (t, J = 4.1 Hz, 0.5H), 3.60 (d, J = 4.5 Hz, 0.5H), 2.54 (s, 1.5H), 2.31 - 2.1 1 (m, 1H), 2.04 (s, 1.5H), 1.75 - 1.16 (m, 6H).
Exampie 96: (±)-(6-methyl-3-(4-methyl- IH-pyrazol- 1 -yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000126_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3-(4- methyl- 1 H-pyrazol- 1 -yl)picolinic acid. MS (EST) mass calcd, for C23H25N5O2, 403.2; m/z 404.2 I M ί 1 1
Example 97: (±)-(6-Tnetbyl-3-(p}TTo]idm- l -y3)pyri
l)methanone.
Figure imgf000126_0002
Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3- (pyrrolidin- l -yl)picoiinic acid (Example 68, Step B). MS (ESI) mass calcd. for C23H28N4O2, 392.2; m/z found 393.2 [M+H]T. The product is present as a mixture of conformers (ratio ca. 50:50). ! ! NMR (300 MHz, DMSO) 8.14 (dd, J = 5.1, 1.4 Hz, 0.5! ! ;. 8.1 1 (dd, J = 5.1 , 1.4 Hz, 0.5H), 7.76 - 7.59 (m, Hi), 7.06 (q, ./ 8.6 Hz, 1 H), 7.01 - 6.90 (m, 11 1 ). 6.85 (d, ./ 8.3 Hz, 0.5H), 6.69 (d, J = 8.3 Hz, 0.5H), 4.61 (t, J = 4,6 Hz, 0.5H), 4.58 (d, J = 4.7 Hz, 0.5H), 4.19 - 3.91 (m, 2.5! i s. 3.88 (d, J = 4.6 Hz, 0.5H), 3.28 - 3.1 1 (m, 3H), 3.10 - 2.98 (m, 1 H), 2.41 - 2.1 8 (m, 2.5H), 2.06 (s, 1.5H), 1.95 - 1.28 (m, 10H).
Example 98: (±)-(3,6'-dimethyl-[2,3'-bip aidm]-2'-yl)(2-(((5-fluoropyrimidm-2-yI)o
7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000126_0003
Step A: (±)-ieri-but l 2-(((5-fluoropyrimidm-2-yl)oxy)meihyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate. To -intermediate B~10 (500 mg, 2.2 mmoi) in THF (1 1 mL) at 0 °C was added NaH (176 mg, 60 wt% in mineral oil, 4.4 mmoi). After 15 min, 2-chloro- 5-fluoropyrimidine (0.3 mL, 2.4 mmoi) was added dropwise and the 0 °C ice bath was removed. After 12h, H20 was added and the reaction extracted with EiOAc. The combined organics dried (Na2S04). Purification via silica gel chromatography (5-30% EtOAc in heptane) gave the title compound (490 mg, 69%) as a white solid. MS (ESI) mass calcd. for C16H22F3N3Q3, 323.4; m/z found 224.1 [M-100]+.
Step B: (±)-2-(((5-fluoropyriimdin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 jheptane. To the title compound from step A (474 mg, 1.5 mmoi) in 1,4-dioxane (1.5 ml.,) was added 6N HO in iPrOH (1 .5 mL). The reaction was heated to 40 °C for 1 ,5b and concentrated to give the title compound that was used without further purification in subsequent steps. MS (ESI) mass calcd. for C,,H,4F 30, 223.1 ; m/z found 224.0 j \ 1 · i 11
Step C: (±)-(3,6!-dimetliyi~[2.,3,~bipyridm]-2 -yl)(2.-((^^
yl)oxy)methyl)-7-azabicyclo[2.2.1]beptan-7-yl)methanone. Prepared analogous to example 2 substituting intermediate A-9 with 3,6'-dimethyl-[2,3'-bipyridme]-2'-carboxylic acid and intermediate B-10 with the title compound of Step B. MS (ESI) mass calcd. for C24H24F 5O2, 433.2; m/z found 434.2 [M+H]+. !H NMR ( DMSO-D6): 8.71 (s, 2H), 8.32 (t, J = 4.5 Hz, IH), 7.74 i d. ./ 7.9 Hz, Hi), 7.66 (t, ./ 7.3 Hz, IH), 7.40 (d, ./ 7.9 Hz, 0.5H), 7.33 - 7.14 (m, 1.5H), 4.39 (br s, 0.5H), 4.34 (d, J= 4.0 Hz, 0.5H), 4.27 (t, J = 10.4 Hz, 0.5H), 4.10 (dd, J= 5.2, 1.0 Hz, 0.5H), 3.90 (d, J = 4.8 Hz, 0.5H), 3.85 (t, J= 3.1 Hz, 0.5H), 3.69 (d, J= 7.9 Hz, IH), 2.55 (s, 1.5H), 2.31 - 2.20 (m, 0.5H), 2.18 (s, 1.5H), 2.16 (s, 1.5H), 2.12 (s, 1.5H) , 2.01 - 1.82 (m, 0.5H), 1.81 - 1.14 (m, 6H). Example 99: (i)-(2-(((5-fluoropyrimidin-2-yl)oxy)metb.yl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- l)pyridin-2-yl)methanone.
Figure imgf000127_0001
Prepared analogous to example 98 substituting 3,6'-dimethyl-[2,3'-bipyridineJ-2'- carboxylic acid with 6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C22H22FN5O3, 423.2; m/z found 424.2 [M+Hf. Ή NMR (DMSO-D6): 8.71 (s, 1H), 8.66 (s, H i ). 8.12. ; d. ./ S. i Hz, 0.4H), 8.09 i d. ./ 8.2 Hz, 0.6H), 7.50 (d, J= 8.2 Hz, 0.4H), 7.40 (d, J = 8.2 Hz, 0.6H), 6.64-6.63 (m, 1 H), 4.68 (t, J= 4.6 Hz, 0.6H), 4.60 (d, J = 4.7 Hz, 0.4H), 4.11 - 3.90 (m, 2H), 3.62 (>. ./ 4.2 Hz, 0.41 i s. 3.55 i d. ./ 4.1 Hz, 0.5H), 2.55 (s, 1.2H), 2.40-2.15 (m, 4! i s. 2.16 (s, 1.8H), 1.88 - 1.12 (m, 6H).
Example 100: (±)-(2-(((5-fluoropyrimidm-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- 2-yl)methanone.
Figure imgf000128_0001
Prepared analogous to example 98 substituting 3,6'-dimethyl-[2,3'-bipyridine]-2'- carboxylic acid with intermediate A-43. MS (ESI) mass calcd. for C21H20F 5O3, 409.2; m/z found 410.2 [M+H]+. JH NMR ( DMSO-D6): 8.74 (s, 0.8H), 8.66 (s, 1.2H), 8.31 - 8.16 (m, 2H), 7.50 i d. ./ 8.2 Hz, 0.4H), 7.38 i t. ./ 8.9 Hz, 1.6H), 4.67 i s. ./ 4.5 Hz, 0.6H), 4.62 (d, ./ 4.7 Hz, 0.4H), 4.23 (t, J = 10.1 Hz, 0.4H), 4.07 (dt, J = 10.0, 6.2 Hz, 1.6H), 3.72 (t, J = 4.2 Hz, 0.4! U. 3.62 (d, J = 4.4 Hz, 0.6H), 2.56 (s, 1.2H), 2.43 - 2.19 (m, 1 H), 2.16 (s, 1.8H), 1.93 - 1.23 (m, 6H).
Example 101 : (±)-(2-(((5-fluoropyrimidm-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- din-2-y1)metlianoiie.
Figure imgf000128_0002
Prepared analogous to example 98 substituting 3,6'-dinietliyl-[2,3'-bipyridine] carboxylic acid with 6-methyl-3-(pyrrohdin-l-yl)picolinic acid (Example 68, Step B) Example 02: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2. ]heptan-7-yl)(6- 2~yi)metha.none.
Figure imgf000129_0001
Prepared analogous to example 98 substituting 3 ^'-dimethyl- [2,3 '-bipyridine] -2'- carboxyiic acid with intermediate A-9, MS (EST) mass calcd. for C22H21FN6O2, 420.2; m/z found 421.2 I M ί 1 1 H NMR ( DM8Q-D6): 8.93 i d. ./ 4.9 Hz, 0.8H), 8.88 (d, J 4.9 Hz, 1.2H), 8.79 (s, 0.8H), 8.72 (s, 1.2H), 8.37 - 8.33 (m, 1H), 7.55 - 7.47 (m, 1.2H), 7.40 (d, J= 8.1 Hz, 0.6H), 4.67 - 4.61 (br s, 0.6H), 4.59 (d, J = 4.0 Hz, 0.4H), 4.33 - 4.22 (m, IH), 4.18 - 4.07 (m, 1H), 3.91 (br s, 0.4H), 3.81 (d, J = 3.4 Hz, 0.6H), 2.59 (s, I AH), 2.48 - 2.25 (m, I H), 2.1 5 (s, 1.8H), 1.93 - 1.34 (m, 6H).
Example 1 03: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyi)-7-azabicyclo[2.2.1 ]heptan-7-yi)(6- l- l -yl)pyridin-2-yl)methanone.
Figure imgf000129_0002
Prepared analogous to example 98 substituting 3 ,6'-dimethyl-[2,3'-bipyridine]-2'- carboxylic acid with 6-methyl-3-(4-methyl- lH-pyrazol- l -yl)picolinic acid. MP:;;:151.2 °C. !H NMR ( DMSO-D6): 8.73 (s, IH), 8.69 (s, IH), 7.92 (d, J = 5.0 Hz, 0.5H), 7.90 (d, J = 5.0 Hz, 0.5H), 7.85 (d, J= 2.3 Hz, IH), 7.51 - 7.54 (m, 1.5H), 7.35 (d, /= 8.4 Hz, 0.5H), 4.57 (t, J = 4.5 Hz, 0.5H), 4.51 (d, ,/ 4.7 Hz, 0.5H), 4.08 - 3.90 fm, 2H), 3.66 (t, ./ 4.0 Hz, 0.5H), 3.60 i d. ./ 4.0 Hz, 0.5H), 2.53 (s, 1.5H), 2.35 -■ 2.14 (m, IH), 2.10 (s, 1.5H), 2.07 (s, 1.5H), 2.04 (s, 1.5H), 1.77 - 1 .14 (m, 6H).
Example 104: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- methy 1-3■ ( 1 H-pyrazol- 1 -yl)pyridin-2 -yl)methanone.
Figure imgf000130_0001
Prepared analogous to example 98 substituting 3 ,6'-dimethyl- [2,3 '-bip ridine] -2'- carboxylic acid wiih 6-methyl-3-( lH-pyrazol-l -yl)picolinic acid. MS (ESI) mass caicd. for C2iH2;FN602, 408.2; m/z found 409.2 [M+H]+. MP- i 19.2 °C.
Example 105: (±)~(2-(((5-fluoropjTidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5- ])p enyl)methanone.
Figure imgf000130_0002
Prepared analogous to Example 7 substituting 6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picoHnk acid with 5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. (ESI) mass calcd. for C22H22FN5O2, 407.2; mix found 408.2 [M+H]+. !H NMR (MeOD): 8.08-7.96 (m, 1H), 7.88 (s, 2H), 7.81-7.73 (m, H), 7.56-7.12 (m, 3H), 6.85-6.62 (m, 1H), 4.70-4.67 (m, I H), 4.25-3.74 (m, 3H), 2.51 -1.97 (m, All), 1.96- 1.31 (m, 6H). Example 106: (±)-(2,6-dime†noxyphenyj 2-(((5-fluoropyridm-2-yl)oxy)met yj.)-7- azab cyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000130_0003
Prepared analogous to example 105 substituting 5-methy3-2-(2H-.l ,2,3-triazoI-2- ylibenzoic acid with 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. for C21H23FN2O4, 386.2 iw'z found 386.9 I W \ ]H NMR (MeOD): 8.02-7.93 (m, IH), 7.57-7.40 (m, H I ). 7.39-7.21 (m, I H), 6.87-6.63 (m, 2H), 6.62-6.38 (m, H i ). 4.83-4.65 (m, 1H), 4.49-4.07 (m, 1H), 4.07-3.52
(m, 8H), 2.48-2.09 (m, IH), 2.06-1.07 (m, 6H). Example 107: (±)~((3-fluoro-2-methoxyphenyl)(2-(((5-fluoropyridin-2~yl)oxy)methyl)-7 azabicyeJo[2.2, 1 ]heptan-7-yl)raethanone.
Figure imgf000131_0001
Prepared analogous to example 105 substituting 5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)benzoic acid with 3-fluoro-2-methoxybenzoic acid, MS (ESI) mass calcd. for C2oH2oF2N2C>3, 374.1 ; m/z found 375.1 j V! · Π j 1 1 Vv! R (MeOD): 8.01 -7.90 (m, l i s }. 7.56-7.38 · η·. 1H), 7.28- 7.06 (m, 2H), 7.02-6.53 (m, 2H), 4.82-4.66 (m, 1H), 4.50-3.73 (m, 6H), 2.85-2.22 (m, 1H), 2.21- 1.10 (m, 6H).
Example 108: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(2- methoxy-6-(2H- l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000131_0002
Prepared analogous to example 105 substitutmg 5-methy3-2-(2H-.l ,2,3-triazoi-2- vlibenzoic acid with 2-methoxy-6-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C22H22.FN5O3, 423.2; m/z found 424.2 [M+H]+ . Ή NMR (MeOD): 8.10-7.74 (m, 3H), 7.66-7.41 (m, 3H), 7.25-6.88 (m, 1H), 6.88-6.43 (m, 1H), 4.78-4.64 (m, 1H), 4.51 -3.57 (m, 6H), 2.48-0.94 (m, 7H). Example 109: (±)-(5-fluoro-2-(lH-pyrazol-5-yl)pheny])(2-(((5-fluoropyridm-2-yl)oxy)met^^ 7-azabicyclo[2.2.1 ]lieptan-7-yl)methanone.
Figure imgf000132_0001
Prepared analogous to example 105 substituting 5-methy1-2-(2H- 1 ,2,3-triazol-2- yl)benzoic acid with 5-fluoro-2-( 1 H-pyrazol-5-yl)benzoic acid. MS (EST) mass calcd. for C22H20F2N4O2, 410.2; m/z found 41 1.2 [M+H]+. 1 1 NMR (MeOD): 8.1 1 -7.90 (m, l i s }. 7.80-7.59 (m, 2H), 7.58-7.40 (m, 1H), 7.36-6.94 (m, 2H), 6.88-6.47 (m, 2H), 4.78-4.58 (m, IH), 4.41-3.47 (m, 3H), 2.69-0.60 (m, 8H).
Example 1 10: (±)-(2-(((5-fluoropyridin-2-yl)oxy)nietb.yl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(2- -yl)phenyl)methanone.
Figure imgf000132_0002
Prepared analogous to example 105 substitutmg 5-methyl-2-(2H~l,2,3-triazol~2- yl)benzoic acid with 2-methyl-6-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C22H22FN5O2, 407.2; m/z found 408.2 [M+H]+. Ή NMR (MeOD): 8.11 -7.62 (m, 4H), 7.59-6.48 (m, 4H), 4.78-4.68 (m, IH), 4.50-3.37 (in, 3H), 2.80-0.82 (m, 10H).
Exampie 1 1 1 : (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6- raethyl-3-(2H- 1 ,2,3-triazol-2-y1)pyridin-2-yl)methanone.
Figure imgf000132_0003
Prepared analogous to example 105 substituting 5-methyl-2-(2H-l ,2,3-triazof-2- ylibenzoic acid with 6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C2iH2iF 602, 408.2; m/z found 409.2 [M+Hf . Ή NMR (MeOD): 8.28-8.19 (m, IH), 8.06-7.88 (m, 3H), 7.57-7.35 (m, 11 1 ). 6.89-6.60 (m, 1H), 4.76-4.73 (m, 1H), 4.32-4.02 (m, 2l . 3.93-3.80 (m, 1H), 2.70-2.20 (m, 4H), 2.05- 1.42 (m, 6H).
Example 1 12: (±)-(5-chloro-3-(2H-l,2,3-triazol-2-yl)pyridin-2-y1)(2-(((5-fluoropyridin-2- 1 ]heptan-7-yl)methanone.
Figure imgf000133_0001
Prepared analogous to example 105 substituting 5-methyl-2-(2H- l ,2,3-triazoI-2- yl)benzoic acid with sodium 5-chloro-3-(2H- 1 ,2,3-triazol-2-yl)picolinate. MS (ESI) mass calcd. tor C20H18ClFN6O2, 428.1 ; m/z found 429.1 [Μ+ΗΓ Ή NMR (MeOD): 8.74-8.17 (m, 4H), 8.13-7.96 (m, 11 1 ). 7.59-7.46 (m, 1H), 4.90-4.18 (m, 3H), 3.99 (s, Hi), 2.98-2.39 (m, 1 H), 2.10- 1.19 (m, 6H).
Example 1 13 : (±)-(2-(((5-fiuoropyridin-2-yl)ox )methyl)-7-azabicyclo[2.2.1 ]heptan-7-yi)(5- methoxy-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)niethanone.
Figure imgf000133_0002
Prepared analogous to example 105 substituting 5-methyl-2~(2H- l ,2,3-triazoI-2- yl)benzoic acid with sodium 5-methoxy-3-(2H-l ,2,3-triazol-2-yl)picolinate. MS (ESI) mass calcd. for C2iH2iFN60j, 424.2; m/z found 425.1 [M+H]+. fH NMR (MeOD): 8.37-7.79 (m, 5H), 7.56-7.40 (m, 1H), 6.87-6.59 (m, 1H), 4.73 (s, 1H), 4.30-3.82 (m, 6H), 2.48-2.1 1 (m, 1H), 2.07- 1.42 (m, 6H).
Example 1 14: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5- methoxy -2~(2H- 1 ,2,3 -triazol-2 -y l)phenyl)methanone.
Figure imgf000134_0001
Prepared analogous to example 105 substitutmg 5-methy3-2-(2H-.l ,2,3-triazoi-2- ylibenzoic acid with sodium 5-methoxy-2-(2H- 1 ,2,3-triazol-2-yl)benzoate. MS (ESI) mass caicd. for C22H22FN5O3, 423.2; m/z found 424.2 [M+H]+. ¾ NMR (MeOD): 8.18-7.68 (m, 4H), 7.58-7.38 (m, IH), 7.24-6.85 (m, 2H), 6.85-6.57 (m, IH), 4.78-4.55 (m, IH), 4.23-3.40 (m, 6H), 2.77-2.18 (m, IH), 2, 13-1.1 1 (m, 6! i :·.
Example 1 15: (±)-(2-fluoro-6-(2H-l,2,3-ttiazo{-2-yl)phenyl)(2-(((5-fluoropyridin-2- .2.1]heptan-7-yl)methanone.
Figure imgf000134_0002
Prepared analogous to example 105 substituting 5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)benzoic acid with 2-fluoro-6-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C2iHi9F2N;02, 41 1.2; m/z found 412.2 j M · Π j i i NMR (MeOD): 8.1 1 -7.71 (m, 4H), 7.69-7.24 (m, 3H), 6.98-6.43 (tn, IH), 4.83-4.67 (m, IH), 4.53-3.34 (m, 3H), 2.50-0.96 (m, 7Ii).
Example 1 16: (±)-(4-fluoro-2-(2H- 1 ,2,3-triazoI-2-yl)phenyl)(2-(((5- ■fiuoropyridin-2- 1 ]heptan-7-yl)methanone.
Figure imgf000134_0003
Prepared analogous to example 105 substituting 5-methyl-2-(2H- l,2,3-iriazol-2- nzoic acid with 4-f!uoro-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C2iHi9F? 50?, 41 1.2; m/z found 412.2 j V! · Π j 1 1 NMR (MeOD): 8.1 1 -7.71 (m, 41 s ). 7.69-7.24 (m, 3H), 6.98-6.43 (m, 1H), 4.83-4.67 (m, 1H), 4.53-3.34 (m, 3H), 2.50-0.96 (m, 7H).
Example 1 17: (±)-(3-fluoro-2-(2H-l ,2,3-triazol-2-yl)phenyi)(2-(((5-fluoropyridin-2- [2.2.1]heptan-7-yl)methanone.
Figure imgf000135_0001
Prepared analogous to example 105 substituting 5-methyl-2-(2H- 1 ,2,3-triazol-2- y])benzoic acid with 3-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C21H19F2N5O2, 41 1.2; m/z found 412.2 [M+H]1". !H NMR (MeOD): 8.14-7.85 (m, 3H), 7.70-7.18 (m, 4H), 6.81-6.65 (m, 1H), 4.67-4.32 (m, 1H), 4.24-3.79 (m, 3H), 2.42-2.24 (m, 1H), 1.97- 1.32 (m, 6H).
Example 1 18: (±)-(3-ethoxy-6-methylpyridin-2-yl)^
azabicyclo[2.2.1 ]heptan-7-yl)raethanone.
Figure imgf000135_0002
Prepared analogous to example 105 substituting 5-methy1-2-(2H- 1 ,2,3-triazol-2- ylibenzoic acid with 3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C21H24FN3O3, 385.2; m/z found 385.9 [M+H]+. Ή NMR (MeOD): 8.23-7.90 (m, IH), 7.57-7.11 (m, 3H), 6.87- 6.53 (m, 1H), 4.85-4.69 (m, IH), 4.51-3.56 (m, 5H), 2.84-2.09 (m, 4H), 2.06-1.49 (m, 5H), 1.47- 1.05 (m, 4H).
Example 1 19: (±)-(2-(((5-fluoropyridin-2-yl)oxy)niethyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(4- methoxy-2-(2H- l ,2,3-triazol-2-yl)pheny])methanone.
Figure imgf000136_0001
Prepared analogous to example 105 substituting 5-methy3-2-(2H-.l ,2,3-triazoi-2- ylibenzoic acid with 4-methoxy-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C' . l ] . i;N.= ;. 423.2; m/z found 424.2 | \1 · i i j Ή NMR (MeOD): 8.12-7.81 (m, 3H), 7.58- 7.22 (m, 3H), 7.15-6.57 (m, 2H), 4.75-4.58 (m, H), 4.48-3.74 (ra, 6H), 2.83-2.08 (m, 1H), 2.02- 0.98 (m, 6H).
Example 12.0: (±)-(5-chloro-2-(2H-l,2,3-triazol-2-y1)phenyl)(2-(((5-f1uoropyridin-2- .1]heptan-7-yr)methanone.
Figure imgf000136_0002
Prepared analogous to example 105 substituting 5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoie acid with 5-chloro-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C21H19CIFN5O3, 427.2; m/τ found 428.2 [M+H]+. !H NMR (MeOD): 8.13-7.77 (m, 4H), 7.70- 7.31 (m, 3H), 6.87-6.60 (m, IH), 4.80-4.60 (m, IH), 4.51 -3.67 (m, 3H), 2.84-2.22 (m, 1H), 2.07- 1.1 1 un. 6H).
Example 12.1 : (±)-(2-(((5-fiuoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(4- phenyl)methanone.
Figure imgf000136_0003
Prepared analogous to example 105 substituting 5-methyl-2-(2H-l,2,3-triazol-2- •enzoic acid with 4-methyl-2-(2H- 1 ,2,3 -triazol-2-yl)benzoie acid. MS (ESI) mass calcd. for C22H22FN5O2, 407.2; m z found 408.2 [M+H]+. Π NMR (MeOD): 8.10-7.84 (m, 3H), 7.76-7.69 (m, 1H), 7.56-6.87 (m, 3H), 6.87-6.53 (m, 1H), 4.75-4.59 (m, 1H), 4.49-3.65 (m, 3H), 2.80-2.09 (m, 4H), 2.01 - 1.00 (m, 6H). Example 122: (±)-(2-(((5-fiuoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(4- l)methanone.
Figure imgf000137_0001
Prepared analogous to example 105 substituting 5-methyl-2-(2H- l ,2,3-triazol-2- y])benzoic acid with 4-metbyl-2-(pyrimidiii-2-yl)benzoic acid. MS (ESI) mass calcd. for C24H23F 4O2, 418.2; m/z found 419.2 [M+H !H NMR (MeOD): 8.94-8.89 (tn, 1 H), 8.84-8.81 (m, 1H), 8.08-7.94 (m, 2H), 7.60-7.46 (m, 1H), 7.45-7.33 (m, 11 1 ) . 7 '.22-6.99 (m, 1H), 6.90-6.58 (m, 1H), 4.78-4.62 (m, I I I ). 4.52-3.78 (m, M l ). 2.73-2.1 9 (m, 4H), 2.07- 1 .05 (m, 6H).
Example 123 : (±)~(2-(J 5-fluoropyTidin-2-yl)oxy)niethyl)-7-aza.bicyclo[2.2.1 ]heptan-7-yl)(2- j.)methanone.
Figure imgf000137_0002
Prepared analogous to example 105 substitutmg 5-methy3-2-(2H- .l ,2,3-triazoI-2- ylibenzoic acid with 2-methyl-6-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C24H73FN4O2, 418.2; m/z found 419.2 [M+Fif. Ή NMR (MeOD): 8.99-8.63 (m, 2H), 8.14-7.70 (m, 2H), 7.61 -7.27 (m, 4H), 7.15-6.45 (m, 1H), 4.86-4.65 (m, 1 H), 4.55-3.44 (m, 3H), 2.53-2.35 (m, 3H), 2.34-0.78 (m, 7H).
Example 124: (±)-(3-fluoro-2-(pyriraidm-2-yl)phenyl)(-2-(((5-fluoropyridin-2-y{)o
azab cyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000138_0001
Prepared analogous to example 105 substituting 5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)benzoic acid wiih 3-iluoro-2~(pyrimidin-2~yi)benzoic acid. MS (ESI) mass calcd. for C23H2 F2N4O2, 422.2; m/z found 422.8 [M+H]+. !H NMR (MeOD): 9.03-8.62 (m, 2H), 8.19-7.82 (m, 1H), 7.67-7.1 1 (m, 5H), 6.85-6.62 (m, 1 H), 4.54 (s, I E), 4.26-3.76 (m, M l ). 2.33 (s, i 1 1 h 2.01 - 1.32 (m, 6H).
Example 125 : (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- -y3)phenyl)methanone.
Figure imgf000138_0002
Prepared analogous to example 105 substituting 5-methyl-2-(2H- 1 ,2,3- iriazoi-2- yljbenzoic acid with 3-raethyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C22H22FN502, 407.2; m/z found 408.2 [M+H . Ή NMR (MeOD): 8.05-7.95 (m, 1 H), 7.93-7.84 (m, 2H), 7.57-7.05 (m, 4PI), 6.81 -6.65 (m, Hi), 4.61 -3.98 (m, 2H), 3.97-3.75 (m, 2H), 2.38-2.23 (m, 1H), 2.19-2. 14 (m, 3H), 1.97- 1.32 (m, 6H).
Example 126: (±)-(2-(((5-fluoropyridin-2-yl)ox )methyi)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5-
Figure imgf000138_0003
yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to example 105 substituting 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid with 5-bromo-2-(2H- 1 ,2,3-triazol-2- yl) benzoic acid.
Step B: (±)-methyl 3-(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1 ]heptane-7-carbonyl)-4-(2H- 1 ,2,3-triazol-2-yl)benzoate. The title compound of step A (100 mg, 0.2 mmol) and Pd(dppf)Cl2 (35 mg) in MeOH (10 mL) was heated to 120 °C for 24h in a sealed tube under an atmosphere of CO, The reaction was allowed to cool to rt and filtered. The filtrate was concentrated and purified via preparative TLC to give the title compound (20 mg, 21 %).
Step C: (±)-(2-(((5-fluoropyridm-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5- (hydroxyraethyl)-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)methanone. To the title compound of step B (40 mg, 0.1 mmol)) in MeOH (0.2 mL) and THF (6 mL) at 0 °C was added NaBH4 (4 mg, 0.1 mmol). After stirring overnight at rt, the reaction was concentrated and purified directly via silica gel chromatography (EtOAc in petroleum ethers) to give the title compound. MS (ESI) mass calcd. for C2iH21FN602, 408,2; mix found 409.2 [M+H]+. !H NMR (MeOD): 8.07-7.82 (m 4H), 7.66-7.29 (m, 3H), 6.85-6.60 (m, I H), 4.70 (d, J - 8.7 Hz, 2H), 4.50-3.73 (m, 4H), 2.43- 2.20 (m, IH), 2.04-1.28 (m, 6H).
Example 127: (±)-(2-(3-methyl-l ,2,4-oxadiazof-5-yl)phenyl)(2-((pyTidin-2-ykixy)methyi)-7- -yl)methanone.
Figure imgf000139_0001
Prepared analogous to Example 2 substituting intermediate A-9 with 2-(3-methyi- 1,2,4- oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C22H22N4O3, 390.2; m/z found 391.1 i v! Ι Π ¾ NMR (MeOD): 8.12-8.00 (m, 2H), 7.75-7.58 (m, 2H), 7.55-7,49 (m, IH), 7.38-7.28 (m, IH), 6.95-6.91 (m, IH), 6,85-6,55 (m, I H), 4.81 -4.78 (m, IH), 4.27-4.14 (m, IH), 4.01-3.97 (m, IH), 3.77-3.75 (m, IH), 2.44-2.26 (m, 4H), 2.10-1.95 (m, IH), 1.87-1.62 (m, 3H), 1.56-1.46 (m, 2H).
Example 128: (±)~(6-methyf-2~(2H~l
Figure imgf000139_0002
7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000140_0001
Prepared analogous to Example 127 substitutmg 2-(3~memyl- l ,2,4~oxadiazol~5~ ylibenzoic acid with 6-methyl-2-(2H- 1 ,2,3-triazol-2-yl)nicotinic acid. MS (ESI) mass calcd. for C21H22N6O2, 390.2: ni/z found 391.2 i v! - ! ! j 5H NMR (MeOD): 8.15-8.09 (m, 1H), 7.99 (s, 2H), 7.91 -7.71 (m, I H), 7.69-6.92 (m, 3H), 6.83-6.59 (m, 1H), 4.71 -4.68 (m, I H), 4.22-4.09 (m, I M i. 4.01 -3.76 (m, 2H), 2.64-2.52 (m, 3H), 2.43-2.23 (m, I M i. 2.00- 1.36 (m, 6H).
Example 12.9: (±)-(3-fluoro-2-(2H- 1 !2,3-ffiazol-2-yl)phenyl)(2-((pyridin-2-y1oxy)methyl)-7- -yl)methanone.
Figure imgf000140_0002
Prepared analogous to Example 127 substituting 2-(3-methyl- l ,2,4-oxadiazol-5- yl)benzoic acid with 3-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C21H20FN5O2, 393.2; m z found 394.0 [M+H]+. JH MR (MeOD): 8.14-8.12 (m, IH), 7.95-7.93 (m, 2H), 7.69-7.46 (tn, 2H), 7.40-7.31 (m, IB), 7.22-7.12 (m, IH), 6.99-6.91 (m, IH), 6.80-6.66 (m, IH), 4.57-4.56 (m, IH), 4.04-3.88 (m, 3H), 2.38-2.27 (m, IH), 1.85- 1.43 (m, 6H).
Example 130: (±)-(6-methyi-2-(l H- l ,2,3-triazol- l -yl)pyridin-3-yl)(2-((pyridin-2-yloxy)methyl)- -azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000140_0003
Prepared analogous to Example 127 substituting 2-(3-methyl- l ,2,4-oxadiazol-5- yl)benzoic acid with 6-methyl-2-(lH- 1 ,2,3-triazol- 1 -yl)nicotinic acid. MS (ESI) mass calcd. for C21H22N6O2, 390.2; m/z found 391.2 ; \ I · Π j 1 1 Vv! R (MeOD): 8.62-8.61 (m, l i s }. 8.12-8.09 (m, 1H), 7.99-7.73 (m, 2H), 7.71-7.62 (m, 1H), 7.50-6.91 (m, 2H), 6.87-6.61 (m, IH), 4.74-4.71 (m, I H), 4.17-3.79 (m, 3H), 2.64-2.53 (m, 3H), 2.46-2.26 (m, IH), 2.06-1.90 (m, 1H), 1.83-1.38 (m, 5H).
Example 131 : (±)-(6-methyl~2-(2H-l,2,3-triazol-2-yI)pyridin-3-yl)(2-(((4- (trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2. l]heptan-7-yl)methanone.
Figure imgf000141_0001
Step A: (±)- ieri-bu!yl 2-(((4-(trifluoromethyl)pyrimidm-2-yl)oxy)methyl)-7- azabicycio[2.2.1 ]heptane-7-carboxylate. To intermediate B-10 (500 mg, 2.2 mmol) in THF (5 mL) at 0 °C was added NaH (6.6 mmol). After 30 min at rt, 2-cbloro-4-
(trifluoromethyl)pyrimidine (1.8 g, 9.9 mmol). The flask was then heated to 50 °C in an oil bath.
After 3h, ¾Q was added and the reaction extracted with EtOAc (2X). Purification via silica gel chromatography (20% EtOAc in petroleu ethers) gave the title compound (752 mg, 92%).
Step B: (±)-2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptane hydrochloride. To the title compound of step A (752 mg, 2 mmol) in
MeOH (6 mL) was added HCi.
Step C: (±)-tert-butyi 2-(((4-(trifluoromethyl)pyrimidm-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to example 127 substituting 2-(3- methyl- 1, 2,4- oxadiazoi- 5 -yl)benzoic acid with 6-methyl-2-(2H- 1 ,2,3-triazol-2-yl)nicotinic acid with the title compound of step B. MS (ESI) mass calcd. for C21H20F3N7O2, 459.2; m/z found 460.2 | Μ · Μ | Ή NMR (MeOD): 8.89-8.82 (m, I H), 8.02-7.82 (m, 3H), 7.48-7.14 (m, 2H), 4.75-4.71 (m, IH), 4.44-4.07 (m, 2H), 3.91-3.84 (m, IH), 2.64-2.56 (m, 3H), 2.48-2.30 (m, I H), 2.02-1.43 (m, 6H).
Example 132: (±)-(6-methyi-2-(l H- 1 ,2,3-triazol- 1 -yl)pyridin-3-yl)(2-(((4- (trifluoromemyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptari-7-yi)methanone.
Figure imgf000142_0001
Prepared analogous to Example 131 substituting 6-methyl-2-(2H- l,2,3-iriazol-2- yl)nicotinic acid with 6-methyl-2-(lH- 1 ,2,3-lriazol- 1 -yi)nicotinic acid, MS (ESI) mass calcd. for C21H20F3N7O2, 459.2; m/z found 460.2 i \I f f | !H NMR (MeOD): 8.86-8.83 (m, i 1 1 i. 8.63-8.61 (m, I H), 8.03-7.84 (m, 2H), 7.49-7.15 (m, 2H), 4.76-4.72 (m, 1H), 4.41 -4.31 (m, IH), 4.27-4.04 (m, IH), 3.90-3.84 (m, 1H), 2.63-2.54 (m, 3H), 2.47-2.30 (m, IH), 2.03-1.43 (m, 6H).
Example 133 : (±)-(2-(3-methyl- 1 ,2,4-oxadiazol-5-y1)phenyl)(2-(((4-(trif1uoromethyl)pyriinidin- -yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000142_0002
Prepared analogous to Example 131 substituting 6-methyl-2-(2H- l,2,3-iriazol-2- yl)nicotinic acid with 2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C22H2QF3N5O2, 459.2; m/z found 460.2 i \) H I !H NMR (MeOD): 8.88-8.80 (m, I ! n. 8.08-8.00 (m, 1H), 7.74-7.62 (m, 1H), 7.63-7.51 (m, 1H), 7.48-7.37 (m, 11 1 ). 4.83-4.80 (m, 1H), 4.49-4.33 (m, 1H), 4.23-4.11 (m, 1H), 3.81-3.77 (m, I H), 2.53-2.36 (m, 4H), 2.07-2.98 (m, IH), 1.90-1.51 (m, 5H).
Example 134: (±)~(3-fluoro-2-(2H- 1 ,2,3 -triazol-2-yl)phenyI)(2-(((4-(trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)-7-azabicycJo[2.2.1 ]heptan-7-yl)metbanone.
Figure imgf000143_0001
Prepared analogous to Example 131 substituting 6-methyl-2-(2H- 1 ,2,3-triazol-2- yl)nicotinic acid with 3-fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid, MS (ESI) mass calcd. for C21H18F4N6O2, 462.2; rn/z found 463.2 [M+H]+. !H NMR (MeOD): 8.89-8.84 (m, 1H), 7.96-7.94 (m, 2H), 7.69-7.28 (m, 4H), 4.61 -4.58 (m, 1 H), 4.29-4.06 (m, 2H), 3.97-3.93 (m, i 1 1 i. 2.46-2.37 (m, 1H), 1.88- 1.40 (m, 6H).
Example 135: (±)-(6-methyl-2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)(2-(((5-methyipyridin-2- 2.1 ]heptan-7-yl)methanone.
Figure imgf000143_0002
Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoroniethyl)pyrimidine with 2-chloro-5-methylpyridine. MS (ESI) mass calcd. for C22H24 6O2, 404.2; m/'z found 405.2 [M+H]+ . ]H NMR (MeOD): 7.99-7.71 (m, 4H), 7.51 -7.00 (m, 2H), 6.73-6.50 (m, i l l !. 4.69 (d, J - 3.6 Hz, 1H), 4.17-4.04 (m, 1H), 3.96-3.72 (m, 2H), 2.64-2.53 (m, 3H), 2.43-2.20 (m, 4H), 2.03- 1.35 (m, 6H).
Example 136: (±)-(6-met yi-2-(l H-l ,2,3-triazol- l -yl)pyridin-3-yi)(2-(((5-methylpyridin-2- 2.1]heptan~7-yl)methanone.
Figure imgf000143_0003
Prepared analogous to Example 135 substituting 6-methyl-2-(2H- 1 ,2,3-triazol-2- yl)nicotinic acid with 6-methy3-2-(lH- l ,2,3-tr azol-l-yl)n cotin c acid. MS (ESI) mass calcd. for C22H24N6O2, 404.2; τη/ζ found 405.2 ; \ I · Π j 1 1 NMR (MeOD): 8.62-8.55 (m, l i s }. 8.19-7.88 (m, 3H), 7.75-7.47 (m, 2H), 7.05-6.52 (m, 1H), 4.72-4.71 (m, 1H), 4.08-4.02 (m, IH), 3.98-3.74 (m, 2H), 2.64-2.53 (ra, 3H), 2.37-2.24 (m, 4H), 1.96 (brs, IH), 1.82-1 .35 (m, 5H).
Example 137: (±)-(2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)phenyl)(2-(((5-methylpyridin- 2.2.1]heptan-7-yl)methanone.
Figure imgf000144_0001
Prepared analogous to Example 135 substituting 6-methyl-2-(2H-l ,2,3-triazoI-2- yl)mcotinic acid with 2-(3-raethyl-l ,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C23H24N4O3, 404.2; m/z found 405.2 I M - ! ! ] i i NMR (MeOD): 8.09-8.00 (m, IH), 7.92-7.88 (m, IH), 7.75-7.63 (tn, IH), 7.55-7.43 (m, 2H), 7.38-7.29 (m, IH), 6.76-6.47 (m, IH), 4.81-4.77 (m, IH), 4.22-4.09 (m, IH), 3.95 i d . .; S i Hz, IH), 3.76-3.74 (m, IH), 2,44-2,20 (m, 7H), 2.07-1.97 (ra, IH), 1 .86-1.62 (m, 3H), 1.55-1.42 (m, 2H).
Example 138: (±)-(3-fluoro-2-(2H-l ,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2- [2.2.1]heptan-7-yl)methan.one.
Figure imgf000144_0002
Prepared analogous to Example 135 substituting 6-methyl-2-(2.H-l ,2,3-triazol-2- yl)nicotmic acid with 3-fiuoro-2-(2H-l ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C22H22FN5O2, 407.2; m/z found 408.2 [Μ+Η]+. ¾ NMR (MeOD): 7.96-7.93 (m, 3H), 7.69-7.49 (m, 2H), 7.40-7.33 (m, IH), 7.22-7.13 (m, IH), 6.71-6.58 (m, IH), 4.58-4.55 (m, IH), 4.02-3.83 (m, 3H), 2.37-2.23 (ra, 4H), 1 .85-1.41 (m, 6H).
Example 139: (±)-(6-methyl~2-(2H- 1 ,2,3-triazol-2-yI)pyridin-3-yl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000145_0001
Prepared analogous to Example 135 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chioro-6-methylpyriditie. MS (ESI) mass calcd. for C22H24N6Q2, 404.2; m/z found 405.2 j \! H i . H WI R (MeOD): 7.99 (s, 2H), 7.91 -7.69 (m, 1 H), 7.56-6.77 (m, 3H), 6.60-6.38 (m, IB), 4.70-4.69 (m, Hi), 4.21 -4.05 (m, 1 H), 3.98-3.77 (m, 2H), 2.64-2.51 (m, 3H), 2.43-2.20 (m, 4H), 2.03- 1.37 (m, 6H).
Example 140: (±)-(6-methyl-2-(lH- 1 ,2,3-triazol- 1 -yl)pyridin-3-yl)(2-(((6-methylpyridin-2- 2.1 ]heptan-7-yl)methanone.
Figure imgf000145_0002
Prepared analogous to Example 139 substituting 6-methyl-2-(2H- 1 ,2,3-triazol-2- y])nicotinic acid with 6-methyl-2-(lH- 1 ,2,3-triazol- 1 -yl)nicotinic acid. MS (EST) mass calcd. for C22H24 6O2, 404.2; m/z found 405.2 [M+H] 'H NMR (MeOD): 8.34 (d, J - 7.1 Hz, Hi), 7.77- 7.42 (m, 3H), 7.28-6.35 (m, 3H), 4.82-4.79 (m, 1H), 4.24-3.94 (m, 2H), 3.87-3.81 (m, 1H), 2.63- 2.22 (m, 7H), 2.15- 1.98 (m, 1H), 1 .84- 1.34 (m, 5H).
Example 141 : (±)-(2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)phenyl)(2-(((6-methylpyridin-2- [2.2.1 ]heptan~7-yl)methanone.
Figure imgf000145_0003
Prepared analogous to Example 139 substituting 6-methyl-2-(2H- l ,2,3-rriazoi-2- yl)nicotinic acid with 2-(3-methyi- l ,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C2JH24N4OJ, 404.2; m/z found 405.2 j V! · Π j 1 1 NMR (MeOD): 8.10-8.00 (m, l i s }. 7.75-7.63 (m, 1H), 7.57-7.47 (m, 2H), 7.37-7.26 (m, 1H), 6.79 (dd, J = 7.2, 2.8 Hz, 1H), 6.64-6.35 (m, 1H), 4.81 -4.78 (m, 1H), 4.25-4.1 1 (m, 1H), 3.98-3.95 (m, I H), 3.79-3.74 (m, 1H), 2.42-2.25 (m, 7H), 2.08-1.95 (m, IH), 1 .86-1.63 (m, 3H), 1.58-1.44 (m, 2H).
Example 142: (±)-(3-fluoro-2-(2H-l,2,3- azol-2-yl)phenyl)(2-(((6-methylpyridin-2- [2.2.1]heptan-7-yl)methan.one.
Figure imgf000146_0001
Prepared analogous to Example 139 substitutmg 6-methy3-2-(2H-.l ,2,3-triazoi-2- ylinicotinic acid with 3-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)benzQic acid. MS (ESI) mass calcd. for C22H22FN5O2, 407.2; m/z found 408.2 [M+Fi . ¾ NMR (MeOD): 7.95-7.93 (m, 2H), 7.68-7.47 (m, 2H), 7.40-7.31 (m, IE), 7.21-7.09 (m, 1H), 6.80 (t, J - 8.3 Hz, 1H), 6.58-6.46 (m, 1H), 4.56 (s, H i !. 4.01 (d, J === 7.3 Hz, i l l ). 3.91 i d. J === 7.4 Hz, 2H), 2.43 fd, J === 2.5 Hz, 3H), 2,38-2.28 (m, 1H), 1.83-1.45 (m, 6H).
Example 143 : (±)-(6-metliyl-2-(2H- 1 ,2,3-triazol-2-yf)pyridm-3-yl)(2-(((6- methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000146_0002
Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoromethyl)pyrimidme with 2-clik)ro-6-(trifluoromethyl)pyridme, MS (ESI) mass calcd. for C22H21F3 6O2, 458.2; m/z found 459.2 j VI · Π ; JH NMR (MeOD): 7.91 (s, IH), 7.84 (s, Hi), 7.73-7.65 (m, 2H), 7.29-7.25 (m, 2H), 6.93-6.69 (m, IH), 4.85-4.82 (m, 1H), 4.25-4.16 (m, IH), 3.98-3.96 (m, IH), 3.79-3.69 (m, IH), 2.69-2.56 (m, 3H), 2.38-2.16 (m, I H), 2.05-1.24 (m, 6H). Example 144: (± (6-methyl-2-(lH- 1 ,2,3-triazol- i -yl)pyridin-3-yl)(2-(((6- (trifluoromethyl)pyridin~2-yl)oxy)methyl)-7-azabicycio[2.2 ]heptan-7-yl)meth^
Figure imgf000147_0001
Prepared analogous to Example 143 substituting 6-methyl-2-(2H- 1 ,2,3-triazol-2- yl)nicotinic acid with 6-methyl-2-(lH-l,2,3-triazol-l-yl)nicotinic acid. MS (ESI) mass calcd. for C22H2iF, 602, 458.2; m/z found 459.2 I f 11 M NMR (MeOD): 8.61 (t, J - 1.1 Hz, IH), 8.00-7.72 (m, 3H), 7.49-6.83 (ra, 3H), 4.75-4.71 (ni, IH), 4.31-4.10 (m, IH), 4.08-3.95 (sn, I H), 3.89-3.77 (m, I H), 2.64-2.52 (m, 3H), 2.43-2.27 (m, IH), 2.06-1 .89 (m, IH), 1.82- 1.37 (m, 5H). Example 145: (±)-(2 -(3 -methyl- 1,2,4-oxadiazoi^
.1 ]heptan-7-yl)methanone.
Figure imgf000147_0002
Prepared analogous to Example 143 substituting 6-methyl-2-(2H- l,2,3-iriazol-2- yljnicotinic acid with 2-(3-methyJ-l,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for u h FX ·(.) ;. 458.2; m/z found 459.2 [M+Hjf . Ή NMR (MeOD): 8.10-8.01 (m, I H), 7.88-7.77 (m, I H), 7.75-7.63 (m, IH), 7.54-7.49 (m, Hi), 7.39-7.25 (m, 2H), 7.07-6.78 (m, I PI), 4.82-4.79 (m, IH), 4.35-4.24 (m, IH), 4.10-4.07 (m, IH), 3.78-3.74 (m, IH), 2.48-2.29 (m, 4H), 2.09- 1.96 (m, IH), 1.88-1 .63 (m, 3H), 1.58-1.47 (m, 2H). Example 146: (±)-(3-fluoro-2-(2H- 1,2,3 -triazol-2-yl)phenyl)(2-(((6-(trifluoromeihyI)pyridin-2- y])oxy)methyI)-7-azabicyclo[2.2.1 ]heptan-7-yl)niethanone.
Figure imgf000148_0001
Prepared analogous to Example 143 substituting 6-methyl-2-(2H-l,2,3-triazol-2- yl)nicotinic acid with 3-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C22H19F4N5O2, 461 .2; m/z found 462.0 [M+H] i NMR (MeOD): 7.95-7.93 (m, 2H), 7.86-7.80 (m, 1 H), 7.68-7. 12 (m, 4H), 7.02-6.86 (m, Hi), 4.59-4.56 (m, 1 H), 4.10-3.86 (m, 3H), 2.38-2.30 (m, 1H), 1.95- 1.45 (m, 6H).
Example 147: (±)-(6-methyl-2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)(2-((quinoxalm-2- heptan-7-yl)methanone.
Figure imgf000148_0002
Prepared analogous to Example 131 substituting 2-chJoro-4-(trifluoromethyJ)pyrimidme with 2-chloroquinoxaline. MS (ESI) mass calcd. for C2 H23 7O2, 441.2; m/z found 442.2
[M+H]1". 'H MR (MeOD): 8.47-8.04 (m, 2H), 7.98-7.69 (m, 5H), 7.65-7.56 (m, 1H), 7.45-6.73 (m, 1H), 4.77-4.71 (m, 1H), 4.46-4.10 (m, 2H), 3.91-3.79 (m, 1H), 2.64-2.32 (m, 4H), 2.03-1.38 (m, 6H).
Example 148: (±)-(6-methyl-2-( 1 H- 1 ,2,3-triazol- 1 -yl)pyridin-3-yl)(2-((quinoxalm-2- yloxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000148_0003
Prepared analogous to Example 147 substituting 6-methyl-2-(2H-l,2,3-triazol-2- yl)nicotinic acid with 6-methyl-2-(lH-l,2,3-triazol-l-yl)nicotinic acid. MS (ESI) mass calcd. for C24H23N7O2, 441.2; m/z found 441.2 [M+Hf. 'HNMR (MeOD): 8.61-8.59 (m, 1H), 8.46-8.25 (m, 1H), 8.04-7.55 (m, 6H), 7.48-6.74 (m, 1H), 4.78-4.74 (m, 1H), 4.43-4.30 (m, IE), 4.21-4.18 (m, 1H), 3.92-3.82 (m, 1H), 2.63-2.34 (m, 4H), 2.08-1.89 (m, 1H), 1.88-1.39 (m, 5H).
Example 149: (±)-(2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7- thanone.
Figure imgf000149_0001
Prepared analogous to Example 147 substitutmg 6-methy3-2-(2H-.l ,2,3-triazol-2- ylinicotinic acid with 2-(3-methyl-l,2,4-oxadiazol-5-yi)benzoic acid. MS (ESI) mass calcd. for C25H23N5O3, 441.2: m/z found 442.2 ί XI I i J II NMR (MeOD): 8.48-8.20 (m, ! i i :·.8.08-7.91 (m, 2H), 7.83-7.12 (m, 6H), 4.86-4.81 (m, 1H), 4.50-4.36 (m, 1H), 4.26-4.18 (m, 1H), 3.80-3.77 (m, 1H), 2.55-2.34 (m, 4H), 2.09-1.97 (m, 1H), 1.91-1.64 (m, 3H), 1.61-1.50 (m, 2H).
Example 150: (±)-(3-fluoro-2-(2H- 1 ,2,3-triazoi-2-yl)phenyl)(2-((quinoxaiin-2-yloxy)methyi)-7- one.
Figure imgf000149_0002
Prepared analogous to Example 147 substitutmg 6-methy3-2-(2H-.l,2,3-triazoI-2- ylinicotinic acid with 3-fluoro-2-(2H- 1 ,2>3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for CVH; i;N )..444.2; m/z found 445.1 [M+H]+. Ή NMR (MeOD): 8.47-8.33 (m, 1H), 8.01-7.60 (m, 6H), 7.54-6.92 (m, 3H), 4.65-4.60 (m, 1H), 4.31-4.13 (m, 2H), 3.96-3.95 (m, 1H), 2.52-2.40 (m, 1H), 1.96-1.44 (m, 6H). Example 151 : (±)-(2-(((4,6-oUmeihylpyrirrudm^ 1 ]heptan-7- -methyl-2-(2H- l,2,3-iriazol-2-yl)pyridin-3-yl)methanone.
Figure imgf000150_0001
Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoTornethyl)pyrirnidine with 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C22H25N7O2, 419.2; m/z found 420.2 I Λ 1 · i 1 1 ' H NMR (MeOD): 8.02-7.99 (m, 2H), 7.94-7.46 (m, IH), 7,48-7.10 (m, IH), 6.87 (s, I H), 4.72-4.71 (m, I H), 4.38-3.97 (m, 2H), 3.89-3.84 (m, IH), 2.65-2.17 (m, 10H), 1.98- 1.37 (m, 6H). Example 152: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)nietliyl)-7-aza.bicyclo[2.2.1 ]hepfan- -methyl-2-( 1 H- 1 ,2,3-triazol- 1 -yl)pyridin-3-y])methanone.
Figure imgf000150_0002
Prepared analogous to Example 151 substituting 6-methyl-2-(2H- 1 ,2,3-triazol-2- yl)nicoimic acid with 6-methyl-2-(lH- 1 ,2,3-triazol- 1 -yl)nieotinic acid. MS (ESI) mass calcd. for C22H25N7O2, 419.2; m/z fou d 420.2 [M+H]+. !H NMR (MeOD): 8.62-8.61 (m, IH), 7.98-7.78 (m, 2H), 7.50-7.1 i (tn, I H), 6.86 (d, J = 9.7 Hz, I H), 4.75-4.71 (m, IH), 4.25-4.23 (m, IH), 4.16-3.84 (m, 2H), 2.64-2.55 (m, 3H), 2.46-2.25 (m, 7H), 2.06- 1.88 (m, IH), 1.85- 1.39 (m, 5H).
Example 153 : (±)-(2-(((4,6-dimetbylpyrirmd n-2-^ Jheptan- -(3-methy 1- 1 ,2,4-oxadiazol-5-yi)phenyl)methanone.
Figure imgf000150_0003
Prepared analogous to Example 151 substituting 6-methyl-2-(2H-l,2,3-triazol-2- yl)nicotinic acid with 2-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)benzoic acid.MS (ESI) mass calcd. for C23H25N5O3, 419.2; m/z found 420.2 [M+Hf. 'H NMR (MeOD): 8.10-8.01 (m, 1H), 7.76-7.64 (m, H), 7.58-7.51 (ra, IH), 7.42-7.36 (m, 1H), 6.86 ($, 1H), 4.83-4.80 (m, H), 4.42-4.22 (ra, I M i. 4.13-4.00 (m, 1H), 3.83-3.76 (m, 1H), 2.49-2.28 (m, 10H), 2.08-1.98 (m, IH), 1.89-1.65 (m, 3H), 1.58-1.48 (m, 2H).
Example 154: (±)-(2-(((4,6-dimelhylpyrirnidm-2-yl)oxy)methyl)-7-azabicyclo[2.2.1 ]heptan-7- -fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)ineihanone.
Figure imgf000151_0001
Prepared analogous to Example 151 substituting 6-methyl-2-(2H- l,2,3-iriazol-2- yl)nicotinic acid with 3-fluoro-2-(2H-l,2,3-triazo]-2-yj.)benzoic acid. MS (ESI) mass calcd. for C22H23FN602, 422.2; m/z found 423.1 [M+Hf. !H NMR (MeOD): 7.96-7.95 (m, 2H), 7.69-7.22 (m, 3H), 6.87 (d, J = 5.8 Hz, 1H), 4.58-4.56 (m, 1H), 4.19-3.89 (m, 3H), 2.42-2.34 (m, 7H), 1.90-1.37 (m, 6H).
Example 155: (±)-(2-ethoxy-4-methylpyridm-3-yl)(2-((pyridin-2-yloxy)methyl)-7- -yl)methanone.
Figure imgf000151_0002
Prepared analogous to Example 1 substituting intermediate B-9 with B-10 and 5-fluoro- 2-(pyrimidin-2-yf)beiizoic acid with 2-ethoxy-4-methylnicotinic acid. MS (ESI) mass calcd. for C2IH2SNJOJ, 367.2; m/z found 368.3 | VI · Π i ]H NMR (CDCI3): 8.13 - 8.05 (m, IH), 7.99 - 7.87 (m, IH), 7.58 - 7.46 (m, ! i i :·. 6.87 - 6.79 (m, l i b. 6.76 - 6.67 (m, IH), 6.55 - 6.49 (m, U I s. 4.92 - 4.84 (ra, IH), 4.43 - 3.64 (m, 5H), 2.43 - 1.22 (m, 13 H). Example 156: (±)-(6-methylimidazo[2, 1 -b]thiazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7- l)methanone.
Figure imgf000152_0001
Prepared analogous to Example 1 substituting intermediate B-9 with B-10 and 5-fluoro- 2-(pyrimidm-2-yl)benzoic acid with 6-methylimidazo[2, 1 -bjthiazole-5-earhoxylic acid, Ή NMR (CDCI3): 8.05 - 7.98 (m, 1H), 7.79 (d, J= 4.5 Hz, IH), 7.54 - 7.47 (m, 1H), 6.84 - 6.78 (m, IH), 6.76 (d, ./ 4.5 Hz, HI), 6.62 (d, J 8.4 Hz, 1H), 4.54 - 4.35 (m, 2H), 4. 1 - 4.03 (m, i l l ). 4.02 - 3.88 (m, 1H), 2.46 (s, 3H), 2.39 - 2.28 (m, 1H), 2.07 - 1.97 (m, IH), 1.80 - 1.70 (m, 2H), 1.65 - 1 .52 (m, 3H).
Example 157: (±)-(5-bromo-2-etlioxypyridm-3-yl)(2-((pyrid"in-2-yloxy)methyl)-7- methanone.
Figure imgf000152_0002
Prepared analogous to Example 1 substituting intermediate B-9 with B-10 and 5-fluoro- 2-(pyrimidin-2-yl)benzoic acid with 5-bromo-2-ethoxynicotinic acid. MS (ESI) mass calcd. for ( · >..,! I > >lirVO .. 431.1 ; m/z found 432.2. [M+H]+ . Ή NMR (CDCI3): 8.33 - 8.07 (m, 2H), 7.74 (d, J= 2.5 Hz, 0.5H), 7.61 (d, J = 2.5 Hz, 0.5H), 7.59 - 7.49 (m, 1H), 6.89 - 6.81 (m, I H), 6.75 (d, J - 8.3 Hz, 0.5H), 6.55 (d, J= 8.4 Hz, 0.5H), 4.86 - 4.80 (m, I H), 4.48 - 3.78 (m, 5H), 2.43 - 2.33 (m, 0.5H), 2.32 - 2.23 (m, 0.5H), 2.03 - 1.39 (m, 6H), 1.37 - 1.29 (m, 3H).
Example 158: (±)-(2-ethoxy-6-methylpyridm-3-yl)(2-((pyridin-2-yloxy)methyl)-7- azab cyclo[2.2.1 ]heptan-7-yi)methanone.
Figure imgf000153_0001
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-ethoxy-6-meihylmcotinic acid, MS (ESI) mass calcd. for 0>;Η25Ν3 (¾, 367.2; m/z found 368.3 [M+H]÷. !H NMR (CDC13): 8.14 - 8.08 (m, 1H), 7.57 - 7.47 (m, 1.5H), 7.38 (d, J= 7.4 Hz, 0.5H), 6.86 - 6.82 (m, 1H), 6.74 (d, J= 8.3 Hz, 0.5H), 6.72 (d. ,/ 7.4 Hz, 0. H i. 6.51 i d. ./ 8.3 Hz, 0.5H), 6.46 (d, ,/ 7.4 Hz, 0.51 1 ;. 4.84 - 4.79 (m, 1H), 4.44 - 4.34 (m, 1.5H), 4.27■■ 4.09 (m, 1.5H), 4.06■ 4.01 (m, 0.5H), 3.92■■ 3.80 (m, 1.5H), 2.43 (s, 1.5H), 2.38 - 2.32 (m, 2H), 2.26 - 2.20 (m, 0.5H), 2.01 - 1.40 (m, 6H), 1.36 - 1.28 (m, 3H).
Example 159: (±)-(7-hydroxyquinolin-8-yl)(2-((pyridin-2-yioxy)raelJiyl)-7- l)methanone.
Figure imgf000153_0002
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidm-2-yl)benzoic acid with 7-hydroxyquinoline-8-carboxylic acid (mtermediate A-29 step B). MS (ESI) mass calcd. for C22H2JNJOJ, 375.2; m/z found 376.3 I f ϊ J Ή NMR (CDCI3): 8.88■■ 8.66 (m, 1H), 8.19 ·■ 7.93 (m, 2H), 7.80 - 7.41 (m, 2H), 7.26 6.25 (series of m, 4H), 5.10 - 4.87 (m, 1H), 4.34 - 3.60 (m, 3H), 2.51 - 1.00 (series of m, 7H). Example 160: (±)-(2-eihoxy-5-phenylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000153_0003
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-emoxy-5-phenylnicotinic acid. MS (ESI) mass calcd. for C26-H27N3O3, 429.2; ro/z found 430.2 [M+Hf. ]H NMR (CDCI3): 8.40 and 8.30 (2d, J= 2.5 Hz, H), 8.15 - 8.12 and 7.98 - 7.94 (2m, IH), 7.87 and 7.74 (2d, J = 2.5 Hz, I H), 7.59 - 7.28 (m, 6H), 6.88 - 6.83 and 6.72 - 6.68 (2m, i l l ). 6.76 and 6.47 (2d, J- 8.3 Hz, 1H),
4.89 .. 4.84 (m, IH), 4.34 - 3.84 (series of m, 5H), 2.43 - 2.34 and 2.32 - 2.23 (m, IH), 2.06 - 1.45 (series of m, 6H), 1.42 - 1.32 (m, 3H).
Example 161 : (±)~( -bronio-2-ethoxypyridin-3-yl)(2~((pyridin-2~yloxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)metbanone.
Figure imgf000154_0001
Prepared analogous to Example 1 substituting mtermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 4-bromo-2-ethoxynicotinic acid. MS (ESI) mass caled. for ( 1 > .BrN ;() ;. 431.1; m/z found 432.2 I U ; . ]H NMR (CDCI3): 8.15 - 8.08 (m, I H), 7.96 - 7.87 (m, I H), 7.60 - 7.49 (m, IH), 7.11 - 6.92 (series of m, I H), 6.88 - 6.82 (m, IH), 6.78 - 6.52 (series of m, IH), 4.94 - 4.87 (m, IH), 4.47 - 3.67 (series of m, 5H), 2.45 - 1.41 (series of m, 7H), 1.38 - 1.27 (m, 3H).
Example 162: (±)-(2-chloro-4-ethox ^yridin-3-yI)(2-(( yridin-2-yIoxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000154_0002
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-chloro-4-ethoxynicotinic acid. MS (ESI) mass calcd. for C20H22CIN3O3, 387.1 ; m z found 388.3 [M+H]+ . ]H NMR (CDC13):8.27 - 8.17 (m, IH), 8.15 - 8.07 (m, IH), 7.60 - 7.48 (m, IH), 6.88-6.82 (m, IH), 6.80 - 6.73 (m, IH), 6.58 6.49 (in, I H), 4.93 - 4.87 (m, 1H), 4.27 - 4.02 (m, 3H), 3.92 - 3.58 (series of m, 2H), 2.44 - 1.35 (series of m, 10H).
Example 163 : (±)-(2,4-diethoxypyridin-3-yi)(2-((jpyridin-2-yioxy)methyl)-7- azabicyclo 2.2.1 ]heptan-7-yl)methanone.
Figure imgf000155_0001
Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B- 10 and 5-fluoro-2-(pyrimidin-2-yj.)benzoic acid with 2,4-diethoxynicotmic acid. MS (EST) mass calcd. for ( \ M.Hir\ .0... 397.2; m/z found 398.2 [M+Hf . JH NMR (CDCk): 8.15 - 8.07 (m, IH), 8.03 - 7.94 (m, I H), 7.60 - 7.46 (m, IH), 6.87 - 6.80 (m, IH), 6.77 - 6.73 (m, 0.5H), 6.56 - 6.45 (m, 1H), 6.30■■ 6.27 (m, 0.5 H) 4.88 - 4.83 (m, 1H), 4.50 - 3.51 (series of m, 7H), 2.40■ 1.15 (series of m, 13H),
Example 164: (3-ethoxyisoqumoIm-4-yl)((l S,2R,4R)~2-((pyridin-2-yloxy)inethyI)-7- l)methanone.
Figure imgf000155_0002
Prepared analogous to Example 1 substituting 5-f!uoro-2-(pyrim din-2-yl)benzoic acid with intermediate A-22. MS (ESI) mass calcd. for C24H25N3CH, 403.2; m/z found 404.2 [M+H]+. Ή NMR (400 MHz, CDCi3) 8.97 - 8.89 (m, 0.7H), 8.87 - 8.81 (m, 0.3H), 8.22 - 8.07 (m, 0.7H), 7.95 - 7.85 (m, I H), 7.82 (dq, J= 8.6, 0.9 Hz, 0.2H), 7.78 - 7.69 (m, 0.6H), 7.69 - 7.47 (m, 2H), 7.43 - 7.28 (m, 1.2H), 7.10 (ddd, J= 8.0, 6.8, 1.0 Hz, 0.3H), 6.93 - 6.68 (m, 1.5H), 6.52 - 6.46 (m, 0.2H), 6.16 - 6.09 (m, 0.3H), 5.02 (id, J = 9.5, 4.6 Hz, IH), 4.65 - 3.99 (m, 3.5H), 3.92 (dd, J = 10.5, 5.6 Hz, 0.25H), 3.74 - 3.58 (m, 1 .25H), 2.52 - 2.29 (m, 0.5H), 2.27 - 1.93 (m, 2H), 1.86 - 0.78 (m, 7.5H). Example 165 : (±)-(2-ethoxyphen l)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- methanone
Figure imgf000156_0001
Prepared analogous to Example 7 substituting 6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picolinic acid with 2-etlioxybenzoic acid. Ή NMR (400 MHz, CDC13): 7.95 (dd, J= 7.3, 3.1 Hz, I H), 7.37 - 7.18 (m, 2.5H), 7.14 (dd, ./ 7.4, 1.7 Hz, O.SH), 6.95 (id, ./ 7.5, 0.9 Hz, O.SH), 6.90 (dd, J= 8.4, 1.0 Hz, O.SH), 6.83 - 6.68 (m, 1.5H), 6.47 (dd, J= 9.0, 3.6 Hz, 0.5H), 4.88 - 4.80 (m, IH), 4.17 - 3.72 (m, 5H), 2.40 - 2.28 (m, O.SH), 2.26 - 2.14 (ni, O.SH), 2.07 - 1.85 (m, 2H), 1.83 - 1 .17 (m, 7H).
Example 166: (±)-(5-fluoro-2-(2H- 1 ,2,3-triazoi-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyi)-7- anone
Figure imgf000156_0002
Prepared analogous to Example 2 substituting 6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picolinic acid with intermediate A- 10 and 2-fluoropyridine with 2-chloroquinoxaline, MS (ESI) mass calcd. for -! FW.O... 444.2; m/z found 445.2 [M+H]+. lB NMR (400 MHz, CDCI3): 8.49 (s, 0.4H), 8.30 (s, 0.4H), 8.04 (ddd, J = 8.2, 6.9, 1.5 Hz, IH), 7.90 - 7.76 (m, 2.5H), 7.75 - 7.66 (m, i.SH), 7.65 - 7.55 (m, 1 ,5H), 7.44 (dd, J = 8.5, 5.8 Hz, O.SH), 7.32 (dd, J = 8.5, 5.8 Hz, O.SH), 7.29 - 7.22 (m, 0.2H), 7.21 - 7.10 (m, IH), 6.49 fs, O.SH), 4.93 - 4.84 (m, IH), 4.52 - 4.30 (m, IH), 4.23 - 4.07 (m, IH), 3.87 - 3.78 (m, IH), 2.48 - 2.25 (m, 1.8H), 2.10■- 1.88 (m, 1.2H), 1.83 - 1.31 (m, 4H). Example 167: (±)-5-methyi-2-(2H- 1,2 ,3-triazol-2-yl)phenyi)(2-(((5-methyipyTidin-2- yl)oxy)methyi)-7-azabicyclo[2.2.1]heptan~7-yl)methanone
Figure imgf000157_0001
Prepared analogous to Example 13 substituting 2-chloro-4-trif1uoromethylpyrimidine with 2-fluoro-5-methylpyridine. MS (ESI) mass calcd. for C23H25N5O2, 403.2; m/z found 404.2 I i i ; . jH NMR (400 MHz, CDCI3): 7.99 - 7.92 (m, 1H), 7.81 - 7.68 (m, 2.5H), 7.42. - 7.29 (m, 1.SB), 7.26 - 7.21 (m, 0.5H), 7.21 - 7.10 (m, 1 H), 6.66 (d, J= 8.4 Hz, 0.5H), 6.45 (d, J = 8.4 Hz, 0.5H), 4.85 - 4.73 (m, 1 H), 4.16 - 3.68 (m, 3H), 2.42 (s, 1 .3H), 2.34 - 2.14 (m, 3.7H), 2.02 - 1.79 (m, 2.51 . 1.72 - 1.21 (tn, 5.5H). Example 168: (±)-(6-methyl-2-(2H- l ,2,3-triazol-2-yl)pyridin-3-yl)(2-((quinoxalin-2- yloxy)methyI)-7-azabicyclo[2.2.1 Jheptan~7-yl)niethanone
Figure imgf000157_0002
Prepared analogous to Example 1 substituting mtermediate B-9 with intermediate B-10, 2-fluoropyridine with 2-chloroquinoxaline and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-3 to give the title compound. MS (ESI) mass calcd. for C24H23N7O2, 441.2; m/z found 442.2 i Π ; 1H NMR CD3OD: 8.47-8.04 (m, 2H), 7.98-7.69 (m, 5H), 7.65-7.56 (m, 1 H), 7.45-6.73 (m, 1 H), 4.77-4.71 (m, 1H), 4.46-4.10 (m, 2\ i ). 3.91 -3.79 (m, 1 H), 2.64-2.32 (m, 4H), 2.03- 1.38 (m, 6H).
Example 169: (±)-(5-fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)(2-((pyridin-2-ylammo)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000158_0001
Prepared analogous to example 170 substituting 2-cbloi -4,6-dimethylpyrimidine with 2- fluoropyridine. MS (ESI) mass calcd. for QilfeiFNA 392.2; m/z found 393.1 [M+H]+. 1 H MR (CD30D): 8.02-7.83 (m, 4H), 7.47-7.23 (m, 3H), 6.59-6.38 (m, 2H), 4.73-4.55 (m, Hi), 3.87-3.70 (m, H i ). 3.24-2.80 (m, 2H), 2.27-2.03 (m, 1H), 1.97-1.34 (m, 6H).
Example 170: (±)-(2-(((4,6-dimethylpyrimidm
y1)(5-fiuoro-2-(2H- 1 ,2,3-triazol-2-yJ)phenyl)methanone
Figure imgf000158_0002
Step A: (±)-tert -but l 2-(((methyisulfonyl)oxy)methyi)-7-azabicyclo[2.2.1 ]heptane-7- carboxylate. To intermediate B- 1Q (2.6g, 1 1.5 mmol) and TEA (1.7g, 17.2 mmol) in DCM ( 15 ml.) at 0 °C was added MsCl (1.6g, 13.7 mmol) dropwise over 10 minutes. This ice bath was removed and the reaction was allowed to stir at rt for 12h and H20 was added. The layers were separated and the organic layer was washed with brine and dried (Na^SC ). Purification via silica gel chromatography; 15% EtO c in petroleum ethers) gave the title compound (3.5g). Step B: (±)-tert-butyl 2-(azidomethyl)-7-azabicyclo[2.2.1 ]heptane-7-carboxylate. To the title compound of step A (3.4g, 1 1.1 mmol) in DMF (15 mL) was added sodium az de (2.1g, 33.4 mmol). The mixture was heated at 100 °C overnight, cooled to rt, poured into H20 and extracted with DCM, The combined organics were washed with brine and dried (Na2S04). Purification via silica gel chromatography (10% EtOAc in petroleum ethers) gave the title compound (2.6g). Step C: (±)-2-(azidomethyl)-7-azabicyclo[2.2.1 ]heptane. To the title compound of step B in DCM was added TFA. After 3h at rt, the reaction mixture was concentrated to give the title compound (1.7g) as the TFA salt.
Step D: (±)-2-(azidomethyl)-7-azabicyelo[2.2.1 ]heptan-7-yl)(5-fluoro-2-(2H- 1 ,2,3- triazol-2-yl)phenyl)methanone. Prepared analogous to example 22 substituting 2-(2H- .1 ,2,3- triazol-2-yl)benzoic acid with 5-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid and using the title compound of step C.
Step E: 2-(aminomethyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5-fluoro-2-(2H- 1 ,2,3 -triazol-2- y.l)phenyl)methanone. The title compound of step D in MeOH was placed under an atmosphere of hydrogen in the presence of 10 wt% Pd/C for 4h. The catalyst was removed by filtration. Purification via silica gel chromatography (7% MeOH in DCM) gave the title compound.
Step F: (±)-(2-(((4,6-dimethylpyrimidm^
7-yl)(5-fluoro-2-(2H- 1 ,2,3-triazoi-2-yl)phenyl)methanone. To the title compound of step E (30 mg) i MP (3 mL) was added 2-chloro-4,6-dimethylpyrimidine (16 mg) and CS2CO3 (43 mg). The reaction was heated to 1 80 °C for 2h. After cooling to rt, H20 was addd and the mixture extracted with EtOAc. Purification via prep-HPLC gave the title compound. MS (ESI) mass calcd. for C22H24FN7O, 421.2; m/z found 422.2 I M - i i i . 1H NMR (CD30D) 7.90-7.73 (m, 3H), 7.34-7.14 (m, 2H), 6.31 -6.26 (m, 1H), 4.62-4.41 (m, 1 H), 3.74-3.57 (m, IH), 3.46-3.22 (m, IH), 3.18-2.93 (m, IH), 2.40- 1 .91 (m, 7H), 1.85- 1.20 (m, 6H).
Example 171 : (±)-(5-fluoro-2-(2H- 1 ,2,3-JTiazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrirnidin- 2-yl)amino)methyl)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000159_0001
Prepared analogous to example 170 substituting 2-chloro-4,6-dimethy3pyrimidine with 2- chloro-4-(trifiuoromethyl)pyrimidine. MS (ESI) mass calcd. for C21H19F4N7O, 461.2; m/z found 462.1 ! \ 1 · i ! I . IH NMR (CD30D): 8.51 (s, IH), 7.99-7.83 (m, 3H), 7.46- 7.16 (m, 2H), 6.88 (d, J = 4.9 Hz, Sin.4.74-4.53 (in, ill).3.87-3.66 (m, ill), 3.34 (s, III;.3.30-3.02 (m, I Hi.2.33- 2.08 (m, HI).1.97-1.32 (m, 6H).
Example 172: (±)-(5-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyrM yl)amino)methyl)-7-azabicyclo[2.2.1] eptan-7-yl)methanone
Figure imgf000160_0001
Prepared analogous to example 170 substituting 2-chloro-4,6-dnnethylpyrimidine with 2- chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for ('>>! i .>.,!·' :NV.O.460,2; m/z found 461.2 [M+H]÷. 1H NMR (CD30D): 8.07-7.84 (m, 3H), 7.60-7.22 (m, 3H), 6.90 (d, J = 7.2 Hz, ii-I), 6.74-6.58 (m, 1H), 4.77-4.58 (m, IH), 3.90-3.72 (m, IH), 3.30-3.05 (m, 2H), 2.37-2.12 (m, ill), 1.99-1.37 (m, 6H).
Example 173: (±)-(3-fluoro-2-methoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000160_0002
Prepared analogous to Example 7 substituting 6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)picolinic acid with 3-ffuoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C20H20F2N2O3, 374.1 ; m/z found 375.1 j VI · Π ; .1HNMR (CD30D): 8.01-7.90 (m, IH), 7.56-7.38 (m, llh.7.28-7.06 (m, 2H), 7.02-6.53 (m, 2H), 4.82-4.66 (m, IH), 4.50-3.73 (m, 6H), 2.85-2.22 (m, IH), 2.21-1.10 (m, 61!)
Example 174: (±)-(5-ffuoro-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-ylamino)methyl)- 7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000161_0001
Prepared analogous to example 170 substituting 2-chloro-4,6-dimethylpyrimidme with chloroquinoxalme, MS (ESi) mass calcd. for C24H22FN7O, 443.2; m/z found 444.2 [M+H]1".
Example 175: (±)-(2-(((5-fluoropyrimidin-2-y3)oxy)methyi)-7-azabicyclo[2.2.1 ]heptan~7-yl)(6 methyl-3-(pyrimidin-2-yl)pyridin-2-yi)methanone
Figure imgf000161_0002
Prepared analogous to example 98 substituting 3,6'-dimethyl-[2,3'-bipyridme]-2'- carboxylic acid with intermediate A-9. MS (ESI) mass calcd. for C22H21FN6O2, 420.2; m/z found 421 i \ I · I ! ; . Example 176: (±)-(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2- yl)oxy)methyI)-7-azabicyclo[2.2.1]heptan~7-yl)methanone
Figure imgf000161_0003
Prepared analogous to example 7 substituting 5-fluoropyridin-2(.lH)-one with 3- methylpyridin-2-ol. MS (ESI) mass calcd. for C^E^NeC^, 404.2; m/z found 405 [M+H Example 177: (±)-(2-(((5-fluoropyridin-2-yl)ox )methyl)-7-azabicyelo[2.2.1 ]heptan-7-yl)(6- methy 1-3■ (4~methyloxazol-2-yl)pyridin-2 -yl)methanone
Figure imgf000162_0001
Prepared analogous to Example 7 substituting 6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pico1inic acid with mtermediate A-54. MS (ESI) mass calcd. for C23PI2.3FN4O3, 422.2; m/z found 423 I i i ; .
Example 178 (6-methyi-3-(4-methyloxazol-2-yl)pyridiii-2-yl)((lS,2 ,4R)-2-((pj'ridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000162_0002
Prepared analogous to Example 1 substituting intermediate A- 7 with intermediate A-54. MS (ESI) mass calcd. for C23H24N4O3, 404.2; m/z found 405 I U j .
Example 179: ((lS,2R,4R)-2-(((5-fluoropyriniidin-2-yl)oxy)nieth.yl)-7-azabicyclo[2.2.1 jheptan- 7-yl)(6-meihyi-3-(4-methyloxazol-2-yl)pyridin-2-yl)methanone
Figure imgf000162_0003
Prepared analogous to Example 98 substituting intermediate 3,6'-dimethyl-[2,3'- bipyridine] -2'-carboxylic acid with intermediate A-54. MS (ESI) mass caicd. for C22H22FN5Q3, 423.2; mix found 424 [M+H
Example 1 80: (±)-(5-methyl-2-(2H- 1 ,2,3-lriazo{-2-yl)phenyl)(2-(((6-methyl-2- i)oxy)methyl)-7-azabicyclo[
Figure imgf000163_0001
Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 4-cUoro-6-methyl-2-(trifluoromethyl)pyrimidine. MS (ESI) mass caicd. for C23H23F3N6O2, 472.2; mix fou d 473.2 [M+H]+. !H NMR (CDCI3): 7.88 - 7.72 (m, 3H), 7.38 - 7.12 (m, 2H), 6.74 - 6.70 (s, 0.6H), 6.55 - 6.50 (s, 0.4H), 4.89 - 4.75 (m, 1H), 4.30 - 3.87 (m, 2H), 3.85 - 3.46 (m, Ml), 2.56 - 2.49 (m, 3H), 2.46 - 2.39 (s, 111), 2.32 - 1.80 (m, 3H), 1.74 - 1.1 1 (m, 5H).
Example 1 81 : (2-(2H- l ,2,3-triazol-2-yl)phenyl)((lS,2R,4R)-2-((5-(trif!uorome l)pyrazin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000163_0002
Step A: ( 1 S,2R,4R)-tert-butyl 2-((5-(trifluoromethyI)pyrazin-2-yl)aniino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. To intermediate B-5 (1.6g, 7.3 mmol) and K2CO3 (1.5g, 10 mmol) in DMF ( 1 1 mL) was added 2-chloro-5-(trifiuoromethyl)pyrazine (1.1 mL, 8.8 mmol). After heating at 70 °C for 2h, the mixture was cooled to rt, diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (3X). The combined organics were washed with 4% (aq) and dried (MgS04). Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (1.8g, 67%). MS (ESI) mass caicd. for C16H21F3N4O2, 358.2; m z found 359.2 I M ί 1 1 1 H NMR (CDCi3): 8.32 (s, IB), 7.86 - 7.82 i ni. ill), 5.33 (s, i l l !. 4.38 - 4.15 (m, 2H), 4.10 - 3.96 (m, ! i i :·. 2.14 - 1.98 (m, l i b. 1.93 - 1.67 (m, 2H), 1.61 - 1.36 (m, 12H).
Step B: (lS,2R!4R)-N-(5-( fluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2- amine. To the title compound of step A (200 mg, 0.6 mmol) in EtOAc (1 mL) was added 4M HCl in dtoxane (3 mL). After 2h, the reaction was concentrated, neutralized with 5% a^CCb (aq) and extracted with DCM (2X). The combined organics were dried (Na2S04) to give the title compound of step B that was used without further purification. MS (ESI) mass calcd. for CnH13FjN4, 258.1 ; m/z found 259.1 j V! · Π j
Step C: (2~(2H- 1 ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2~ yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of step B (140 mg, 0.5 mmol) and intermediate A- 1 ( 1 13 mg, 0.6 mmol) in DMF (4 mL) was added DIPEA (230 μΕ, 1.4 mmol) and HATU (155 mg, 0.6 mmol). Upon completion of the reaction, purification was performed using Agilent prep method X to give the title compound (172 mg, 74%). MS (ESI) mass calcd. for C20H18F3N7O, 429.2; m/z found 430 [M+H]+. 1H NMR (CDC13): 8.32 (s, 0.3H), 8.17 (s, 0.7Ή), 7.99 - 7.89 (m, 1 .5H), 7.88 - 7.77 (m, 1.5H), 7.62 - 7.30 (m, 4H), 6.24 - 6.15 (m, 0.3I-I), 4.86 (s, 0.7H), 4.76 (d, ,/ 5.4 Hz, 0.31 0. 4.45 - 4.23 (m, Hi), 4.08 - 3.90 (m, 1H), 2.23 - 1.34 (m, 6H).
Example 182: (±)-((2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazin- -azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000164_0001
Step A: (±)-tert-buty3 2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. Prepared analogous to Example 181 step A substituting intermediate B-5 with intermediate B-6.
Step B: (i)-N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1 ]heptan-2-amine. Prepared analogous to Example 181 step B substituting (1 S,2R,4R)-tert-butyl 2-((5- (trifluoromethyl)pyrazin-2-yl)arriino)-7-azabicycIo[2.2.1 ]heptane-7-carboxylaie with (±)-tert- butyl 2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Step C: (±)-((2-(2H- 1 ,2,3-triazoi-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazin-2- yl)ainmo)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone.
To 2-(2H- l,2,3-triazol-2-yl)benzoic acid (125 mg, 0.6 mmo!) and DMF (4 mL) was added (i- Pr)2NEt (0.23 mL, 1.3 mmol) and HBTU (155 mg, 0.6 mmol). After 10 mm, the title compound from step B ( 146 mg. 0.4 mmol) was added. After stirring overnight at rt, saturated NaHCCb (aq.) was added and the mixture extracted with EtOAc (3X). The combined organies were dried (MgSO/j) and concentrated. Purification via preparative HPLC gave the title compound (89 mg, 47%) as a beige solid. MS (ESI) mass calcd. for C20H1SF3 7O, 429.2; m/z found 430 [M+Hf. 1H NMR (DMSO-Dfi): 8.47 (s, 0.3! I ·. 8.24 (s, 0.7H), 8.14 - 8.05 (m, 2.2H), 8.02 (s, 0.7H), 7.85 (d, J = 7.2 Hz, 1.3H), 7.72 - 7.55 (m, 1 ,7H), 7.49 - 7.34 (m, 1.4H), 7.13 (t J = 7.4 Hz, 0.7H), 4.58 (I, J= 4.3 Hz, 0.7H), 4.44 (d, ,7 - 4.7 Hz, 0.3H), 4.04 - 3.93 (m, 0.3H), 3.82 (t .7 - 4.1 Hz, 0.3H), 3.79 - 3.70 (m, 0.7H), 3.54 (d, J= 4.8 Hz, 0.7H), 2,07 - 1.90 (m, 1H), 1.85 - 1.07 (m, 5H).
Example 183a: (2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluorometb.yl)pyraz n- ] eptan-7-yl)methanone.
Figure imgf000165_0001
and Example 183 b: (2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((lR,2S,4S)-2-((5- -2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000165_0002
The title compounds were obtained by chiral SFC (CHIRALPAK OD-H 5 μΜ 250 X 20mm) resolution of Example 182 (81 mg) using 70% CO2/30% EtOH as the mobile phase to give enantiomer A (37 mg, 1st eluting enantiomer, example 183a) and enantiomer B (38 mg, 2" eluting enantiomer, example 183b). Example 183a: >98% single enantiomer, 2.45 min retention time; Example 183b >98% single enantiomer, 3.33 min retention time. Example 183a: Enantiomer A: MS (ESI) mass calcd. for C2oi½F3 70, 429.2; m/z found 430
Example 183b: Enantiomer B: MS (ESI) mass calcd. for C20H18F3N7O, 429.2; m/z found 430 I i i ; .
Example 184: (±)-(5-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- )-7-azab"icyclo[2.2.1]heptan-7-yl)rnethanone.
Figure imgf000166_0001
Prepared analogous to Example 182 substituting intermediate A-l with intermediate A- 19 and HBTU with HATU. MS (ESI) mass calcd. for C20Hi9F3N8O, 444.2; m/z found 445.1 I i i ; .
Example 185: (±)-(5-methyi-3-(l H-l ,2,3-triazol- 1 -yl)pyridin-2-yl)(2-((5- ino)-7-azabicyclo[2.2.1]heptan-7-yl)rnethanone.
Figure imgf000166_0002
Prepared analogous to Example 184 substitutmg intermediate A- 19 with intermediate A- 20. MS (ESI) mass calcd. for CV.H ,;i; ;N ,<>. 444.2; m/z found 445.1 i \) H I l i PS .C R 1 . 1 . Example 186:
Figure imgf000167_0001
,2,3-triazol-2-yl)pyridin-2-yi)(2-((5- (trifjuororaethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2J]heptan-7-yl)meihanone^
Figure imgf000167_0002
Prepared analogous to Example 184 substitutmg mtermediate A- 19 with intermediate A-
21. MS (ESI) mass caled. for C20H19F3N8O, 444.2: m/z found 445.1 | I 1 1 J ¾ NMR (CDCI3): 8.36 - 8.32 (s, 0.2H), 8.27 - 8.23 (s, 0.8H), 8.22 - 8.18 (d, J = 8.4 Hz, 0.2H), 8.13 - 8.08 (d, J = 8.3 Hz, 0.8H), 7.93 - 7.84 (m, 2H), 7.79 - 7.75 (m, 0.81 s ). 7.40 - 7.36 i d. J = 8.4 Hz, 0.2H), 7.36 - 7.31 (d, J = 8.4 Hz, 0.8H), 7.26 - 7.22 (m, 0.2H), 6.26 - 6.19 (d, J - 8.5 Hz, 0.2H), 4.96 - 4.86 (†, J = 4.8 Hz, 0.8H), 4.83 - 4.75 (d, J = 5.4 Hz, 0.2H), 4.36 - 4.19 (m, IH), 4.13 - 3.92 (d, J = 5.0 Hz, I H), 2.69 - 2.56 (m, M ' l ). 2.29 - 2.14 (del J - 13.1 , 7.5 Hz, i 1 1 i. 2.14 - 1.87 (m, 2H), 1.81 - 1.78 (m, i l l ). 1.63 - 1.56 (m, 2D ).
Example 187: (±)-(6-methyl-3-(2H-l ,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- (tTifluoromethyl)pyTidm-2-yl)amino)-7-azabicyclo[2.2. i]heptan-7-yl)methano"ne.
Figure imgf000167_0003
Step A: (±)-tert- butyl 2-((5-(trifluoromeihy{)pyridm-2-yl)aniino)-7- azabicyclo[2.2..1 ]heptane-7-carboxylate. To mtermediate B-6 ( 150 mg, 0.7 mmol) in DMSO (10 mL) was added DIPEA (244 μΕ, 1.4 mmol) and 2-chloro-5-(tTifluoromethyl)pyridme ( 170 aL, 1.4 mmol). After heating at 100 °C for 4h, the mixture was cooled to rt and saturated NaHCOj (aq) was added. The mixture was extracted with DCM (3X). The combined organics were washed with brine and dried (MgSO^. Purification via silica gel chromatography (0-13% EtOAc in heptanes) gave the title compound. MS (ESI) mass calcd. for C17H22F3 7O2, 357.2; m/z found 358.0 I U ; .
Step B: (±)-N-(5-(trifluororaetiiyl)pyridin-2-yl)-7-azabicyclo[2.2.1 ]heptan-2-amine hydrochloride. To the title compound from step A (262 mg, 0.7 mmol) in 1,4-dioxane (.10 mL) was added 6N HCl in iPrOH (700 μΕ). The reaction was heated to 70 °C for 2h, cooled to rt, concentrated and used without further purification in subsequent steps.
Step C: (±)-(6-methyJ-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)(2-((5-
(trifluoroniethyi)pyridin-2-yl)amino)-7-azabicyclo[2.2. l]heptan-7-yl)methanone.
Prepared analogous to Example 182 substituting intermediate A- 1 with intermediate A-21 and (±)-N-(5-(trifluoromethyl)pyrazin-2-y1)-7-azabicyc{o[2.2.1 ]heptan-2-amine with the title compound of step B. M P 1 3.9 °C. ]H NMR (DMSO-D6): 8.38 (s, 0.3H), 8.24 - 8.16 (m, I H),
8.15 - 8.1 1 (m, 2H), 8.05 i d. 8.3 Hz, 0.7H), 7.69 (dd, ./ 8.9, 2.3 Hz, 0.3H), 7.63 (dd, ./
8.9, 2.4 Hz, 0.7H), 7.57 (d, J = 8.4 Hz, 0.3H), 7.37 (d, J = 8.4 Hz, 0.7H), 7.33 (d, J = 5.8 Hz,
0.7H), 7.14 (d, J = 4.5 Hz, 0.3H), 6.75 (d, J = 8.9 Hz, 0.3H), 6.61 (d, J= 8.9 Hz, 0.7H), 4.60 (t, J - 4.5 Hz, 0.7H), 4.51 (d, J- 4.8 Hz, 0.3H), 3.99 - 3.90 (m, 0.6H), 3.89 - 3.77 (m, 1 ,4H), 2.60 (s,
0.9! ! ·. 2.23 (s, 2.1 H), 1.99 i dd. ./ 12.6, 7.6 Hz, 1H), 1.83 - 1.21 (m, 5H).
Example 188: (±)-(5-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- o)-7-azabicyclo[2.2.1 ]heptaii-7-yl)methanone.
Figure imgf000168_0001
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 19. MS (ESI) mass calcd. for (' · i h.F ;\ -i). 443.2; m/z found 444.1 i \I ! i i :H MR (CDCI3): 8.49 - 8.44 (dd, J = 1.9, 0.9 Hz, 0.2H), 8.41 - 8.32 (m, IH), 8.28 - 8.21 (m, 0.8H), 8.18 - 8.1 1 (m, 0.2H), 8.06 - 7.98 (m, 0.8H), 7.94 - 7.86 (m, 2H), 7.60 - 7.53 (dd, J = 8.8, 2.4 Hz, 0.2H), 7.45 - 7.35 (dd, J - 8.9, 2.4 Hz, 0.8H), 6.71 - 6.59 (d, J - 8.7 Hz, 0.8H), 6.45 - 6.37 (d, J - 8.8 Hz, 0.2H), 6.27 - 6.17 (d, J = 8.8 Hz, 0.8H), 5.82 - 5.72 (m, 0.2H), 4.95 - 4.84 (t, J = 4.6 Hz, 0.8H), 4.82 - 4.74 (d, J = 5.2 Hz, 0.2H), 4.36 - 4.18 (m, IH), 4.08 - 3.97 (m, IH), 2. 1 - 2.47 (s, 0.71 ! ·. 2.45 - 2.41 (m, 231 1 ). 2.22 - 2.14 (d l, J - 13.0, 7.7 Hz, 0.8H), 2.1 1 - 1.90 (m,
1.82 - N O On . 3H).
Example 189: (±)-(6-methyi-2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)(2-((5- o)-7-azabicyclo[2.2.1 ]heptaii-7-yl)methanone.
Figure imgf000169_0001
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 3. MS (ESI) mass calcd. for C21H20F3N7Q, 443.2; m/z found 444.1 [M+H]+. !H NMR (CDCI3): 8.40 - 8.33 (s, 0.4H), 8.26 - 8.19 (d, J - 2.0 Hz, 0.6H), 7.98 - 7.88 (m, 2H), 7.78 - 7.71 (d, J = 7.7 Hz, 0.4H), 7.64 - 7.55 (m, IH), 7.41 - 7.27 (m, 1.6H), 7.20 - 7.08 (m, 0.7H), 6.43 - 6.35 (d, J - 8.8 Hz, 0.3H), 6.13 - 6.01 (d, J - 8.7 Hz, 0.71 i s. 5.74 - 5.56 (m, 0.3H), 4.90 - 4.81 (m, 0.7H), 4.78 - 4.71 (d, J = 5.3 Hz, 0.3H), 4.38 - 4.14 (m, ill), 3.99 - 3.85 (m, IH), 2.78 - 2.55 (m, 3H), 2.24 - 2.10 (dd, J = 13.2, 7.9 Hz, IH), 2.08 - 1.39 (m, 5H).
Example 190: (±)-(6-methyl-2-(lH- 1 ,2,3-triazol- 1 -yl)pyridin-3-yl)(2-((5- (trifluoroinemyi)pyridm-2-yl)amin^
Figure imgf000169_0002
Prepared analogous to Example 1 87 substituting intermediate A-21 with intermediate A- 4. MS (ESI) mass calcd. for
Figure imgf000169_0003
443.2; m/z found 444.1 [M+H]1". !H NMR (CDCI3): 8.50 - 8.46 (m, 0.6H), 8.37 - 8.34 (d, J = 1.2 Hz, 0.4H), 8.34 - 8.31 (s, 0.6H), 8.24 - 8.17 (s, 0.4H), 7.90 - 7.84 (m, IH), 7.75 - 7.69 (d, J - 7.7 Hz, 0.6H), 7.65 - 7.60 (d, J - 7.8 Hz, 0.4H), 7.55 - 7.47 (dd, J ===: 8.7, 2.4 Hz, 0.7H), 7.36 - 7.27 (m, 1.3H), 7.22 - 7.14 (m, 0.4H), 6.94 - 6.83 id, J = 8.7 Hz, 0.6! ! ·. 6.29 - 6.1 1 (d, J = 8.9 Hz, Hi), 4.91 - 4.74 (d, J = 5.3 Hz, 1H), 4.55 - 4.28 (m, 1H), 4.04 - 3.90 (m, i l l s. 2.66 - 2.62 (s, 1.9H), 2.59 - 2.55 (s, 1.1H), 2.23 - 2.15 (dd, J - 13.1 , 8.1 Hz, 0.5H), 2.06 - 1.79 (m, 2.5H), 1.77 - 1.68 (m, IH), 1.55 - 1 .47 (m, 2H). Example 191 : (±)-(4-methoxy-2-(2H- ,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2- an-7-yi)meihanone.
Figure imgf000170_0001
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 5. MS (ESI) mass calcd. for ( ' -! ! > !; :N,.() >. 458.2; m/z found 459.1 [M+H]+. Ή NMR (CDC13): 8.38 - 8.32 (s, 0.3H), 8.26 - 8.19 (s, 0.7H), 7.93 - 7.87 (s, 1.3H), 7.87 - 7.80 (s, 0.7H), 7.60 - 7.53 (m, 0.4H), 7.49 - 7.43 (d, J - 2.5 Hz, 0.4H), 7.40 - 7.26 (m, 2.7H), 7.00 - 6.93 (dd, J - 8.5, 2.5 Hz, 0.41 n. 6.90 - 6.80 (d, J = 8.4 Hz, 0.7H), 6.43 - 6.35 id, J = 8.7 Hz, 0.4H), 6.12 - 6.04 (d, J = 8.8 Hz, 0.7H), 5.77 - 5.67 (m, 0.3H), 4.84 - 4.79 (m, 0.7H), 4.74 - 4.68 (m, 0.3H), 4.36 - 4.15 (m, H), 4.02 - 3.95 (m, I H), 3.94 - 3.87 (s, H), 3.87 - 3.81 (s, 2H), 2.20 - 2.1 1 (dd, J = 13.0, 8.0 Hz, 0.71 ! ·. 2.07 - 1 .99 (dd, J = 12,9, 7.6 Hz, 0.31 1 K 1.99 - 1 .83 (s, 21 1 }, 1.79 - 1.34 fm, 3H).
Example 192: (±)-(3-ffuoro-2-(pyTimid
]heptan-7-yl)methanone.
Figure imgf000170_0002
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 6. MS (ESI) mass calcd. for CaHuF^sO, 457.2; m/z found 458.1 [M+H]+. ]H NMR (CDCI3): 8.91 - 8.76 (m, 2l . 8.36 - 8.18 (m, 1H), 7.68 - 7.52 (in, 1 H), 7.40 - 7.27 (m, 3H), 7.24 - 7.14 (m, 2H), 6.29■■ 6.15 (m, 1H), 4.78 ·■ 4.66 (t, J = 4.9 Hz, 1H), 4.44■■ 4.30 (m, 1H), 4.16■■ 4.02 (d, J - 5.0 Hz, 1H), 2.19 - 2.1 1 (dd, J = 12.9, 8.2 Hz, W D. 2.08 - 1 .97 (m, 1H), 1.97 - 1.85 (m, 1H), 1.77 - 1.60 (m, 2H), 1.54 - 1.49 (m, 1 H).
Example 193: (-t)-((3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pjTidin-2-yl)a.mino)-7- azabicyclo[2.2.1 ]heptan-7-yJ)methanone,
Figure imgf000171_0001
Prepared analogous to Example 187 substituting intermediate A-21 with 3-fluoro-2- methoxybesizoic acid. MS (ESI) mass caicd. for
Figure imgf000171_0002
409.1 ; m/z found 410.4 [M+H] ; . i ! NMR (MeOD): 8.39 (s, 0.3H), 8.18 (s, 0.7H), 7.69 (dd, J= 8.9, 2.3 Hz, 0.3H), 7.60 (dd, J- -----
8.9, 2.4 Hz, 0.7H), 7.36 (ddd, J= 1 1.7, 7.6, 2.1 Hz, 0.3H), 7.30 - 7.05 (m, 2.3H), 7.01 (d, J= 7.6 Hz, 0 71 n.6.85 - 6.73 (m, 0.7H), 6.68 (d, J= 8.8 Hz, 0.3H), 6.59 (d, J= 8.9 Hz, 0.7H), 4.66 ( br s, 0.7H), 4.54 (d, J= 4.8 Hz, 0.3H), 4.00 - 3.90 (m, 0.3H), 3.89 - 3.77 (m, 3.7H), 3.75 (t, J= 4.3 Hz, 0.3H), 3.64 ( br s, 0.7H), 2.08 --- 1.91 (m, IH), 1.80 -- 1.37 (m, 5H).
Example 194: (±)-(3-ethoxy-6-raelbylpyridin-2-yl)(2-((5-(trifluoromethyi)pyrid
7-azabicyclo[2.2.1 ]heptan-7-yl)methanoi e.
Figure imgf000171_0003
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 8. MP 147 °C. ]H NMR (DMSO-D6): 8.38 (s, 0.3H), 8.16 (s, 0.7H), 7.68 (dd, J : 8.9, 2.3 Hz, 0.3H), 7.59 (dd, J= 8.9, 2.4 Hz, 0.7H), 7.46 (d, J= 8.6 Hz, 0.3H), 7.36 - 7.18 (m, 2H), 7.05 (d, = 8.6 Hz, 0.7! i ). 6.71 i d. J 8.9 Hz, 0.31 n. 6.57 ·: d. 8.9 Hz, 0.7H), 4.65 (br s, 0.7H), 4.55 (d, J= 2.8 Hz, 0.3H), 4.13 - 3.84 (m, 2.3H), 3.83 - 3.72 (m, 0.7H), 3.67 (d, J = 3.5 Hz, 1H), 2.41 (s, 0.9H), 2.16 (s, 2.1H), 2.04 - 1.91 (m, H i ). 1.80 - 1 .37 (m, 5H), 1.31 - 1.19 (m, 3H). Example 195: (±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyri
tan-7-yi)meihanone.
Figure imgf000172_0001
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 9. MS (EST) mass calcd. for C23H2iF3 60, 454.2; m/z found 455 [M+H]+ . !H NMR (DMSO-D6): 8.95 - 8.81 (m, 2H), 8.37 is, 0.3H), 8.32 (d. ,/ 8.0 Hz, 0.3H), 8.25 - 8.13 fm, 1.4H), 7.68 (dd, ,/
- 8.8, 2.1 Hz, 0.3H), 7.60 (dd, J= 8.9, 2.2 Hz, 0.7H), 7.52 - 7.39 (m, 2H), 7.30 (d, J= 8.1 Hz, 0.7H), 7.25 (d, J = 3.7 Hz, 0.3H), 6.75 (d, J = 8.8 Hz, 0.3H), 6.54 (d, J= 8.9 Hz, 0.7H), 4.61 (t, J
- 4.2 Hz, 0.7! 4.51 (d, J= 4.2 Hz, 0.3H), 4.01 - 3.82 (m, 2H), 2.58 (s, 0.9H), 2.24 (s, 2. i l l }. 2.07 - 1.95 (m, IH), 1.86 - 1.32 (m, 5H).
Example 196: (±)-(2-(2H-l,2,3-!riazo1-2-yl)pheny
-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000172_0002
Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A- 1. MS (ESI) mass calcd. for (:21Η19Ρ3Ν60, 428.2; m/z found 409.2 [M+Hf. lH NMR (MeOD): 8.38 (s, 0.3H), 8.16 (s, 0.7H), 8.08 (s, 2H), 7.85 (d, J= 7.2 Hz, 0.3H), 7.74 - 7.53 fm, 3H), 7.46 - 7.35 (m, 1.3H), 7.31 (d, J= 6.1 Hz, 0.7H), 7.14 ( !. ./ 7.5 Hz, 0.7H), 6.68 (d, J= 8.9 Hz, 0.3H), 6.62 (d, ,/ 8.9 Hz, 0.7H), 4.57 (t, J- 4.5 Hz, 0.7H), 4.41 (d, J= 4.8 Hz, 0.3H), 4.04 - 3.95 (m, 0.3H), 3.88 - 3.76 (m, 1H), 3.55 (br s, 0.7H), 1.97 uid. J 12.7, 8.0 Hz, 1H), 1.79 - 1.23 (mi, 5H). Example 197: (-i)-(2-((4,6-dimeihylpyrimidm-2-yl)ammo)
-yl)phenyl)niethanone.
Figure imgf000173_0001
Step A: (±)-teri-butyl 2-((4,6-dimethylpyrimidin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. To a microwave vial was weighed intermediate B-6 (210 mg, 1 ffliKiol), 2-chloro-4,6-dimethylpyrimidine (212 mg, 1.5 mmol), sodium tert-butoxide (142 mg, 1 .5 mmol), Pd(dba)2 (28 mg, 5 mol%), Ctc-Q-Phos (44 mg, 10 moi). The vial was capped, evacuated and refilled with N2 (2X). Then PhCH3 ( 1 mL) was added and the reaction was heated at 125 °C for 4h. The reaction allowed to cool to it, applied directly purified via silica gel chromatography 1-7% 2M NH3/MeOH in DCM to give Pi (125 mg, 40%). MS (ESI) mass calcd. for Cnil^Oi, 318.2; m/z found 319.3 I M ί 1 1 Ή NMR (CDCU): 6.31 f s, 1H),
5.18 - 4.94 (m, 1H), 4.35 - 4.13 (m, 2H), 4.08 (td, J= 7.9, 3.2 Hz, I I I ) . 2.27 (s, 6H), 1.97 (dd, J = 12.9, 7.8 Hz, 1H), 1.82 - 1.62 (m, 21 1 ). 1.62 - 1 .30 (m, 12H).
Step B: (±)-N-(4,6-dimethylpyrimidin-2-yl)-7-azabicyclo[2.2.1]hq)tan-2-amine. To the title compound of step A (125 mg, 0.4 mmol) in DCM (3 mL) was added TFA (3 mL). After siarting material was consumed, the reaction was concentrated, neutralized with 5% Na2COs and extracted with DCM, The combined organics were dried (Na2S04) to give the title compound that was used in subsequent reactions without further purification. MS (ESI) mass calcd. for C] 2H] SN4, 218.2; m/z found 219.2 j YM I j
Step C: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(5- fluoro-2-(2H- 1 ,2,3-triazol-2-y!)phenyl)tnethanone. Prepared analogous to Example 1 81 substituting intermediate A- 1 with intermediate A- 10 and (l S,2R,4R)-N-(5- (trifluorometliyl)pyrazin~2-yl)-7-azabicyclo[2.2.1 ]heptan-2-amine with the title compound of step B. MS (ESI) mass calcd. for C2jH22FN?G, 407.2; m/z found 408.2 [M+Hf . Ή NMR (CDC13): 8.23 - 7.67 (m, 2.5H), 7.54 - 6.93 (m, 2.5H), 6.40 - 6.19 ·: m. 1H), 4.89 - 4.65 (m, Hi), 4.41 - 3.66 (m, 2H), 2.39 - 1.34 (m, 12H).
Example 198: (±)-(2-((4,6-dimethylpyrimidin-2-yi)ammo)-7-azabkyclo[2.2.1 ]heptaii-7-y])(2- 2-yl)phenyl)methanone.
Figure imgf000174_0001
Prepared analogous to Example 197 substituting intermediate A- 10 with intermediate A- 1 1. MS (ESI) mass calcd. for ('., I ;X <>. 407.2; mix found 408.2 ! M 1 1 1 Example 199: (±)-(2-f(4,6-diinethyipyri ljheptan-7-j
3)phenyl)methanone.
Figure imgf000174_0002
Prepared analogous to Example 197 substituting intermediate A- 10 with intermediate A. 12. MS (ESI) mass calcd. for C2iH22FN70, 407.2; m/z found 408.2 [M+H . Hi NMR (MeOD): 8.23 - 7.33 (m, 4H), 7.22 - 6.75 (m, Hi), 6.42 - 6.21 (m, Hi), 4.91 - 4.73 (m, I I I ). 4.44 - 4.01 (m, IH), 3.97 - 3.71 (m, 1H), 2.41 - 1.30 (m, 12H).
Example 200: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7~yi)(6- methyl-3-(pyTimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000175_0001
Prepared analogous to Example 187 substituting 2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-4,6-dimethylpyrimidine and intermediate A-21 with intermediate A-9, MS (ESI) mass calcd. for C23H25N70, 41 5.2; m/z found 416 [M+H]+. fH NMR (DMSO-D6): 9.05 (d, J - 4.9 Hz, 0.6H), 8.90 ·: d. 4.9 Hz, 1.4H), 8.37 (d, J= 8.1 Hz, 0.3H), 8.28 (d, ./ 8.0 Hz, 0.7H), 7.57 - 7.45 (m, 1.3H), 7.41 (d, J= 8.1 Hz, 0.7H), 7.09 (d, J = 7.8 Hz, 0.7H), 6.46 (s, 0.3H), 6.43 - 6.29 (m, 1H), 4.62 (hr s, 0.7H), 4.51 (d, J= 4.4 Hz, 0.3H), 4.15 - 3.97 (m, 1H), 3.97 - 3.92 (m, 0.3H), 3.89 (d, ,/ 3.7 Hz, 0.7H), 2.59 (s, 0.9H), 2.50 (s, 2.1H), 2,26 (s, 1.8H), 2.14 (s, 4.2H), 2.05 (dd, . 12.5, 7.6 Hz, IH), 1.99 - 1.37 (m, 5H).
Example 201 : (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2. l]heptan-7-yl)(6- 2-yl)p ridin-2-yl)methanone.
Figure imgf000175_0002
Prepared analogous to Example 200 substitutmg intermediate A-9 with intermediate A-
1. MP=171.9 °C. Ή NMR (DM80-D6): 8.28 - 8.17 (m, 1.2H), 8.17 - 8.09 (m, 1 .8H), 7.57 (d, = 8.4 Hz, 0.4H), 7.46 (d, J = 8.4 Hz, 0.6H), 6.89 (d, J = 7.0 Hz, 0.6H), 6.46 (s, 0.4H), 6.42 (d, J 7.5 Hz, 0.4H), 6.35 (s, 0.6H), 4.59 (t, J= 4.2 Hz, 0.6H), 4.50 (d, J = 4.9 Hz, 0.4H), 4.08 (id, J 7.8, 3.0 Hz, 0.4H), 4.00 - 3.86 (m, 1 .6H), 2.60 (s, 1.2H), 2.45 (s, 1 .8H), 2.26 (s, 2.4H), 2.15 (s, .6H), 1.97 i ddd. ./ 16.3, 12.6, 7.9 Hz, i l l ). 1.83 - 1.35 (m, 5H).
Example 202: (±)-(2~(2H- l ,2,3 riazoi-2-yl)plienyJ)(2~((4,6-dimethylp
azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000176_0001
Prepared analogous to Example 200 substituting intermediate A-9 with intermediate A- l . MP=154.2 °C. Ή NMR (DMSO-D6): 8.12 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 7.7 Hz, 0.5H), 7.77 (d, J = 6.8 Hz, 0.5H), 7.72 - 7.61 (m, 1H), 7.58 (dd, J = 10.7, 4.2 Hz, 0.5H), 7.49 - 7.39 (m, IH), 7.15 it, J= 7.5 Hz, 0.5H), 6.99 (d, J= 6.1 Hz, 0.5H), 6.87 (br s, 0.5H), 6.43 (s, 0.5H), 6.33 (s, 0.5H), ), 4.51 ft, J= 4.1 Hz, 0.5H), 4.37 (d, J= 3.9 Hz, 0.5H), 4.12 - 3.97 (m, 0.5H), 3.88 - 3.72 (m, IH), 3.68 (d, J = 4.4 Hz, 0.5H), 2.24 (s, M l ). 2.15 (s, 3H), 1.97 - 1 .21 (m, 6H).
Example 203 : (±)-(2- ((4,6-dimet^^
l)methanone.
Figure imgf000176_0002
Prepared analogous to Example 200 substituting intermediate A-9 with intermediate A-8. MS (ESI) mass calcd. for QiEbNsCb, 381.2; ro/z found 382.5 [M+H]+. MP=137.8 °C. Ή NMR (DMSO-D6): 7.20 - 7.01 (m, 2H), 6.45 (d, J= 8.5 Hz, 0.7H), 6.31 (s, 0.3H), 6.24 (s, 0.7H), 5.31 id, J - ---- 8.6 Hz, 0.3H), 4.91 (t, ,/ 4.5 Hz, 0.7H), 4.80 (d, ./ 5.1 Hz, 0.3H), 4.32 - 4.14 (m, 1.7H), 4.14 - 3.98 (m, 1.3H), 3.80 (t, J= 4.7 Hz, 0.3H), 3.75 (d, J= 4.6 Hz, 0.7H), 2.53 (s, 2.1 H), 2.49 (s, 0.9H), 2.26 (s, 1.8H), 2.22 (s, 4.2H), 2.20 - 2.08 (m, IH), 2.05 - 1 .49 (m, 5H), 1.48 - 1.40 (m, 3H).
Example 204: (±)-(2-(2H ,2,3-triazol-2-yl)phenyl)(2-(quinoxalin-2-ylamino)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000177_0001
Step A: (±)-tert-butyl 2-(quinoxalin-2-ylammo)-7-azabicyclo[2.2.1 ]heptane-7- carboxylate. To intermediate B-6 (500 mg, 2.4 mmol) in dry DMA (7 mL) was added K2CO3 (650 mg, 4.7 mmol) and 2-ehloroquinoxalme (580 mg, 3.5 mmol). After heating at 80 °C for 48h, the mixture was cooled to rt and saturated NaHCCh (aq) was added. The mixture was extracted with EtOAc (3X). The combined organics were washed with brine and dried (MgS04). Purification via silica gel chromatography (0-25% EtOAc in heptanes) gave the title compound. MS (ESI) mass calcd. for Ci^^C , 340.2; m z found 341.0 j \1 I f ] .
Step B: N-((±)-7-azabicyclo[2.2J]heptan-2-yl)quinoxalin-2-amine hydrochloride. To the title compound from step A (343 mg, 1 mmol) in 1,4-dioxane (10 mL) was added 6N HC1 in iPrOH (1 mL). The reaction was heated to 70 °C for 2b, cooled to rt, concentrated and used without further purification in subsequent steps.
Step C: (±)-(2-(2H- 1 ,2,3 riazol~2-yl)pheny!)(2-(quinoxalin-2-y!amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 187 substituting intermediate A-2I with intermediate A-l and (±)-N-(5-(trifiuoromethyl)pyridin-2-yl)-7- azabicyclo[2.2.1]heptan-2-amine hydrochloride with the title compound from step B. MS (ESI) mass calcd. for C23H21N7O, 41 1.2; m/z found 412 [M+Hf. Ή NMR (DMSO-D6): 8.38 (s, 0.3H), 8.31 (s, 0.7H), 8.08 (s, 2H), 7.88 - 7.73 (m, 1.3H), 7.72 - 7.20 (m, 7Ή), 7.14 - 7.04 (m, 0.7H), 4.60 (i, J= 4.4 Hz, 0.7H), 4.54 (d, J= 4.7 Hz, 0.3H), 4.15 - 4.03 (m, 0.3H), 3.97 - 3.87 (m, 0.7H), 3.82 (t, J= 3.9 Hz, 0.3H), 3.65 (d, J= 3.2 Hz, 0.7H), 2.12 - 1.96 (m, 1H), 1.84 - 1.28 (m, 5H).
Example 205: (±)-(6-methyl-3-(2H-l,2,3-triazol-2-y^
ethanone.
Figure imgf000178_0001
Prepared analogous to Example 204 substituting with intermediate A-l with intermediate A-21. M P 26U.S °C. 1 1 NMR (DMSO-D6): 8.44 (s, 0.3H), 8.32 (s, 0.7H), 8.19 i d. J = 8.4 Hz, 0.3H), 8.13 (s, 2H), 7.96 (d, J= 8.3 Hz, 0.7H), 7.83 - 7.72 (m, IH), 7.68 - 7.27 (m, 4.3H), 7.19 (d, J = 8.4 Hz, 0.7H), 4.64 (br s, 1H), 4.06 - 3.86 (m, 21 n. 2.61 (s, 0.9H), 2.09 (s, 2. i l l !. 2.06 - 1.99 i n:. I i n. 1.88 - 1.62 fm, 2) 1 ;·. 1.62 - 1.38 (m, 3H). Example 206: (±)-(3-fluoro-2-memoxyphenyl)(2-(quinoxalin-2-y{aimno)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000178_0002
Prepared analogous to Example 204 substituting intermediate A-l with 3-f!uoro-2- methoxybenzoic acid. MP=179.2 °C. :H NMR (DMSO-D6): 8.38 (s, 0.3H), 8.27 (s, 0.7H), 7.80 id, J - ---- 8.0 Hz, 0.3H), 7.73 (d, J -- 8.0 Hz, 0.7H), 7.65 - 7.52 (m, 1.4H), 7.52 - 7.28 (m, 2.7H), 7.28 - 7.15 (m, 0.7H), 7.09 (d, J = 7.6 Hz, 0.7H), 6.96 (ddd, J= 1 1.7, 8.2, 1.4 Hz, 0.7H), 6.75 (td, J= 7.9, 4.8 Hz, 0.7Ή), 4.75 - 4.63 (m, I H), 4.1 1 - 4.01 (m, 0.4H), 3.99 - 3.90 (m, 0.7H), 3.86 (br s, 0.9H), 3.83 - 3.73 (m, 2.1H), 2.06 (dt, ,/ 16.7, 8.4 Hz, IH), 1.87 - 1.45 (m, 6H). Example 207: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(quinoxalin-2-ylamino)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000179_0001
Prepared analogous to Example 204 substituting with intermediate A- 1 with intermediate
A-8. MS (ESI) mass calcd. for C23H25N502, 403.2; m/z found 404 [M+H]+. MP=1 84.9 C. lE NMR (DMSO-Df,): 8.41 (s, 0.3H), 8.26 (s, 0.7H), 7.79 ·: d. 8.1 Hz, 0.3H), 7.72 (d, J= 8.0 Hz 0.7H), 7.64 - 7.53 (m, 1.7H), 7.50 - 7.22 (m, 2.9H), 7.18 (d, J= 8.6 Hz, 0.7H), 6.86 (d, J - 8.6 Hz, 0 71 n.4.68 ( br s, IH), 4. 12 - 3.83 (m, M l ). 3.79 (d, J = 4.1 Hz, 0.71 ! ) 3.71 ( br s, 0.3H), 2.41 (s, 0.9H), 2.1 1 - 1 .96 fm, 3.1 H), 1.89 - 1.42 (m, 5H), 1.25 i t. ./ 6.9 Hz, 3H).
Example 208: (±)-(6-methyl-3-(pyrimidm-2-yl)p
ethanone.
Figure imgf000179_0002
Prepared analogous to Example 204 substituting with intermediate A- l with intermediate
A-9. MS (ESI) mass calcd. for C25H23N70, 437.2; m/z found 438 [M+H] ;. !H NMR (DMSO- D6): 8.93 - 8.82 (m, 2H), 8.46 (s, 0.3H), 8.33 i d. ./ 8.1 Hz, 0.3H), 8.27 (s, 0.7H), 8.14 (d, ./ 8.0 Hz, 0.7H), 7.81 --- 7.26 (m, 6.3H), 7.17 (d, J = 8.1 Hz, 0.7H), 4.66 (br s, 1H), 4.06 - 3.94 (m, 2H), 2.60 (s, 0.9H), 2.13 - 2.01 (m, 3.1H), 1.92 - 1 .36 (m, 5H).
Example 209: (±)-(2 -(2H- l ,2,3 iiazol-2-yl)plienyl)(2"((6-(iriiluoiOm
7-azabieyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000180_0001
Step A: (±)-tert-but l-2-((6-(trifiuorornethyl)pyridin-2-yl)amino)-7- azabicyclo[2.2.1]heptane-7-carboxylate. To 2-chloro-6-(trifluoromethyi)pyridine (1 13 mg, 0.6 ramol) in THF (3 mL) was added sodium tert-butoxide (120 mg, 1.2 mmo!), Xanphos (26 mg, 7 mol%) nd Pd2(dba)s (23 mg, 4 mol%) at rt while N2 was bubbled through the solution. After 10 minutes, intermediate B-6 (132 mg, 0.6 mmol) was added. The reaction mixture was heated at 90 °C for 3h. After allowing to cool to rt, saturated NaHCCb (aq) the mixture extracted with EtOAc (2X). The combined organics were dried (MgS04). Purification via silica gel chromatography (0-7% EtOAc in heptane) gave the title compound. MS (ESI) mass calcd. for C] 7H22F3N3O2, 357.2: m found 358.4 i v! - ! i ]
Step B: (±)-N-(6-(trifluororaethyl)pyridin-2-y1)-7-azabicyclo[2.2.1 ]heptan-2-amine hydrochloride. Prepared analogous to Example 204 substituting (±)-tert-butyl 2-(quiiioxafin-2- ylamino)-7-azabicyclo[2.2.1]heptane-7-carbox late with the title compound of step A.
Step C: (±)-tert-butyl-2-((6-(triiluoroniethyl)pyridin-2-yl)amino)-7
azabicyclo[2.2.1 jheptane-7-carboxyiate. Prepared analogous to Example 204 substituting N- ((i)-7-azabicyclo[2.2, l ]heptan-2-yl)quinoxalin-2-amine hydrochloride with the title compound of step B. MS (ESI) mass calcd. for CaiH^FsNeO, 428.2; mix found 429. [M-MIf . MP-96.8 °C. Ή NMR (DMSO-D6): 8.07 (s, 2H), 7.85 (d, J = 7.9 Hz, 0.3H), 7.74 - 7.51 (m, 2.7H), 7.46 - 7.36 (m, 1.3H), 7.17 - 6.94 (m, 2H), , 6.86 (d, J = 7.2 Hz, 0.7H), 6.82 (d, J= 8.6 Hz, 0.3H), 6.74 (d, ,/ 8.4 Hz, 0.7H), 4.55 i \. J 4.5 Hz, 0.7H), 4.41 (d, J= 4.6 Hz, 0.3H), 3.94 - 3.84 (m,
0.3H), 3.84 - 3.71 (m, 1H), 3.61 ( d, J = 4.6 Hz, 0.7H), i .96 (dd, J- 12.6, 8.0 Hz, 1H), 1.80 - 1.21 (m, 5H).
Example 210: (±)-((2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((4-(trifluoromethyl)pyridin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000181_0001
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridme with 2-cliloro-4-(trifiuoromethy])pyridiiie. MP- 153.5 °C. MS (ESI) mass calcd. for
C21H19F3N60, 428.2; m/z found 429 [M+H . *H NMR (DMSO-D6): 8.27 (d, 7= 5.3 Hz, 0.3H), 8.12 - 7.99 (m, 2.7H), 7.85 (d, J= 7.9 Hz, 0.3H), 7.72 - 7.54 (m, 1.6H), 7.50 - 7.33 (m, 1.4H), 7.13 - 6.92 (m, 2H), 6.82 (d, J = 12.6 Hz, 0.3H), 6.78 (s, 0.7H), 6.67 (d, J = 5.3 Hz, 0.7H), 4.56 (t, J = 4.5 Hz, 0.7H), 4.41 (d, ,7 - 4.6 Hz, 0.3H), 4.04 - 3.93 (m, 0.3H), 3.86 - 3.72 (m, I H), 3.52 f br s, 0.7H), 1.96 ·: ckl. . 12.6, 8.0 Hz, i l l ;. 1.78 - 1.17 fm, 5H). Example 21 1 : (±)-(2-(2H- 1 ,2,3 riazol-2-yI)phenyl)(2-((5-chloropyrid n-2-yl)amino)-7- yl)methanone.
Figure imgf000181_0002
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyJ)pyridine with 5-chforo-2-iodopyridine. MS (ESI) mass calcd. for
Figure imgf000181_0003
394, 1 ; m/z found 395 [M Hf . MP-157.0 °C, H NMR (DMSO-D6): 8.14 - 7.99 (m, 2.3H), 7.87 - 7.79 (m, IH), 7.71 - 7.52 (m, 1.7H), 7.52 - 7.36 (m, 2.6H), 7.23 - 7.11 (ni, 0.7H), 6.80 (d, J = 6.4 Hz, 0.7H), 6.58 (d, J = 9.0 Hz, 0.3H), 6.52 (d, J= 8.9 Hz, 0.7H), 4.53 (t, J= 4.6 Hz, 0.7H), 4.37 (d, J= 4.6 Hz, 0.31 1 ). 3.92 - 3.82 (m, 0. 1 1 ;. 3.81 --- 3.68 fm, IH), 3.52 (d, ,/ 4.3 Hz, 0.7H), 1.94 (dd, ./ 12.5, 8.1 Hz, IH), 1.73 - 1.22 (m, 5H).
Example 212: (±)-(2-(2H- 1 ,2,3-triazol-2-yl)phenyI)(2-((6-(trifluoromethyl)pyridazin-3- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000182_0001
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 3-chloro-6-(trifluoromethy])pyri.dazine. MP=134.0 °C. MS (EST) mass calcd. for
C2oHigF3N70, 429.2; m/z found 430 [M+Hf . 'H MR (DMSO-D6): 8.08 (s, 1.4H), 8.07 (s, 0.6PI), 7.85 (d, J= 7.8 Hz, 0.3H), 7.77 - 7.46 (m, 3.6H), 7.44 - 7.31 (m, 1.4H), 7.20 - 7.09 On. 0.7H), 7.06 (d, J = 9.4 Hz, 0.3H), 6.98 (d, J= 9.3 Hz, 0.7H), 4.59 (t, J= 4.4 Hz, 0.7H), 4.48 (d, J = 4.7 Hz, 0.3H), 3.97 - 3.87 (m, 0.7H), 3.81 (t, J = 4.0 Hz, 0.3H), 3.58 - 3.56 (m, 1H), 2.01 (dd, 12.9, 8.0 Hz, 1H), 1.82 - 1.18 (m, 5H). Example 213 : (±)-(2-(2H- 1 ,2,3-triazo1-2-yl)pheiiyl)(2-((5-methoxypyridin-2-yl)amino)-7- )methanone.
Figure imgf000182_0002
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 2-chloro-5-methoxypyridine. MS (EST) mass calcd. for C2iH22N602, 390.2; m/z found 391 i V! · Π ; M P Ι 74.Π °C. i NMR (DMSO-De): 8.31 fs, 0.3H), 8.13 - 8.02 (m, 2H), 7.84 ul J
8.0 Hz, 0.3H), 7.79 i d../ 3.0 Hz, 0.3H), 7.71 - 7.61 (m, 1.3H), 7.60 - 7.53 (m, I I I ). 7.50 - 7.37 (m, 1 ,4H), 7.22 - 7.04 (m, 1.7H), 6.52 (d, J= 9.0 Hz, 0.3H), 6.46 (d, J= 9.0 Hz, 0.7H), 6.21 (d, J - 6.9 Hz, 0.7H), 4.52 (t, J= 4.5 Hz, 0.7H), 4.37 (d, J= 4.5 Hz, 0.2F1), 3.90 - 3.79 (m, 0.3H), 3.79 --- 3.68 (m, 1.9H), 3.64 (s, 2.1H), 3.57 (d, ./ 4.0 Hz, 0.7H), 1.98 - 1.84 (m, ill), 1.76 - 1.21 (m, 5H).
Example 214: (±)-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-((5-methylpyridin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000183_0001
Prepared analogous to Example 209 substituting 2-chloro-6-(trifiuoromethyl)pyridine with 2-chloro-5-methylpyridine. MS (ESI) mass calcd. for C^H^NeQ, 374.2; m/z found 375.2 I i i i . ]H NMR (DMSO-De): 8.32 (s, 0.7H), 8.09 (s, 0.6H), 8.07 (s, 1.4H), 7.89 - 7.80 (m, 0.6H), 7.72 - 7.53 (m, 2.1H), 7.52 - 7.37 (m, 1 ,3H), 7.27 (dd, J= 8.5, 2.2 Hz, 0.3H), 7.23 - 7.1 1 (m, 1.3H), 6.47 (d, J = 8.5 Hz, 0.3H), 6.41 i d. J= 8.2 Hz, 0.7H), 6.35 i d. J -- 6.9 Hz, 0.7H), 4.53 (t, J = 4.5 Hz, 0.7H), 4.37 (d, J - 4.4 Hz, 0.3H), 3.95 - 3.84 (m, 0.3H), 3.84 - 3.70 (m, 1H), 3.56 (d, J= 4.3 Hz, 0.7H), 2.12 (s, 0.9H), 2.04 (s, 2.1H), 1.99 - 1.86 (m, 1H), 1.78 - 1.24 (m, 5H).
Example 215: (±)-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-(pyridin-2-ylamino)- azabicyclo[2.2.1 ]heptan-7-yl)raethanone.
Figure imgf000183_0002
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridme with 2-iodopyridine. MS (ESI) mass calcd. for 02οΗ2οΝ60, 360.2; m/z found 361 [M+H]1". MP=167.9 °C. !H NMR (DMSO-D6): 8.12■- 8.00 (m, 2.3H), 7.88 - 7.79 (m, 1H), 7.73 - 7.53 (ni, 1.5H), 7.50 - 7.28 (m, 2.5H), 7.13 (t, /= 7.4 Hz, 0.7H), 6.63 - 6.37 (m, 3H), 4.54 (t, J = 4.5 Hz, 0.7Ή), 4.39 (d, J= 4.4 Hz, 0.3H), 3.92 (td, J = 7.5, 3.2 Hz, 0.3H), 3.86 - 3.73 (m, 1H), 3.58 id, J - ---- 4.3 Hz, 0.7H), 2.02 - 1.86 (m, i l l ). 1.78 - 1.23 (m, SH). Example 216: (±)-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((5-chlorobenzo[d]oxazol-2-yi)araino)-7- azabicyclo 2.2.1 ]heptan-7-yl)methanone.
Figure imgf000184_0001
Step A: (±)-tert-butyi 2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7- azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-6 (1 16 mg, 0.6 mmol) in 1 ,4-dioxane (3 niL) was added DIPEA (190 μί-, 1.1 mmol) and 5-chloro-2-(methylsulfinyl)benzo[d]oxazole (235 mg, 1 .1 mmol). After heating at 80 °C for 4h, the mixture was cooled to rt and saturated NaHCCh (aq) was added. The aqueous layer was extracted with EtOAc (3X). The combined organics were dried (MgSC ). Purification via silica gel chromatography (0- 10% EtOAc in hexanes) gave the title compound (130 mg, 66%). MS (ESI) mass calcd. for C18H22GN3G3, 363.1 ; m/z found 364.0 [M+H]+.
Step B: N-((±)-7-azabicyclo[2.2.1 ]heptan-2-yl)-5-cUorobenzo[d]oxazol-2-amine hydrochloride. Prepared analogous to Example 209 substituting (±)-tert-butyl-2-((6- (trifluoromethyl)pyridin-2-yl)amino)-7-azabicyc{o[2.2.1 ]heptane-7-carboxylate with the title compound of step A, MS (ESI) mass calcd. for CBHMCINJO, 263.1 ; m/z found 264.0 [M+H .
Step C: (±)-(2-(2H- l,2,3-triazol-2-yl)phenyl)(2-((5-cUorobenzo[d]oxazoI-2-yl)amino)-7- azabicyclo[2.2.1 ]heptan~7-yl)methanone. Prepared analogous to Example 209 substituting (±)- N-(6-(trifluoromethyl)pyridin-2-yl)-7-azabicycfo[2.2.1 jheptan-2-amine hydrochloride with the title compound of step B. MS (ESI) mass calcd. for C?2Hi 9CIN602, 434.1 ; m/z found 435
[M+Hf. !H NMR (DMSO-D6): 8.20 (d, J = 5.6 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.85 (d, J= 7.4 Hz, 0.3H), 7.76 (d, J = 7.3 Hz, 0.3H), 7.72 - 7.55 (m, 1.3H), 7.53 - 7.44 (m, 0.7H), 7.44 - 7.29 (m, 2H), 7.24 (d, J= 2. 1 Hz, 0.71 1 ). 7.16 - 7.08 (m, 0.7H), 7.08 - 6.98 (m, IH), 4.66- 4.47 (m, ill), 3.97 - 3.86 (m, 0.31 n. 3.82 ft, J = 3.9 Hz, 0.3H), 3.79 - 3.66 (m, 1.4H), 2.07 - 1.92 (m, 1H), 1.88 - 1.22 (m, 5H).
Example 217: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(6-methyl-3- (pyrimidin-2-yl)pyrid"in-2-yl)methanone.
Figure imgf000185_0001
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethy{)pyridine with 5-bromo-2-iodopyridine and intermediate A-1 with intermediate A-9, MS (ESI) mass calcd. for CaaHaiBrNeO, 464.1; m/z found 466 [M+H . MP=221.8 °C. !H NMR (DMSO-D6): 8.96 - 8.78 (m, 2H), 8.32 (d, J = 8.0 Hz, 0.3H), 8.19 (d, J= 8.0 Hz, 0.7H), 8.10 (d, J = 2.4 Hz, 0.3H), 7.93 (d, J= 2.4 Hz, 0.7H), 7.56 (dd, J = 8.9, 2.5 Hz, 0.3H), 7.51 - 7.39 (m, 2H), 7.33 (d, J = 8.1 Hz, 0.7H), 6.93 i d. ./ 7.1 Hz, 0.7H), 6.66 (d, ,/ 5.6 Hz, 0. H i. 6.61 (d, .1 9.0 Hz, 0.3H), 6.36 (d, J = 8.9 Hz, 0.7H), 4.59 (t, J= 4.1 Hz, 0.7H), 4.47 (d, J= 4.3 Hz, 0.3H), 3.96 - 3.75 (m, I), 2.58 (s, 0.9H), 2.31 (s, 2.1H), 2.07 - 1.91 (m, 1H), 1 .88 - 1.30 (m, 5H).
Example 218: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3-fluoro- .
Figure imgf000185_0002
Prepared analogous to Example 217 substituting intermediate A-9 with 3-fluoro-2 - methoxybenzoie acid. MS (ESI) mass calcd. for
Figure imgf000185_0003
419.1 ; m/z found 420.1
1 X1 M l MP-175.2 °C. Ή NMR (DMSO~D6): 8.10 (d, J = 2.4 Hz, 0.3H), 7.90 (d, J= 2.4 Hz, 0.7H), 7.56 (dd, J = 8.9, 2.5 Hz, 0.3H), 7.47 (dd, ,/ 8.9, 2,5 Hz, 0.7H), 7.34 (ddd, J = 1 1.7, 7.5, 2.3 Hz, 0.3H), 7.24 - 7.08 (m, 1.3H), 7.02 (d, J= 7.6 Hz, 0.7H), 6.87 - 6.66 (m, 1.7H), 6.54 (d, J = 8.9 Hz, 0.3H), 6.46 (d, J= 8.9 Hz, 0.7H), 4.63 (br s, 0.7H), 4.50 (d, J = 4.8 Hz, 0.3H), 3.88 - 3.68 (m, 4.3H), 3.58 (d, J= 2.9 Hz, 0.7Ή), 2.05 - 1.87 (m, 1 H), 1.78 - 1.20 (m, 5H).
Example 219: (±)-(2-((5-bromopyridin-2-yl)aniino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3-ethoxy-6- m ethylpyridin -2 -yl )methanone.
Figure imgf000186_0001
Prepared analogous to Example 217 substituting intermediate A-9 with intermediate A-8, MS (EST) mass calcd. for (' ·..! ί · .Br.V.O , 430.1 ; m/z found 431.1 j M · Π ; MP 134.5 °C. I ! NMR (DMSO-Dc): 8.10 (d, ./ 2.4 Hz, 0.3H), 7.88 (d, J= 2.4 Hz, 0.7H), 7.55 (dd, ./ 8.9, 2.5 Hz, 0.3H), 7.50 - 7.41 (m, 1H), 7.30 (d, J - 8.6 Hz, 0.7H), 7.24 (d, J = 8.6 Hz, 0.3H), 7.08 (d, J = 8.6 Hz, 0.7H), 6.76 (d, /= 5.7 Hz, 0.7H), 6.63 (d, J = 5.3 Hz, 0.3H), 6.57 (d, J= 8.9 Hz, 0.3H), 6.43 i d. ./ 8.9 Hz, 0.7H), 4.62 (br s, 0.7H), 4.51 (d, ./ 2.8 Hz, 0.3H), 4.13 - 3.88 (m, 2H), 3.83 - 3.73 (m, 0.3H), 3.72 - 3.61 (m, 1H), 3.59 (d, J = 3.5 Hz, 0.7H), 2.39 (s, 0.9H), 2.21 (s, 2.1H), 2.02 - 1.85 (m, 1H), 1.75 - 1.33 (m, 5H), 1.25 (td, J = 6.9, 3.6 Hz, 3H).
Example 220: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptaii-7-yl)(6-rnethyl-3- -l,2,3-triazoI-2-yl)pyridin-2-yl)methanone.
Figure imgf000186_0002
Prepared analogous to Example 217 substitutmg intermediate A-9 with intermediate A- 21. MS (ESI) mass calcd. for C2oH2oBrN70, 453.1 ; m/z found 454.1 [M+H]+. MP-214.9 °C. !H NMR (DMSO-D6): 8.18 (d, J = 8.4 Hz, 0.3H), 8.14 - 8.09 (m, 2.3H), 8.05 (d, /= 8.4 Hz, 0.7H), 7.93 (d, J = 2.4 Hz, 0.7H), 7.62 - 7.53 (m, 0.6H), 7.50 (dd, J= 8.9, 2.5 Hz, 0.7H), 7.40 (d, ./ = 8.4 Hz, 0.7H), 6.76 ·: cL ./ 6.3 Hz, 0.7H), 6.61 (d, J= 8.9 Hz, 0.3H), 6.52 (d, ./ 5.7 Hz, 0.3H), 6.45 (d, J = 8.9 Hz, 0.7H), 4.58 (t, /= 4.5 Hz, 0.7H), 4.47 (d, /= 4.8 Hz, 0.3H), 3.91 (t, J = 4.3 Hz, 0. i i h 3.88 - 3.68 (m, 1.7H), 2.60 (s, 0.9H), 2.31 (s, 2.1H), 2.03 -- 1.90 (m, IH), 1.81 ~ 1.29 (m, 5H). Example 221 : (±)-(2-(2H- 1 ,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyriniidin-2- ] eptan-7-yl)methanone.
Figure imgf000187_0001
Prepared analogous to Example 220 substituting 5-bromo-2-iodopyrid ne with 2-chloro- 5-(trifluoromethyl)pyrimidine and intermediate A-21 with intermediate A-1. MP 167. 1 °C. i NMR (DMSO-D6): 8.75 (s, 0.4H), 8.70 (s, 0.4H), 8.66 (s, 0.6H), 8.53 (s, 0.6H), 8.12 - 8.03 (m, 2.6H), 7.86 (d, J = 7.3 Hz, 0.4H), 7.80 (d, J= 7.2 Hz, 0.4H), 7.72 - 7.54 (m, 1.6H), 7.48 - 7.34 (m, 1.4H), 7.16 (t, 7.4 Hz, 0.6H), 4.56 (br s, 0.6H), 4.41 (d, J= 4.3 Hz, 0.4H), 4.08 (dd, ,/ 11.1, 6.8 Hz, 0.4H), 3.90 - 3.75 (m, 1H), 3.61 (d, ,7= 4.3 Hz, 0.6H), 2.01 - 1.27 (m, 61 1 :·.
Example 222: (±)-(3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyrtmidm
methanone.
Figure imgf000187_0002
Prepared analogous to Example 221 substituting intermediate A-1 with 3-fluoro-2- methoxybenzoic acid. ]H NMR (DMSO-D6): 8.72 (br d, J= 22.6 Hz, 0.8H), 8.58 (br d, ,1= 24.1 Hz, 1.2H), 8.12 (br d, J= 5.6 Hz, 0.4! U. 7.99 (br d, J= 5.0 Hz, 0.6H), 7.45 - 7.23 (m, 0.8H), 7.26 - 7.06 (m, 1.2H), 6.97 (d, J= 7.5 Hz, 0.6H), 6.90 - 6.72 (m, 0.6H), 4.65 (br s, 0.6H), 4.53 (d, J = 4.8 Hz, 0.4H), 3.97 (dd, J- 1 1.4, 6.0 Hz, 0.4H), 3.84 (s, 1.2H), 3.93 - 3.71 (m, 1H), 3.78 (8, 1.8H), 3.69 (br d, J= 2.9 Hz, 0.6H), 2.06 - 1.35 (m, 6H)
Example 223 : (±)- 6--metixyi-3-(2H- 1 ,2,3-triazol-2-yl)pyridm-2-yl)(2-((5- (trifluoromethyl)pyrimidin-2-yl)aniino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000188_0001
Prepared analogous to Example 221 substituiing intermediate A- 1 with intermediate A- 21. Ή NMR (DMSO-D6): 8,74 (br d, J = 12.1 Hz, 0.4H), 8.63 (br d, J = 13.2 Hz, 1 .2H), 8.26 - 8.01 (m, 3.4H), 7.61 (dd, J = 21.8, 7.4 Hz, 0.4H), 7.43 (d, J = 8.4 Hz, 0.6H), 4.61 (br s, 0.6H), 4.55 i d. 5.0 Hz, 0.4H), 4.1 1 - 4.01 (m, 0.4H), 4.02 - 3.93 (m, l ! . 3.88 (dd, ./ 10.1 , 6.1 Hz, 0.6H), 3.22 - 3.06 (m, 1H), 2.60 (s, 1H), 2.30 (s, 11 1 ). 2.06 - 1.34 (m, 61 1 :·.
Example 224: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2- yl) amino) -7-azabic cio[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000188_0002
Prepared analogous to Example 221 substituting intermediate A- 1 with intermediate A-8. ]H NMR (DMSO-De): 8.79 (br d, /= 22.9 Hz, 0.6H), 8.65 (br d, J = 17.4 Hz, 1.4H), 8.21 (d, J = 5.3 Hz, 0.7H), 7.92 (d, J = 5.2 Hz, 0.3H), 7.52 (d, J= 8.6 Hz, 0.3H), 7.42 i d. ./ 8.6 Hz, 0.7Ή), 7.32 (d, ./ 8.6 Hz, 0.3H), 7.18 (d, ./ 8.6 Hz, 0.7H), 4.71 (br s, 0.7H), 4.64 (br d, J= 4.7 Hz, 0.3H), 4.23 - 3.93 (m, 2.5H), 3.93 - 3.78 (m, 1.4H), 3.78 - 3.55 (m, 1.7H), 3.31 - 3.07 (m, 1.4H), 2.47 (s, 1H), 2.31 (s, 2H), 2.06 - 1.40 (m, 6H).
Example 225: (±)-(6-metliyi-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((5-(tt
yl)amino)-7-azabicyclo[2.2. l ]heptan-7-yl)methanone.
Figure imgf000189_0001
Prepared analogous to Example 221 substituting intermediate A-l with intermediate A-9. M P 203 °C. MS (ESI) mass calcd. for C22H20F3N7O, 455.2; m/z found 427.5 j \M 11 Ή NMR (DMSO-D6): 8.94 (d, J = 4.9 Hz, 0.4H), 8.89 (d, J - 4.9 Hz, 1.6H), 8.77 (s, 0.2H), 8.71 (s, 0.2H), 8.61 (s, 1.4H), 8.36 (d, J= 8.1 Hz, 0.2H), 8.24 (d, J = 7.9 Hz, 1.8H), 7.72 (d, J = 6.0 Hz, 0.2H), 7.54 - 7.44 (m, 1.2H), 7.38 (d, J= 8.1 Hz, 0.8H), 4.64 (br s, 0.8H), 4.58 (d, J= 4.6 Hz, 0.2H), 4.06 - 3.90 (m, 2H), 2.60 (s, 0.6H), 2.35 f s, 2.4H), 2.1 1 - 1.73 (m, 4H), 1.62 - .35 (m, 2H).
Example 226: (i)-(3-fluoro-2-methox phenyl)(2-((5-(trif{uoromethyl)pyrimidm
yl)methanone.
Figure imgf000189_0002
Prepare analogous to Example 222 substituting intermediate B-6 with intermediate B-7. MS (EST.) mass calcd. for C^ft^N^, 410.2; m/z found 41 1.3 [M+Hf . ! i NMR (DMSG-D6): 8.75 (s, 0.5H), 8.68 (s, 0.5H), 8.61 (s, 0.5H), 8.57 (s, 0.5H), 8.52 (d, J= 6.3 Hz, 0.5P1), 8.44 (d, J = 6.3 Hz, 0.5H), 7.44 - 7.29 mi. 1H), 7.23 - 7.08 ·: m. 2H), 4.82 (t, J = 3.9 Hz, 0.5H), 4.58 ft, ./ 4.5 Hz, 0.5H), 4.34 - 4.12 (m, IH), 3.94 - 3.81 (m, 3.5H), 3.68 (i, J= 4.2 Hz, 0.5H), 2.31 - 2.1 1 (m, I H), 1.93 - 1.40 (m, 5H).
Exampie 227: (±)-(3-emoxy-6-methylpyridin-2-yl)(2-((5-(to
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7~yl)methanone.
Figure imgf000190_0001
Prepare analogous to Example 224 substituting intermediate B-6 with intermediate B-7. MP=79.7 °C, MS (ESI) mass calcd. for C20H22F3N5O2, 421.2; m/z found 422.4 [M+Hf. Ή NMR (DMSO-D6): 8.76 (s, 0.5H), 8.68 (s, 0.5H), 8.61 (s, 0.5H), 8.56 (s, 0.5H), 8.52 (d, ./ 6.4 Hz, O.SH), 8.44 fd, J= 6.6 Hz, 0.5H), 7.48 (d, J= 3.2 Hz, 0.5H), 7.45 (d, ,/ 3.2 Hz, 0.5H), 7.28 (d, J= 3.3 Hz, 0.5H), 7.25 (d, J= 3.3 Hz, 0.5H), 4.83 (t, J= 4.2 Hz, 0.5H), 4.59 (t, J= 4.3 Hz, 0.5H), 4.40 - 4.29 (m, 0.5H), 4.28 - 4.19 (m, O.SH), 4.16 - 4.01 (m, 2H), 3.79 (t, J = 4.4 Hz, 0.5H), 3.61 (t, ./ 4.6 Hz, 0.5H), 2.41 (s, l .SH), 2.40 (s, 1.5H), 2.30 - 2.09 (m, Hi), 1.93 - 1.41 (m, 5H), 1.34 - 1.23 (m, 3H).
Example 228: (±)-(6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- -yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000190_0002
Prepare analogous to Example 223 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for
Figure imgf000190_0003
°C. Ή NMR (DMSO-D6): 8.77 (s, 0.6H), 8.68 is, 0.6H), 8.61 (s, 0.4H), 8.55 (s, 0.4H), 8.51 (d, J = 6.3 Hz, 0.6H), 8.44 (d, ,/ 6.3 Hz, 0.4H), 8.24 - 8.16 (m, 1H), 8.13 (s, IH), 8.12 (s, 1H), 7.63 - 7.52 (m, 1H), 4.81 ·! ! . ./ 4.2 Hz, 0.6H), 4.55 (t, ./ 4.2 Hz, 0.4H), 4.40 - 4.21 (m, IH), 4.06 (t, J = 4.4 Hz, 0.4H), 3.79 (t, J= 4.4 Hz, 0.6H), 2.61 (s, 1.2H), 2.58 (s, l.SH), 2.34 - 2.20 (m, 0.6H), 2.19 - 2.03 (m, 0.6H), 1.94 - 1.50 (m, 4.2H), 1.44 (dd, J= 12.3, 4.6 Hz, 0.6H). Example 229: (-t)-(3-ethoxy-6-methylpyridm-2-yl)(2-(qumoxalin-2-ylammo)-7- azabicyelo[2.2, 1 ]heptan-7-yl)raethanone.
Figure imgf000191_0001
Prepare analogous to Example 207 substituting intermediate B-6 with intermediate B-7.
MS (ESI) mass calcd. for C23H25N5O2, 403.2; m/z found 404.5 j \1 H | . M P ! 15.1 °C. ]H NMR (DMSO-D6): 8.37 (s, 0.5H), 8.30 (s, 0.5H), 7.97 (t, J= 5.4 Hz, 1H), 7.80 (d, . 7.4 Hz, 0.5H), 7.75 (d, J= 7.1 Hz, 0.5H), 7.69 - 7.44 (m, 2.5H), 7.43 - 7.23 (m, 2.5H), 4.99 (t J = 4.4 Hz, 0.5H), 4.63 (t, J= 4.6 Hz, 0.5H), 4.48 - 4.27 (m, IE), 4.26 - 4.13 (m, 2H), 3.96 (t, J= 4.4 Hz, 0.5H), 3.64 (t, J === 4.6 Hz, 0.5H), 2.44 fs, i .5H), 2.41 (s, 1.5H), 2.39 - 2.26 (m, i l l ). 1.98 - 1.37 (m, 5H), 1.36 - 1.28 (m, 3H).
Example 230: (±)-(6-methyl-3-(2H-l,2,3-triazo1-2^
l)methanone.
Figure imgf000191_0002
Prepare analogous to Example 205 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for C23¾iM8G, 426.2; m/z found 427.5 j M ! i ! . MP=152.3 °C. Ή NMR (DMSO-D6): 8.37 (s, 0.5H), 8.28 - 8.20 (m, 2H), 8.16 - 8.13 (ro, 2H), 7.95 (dd, /= 5.6, 3.6 Hz, 1H), 7.79 (d, ./=- 8.1 Hz, 0.5H), 7.74 (d, J = 8.1 Hz, 0.5H), 7.70 - 7.48 (m, 2.5H), 7.41 - 7.23 (m, 1.5H), 4.98 i ,/ 4.2 Hz, 0.5H), 4.60 (t, J= 4.6 Hz, 0.5H), 4.36 - 4.24 (m, 1H), 4.19 · ! . ./ 4.5 Hz, O.SH), 3.81 ·: j. ./ 4.6 Hz, O.SH), 2.67 (s, l .SH), 2.60 (s, 1.5H), 2.43 - 2.17 (m, 1H), 1.97 - 1.25 (m, 5H).
Example 231 : (±)-(3-fluoro-2-methoxyphenyl)(2-(quinoxa1in-2-ylammo)-7- -yl)methanone.
Figure imgf000192_0001
Prepare analogous to Example 206 substituting intermediate B-6 with intermediate B-7. 'H NMR (DMSO-D6): 8.36 (s, O.SH), 8.29 fs, O.SH), 8.08 - 7.95 (m, IH), 7.85 - 7.69 (m, 1 H), 7.69 - 7.49 (m, l .SH), 7.49 - 7.27 (m, 2H), 7.27 - 7.12 (m, 2..5H), 5.00 (t, J - 4.2 Hz, O.SH), 4.62 (t, J = 4.2 Hz, O.SH), 4.43 - 4.17 (m, IH), 4.1 1 (t, J = 4.3 Hz, O.SH), 3.95 (s, l .SH), 3.88 (s, 1 .5H), 3.72 (t, J= 4.5 Hz, 0.5H), 2.45 - 2.25 (m, I H), 1.99 - 1.46 (m, 4H), 1.46 - 1.28 (m, I H).
Example 232: (±)-(2-((5-bromopyridm-2-yl)ainmo)
- 1 ,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000192_0002
Prepare analogous to Example 220 substituting intermediate B-6 with intermediate B-7.
M P 196.0 °C. ]H N.M R (DMSO-D6): 8.25 - 8.16 (m, IH), 8.16 - 8.10 (m, 2.6H), 7.90 (d, J =
2.4 Hz, 0.4H), 7.63 - 7.53 (m, 1.6H), 7.S0 fdd, J= 8.9, 2.5 Hz, 0.4H), 7.19 (d, ./ 6.0 Hz, 0.6H), 7.12 (d, J= 6.1 Hz, 0.4H), 6.54 (d, J= 8.9 Hz, 0.6H), 6.44 i d. ./ 8.9 Hz, 0.4H), 4.81 (t, J= 4.2 Hz, 0.6H), 4.54 (t, J= 4.2 Hz, 0.4H), 4.23 - 4.07 (m, IH), 4.04 (t, J= 4.5 Hz, 0.4H), 3.75 (t, ./
4.5 Hz, 0.6H), 2.61 fs, 1.2H), 2.58 (s, 1.8H), 2.36 - 2.05 (m, IH), 1 .92 - 1.41 (m, 4H), 1.30 (dd, J= 12.4, 4.4 Hz, 0.4H), 1.18 (dd, ./ 12.2, 4.6 Hz, 0.6H). Example 233: (±)~(2-((5-bromopjTidiii-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6- !Ti ethylpyridm -2 -yl )methanone.
Figure imgf000193_0001
Prepare analogous to Example 219 substituting intermediate B-6 with intermediate B-7.
MP 1 76. 1 °C. !H NMR (DMSOD6): 8.1 1 i d. ./ 2.4 Hz, 0.5H), 7.91 (d, ./ 2.4 Hz, 0.5H), 7.61 - 7.43 (m, 2H), 7.33 - 7.20 (m, 1.5H), 7.15 (d, J= 6.1 Hz, 0.5H), 6.55 (d, J= 8.9 Hz, 0.5H), 6.46 (d, J = 8.9 Hz, 0.5H), 4.83 ft, J = 4.3 Hz, 0.5H), 4.57 (t, J = 4.6 Hz, 0.5H), 4.20 (d, J = 5.5 Hz, 0.5H), 4.09 (dq, J= 10.2, 6.9 Hz, 2.5H), 3.79 (t, J= 4.3 Hz, 0.5H), 3.58 (t, J= 4.6 Hz, 0.5H), 2.41 (s, 1.5H), 2.40 (s, l .SH), 2.32 - 2.14 (m, 1 H), 1.93 - 1.45 (m, 4H), 1.36 - 1.17 (m, 4H).
Example 234: (±)-(2-((5-bromopyridm-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3-f!uoro-2- ne.
Figure imgf000193_0002
Prepare analogous to Example 217 substituting intermediate B-6 with intermediate B-7.
MP 144.5 °C. :H NMR (DMSO-D6): 8.1 1 (d, J= 2.4 Hz, 0.6! i s. 7.91 (d, J= 2.4 Hz, 0.4H), 7.56 (dd, J------ 8.9, 2.5 Hz, 0.6H), 7.50 (dd, J= 8.9, 2.5 Hz, 0.4H), 7.43 - 7.30 (m, 1H), 7.27 - 7.05 (m,
3H), 6.54 (d, J= 8.9 Hz, 0.6H), 6.46 (d, J= 8.9 Hz, 0.4H), 4.83 (t, J = 4.3 Hz, 0.6H), 4.57 (t, J= 4.7 Hz, 0.4H), 4.21 - 3.99 (m, 1H), 3.95 - 3.81 (m, 3.4H), 3.66 (t, J= 4.7 Hz, 0.6H), 2.36 - 2.14 (m, IH), 1.94 - 1.43 (m, 4H), 1.36 - 1 .14 (m, 1H). Example 235: (± -((2-(2H-l ,2,3-triazol-2-yl)phenyl)(2-((4-(tri^
]heptan-7-yl)methanone.
Figure imgf000194_0001
Prepare analogous to Example 210 substituting intermediate B-6 with intermediate B-7.
MS (ESI) mass calcd. for C2iH19F3N60, 428.2; m/z found 429 [M+H]+. MP=274.2 °C. Ή NMR (DMSO-D6): 8.27 i d. ./ 5.2 Hz, 0.5H), 8.13 - 8.01 (m, 2.SH), 7.89 - 7.80 (m, i l l ). 7.73 - 7.61 (m, 1H), 7.61 - 7.51 (m, 2H), 7.44 (d, J= 6.1 Hz, 0.5H), 7.38 (d, J= 5.9 Hz, 0.5H), 6.83 - 6.75 (m, I H), 6.73 - 6.63 (m, I H), 4.78 (t, J= 3.9 Hz, 0.5H), 4.50 (t, J= 4.6 Hz, 0.5H), 4.27 - 4.04 (m, IH), 3.96 (t, ,7 = 4.1 Hz, 0.5H), 3.64 (t, J= 4.1 Hz, 0.5H), 2.40 - 2.21 (m, 0.5H), 2.17 - 1.99 (m, 0.5H), 1.88 - 1.32 (m, 4H), 1.27 ( dcL ./ 12.3, 4.3 Hz, 0.5H), 1.12 (dd, J= 12.2, 4.5 Hz,
0.5H).
Example 236: (±)-(2-((5-fluoropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3- -l,2,3-triazoI-2-yl)pyridin~2-yl)methanone.
Figure imgf000194_0002
Prepared analogous to Example 209 substituting 2-chloro-6-(trifiuoromethyl)pyridine with 5-fluoro-2-iodopyridine and intermediate A-l with A-21. MP= 100.1 °C, MS (ESI) mass calcd. for C2oH20FN70, 393.2; m/z found 394.2 | M 1 11 Ή NMR (DMSO-D6): 8.24 - 8.15 (m, IH), 8.12 (s, 1.2H) 8.1 1 (s, 0.8H), 8.00 (d, ./ 2.9 Hz, 0.6H), 7.80 i d. ./ 2.8 Hz, 0.4H), 7.63 - 7.51 (m, IH), 7.43 - 7.26 (m, IH), 6.94 (d, J= 5.9 Hz, 0.6H), 6.87 (d, J= 6.0 Hz, 0.4H), 6.55 (dd, J= 9.1, 3.6 Hz, 0.6H), 6.45 (d l, ,/ 9.1, 3.7 Hz, 0.4H), 4.81 > \. 4.2 Hz, 0.6H), 4.52 (t, ./ = 4.6 Hz, 0.4H), 4.19 - 3.99 (m, 1.4H), 3.73 (t, J= 4.6 Hz, 0.6H), 2.60 (s, 1.2H), 2.58 (s, 1.8H), 2.35 - 2.20 (m, 0.6H), 2.19 - 2.05 (m, 0.4H), 1.96 - 1.38 (m, 4H), 1.27 (dd, J= 12.5, 4.2 Hz, 0.6! U. 1.15 (dd, J = 12.2, 4.8 Hz, 0.4H).
Example 237: (±)-(3-fluoro-2-methoxyphenyl)(2~((5-fluoropyridin-2-yl)amino)-7- azabicyclo[2.2.1 ] eptan-7-y])methanone.
Figure imgf000195_0001
Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 5-fluoro-2-iodopyridine and intermediate A- l with 3-fluoro-2-methoxybenzoic acid. MS (EST) mass calcd. for dstfiisfoNsCh, 359.1 ; m/z found 360.2 [ VI 1 11 MP=134.7 °C. !H NMR (DMSO-D6): 8.00 (d, J = 2.9 Hz, 0.51 s ). 7.80 ul. ./ 2.9 Hz, 0.5 H i. 7.45 - 7.26 (m, 2H), 7.24 - 7.06 (m, 2H), 6.96 (d, J= 6.0 Hz, 0.5H), 6.89 (d, J = 5.8 Hz, 0.5H), 6.56 (dd, J= 9.1, 3.6 Hz, 0.5H), 6.48 (dd, J = 9.2, 3.6 Hz, 0.5H), 4.83 (t, J= 4.3 Hz, 0.5H), 4.56 (t, J = 4.7 Hz, 0.5H), 4.18 - 3.98 (m, 1H), 3.95 - 3.81 an. 3.5H), 3.64 (t, ./ 4.6 Hz, 0.5H), 2.35 - 2.14 (m, 1H), 1.96 - 1.43 (m, 4H), 1.30 - 1.13 (m, 1H).
Example 238: (3-fluoro-2-(pyrimidin-2-yl)pheny3)((l S,2R,4R)-2-((5-(trifiuoromethyl)pyrazin-2- ]heptan-7-yl)methanone.
Figure imgf000195_0002
Step A: ( 1 S,2R,4R)-N-(5-(trifluoromethyl)pyrazia-2-yl)-7-azabicyclo[2.2.1 ]heptan-2- ainine hydrochloride. To the intermediate of Example 181 Step A (100 mg, 0.3 mmol) in DCM (3 mL) was added 4M HO in dioxane (0.8 mL). The reaction was allowed to proceed overnight then concentrated neutralized with 5% \ a>( () : (aq) and extracted with DCM (2.X). The combined organics were dried (Na2S04 to give the title compound of step A that was used without further purification,
Step B: ( 3-fluoro-2- pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazm-
2-yl)arnino)-7-azabicyclo[2.2.1Jheptan-7-yl)niethanone. To the title compound of step A (1.44 g, 5.6 mmol) in DCM (56 mL) was added DIPEA (1.25 mL, 7.3 mmol) and intermediate A-2 ( 1.43 g, 6.1 mmol). Then T3P (50% solution in DMF, 10 mL, 17 mmol) was added drop wise and the reaction heated at 45 °C for 16h. After allowing to cool to rt, DCM was added and the mixture washed with H20 then saturated aHC(¾ (aq). The combined aq layers were extracted with DCM. The combined organic layers were dried (Na2S04). Purification via silica gel chromatography (10-100% EtOAc in hexanes) gave the title compound (2 g, 78%). MS (ESI) mass calcd. for C22Hi8F4N60, 458.2; m/z found 459.1 [M+H]+ . Ή NMR (CDCL) 8.91 - 8.73 (m, 2H), 8.35 - 8.22 (m, I I I ). 8.19 (s, 1H), 7.66 (s, 1 H), 7.44 - 7.13 (m, 4H), 4.79 - 4.68 (m, 1H), 4.46 - 4.35 (m, IB), 4.12 - 4.03 (m, IH), 2.22 - 2.00 (m, 11 1 ). 1.99 - 1 .84 (m, 1H), 1.79 - 1.45 (m, 3H).
Example 238 was also prepared as follows:
Step A: 3-fSuoro-2-(pyrimidin-2-yi)benzonitrile. To a 12-L 4-necked round-bottomed flask equipped with a thermocouple probe, mechanical stirrer, condenser and nitrogen inlet was charged 3-fluorobenzonitrile (140 g, 123.6 mmol), 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane (353.7 mL, 1.699 mol), and THF (2.35 L). The mixture was cooled to -78 °C and lithium diisopropylamide (623 mL, 1.246 moi, 2 M) was added over 45 min maintaining a temperature of < -71 °C. The mixture was stirred for 1 h at -76 °C then quenched with sodium bicarbonate,^) (172 g in 1500 mL water). This mixture was warmed to room temperature to produce an off-white slurry. The slurry was treated with 2-bromopyrimidine (171.8 g, 1.059 mol) and then degassed with bubbling nitrogen. DichIoro[l, l '-bis(di-f- butylphosphino)ferrocene]palladium(Il) (17 g, 25.8 mmol) was then added and the mixture was heated to 66 °C for 1 h. The mixture was cooled and ethyl acetate (5.6 L) was added. Solids were removed by filtration and washed with ethyl acetate (2 x 300 mL). The layers were cut and the aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were washed with brine (2 x 1.2 L) and then concentrated. Ethanol (600 mL) was added and the mixture was further concentrated to provide a dark brown liquid (382.0 g, 96% mass recovery,
75.5% desired, 19.1% regioisomer (3-fluoro-4-(pyrimidin-2-yl)benzomtrile). This liquid was warmed in ethanol (600 mL) at 66 °C until homogeneous and then gradually cooled to 20 °C. The resulting solids were isolated by filtration and washed with cold 1/1 hexanes/ethanol (2 x 100 mL). After drying for 3 hours under air suction, the title compound was obtained as an off- white solid (1 18 g, 30%, 99.2% desired regioisomer). The mother liquor contained -20% additional desired product that could be recovered through chromatography and crystallization. H NMR (400 MHz, ( DC h i δ 8.97 ·: d. J 4.9 Hz, 2l . 7.69 - 7.61 (m, IH), 7.61 - 7.52 (m, 1H), 7.51 - 7.43 (m, IH), 7.41 (t, 5.0 Hz, IH).
Step B: 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. To a 5-L, 4-necked round-bottomed flask equipped with a thermocouple, mechanical stirrer, condenser, and nitrogen inlet was charged the title compound of Step A (100 g, 502.0 mmol) in THF (500 mL) and methanol (500 mL). The mixture was stirred for 5 mm at 20 °C and then sodium hydroxide^, (1.0 L, 3 N) was added. The resulting mixture was warmed to 60 °C for 24 h. The mixture was concentrated to 500 mL and the resulting thick aqueous layer was diluted with water (500 mL) and then transferred into a 5-L, 4-necked round- bottomed flask. The flask was cooled to 4 °C and the pH was adjusted from 14.0 to 2-3 with concentrated hydrogen chloride^ (260 mL, 37%). The resulting off-white slurry was stirred at 0 °C for 20 min, and then the solids were collected by filtration, washed with water (4 x 200 mL), dried under air suction for 20 h, and then placed in a vacuum oven at 60 °C for 20 h to provide the title compound as an off-white solid (106 g, 97%). Ή NMR (400 MHz, DMSO) δ 13.01 (s, IH), 8.89 (d, J= 5.0 Hz, 2H), 7.75 (dd, J = 7.7, 1.2 Hz, IH), 7.69 -■ 7.54 (m, 2H), 7.52 (t, 1 H). HPLC retention time: 1.765 min.
Step C: ( lS,2R,4i?)-tert-butyl 2-(((benzyloxy)carbonyl)aniino)-7-azabicycio[2.2.1 ]·- heptane-7-carboxylate. A racemic mixture of tert-butyi 2-(((benzyloxy)carbonyl)amino)-7- azabicyc!o[2.2.1]-heptane-7-carboxylate (578 g) was separated on a chiralcel OD column ( 1000A, 20 urn (Daicel), 1 10 mm diameter, 42 cm length) with a mobile phase of 90: 10 heptane:ethanol over 126 injections with a run time of 15 min. Peak shaving was employed in conjuction with 1 recycling. The title compound was isolated through filtration after crystallization upon concentration (249.8 g, 86% of theory). T NMR (400 MHz, CD CI 3) δ 7.40 - 7.28 (m, 5H), 5.20 - 5.00 (m, 3H), 4.23 (s, IH), 4.12 i d. ./ 4.9 Hz, IH), 3.78 (td, J = 8.0, 2.9 Hz, IH), 1.93 (dd, J = 13.1, 8.1 Hz, I H), 1.83 - 1.62 (m, 2H), 1.54 - 1.29 (m, 3H), 1.43 (s, 9H). HPLC retention time: 3.46 ! min.
Step D: (15,2i?,4 ?)-teri-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate. To a
2.25 L Parr vessel were added (lS,2R,4R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate (91.2 g, 261.4 mmol) and 5% Pd/C (Johnson Matthey
Al 02038-5, (9.6 g, 2.26 mmol). Ethanol (912 mL) was added and the vessel was agitated under a pressure of hydrogen gas (60 psi) for -2.5 h. Mid-way through that time period the flask was evacuated and recharged with hydrogen gas (60 psi). The mixture was then filtered to remove residual heterogeneous catalyst. After washing the filter cake with ethanol (90 mL) the filtrate was concentrated under reduced pressure and concentrated again from acetonitrile to provide the title compound as a slightly yellow oil (57 g, quant, yield). Ή NMR (400 MHz, CDCI3) δ 4.2 (bs, S i n. 3.88 (bs, 1H), 2.96 (dd, ./ 7.6, 3.1 Hz, i l l ). 1.81 (dd, ./ 12.9, 7.8 Hz, ill), 1.77 - 1.54 (m, 2H), 1.46 (s, 9H), 1.39 - 1.20 (m, 3H).
Step E: (l ,2^,4i?)-tert~butyl 2-((5-(trif!uoromethy{)pyrazin-2-yl)amino)-7- azabicyclo[2.2.1] heptane-7-carboxylate. To a 3 L round-bottomed flask equipped with a mechanical stirring mechanism, temperature probe, reflux condenser, heating mantle, and nitrogen inlet was added (lS,2R,4R)-tert-bu†yl 2-amino-7-azabicyclo[2.2.1 ]heptane-7- carboxylate (56.92 g, 264.4 mmol) in acetonitrile (360 mL). Triethylamine (55, 1 ml,, 396.6 mmol) and 2-chloro-5-trifluoromethylpyrazine (57.91 g, 317.2 mmol) were added in rapid succession and the mixture was then heated to reflux for 16.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue (189.57 g) was taken up in ammonium chloride^ (500 mL, 13 wt%) and ethyl acetate (500 mL). The layers were mixed and separated and the organic was washed with sodium carbonate^ (500 mL, ½ saturated). The organic layer was then dried over magnesium sulphate, filtered, and concentrated to a final mass of 94,73 g. This orange solid was taken up in heptane (500 mL) at 98 °C. 'The homogeneous solution was allowed to cool slowly to room temperature, filtered, and washed with 100 mL of heptane to provide the title compound as a white solid (79.62 g, 84%). Ή NMR (400 MHz, CDCI3) δ 8.31 (s, 1 H), 7.86 (d, J= 1.4 Hz, 1H), 5.45 (bs, 1H), 4.44 - 4.25 (m, 1H), 4.20 i d. ./ 5.2 Hz, I H), 4.05 (id, J = 7.6, 3.0 Hz, i l l }. 2.06 (dd, J= 13.1, 7.6 Hz, IH), 1.92 - 1.70 (m, 2H), 1.61 - 1.38 (m, 3H), 1.44 (s, 9H). HPLC retention time: 3.424 min.
Step F: ( lS,2i?,4R)-N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1 ]heptan-2- amine. In a 2-L round-bottomed flask, (1 S,2R,4/?)-tert-butyl 2-((5-(trifluoromethyl)pyrazm-2- yl)amino)-7-azabicyclo[2.2.1 ] heptane-7-carboxylate (79.52 g, 221.9 mmol) was taken up in IPA (584 mL). Hydrogen chloride ( 121 ,0 mL, 665,7 mmol, 5.5 M in IPA) was added and the reaction was warmed to 60 °C for 14 h. After cooling to room temperature, the mixture was poured over isopropyl acetate (1 L) and sodium carbonate^ (1 kg, 8.1 wt%). The layers were mixed and separated. The aqueous phase was washed with isopropyl acetate (500 mL), and the combined organics were washed with brine (700 mL), dried over MgSO^ filtered, and concentrated to provide the title compound as a pinkish-white solid (57.1 1 g, 99%), Ή NMR (400 MHz, CDCI3) δ 8.31 (s, IH), 7.84 (d, J 1.4 Hz, I H), 5.51 i d. J= 7.7 Hz, IH), 3.95 ( k!. ./ 7.8, 3.0 Hz, 1H), 3.76 (t, J= 4.4 Hz, S i n. 3.60 (d, ,/ 4.9 Hz, 1H), 1.95 fm, ./ 12,9, 7.8 Hz, 1H), 1.69 - 1.39 (m, 5H). HPLC retention time: 1.938 min.
Step G: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)ammo)-7-azabicyc1o[2.2.1]heptan-7-yl)metihanone. A 3 L 3 -necked round-bottom flask was fitted with mechanical stirring and a thermometer and charged with the amine from Step F (51.61 g, 200 mmol), acid from Step B (56.69 g, 260 mmol), and 2-MeTHF ( 1 L), The mixture was stirred at room temperature for several minutes until nearly all the solids had dissolved.
Diisopropylethylamine (45.2 mL, 260 mmol) was added followed immediately by T3P (178 mL of a 50% solution in EtO Ac, 300 mmol). Mild exotherm to 27 °C observed. The reaction was warmed to 40 °C and allowed to stir 9 h. A dark brown reaction mixture resulted. HPLC and MS analysis indicated complete conversion of the amine. The reaction was quenched by addition of 1 : 1 sat'd. NHtCl/water (1 L) and allowed to cool to room temperature. The layers were separated, and the aqueous layer was extracted once with 2-MeTHF (200 mL), The combined organic layers were washed with 3: 1 sat'd. Na2C03/water (1 L). The organic layer was washed with brine (1 L) causing an emulsion which was given several hours to clear.
Layers were separated, and the organic layer was dried (MgSC ) and concentrated to a viscous brown oil. This material was combined with material from two prior smaller scale reactions for product purification. Yield calculations are based upon the total combined amount of limiting amine for the three reactions, 221.3 mmol. The combined crude products were first flash ehromatographed ( 1.5 kg silica gel cartridge, initial linear gradient elution of 50% EtO Ac/hex to 100% EtO Ac then elution with 20% THF/EtOAc and 40% THF/EtOAc, 400 mL/min, material loaded as a CPLCl? solution). Strong reddish purple colored band and several minor spots co- eluted with the initial fractions of product. The latter, less-colored three quarters of the product- containing fractions were combined and concentrated to a thick red-orange syrup (83 g). This material was treated with activated charcoal (17 g) in acetonitrile (1.1 L) at 46 °C for 30 min. The charcoal was removed by vacuum filtration through a pad of Celite, and the filter cake was washed with warm acetonitrile (500 mL) to provide a straw yellow solution. The solvents were removed in vacuo to give the impure crude product as an off-white foam (-70 g). To crystallize the material, the foam was dissolved in hot EtOAc (175 mL, 77 °C) with mechanical stirring. Heptane was added in portions at 76-80 °C. At 300 mL of added heptane, solids were observed to slowly precipitate. Addition of heptane was continued until a total volume of 650 mL was added. Mixture was allowed to cool to room temperature over 5 h. The product was collected by vacuum filtration and washed with excess heptane and allowed to air dry. The product was dense off-white granular crystals (Form 1), HPLC analysis appeared to indicate a minor impurity (0.7% peak area, 2.23 min, 220 nm); therefore, a second crystallization was undertaken under identical conditions. During this crystallization, the product was observed to rapidly crystallize in fluffy white needles (Form 2) which "froze" the mixture preventing controlled stirring. Additional heptane was added, and a spatula was used to mechanically break up the mixture and restore stirring of a suspension of crystalline product. Due to continited observance of the minor peak, the product was crystallized twice more with similar cry stallization beha vior as observed in the second crystallization. It was noted that more EtOAc was necessary to initially dissolve the Form 2 crystals. The final product was dried in a vacuum oven (-10 torr) at 60 °C overnight and then 80 °C overnight to provide crystalline Form 2. (small fluffy white needles). Yield = 54.46 g (54%). By Ή NMR, EtOAc content was 900 ppm, and heptane content was 660 ppm. The remaining product-containing chromatography fractions were concentrated and chromatographed a second time. Mixed fractions were chromatographed a third time. The product fractions were concentrated to give a light orange foam (28.6 g). The foam was decolorized with activated charcoal (5.6 g) in warm acetonitrile (46 °C). Charcoal was removed by vacuum filtration through a pad of Celite. 'The filter cake was washed with warm acetonitrile, and the filtrate was concentrated and crystallized from EtOAc/heptane as before. With this batch, crystalline Form 2 was generated upon the initial crystallization. Product was collected by vacuum filtration, washed with excess heptane, and dried in a vacuum oven (-10 torr) at 50 °C overnight. Yield = 23.69 g (23%). By 1 H NMR, EtOAc content was 3500 ppm, and heptane content was 600 ppm. Total combined yield of two batches = 78.15 g (77%).
]H NMR (400 MHz, CDC13) Major Rotamer (90%) δ 8.87 (d, ,1= 4.9 Hz, 2H), 8.35 (m, 1H), 8.18 (s, 1H), 7.65 (d, J= 1 .3 Hz, Hi), 7.42 - 7.34 (m, 2H), 7.24 - 7.1 8 (m, 2H), 4.72 (t, J = 4.8 Hz, H i !. 4.37 ( id. ./ 8.8, 3.7 Hz, i l l ). 4.07 i d. ./ 4.9 Hz, I I I ;. 2.15 (dd. J 12.8, 8.1 Hz, IH), 2.09 - 1.98 (m, l i b. 1.97 - 1.84 (m, IH), 1.76 - 1.58 (m, M b . 1.56 - 1.44 (m, 2H). Minor Rotamer (10%) unique peaks only 8 8.76 (d, J = 4.88 Hz, 2H), 7.70 (s, 1H), 7.50 - 7.44 (m, I H), 7.33 - 7.27 (m, 2H), 6.21 (m, IH), 4.59 (bd, J 4.1 Hz, I H), 4.20 - 4.13 (m, 2H).
Example 239: (2-ethoxynaphthalen- 1 -yl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000201_0001
Prepared analogous to Example 181 substituting nitennediate A-1 with 2-ethoxy-l- naphthoic acid. MS (ESI) mass calcd. for C24H23F3N4O2, 456.2; m/z found 457.2 [M+H]+ !H NMR (CDCI3): 8.39 - 8.31 (m, 0.3H), 8.18 (s, 0.5H), 8.08 - 7.98 (m, 0.3H), 7.96 - 7.67 (m, 3.6H), 7.57 - 7.32 (m, 2H), 7.31 - 7.16 (m, 1.3H), 7.10 - 7.04 (m, 0.2H), 6.34 (d, J = 9.1 Hz, 0.5H), 5.90 - 5.75 (m, 0. H i. 5.17 - 4.95 (m, 1 H), 4.70 (d, J= 7.1 Hz, 0.2H), 4.49 - 4.07 (m, 2.7H), 3.90 ( id. ./ 7.4, 2.9 Hz, 0.2H), 3.77 - 3.65 (m, 0.3H), 3.62 - 3.56 (m, 0.2H), 3.39 (d, ./ 5.1 Hz, 0.4H), 2.30 - 1.94 (m, 2H), 1.81 - 1.47 (m, 5H), 1.47 - 1.33 (m, 2H). Example 240: isoquinolin-4-yl((l S,2R,4R)-2-((5-(triffuoromethyl)pyrazin-2-yl)ammo)-7- ethanone.
Figure imgf000201_0002
Prepared analogous to Example 181 substituting intermediate A-1 with isoquinoline-4- carboxylic acid. MS (ESI) mass calcd. for C21H18F3N5O, 413.2; m z found 414.2 [M+H]+. Ή NMR (CDCI3): 9.31 (s, 0.51 i s. 9.13 (s, 0.51 ! :·. 8.68 - 8.49 (m, 1 H), 8.40 - 7.53 (m, 5.5H), 7.42 (s, 0.5H), 6.20 (s, 0.5H), 4.99 (s, I.5H), 4.21 (s, 0.5H), 4.06 - 3.77 (m, 1.5H), 2.27 - 1.43 (m, 6H).
Example 241 : (4-methoxy-2-(2H- 1 ,2,3-triazol-2-y1)phenyl)((lS,2R,4R)-2-((5-
(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-y
Figure imgf000202_0001
Prepared analogous to Example 181 substituting intermediate A- 1 with intermediate A-5. MS (ES ) mass calcd. for C2;H2oF3 702, 459.2; m/z found 460.3 [M+H]+. !H NMR (CDC ): 8.31 (s, 0.3H), 8.18 ($, 0.7H), 7.91 (s, 1 .5H), 7.87 - 7.77 (m, 1H), 7.54 ($, 0.8H), 7.48 - 7.39 (m, 0.7H), 7.35 - 7.28 (m, 1.7H), 6.97 (dd, J = 8.5, 2.5 Hz, 0.3H), 6.87 (d, J- 8.3 Hz, 0.7H), 6.29 (s, 0.3H), 4.85 - 4.79 (m, 0.7H), 4.75 - 4.70 (m, 0.3H), 4.40 - 4.22 (m, 1H), 4.09 - 4.03 (m, 0.3H), 3.99 (s, 0.7H), 3.94 - 3.83 (m, 3H), 2.1 9 - 1.41 (m, 6H).
Example 242: (2-methoxy--6 2H ,2,3- iriazoi~2-yl)phenyl)(( l S,2R,4R)--2-((5~
)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methan.one.
Figure imgf000202_0002
Prepared analogous to Example 1 81 substituting intermediate A- 1 with intermediate A- 13. MS (ESI) mass calcd. for C21H20F3N7O2, 459.2; m/z found 460.3 [M+H]+. Ή NMR (CDCI3): 8.37 - 8.30 (m, 0.3H), 8.25 - 8.17 (m, 0.7H), 7.97 - 7.85 (m, 1.5H), 7.84 - 7.74 (m, 0.8H), 7.65 - 7.56 (m, 0.4H), 7.55 - 7.37 (m, 2.7H), 7.05 - 6.94 (m, 1 H), 6.17 - 5.98 (m, 0.2H), 5.90 - 5.66 (m, 0.4H), 5.02 - 4.86 (m, 0.7H), 4.86 - 4.71 (m, 0.3 ! I ·. 4.45 - 4.18 (m, 0.8H), 4.05 (s, 0.7H), 3.97 - 3.75 (m, 3.3H), 3.62 - 3.57 (m, 0.2H), 2.25 - 1.29 (m, 6H).
Example 243 : (5-fluoro-2-(pyrimidin-2-yl)phenyl)(( 1 S,2R,4R)-2-((5-(tritluorometh l)pyrazin-2- yl)amino)-7-azabicycio[2.2.1 ]heptan- 7-yi)methanone.
Figure imgf000203_0001
Prepared analogous to Example 1 81 substituting intermediate A- 1 with intermediate A-7. MS (ESI) mass calcd. for C22H;SF4N60! 458.2; m/z found 459.3 j V! · Π j Ή NMR (CDC13): 8.88 - 8.79 (m, 1.7H), 8.77 - 8.69 (m, 0.3H), 8.36 - 8.14 (m, 1.8H), 8.01 (dd, J = 8.6, 5.4 Hz, 1H), 7.81 (s, 0.2H), 7.42 - 7.30 - 7.02 (m, 3.8H), 6.26 (d, J= 7.8 Hz, 0.2H), 4.90 - 4.81 (m,
0.8H), 4.74 (d, J = 5.2 Hz, 0.2H), 4.42 (s, 0.8H), 4.27 (s, 0.2H), 4.12 - 3.96 (m, IH), 2.29 - 1 .39 (m, 6H).
Example 244: (5-(4-fluorophenyl)-2-methyithiazol-4-yl)((l S,2R,4R)-2-((5- )-7-azabicyclo[2.2.1 ]heptan-7-yl)rnethanone.
Figure imgf000203_0002
Prepared analogous to Example 1 81 substituting intermediate A- 1 with 5-(4- fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) mass calcd. for C22H19F4N5OS, 477.2; m/z found 478.1 [M+Hf. ;H NMR (CDCI3): 8.32 - 8.20 (m, I H), 7.95 - 7.84 (m, I H), 7.56 --- 7.40 (m, 2H), 7.15 --- 7.04 (m, 2H), 6.97 -- 6.77 (m, 0.8H), 6.01 - 5.88 (m, 0.2H), 4.85 (t, ./ = 4.5 Hz, IH), 4.21 - 3.90 (m, 2H), 2.80 - 2.56 (m, 3H), 2.19 - 1.95 (m, 1.7H), 1.93 - 1.31 (m, 4.3H).
Example 245: (3-methyl-2-(2H- l ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- (tiifluoromethyl)pyrazin-2-yl)amino)- 7-azabicyclo[2.2.1 ]heptan-7-yl)me
Figure imgf000204_0001
Prepared analogous to Example 181 substituting intermediate A- 1 with intermediate A- 24. MS (ESI) mass calcd. for C2;H2oF3 70, 443.2; m/z found 444.3 [M+H]+. !H NMR (CDC13): 8.29 - 8.23 (m, 0.2H), 8.21 - 8.15 (m, 0.8H), 7.95 - 7.88 (m, 1.6H), 7.84 - 7.74 (m, 1.3H), 7.62 - 7.39 (m, 1.2H), 7.37 - 7.19 (m, 2.7H), 5.81 (s, 0.2H), 4.79 - 4.65 (m, 0.8H), 4.61 - 4.51 (m, 0.2H), 4.38 - 3.90 (m, 2.H), 2.19 (s, 3H), 2.14 - 1.42 (m, 6H).
Example 246: (3-ethoxyisoqumolin-4-yl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyrazm^ yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000204_0002
Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A- 22. MS (ESI) mass calcd. for C23H22F3N5O2, 457.2; m/z found 458.3 j \ I · ! f | \ Ή NMR i ( IX h): 9.01 - 8.92 (m, 0.81 i s. 8.82 is, 0.2H), 8.35 (s, 0.5 U s. 8.22 (s, 0.3H), 8.05 (s, 0.1H), 8.00
- 7.85 (m, 1.6H), 7.84 - 7.71 (m, Hi), 7.71 - 7.54 (m, 1.2H), 7.50 - 7.39 (m, 0.8H), 7.39 - 7.31 (m, 0.4H), 7.18 (s, 0.3H), 6.1 1 (s, 0.1H), 5.95 (d, J= 8.8 Hz, 0.3H), 5.83 (d, J= 8.0 Hz, 0.4H),
5.15 - 5.06 (m, 0.3H), 5.06 - 4.94 (m, 0.7H), 4.92 - 4.72 (m, 0.5H), 4.68 - 4.41 (m, 1.5H), 4.40
- 4.30 (m, 0.3H), 4.24 - 4.07 (m, 0.4H), 3.89 - 3.81 (m, 0.2H), 3.81 - 3.67 (m, 0.7H), 3.51 (d, J- ---- 5.1 Hz, 0.3H), 2.30 - 1.95 (m, 2.51 s ). 1.91 - 1.21 (m, 6.5H). Example 247: (6-methyl-2-(2H- 1 !2,3-triazol-2-yl)pyridin-3-yl)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2-y3)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000205_0001
Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-3.
MS (ESI) mass calcd. for C2oHi9F3N80, 444,2; m/z found 445.2 [M+H]+. !H NMR (CDC13): 8.32 (s, 0.4H), 8.18 ($, 0.6H), 7.96 (s, 1 .3H), 7.88 (d, J= 4.6 Hz, 1.1H), 7.79 (d, J= 7.7 Hz, O.SH), 7.73 - 7.52 (m, ,5H), 7.35 - 7.27 f m, 0.5H), 7.18 (s, 0.7H), 6.28 (s, 0.4H), 4.89 - 4.70 (m, 1H), 4.42 - 4.19 (m, H I ). 4.03 - 3.81 (m, 1H), 2.76 - 2.56 (m, 3H), 2.26 - 1.40 (m, 6H).
Example 248: (6-methyl-2-(lH-l,2,3-triazol- l-yl)pyridin-3-yl)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2-yl)a^no)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000205_0002
Prepared analogous to Example 181 substituting nitennediate A-1 with intermediate A-4. MS (ESI) mass calcd. for C2oH19F3NgO, 444.2; m/z found 445.2 j V! · Π j 1 1 NMR (CDCI3): 8.51 - 8.35 (m, 1.6H), 8.29 (s, 0.7H), 8.17 (s, 0.3H), 7.92. - 7.80 (m, 1H), 7.76 - 7.60 (m, 1.3H), 7.35 - 7.18 (m, 1.4H), 6.81 - 6.61 (m, 0.7H), 4.95 - 4.85 (m, 0.3H), 4,84 - 4.75 (m, 0.7H), 4.49 - 4.32 (m, 1H), 4.07 (t, J= 4.4 Hz, 0.7H), 3.93 (s, 0.3H), 2.70 - 2.54 (m, 3H), 2,22 ( dcL ./ 13.1, 8.0 Hz, 0.4H), 2.14 --- 1.46 (m, 5.6H).
Example 249: (4-methoxy-2-(p_ Timidin-2-yl)phenyf)((l S,2R,4R)-2-(^
2-yl)amino)-7-azabicyclo [2.2.1 ]heptan-7-yl)methanone.
Figure imgf000206_0001
Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A- 15. MS (ESI) mass calcd. for
Figure imgf000206_0002
470.2; m/z found 471.2 [M+H]+. Ή NMR
(CDC¾): 8.89 - 8.69 (m, 2.H), 8.38 - 8.12 (m, 2H), 7.81 - 7.74 (m, 0.1H), 7.70 - 7.62 (m, 0.1H), 7.49 - 7.28 (m, 3.8H), 6.91 (dd, J= 8.4, 2.6 Hz, 0.9H), 6.48 - 6.39 (m, 0.1 H), 4.85 - 4,77 (m, 0.9H), 4.73 - 4.67 (m, 0.1 H), 4.48 - 4.34 (m, 0.9H), 4.24 (s, 0.1 H), 4.09 (d, J= 5.0 Hz, IH), 3.94 - 3.79 (m, 3H), 2.18 (dd, J- 13.0, 8.1 Hz, IH), 2.13 - 1.37 (m, 5H).
Example 250: (1 H-benzo[d]iraidazoJ-2-yi)((l S,2R,4R)-2-((5-(trifluoromethy1)pyrazin-2- tan-7-yl)methanone.
Figure imgf000206_0003
Prepared analogous to Example 181 substituting intermediate A-1 with 1 H- benzo[d]iniidazole-2-carboxylic acid. MS (ESI) mass calcd. for Ci gHr/FsNeO, 402.1 ; m/z found 403.2 [M+H]+ . !H NMR (CDC13): 8.35 - 7.61 (m, 3.5H), 7.40 - 7.13 (m, 3.5H), 6.26 - 5.75 (m, IH), 5.06 - 4.63 (m, I .5H), 4.27 - 3.95 (m, 1.5H), 2.86 - 2.47 (m, IH), 2.33 - 1.45 (m, 5H).
Example 251 : (1 -methyl- lH-benzo[d]imidazol-2-yl)(( l S,2R,4R)-2-((5-(trifluorometh.yl)pyrazin- 2-yl)amino)-7-azabicyc]o[2.2.1]beptan-7-yl)methanone.
Figure imgf000207_0001
Prepared analogous to Example 181 substituting intermediate A- 1 with 1 -methyl- 1H- benzo[djimidazoie-2-earboxyiic acid, MS (ESI) mass calcd. for
Figure imgf000207_0002
416,2; m/z found 417,2 i V! · ! i I .
Example 252: (3-fluoro-2-(2H- l,2,3-triazoi-2-yl)phenyl)((] S,2R,4R)-2-((5- (trifluoromethyl)pyrazm-2-yl)ainino)-7-azabicyclo[2.2J]heptan-7-yl)m
Figure imgf000207_0003
Prepared analogous to Example 181 substitutmg intermediate A-l with intermediate A- 16. MS (ESI) mass calcd. for C2oH17F4N70, 447.1 ; m/z found 448.3 i \) Π j . Ή MR (CDC13): 8.30 (s, 0.3H), 8.19 (s, 0.7H), 7.96 - 7.75 (m, 2.8H), 7.58 - 7.49 (m, 0.3H), 7,45 - 7.11 (m, 3.7Ή), 5.83 (s, 0.2H), 4.80 - 4.58 (m, 1H), 4.38 - 4.25 (m, 0.8H), 4.24 - 4.13 (m, 0.2H), 4.13 - 4.04 i n:. 0.2H), 3.97 i d. J 4.9 Hz, 0.8H), 2.22 - 2,07 (m, ! l . 2.07 - 1.40 (m, 5H).
Example 253: (4-(difluoromethoxy)-2-(2H-l ,2,3-triazol-2-yl)phenyl)((lS,2R,4R)-2-((5- )-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000207_0004
Prepared analogous to Example 181 substituting intermediate A- 1 with intermediate A- 23. MS (ESI) mass calcd. for€2-,Η-ι8Ρ5Ν7θ2, 495.1 ; m/z found 496.3 [M+Hf. Ή NMR
(CDC ): 8.32 (s, 0.3H), 8.19 (s, 0.7H), 7.98 - 7.81 (m, 2.4H), 7.77 (d, J = 2.3 Hz, 0.4H), 7.61 (d, J= 2.4 Hz, 0.7H), 7.58 - 7.45 (m, I H), 7.39 (d, J= 8.4 Hz, 0.7H), 7.21 (dd, J = 8.4, 2.4 Hz, 0.5H), 7.18 - 7.00 (m, 0.9H), 6.59 (u!. ./ 72.6, 31.4 Hz, IH), 6.33 - 6.16 (m, 0.4H), 4.92 - 4.70 (m, IH), 4.43 - 4.19 < m. IH), 4.09 - 3.83 (m, IH), 2.30 - 1.44 (m, 6H).
Example 254: (3-fluoro-2-(3-methy 1- 1 ,2,4-oxadiazol-5-yI)phenyl)(( I S,2R,4R)-2-((5- )a.niino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000208_0001
Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A- 17. MS (ESI) mass caled. for ί¾Η18Ρ4Ν602, 462.1 ; m/z found 463.3 [M+Hf . i l N MR
(CDC13): 8.31 (s, 0.3H), 8.1 8 (s, 0.7H), 8.09 (s, 0.3H), 7.75 - 7.68 (m, 0.71 ! ) 7.63 (td, J= 8.0, 5.0 Hz, 0.3H), 7.49 (td, ./ 7.9, 5.1 Hz, 0.7H), 7.44 - 7.13 (m, 2.6H), 5.79 (d, ./ 8.0 Hz, 0.41 ! ). 4.88 - 4.67 (m, IH), 4.40 - 4.22 (m, IH), 4.10 - 3.88 (m, IH), 2.52 (s, 3H), 2.28 - 1.54 (m, 6H).
Example 255: (5-methoxy-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- o)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000208_0002
Prepared analogous to Example 181 substituting intermediate A- 1 with intermediate A- 18. MS (ESI) mass calcd. for C21H20F3N7O2, 459.2; m/z found 460.3 [M+Hf. ¾ NMR
(CDCI3): 8.32 (s, 0.3H), 8.19 (s, 0.7H), 7.96 - 7.76 (m, 2.5H), 7.74 - 7.63 (m, 1 H), 7.56 (s, IH), 7.07 (dd, J 8.9, 2.9 Hz, 0.4H), 7.03 - 6.92 (m, 1H), 6.87 i d. ./ 2.9 Hz, 0.81 s ). 6.17 - 6.05 (m, 0.3 ! I ·. 4.89 - 4.70 (m, l i b. 4.43 - 4.19 (m, IH), 4.10 - 3.94 (m, 1H), 3.92 - 3.75 (m, 3H), 2.25 - 1.43 (m, 6H). Example 256: (5-fluoro-2-(2H- 1 ,2,3-triazol-2- l)phenyl)(( 1 S,2R,4R)-2-((5- (triiluoromethyl)pyrazin-2-yl)aniino)-7-azabicyclo[2.2J] eptan-7-yl)m
Figure imgf000209_0001
Prepared analogous to Example 181 substituting iniermediaEe A- 1 with intermediate A- 10. MS (ESI) mass calcd. for C2oHi7F4N7G, 447.2; m/z found 448.3 [M+H} Ή NMR (CDC13) 8.32 (s, 0.3H), 8.20 (s, 0.7H), 8.02 - 7.87 (m, 1 .5H), 7.88 - 7.71 (m, 1.5H), 7.54 (s, 0.7H), 7.38 7.00 (m, 3H), 6.32 - 6.08 (m, 0.3H), 4.92 - 4.68 (m, I H), 4.46 - 4.20 (m, I H), 4.12 - 3.88 (m, IH), 2.28 - 1.39 (m, 6H). )-7-azabicyclo[2.2.1 ]heptan-7-yl)methaiione.
Figure imgf000209_0002
Prepared analogous to Example 1 81 substituting intermediate A- l with intermediate A- 12. MS (ESI) mass calcd. for CJOHI /F-I TO, 447.2; m/z found 448.3 [M+H]+. !H NMR (CD CI 3) 8.33 (s, 0.3H), 8.20 (s, 0.7H), 8.01 - 7.79 (m, 2.4H), 7.73 (dd, J - 9.4, 2.6 Hz, 0.4H), 7.63 - 7.44 (m, 1.7H), 7.38 (dd, J = 8.5, 5.7 Hz, 0.7H), 7.21 - 6.94 (m, 1.4H), 6.20 (d, . / 8.5 Hz, 0.4H), 4.91 - 4.73 (m, IH), 4.46 - 4.17 (m, IH), 4.09 - 3.85 (m, I H), 2.25 - 1.44 (m, 6H). Example 258: (2-fluoro-6-(2H- 1 ,2,3-triazol-2-yl)phenyl)(( 1 S,2R,4R)-2-((5- )a.mino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000210_0001
Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A- 1 1. MS (ESI) mass calcd. for C20H17F4N7O, 447.2; m/z found 448.3 j V! · Π j . Ή NMR (CD CI 3): 8.41 - 8.29 (m, 0.3H), 8.20 (s, 0.7H), 8.01 - 7.60 (m, 3H), 7.60 - 7.1 1 (m, 3.2H), 7.03 - 6.89 (m, 0.2H), 6.20 - 6.06 (m, 0.2.H), 5.45 - 5.34 (m, 0.2H), 5.16 - 5.04 (m, 0.2H), 4.99 - 4.75 (m, 1H), 4.49 - 4.16 (m, Hi), 4.13 - 4.00 (m, 0.3H), 3.88 fd, J= 5.2 Hz, 0.5H), 3.69 (d, J= 5.1 Hz, 0.2H), 2.33 - 1.36 (m, 6H). xampfe 259: (6-metbylimidazo[2, 1 -b]thiazoi-5-yi)(( 1 S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- ]heptan-7-yl)methanone.
Figure imgf000210_0002
Prepared analogous to Example 181 substituting interm Jiate A- 1 with 6- methylimidazo[2,l -b]th azole-5-carboxylic acid, MS (ESI) mass calcd. for CjsHj'/FsNeOS, 422,2; m/z found 423.2 ; \) Π ! !H NMR (CDCI3): 8.26 (s, IH), 7.91 - 7.75 fm, 2H), 6.96 - 6.80 (m, IH), 5.91 (s, H I ). 4.58 i d. ./ 5.0 Hz, l i b. 4.42 (t, ./ 4.8 Hz, IH), 4.21 - 4.05 (m, 1H), 2.49 (s, 3H), 2.25 (dd, J = 13.2, 7.5 Hz, IH), 2.10 - 1.88 (m, 2H), 1 .73 - 1.54 (ni, 3H). Example 260: (3-fluoro-2-( oxazol-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2- yl)amino)-7-azabicyclo[2.2. l]heptan-7~yl)methanone.
Figure imgf000211_0001
Step A: (3-fluoro-2-iodophenyl)((lS,2R,4R)-2- 7-azabicyelo[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 238 substituting intermediate A-2 with 3-fluoro-2-iodobenzoic acid. MS (ESI) mass calcd. for C18H15F4IN4O, 506.0; m/z found 507.2 ; \ I · Π j !HNMR (CDCI3): 8.2? 8.14 (m, Hi).8.10 - 7. 1 im. III;·. 7.48 - 7.32 (m, 0.5H), 7.23 - 6.83 (m, 2.511).6.66 - 5.98 (m, III).4.94 - 4.69 (m, HI).4.31 - 4.14 (m, 0.5H), 4.08 - 3.90 (m, 0.5H), 3.90 - 3.75 (m, 0.5H), 3.72 - 3.44 (m, 0.5H), 2.27 - 1.41 (m, 6H).
Step B: (3-fluoro-2-(oxazol-2-yl)phenyl)((l^
y1)amino)-7~azabicyclo[2.2.1 ]heptan-7-yl)methanone. The title compound of step A. (35 nig) arsd 2-(tributylstannyI)oxazoIe (17 μΕ) were dissolved in DME (I mL). The solution was degassed with N2 as Cul (1 mg) and Pd(PPh3)4 (4 mg) was added. The reaction was heated at 120°Cfo 3h. Additional Cul andPd(PPh3)4 and the reaction purged with N2. Heating was continued overnight. The reaction was cooled to rt, filtered through a pad of celite and purified via prep HPLC to give the title compound (12 mg, 39%). MS (ESI) mass calcd. for
C2]H]7F4N502, 447.1; m/z found 448.3 I Vi II] 11 NMR (CDCI3): 8.34 (s, III;.8.16 (s, Hi), 7.98 - 7.78 (m, 1H), 7.69 (s, 0.8H), 7.60 - 7.06 (m, 4H), 6.80 - 6.61 (m, 0.2H), 4.92 - 4.66 (m, 1H), 4.46 - 4.23 (m, III).4.06 - 3.80 (m, 1H), 2.36 - 1.51 (m, 6H).
Example 261 : (2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- fluoro-2-methoxyphenyl)methanone.
Figure imgf000211_0002
Example 262: (3-fluoro-2-(pyridazin-3-yl)phenyl)((l S,2R,4R)-2~((5-(trifluoromeihyl)pyrazin-2- ]heptan-7-yl)methanone.
Figure imgf000212_0001
Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 3-
(tributylstannyl)pyridazine. MS (ESI) mass calcd. for C22H1gF4N60, 458.1 ; m/z found 459.1 i \I M j . ! i WI R (500 MHz, Chloroform-d) 9.25 - 9.14 (m, 8.50 (s, 0.5 ! 8.28 (s, 0.81 i s. 8.17 (s, 0.5H), 7.97 - 7.80 (m, 1.5H), 7.72 - 7.59 (m, IH), 7.55 - 7.41 (m, 1H), 7.34 - 7.18 (m, 2.2H), 6.96 (d, 8.1 Hz, 0.5H), 4.79 - 4.72 (m, 0.55H), 4.71 - 4.64 (m, 0.45H), 4.53 - 4.43 (m, 0.6H), 4.38 - 4.28 (m, 0.45H), 4.18 (s, 0.4H), 4.1 3 - 4.05 (m, 0.55H), 2.30 - 1.47 (m, 6H). Example 263: (3-methyl-2-(p ridazin-3-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromelhyl)p ^^ -yl)amino)-7-azabicyclo[2.2.1Jheptan-7-yl)niethanone.
Figure imgf000212_0002
Siep A: (2-iodo-3-methylphenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amm^ 7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 238 substituting intermediate A-2 with 2-iodo-3-mefhylbenzoic acid. MS (ESi) mass calcd. for CipHisFs^O, 502.0; m/z found 503.0 [M+Hf. !H NMR (400 MHz, Chloroform-d) 8.26 - 8.03 (m, 1.4H), 7.88 - 6.60 (m, 4.6H), 4.93 - 4.58 (m, 1H), 4.32 - 4.15 (m, 0.4H), 3.92 (s, 0.4H), 3.86 - 3.76 (m, 0.6H), 3.57 (s, 0.6H), 2.51 (s, 1.4H), 2.40 (s, 1 .6H), 2.21 - 0.66 (ni, 6H).
Step B: (3-methyl-2-(pyridazin-3-yl)phenyi)((l S,2R,4R)-2-((5-(trifluoro^
2-yl)atnino)-7-azabicyclo [2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 260 Step B substituting 2-(tributylstannyl)oxazole with 3-(tributylstannyl)pyridazine. MS (ESI) mass calcd. for C23H2!F3N60, 454.2; m/'z found 455.2 [M+H]+. Ή NMR (400 MHz, Chlorofonn-d) 9.22 (dd, J= 4.9, 1.7 Hz, 0.25H), 9.19 (dd, J = 4.8, 1.8 Hz, 0.75H), 8.57 (s, 0.75H), 8.27 (s, 0.25H), 8.21 (s, 0.25H), 8.16 (s, 0.75H), 7.97 (s, 0.751 ! !. 7.72 - 7.56 (m, 11 1 ). 7.44 - 7.27 (m, 2.25H), 7.25 - 7.19 (m, 0.75H), 6.40 fd, ./ 8.0 Hz, 0.25H), 4.68 - 4.62 (m, 0.75H), 4.59 - 4.54 (m, 0.25H), 4.39 (ddd, J= 9.3, 8.1 , 3.9 Hz, 0.75H), 4.28 - 4.15 (m, 0.5H), 4.08 - 4.03 (m, 0.75H), 2.32 (s, 0.75H), 2.21 (s, 2.25H), 2.1 8 - 1.42 (m, 6H).
Example 264 (3-fluoro~2-(p)T'idazin-4~y{)phenyl)((l S,2 ,4 )-2-((5~
y3)ammo)-7-azabicycio[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000213_0001
Prepared analogous to Example 260 substituting 2-(1ributyls†annyl)oxazole with 4- (tributyistaniiyl)pyridazme. MS (EST) mass calcd, for C HigRjNeO, 458.1 ; m/z found 459.2 [M-i-H]+. 'H NMR (400 MHz, Chloroform-d) 9.38 - 9.20 (m, 2H), 8.28 (s, 0.6H), 8.19 (s, 0.4H): 8.00 (s, 0.6H), 7.94 (s, 0.4H), 7.71 - 7.63 (m, 0.6H), 7.62 - 7.50 (m, 1H), 7.40 - 7.29 (m, I I I }. 7.24 - 7.08 (m, I AH), 5.24 (s, 0.4H), 4.80 (s, 0.6H), 4.67 (s, 0.4H), 4.61 (d, J= 5.3 Hz, 0.6H), 4.02 - 3.92 (m, 0.6H), 3.85 - 3.75 (m, 0.4H), 3.70 - 3.59 (m, 1H), 1.90 - 2.07 (m, 1H), 1.84 - 0.79 (m, 5H).
Example 265 (3-fluoro-2-(pyrazin-2-yl)phenyl)(( l S,2R,4R)-2-((5-(trifluoromethyl)pyrazm-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yi)methanone
Figure imgf000214_0001
Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 2- (tributylstannyl)pyrazine. MS (ESI) mass calcd. for C22H18F4N6O, 458.1 ; m/z found 459.2
[M+H j j~. :H NMR (400 MHz, Chloroform-d) 8.99 - 8.94 (m, I I I ). 8.69 (d, J = 2.6 Hz, 1H), 8.58 - 8.51 (m, IH), 8.19 (s, 1H), 8.03 (s, IH), 7.57 (s, 1H), 7.44 - 7.37 (m, I H), 7.25 - 7.20 (in, 2H), 4.80 - 4.74 (m, IH), 4.40 (td, J = 8.6, 3.6 Hz, 1H), 4.05 (d, J = 5.1 Hz, 1H), 2.24 - 2.16 (in, 1H), 1.78 - 1.67 (m, 2H), 1 .62 - 1.51 (m, 2H), 1 .41 - 1.29 (m, lH).
Example 266 (3-methyl-2-(oxazol-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2 yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000214_0002
Prepared analogous to Example 263 substituting 3-(tributylstannyl)pyridazine with 2- (tributylstannyl)oxazole. MS (ESI) mass calcd. for C22H20F3 5O2, 443.2; m/z found 444,2
[M+H]+. H NMR (500 MHz, Chloroform-d) 8.57 (s, 1 H), 8.14 (s, I H), 7.88 (d, J = 0.9 Hz, I I I ). 7.79 (d, J - 1 .4 Hz, 1 H), 7.33 - 7.23 (m, 3H), 7.20 - 7.14 (m, IH), 4.82 - 4.75 (m, I H), 4.29 (td, J - ----- 8.5, 3.7 Hz, IH), 3.94 i d. ./ 4.9 Hz, IH), 2.28 (s, 3H), 2.16 - 1.45 (m, 6H).
Example 267 (4-fluoro-2-(pyrimi(un-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluorometh^
yl)aniino)-7-azabicyclo[2.2.1 ]heptan-7-yi)methanone
Figure imgf000215_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 25. MS (ESI) mass calcd. for : C22Hi8F4N6Q, 458.1 ; m/z found 459.2 [M+H]+. !H NMR (500 MHz, Chloroform-d) 8.89 - 8.81 (m, 1 .7H), 8.80 - 8.73 (m, 0.3H), 8.33 - 7.87 (m, 2H), 7.80 (s, 0.2H), 7.74 - 7.66 (m, 0.8H), 7.56 - 7.31 (m, 2.8H), 7.21 - 7.14 (m, 0.2H), 7.14 - 7.06 (m, 0.8H), 6.58 (s, 0.2H), 4.88 - 4.78 (m, 0.8H), 4.72 (d, J= 5.2 Hz, 0.2H), 4.40 (s, 0.8H), 4.26 (s, 0.2H), 4.1 0 - 3.97 (m, IH), 2.27 - 1.39 (m, 6H).
Example 268 (3-f!uoro-2-(pyridin-4-yl)pheny{)((l S,2R^4R)-2-((5-(trifiuoromethy1)pyrazin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000215_0002
Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 4- (tributylstannyl)pyridine. MS (ESI) mass calcd, for : C23H19F4N5O, 457.2; m/z found 458.2 [M+H]+. !H NMR (500 MHz, Chloroform-d) 8.78 - 8.61 (m, 21 ! ) . 8.28 (s, 0.6H), 8.15 (s, 0.41 ! ) 7.87 (s, 1H), 7.72 - 7.28 (m, 4.2H), 7.23 - 7.02 (m, I AH), 5.49 (s, 0.4H), 4.67 - 4.60 (m, 0.4H), 4.56 i d. ./ 5.3 Hz, 0.6H), 3.99 - 3.89 (m, 0.6H), 3.82 - 3.72 (m, 0.4H), 3.65 -- 3.58 (m, 0.6H), 3.56 i d. ./ 5.4 Hz, 0.4H), 2.00 - 0.80 (m, 6H).
Example 269 (3 -fluoro-2-(2H- 1 ,2,3-triazoI-2-yl)phenyl)((l S,2R,4R)-2-((5 - (trifjuoromemyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000216_0001
Step A: ( 1 S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)pyriinidin-2-yl)amino)-7- azahicyeJo[2.2, l ]heptane-7-carboxylate. To intermediate B-5 (250 nig, 1.2 mmol) and K2CO3 (244 mg, 1 .8 mmol) in DMF (1.7 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (258 mg, 1 .4 mmol). After heating at 70 °C for 17h, the mixture was cooled to rt, diluted with EtOAc and H20. The aqueous layer was extracted with EtOAc (3X). The combined organics were washed with 4% MgS04 (aq) and dried (MgS04). Purification via silica gel chromatography (0- 30% EtOAc in hexanes) gave the title compound (356 mg, 84%). MS (EST) mass calcd. for Cj6H2!FjN402, 358.2; m/z found 359.2 [M+H]+. JH NMR (500 MHz, Chlorofonn-d) 8.58 - 8.37 (m, 2H), 5.70 (s, 1 H), 4.30 (s, 1H), 1 .78 - 1.68 (m, 1H), 4.25 - 4.17 (m, IH), 1.89 - 1 .79 (m, I I I !. 4.12 - 4.03 (m, I H), 2.03 ( ;!■:!. ./ 13.1 , 7.8 Hz, i l l ). 1 .63 - 1.37 (m, 12H).
Step B: ( 1 S,2R,4R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-7-azabicyclo[2.2.1 jheptan-2- amine. To the title compound of step A (355 mg, 1 mmol) in DCM (9.7 mL) was added 4M HCi in dioxane (1.2. mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na2CC>3 (aq) and extracted with DCM (2X). The combined organics were dried (NaaSO-j) to give the title compound of step B that was used without further purification.
Step C: (3-fluoro-2-(2H- 1 ,2,3-triazol-2~yl)phenyl)((t S,2R,4R)-2-((5- (trifluoromeftyl)pyrimi(lin-2-yl)amino To the title compound of step B (25 mg, 0.1 mmol) in DCM ( 1 mL) was added DIPEA (22 aL, 0.13 mmol) and intermediate A- 16 (22 mg, 0.1 mmol). Then T3P (50% solution in DMF, 0.17 mL, 0.29 mmol) was added dropwise and the reaction heated at 45 °C for 12h. After allowing to cool to rt, DCM was added and the mixture washed with H20 then saturated NaHCCh (aq). The combined aq layers were extracted with DCM. The combined organic layers were dried (Na2S04).
Purification was performed using Agilent prep method X to give the title compound (35 mg, 80%). MS (ESI) mass calcd. for: C20H17F4N7O, 447. t ; m/z found 448.2 [M+H]+. !H NMR (400 MHz, Chloroform-d) 8.50 is, 0.9H), 8.41 (s, 1.1H), 8.09 (s, 0.9H), 7.95 (s, 1.1 H), 7.56 - 7.47 (m, 0.5H), 7.44 - 7.32 (m, IH), 7.33 - 7.23 (m, 1.5H), 7.20 - 7.14 (m, 0.5H), 6.18 (d, J - 8.6 Hz, 0.5H), 4.83 - 4.74 (m, 0.5H), 4.67 (d, J= 5.2 Hz, 0.5H), 4.34 - 4.19 (in, i l l ). 4.1 1 - 4.04 (in, 0.5H), 3.99 (d, J= 4.8 Hz, 0.5H), 2.21 - 1.44 (m, 6H).
Example 270 ((lS,2R,4R)-2-((3-bromoimidazo[l,2-a]pyrazin-8-yl)ainino)-7- azabicyclo[2.2.1 ] eptan-7-yl)(3-fluoro-2-Cpyrimidin-2-yl)p enyl)methan.one
Figure imgf000217_0001
Step A: (1 S,2R,4R)-tert-butyl 2-((3-bromoimidazo[l,2-a]pyrazin-8-y1)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. Prepared analogous to Example 269 step A substituting 2-chloro-5-(trifluoromethyl)pyrimidme with 3-bromo-8-chloroimidazo[i,2-a]pyrazine. MS (ESI) mass caled. for : C17H22B1N5O2, 407.1 ; m/z found 408.1 [M+H . !H NMR (500 MHz,
Chloroform-d) 7.45 (s, 1H), 7.43 (d, J = 4.7 Hz, lH), 7.40 (d, J = 4.7 Hz, 1H), 6.15 (s, 1H), 4.37 - 4.27 (m, 2H), 4.27 - 4.21 (m, 1H), 2.08 (dd, J = 13.0, 7.8 Hz, I H), 1.90 - 1.33 (m, 14H).
Step B: N-(( I S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-yl)-3-bromoimidazo[l,2-a]pyrazin- 8-amine. Prepared analogous to Example 2.69 step B using title compound of step A.
Step C: ((! S,2R,4R)-2-((3-bromoimidazo[l,2-a]pyrazin-8-yl)ammo)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone. Prepared analogous to Exampie 269 step C substituting intermediate A- 16 with intermediate A-2. MS (ESI) mass calcd. for : C2.vH19BrFN7Q, 507.1 ; m/z found 508.1 [M+H , 1 H NMR (400 MHz, Chloroform-d) 8.92 (d, .7 - 4.9 Hz, 0.7H), 8.88 (d, J= 4.9 Hz, 1.3H), 7.53 - 7.03 (m, 7.6H), 5.82 (d, J= 7.6 Hz, 0.4H), 4.81 - 4.75 (m, 0.6H), 4.71 (d, J= 5.1 Hz, 0.4H), 4.47 - 4.37 (m, 0.6H), 4.31 - 4.22 (m, 0.4H), 4.13 - 4.07 (m, 0.6H), 4.06 - 3.99 (m, 0.4H), 2.26 - 1.36 (m, 6H).
Exampie 271 (3-fluoro-2-(pyrimidin-2~yl)phenyl)(( 1 S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7-azabicyc1o[2.2.1 ]heptan-7-yl)methanone
Figure imgf000218_0001
Prepared analogous to Example 269 substituting intermediate A- 16 with intermediate A- 2. MS (ESI) mass calcd. for : QaHigF-j eO, 458.1 ; m/z found 459.2 [M+H]+. Ή NMR (400 MHz, Chloroform-d) 8.90 (d, J - 5.0 Hz, 2H), 8.49 (s, IH), 8.44 - 8.31 (m, 11 1 ). 7.43 - 7.32 (m, 2H), 7.26 - 7.14 (m, 2H), 4.80 - 4.75 (m, IH), 4.45 - 4.37 (m, ili), 4.09 (d, ,/ 5.0 Hz, IH), 2.22 i dd. 12.9, 8.0 Hz, IH), 2.1 1 - 1.51 (m, 5H).
Example 272 (3-methyl-2-(2H- 1 ,2,3 -triazol-2-yl)phenyl)((l S,2R,4R)-2-((5-
(trifluoromethyl)pyrimidin-2-yl^^
Figure imgf000218_0002
Prepared analogous to Example 269 substituting mtermediate A- 1 6 with mtermediate A-
24. MS (ESI) mass calcd for : C2iH2oF3N70, 443.2; m/z found 444.2 [M+H . !H NMR (400 MHz, Chloroform-d) 8.49 (s, 0.8H), 8.41 (s, 1.2H), 8.02 (s, 0.8H), 7.91 (s, 1.2H), 7.47 - 7.39 (m, IH), 7.38 - 7.28 (m, 2H), 7.23 - 7.16 (m, 0.6H), 5.98 (d, /= 8.4 Hz, 0.4H), 4.77 - 4.68 (m, 0.6H), 4.60 (d, J = 5.1 Hz, 0.4H), 4.29 - 4.17 (m, IH), 4.1 1 - 4.03 (m, 0.4H), 3.99 ( d. ./ 5.0 Hz, 0.6H), 2.27 (s, 1.3H), 2.24 (s, I .7H), 2.18 - 1.41 (m, 6H). Example 273 (3-methyl-2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2- yl)ainmo)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone
Figure imgf000219_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 26, MS (ESI.) mass calcd. for : C23H2iF3N60, 454.2; m/z found 455.1 [M+Hf. ¾ M.R (400 MHz, Chloroform-d) 8.85 i d. 5.0 Hz, 2H), 8.50 ( d. ,/ 9.2 Hz, IH), 8.17 (s, 1H), 7.66 (d, J = 1.3 Hz, IH), 7.37 (t, J = 5.0 Hz, IH), 7.31 - 7.18 (m, 3H), 4.73 - 4.67 (m, IH), 4.35 (td, J = 8.7, 3.7 Hz, i l l }. 4. 14 - 4.09 (m, I I I ) . 2.29 (s, 3H), 2.19 - 1 .45 (m, 6H).
Example 274 (3-fluo"ro-2-(pyrimidin-2~yl)phenyl)(( 1 S,2R,4R)-2-((3-(trifluoromethyl)- [1 ,2,4]triazolo[4,3-a]pyrazin-8-yl)ammo)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000219_0002
Step A: ( l S,2R,4R)-tert~ butyl 2-((3-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyrazin-8- yl)amino)-7-azabicyclo[2.2.1 ]heptane-7-carboxylate. Prepared analogous to Example 269 step A substituting 2-chloro-5-(trifluoromethyl)pyrimidine with 8-chloro-3 -(trifluoromethyl)- [l,2,4]triazolo[4,3-a]pyrazine. MS (ESI) mass calcd. for : C17H21F3N6O2, 398.2; m/z found 399.2
[M+H j 1". ]H NMR (500 MHz, Chloroform-d) 7.51 (m, I FT), 7.48 - 7.45 (m, IH), 6.58 (d, ./ 7.6 Hz, H i ). 4.41 - 4.25 (m, 3H), 1.94 - 1.83 (m, 1H), 2. 12 uk!. ./ 13.1, 7.8 Hz, 1H), 1.83 - 1.70 (m, 2H), 1.59 - 1.52 (m, 1H), 1.50 - 1.41 (m, 10H).
Step B: N-((l S,2R,4R)-7-azabieyclo[2.2.1 ]heptan-2-yl)-3-(trifluoromethy{)- [l ,2,4]triazolo[4,3-a]pyTazin~8-amme. Prepared analogous to Example 269 step B using title compound of step A.
Step C: (3-fluoi -2-(pyi½iidin-2-yl)phenyl)((lS,2R,4R)-2-((3-(trifluoroniethyl)- [l,2,4] riazolo[4,3-a]pyrazin-8-yl)aniino)-7-azabicyclo[2 J]heptan-7-yl)methaiione. Prepared analogous to Example 269 step C substituting intermediate A- 16 with intermediate A-2. MS (ESI) mass calcd. for : C23HlsF4NsO, 498.2; m/z found 499.2 j \ 1 · i 11 . ' H NMR (400 MHz, Chloroform-d) 8.99 (d, J = 4.9 Hz, 0.6H), 8.95 (d, J = 5.0 Hz, 1.4H), 8.72 (s, 0.7H), 7.55 - 7.28 (m, 4.6H), 7.21 - 7.10 (m, 1.4H), 6.18 (d, J= 7.5 Hz, 0.3H), 4.88 - 4.80 (m, 0.7H), 4.75 (d, J = 5.1 Hz, 0.31 n. 4.67 (s, 0.7H), 4.33 (s, 0.3H), 4.16 - 4.06 (m, i l l ). 2.27 ! cki. ./ 12.7, 8.2 Hz, 0.71 1 ). 2.1 1 (dd, J= 13.0, 8.1 Hz, 0.3H), 2.04 - 1.41 (m, 51 .
Example 275 methyl 5-(((l S,2R,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7- azabicycJo[2.2.1 ]heptan-2-yl)amino)pyrazme-2-carboxy1ate
Figure imgf000220_0001
Step A: (1 S,2R,4R)-tert-butyl 2-((5-(methoxycarbonyl)pyrazin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. Prepared analogous to Example 269 step A substituting 2-cUoro-5-(trifluoromethyl)pyrhnidine with methyl 5-chloropyrazine-2-carboxylate. MS (ESI) mass calcd. for : C17H24>J404, 348.2; m/z found 349.2 1 M · ί 1 | . ' H NMR (400 MHz, Chloroform- d) 8.77 (d, J= 1.4 Hz, IH), 7.88 (d, ./ = 1 .4 Hz, IH), 5.55 (s, IH), 4.34 - 4.27 (m, 1H), 4.25 - 4.18 (m, IH), 4.12 - 4.06 (m, I H), 3.95 (s, 3H), 2.12 - 2.05 (m, IH), 1.92 - 1.72 (m, 2H), 1.63 - 1.38 (m, 12H).
Step B: methyl 5-((I S,2R,4R)~7-azabicyclo[2.2.1 ]lieptan-2-ylamino)pyrazine-2- carboxylate. Prepared analogous to Example 269 step B using title compound of step A. Step C: methyl 5-(((l S,2 ,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7- azabicyclo[2.2.1 ]heptan-2-yl)amino)pyrazine-2-carboxylate. Prepared analogous to Example 269 step C substituting intermediate A- 16 with intermediate A-2. MS (EST) mass caicd. for :
l-Wf.O ;. 448.2; m/z found 449.2 [M+H] 1". !H NMR (500 MHz, Chlorofonn-d) 8.87 (d, J = 4.9 Hz, 2H), 8.65 (s, lH), 8.37 i d. ./ 9.4 Hz, 1H), 7.67 (s, IH), 7.42 - 7.34 (m, 2H), 7.24 - 7.17 (m, 2H), 4.77 - 4.70 (m, H I ). 4.48 - 4.39 (m, IH), 4.07 (d, J - 5.1 Hz, IH), 3.90 (s, 3H), 2.18 (dd, J= 13.0, 8.1 Hz, IH), 2. 1 1 - 2.00 (m, IH), 1.97 - 1 .62 (m, M l ). 1.58 - 1 .48 (m, IH).
Example 276 (2-iodo-3-methylphenyl)((l S,2R,4R)-2-((5-(trifluoromethy{)pyrimidin-2- y3)ammo)-7-azabicycIo[2.2.1 ]heptan-7-yl)methanoi e
Figure imgf000221_0001
Prepared analogous to Example 269 substituting intermediate A- 16 with 2-iodo-3 - methylbenzoic acid. MS (ESI) mass caicd. for : C19H1 SF3IN4O, 502.0; nvz found 503.0 [M+H]1". I ! NMR (400 MHz, Chloroform-d) 8.59 - 8.30 (m, 2H), 7.32 - 7.22 (m, 1.4H), 7.19 - 6.96 (m, IH), 6.93 - 6.83 (m, 0.6H), 6.02 (s, 0.5H), 5.54 (s, 0.5H), 5.01 - 4.91 (m, 0. H i. 4.84 (d, 5.1 Hz, 0.5H), 4.28 (s, 0.5H), 4.02 (s, 0.5H), 3.84 - 3.66 (m, IH), 2.50 (s, 1.5H), 2.43 (s, 1.5H), 2.24 - 1.39 (m, 6H).
Example 277 (3-fluoro-2-iodophenyl)((l S,2R,4R)-2-((5-(
7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000221_0002
Prepared analogous to Example 269 substituting intermediate A- 16 with 3-fluoro-2- iodobenzoic acid. MS (ESI) mass calcd. for : C1 8H15F4lN40, 506.0; m/'z found 507.0 [M+Hf. Ή NMR (400 MHz, Chloroform-d) 8.57 - 8.33 (m, 2H), 7.42 - 7.32 (m, 0.5H), 7.16 - 7.02 (m, 1 M l ). 6.99 - 6.88 (m, 1H), 5.99 (d, J = 7.6 Hz, 0.5! ! ;. 5.55 (s, 0.5H), 5.00 - 4.91 (m, 0.5H), 4.85 (d, J= 5.3 Hz, 0.5H), 4.32 - 4.24 (m, 0.5H), 4.05 - 3.97 (m, 0.5H), 3.81 - 3.71 (m, 1H), 2,22 - 1.93 (m, 11 1 ). 1.91 - 1.43 (m, 4H).
Example 278 (3-fluoro-2-(pyrimidin-2-yl)phenyl)(( lS,2R¾4R)-2-((5-methylpyrazm-2-yl)am 7-azahicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000222_0001
Step A: (1 S,2R,4R)-tert.-butyl 2-((5-methylpyrazm-2-yl)ammo)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. Prepared analogous to Example 279 step A substituting 2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-5-methylpyrazine. MS (ESI) mass calcd. for : C16H24 4O2, 304.2; m/z found 305.2 [M+Hf. !H NMR (400 MHz, Chloroform-d) 7.86 (s, IH), 7.78 (d, J = 1 .5 Hz, IB), 4.71 (s, 1H), 4.28 (s, IH), 4.19 (d, J = 4.9 Hz, 1 H), 3.95 - 3.85 (m, 1 H), 2.38 (s, 3H), 2.1 1 - 1.96 (m, I H i. 1.89 - 1.66 (m, 11 1 ). 1.58 - 1.33 (m, 12H).
Step B: (l S,2R,4R)-N-(5-methylpyrazm-2-yl)-7-azabicyclo[2.2.1]heptan-2-arnine.
Prepared analogous to Example 279 step B using title compound of step A.
Step C: (3-fluoro-2-^yrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-methylpyrazin-2- yl)amino)-7-azabicycio[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 279 step C. MS (ESI) mass calcd. for : C22H2iFN60, 404.2; m/z found 405.2 [M+Hf. ¾H NMR (500 MHz, Chloroform-d) 8.87 (d, J = 5.0 Hz, 2H), 7.74 (s, IH), 7.60 (s, IH), 7.41 - 7.30 (m, 3H), 7.23 - 7.12 (m, 2H), 4.76 - 4.68 (m, IH), 4.30 - 4.17 (m, I H), 4.08 - 4.01 (m, I H), 2.30 (s, 3H), 2.15 (dd, . / 12.9, 8.1 Hz, IH), 2.07 -- 1.95 (m, IH), 1.95 - 1.84 (m, IH), 1.74 - 1.46 (m, 3H).
Example 279 (3-iluoro-2-(py imidin-2-yl)phenyl)((l S,2R,4R)-2-((5^
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yi)methanone
Figure imgf000223_0001
Step A: (1 S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)arnmo)-7- azabicyclo[2.2.1 ]heptane-7-carboxyiate. In a microwave vial, toluene (8,3 niL) was degassed with N2 for 10 minutes then Pd(OAc)2 (22 mg, 0.03 mmol) and racemic BiN.AP (21 mg, 0.03 mmol) were added and the solution was degassed with N2 for 5 minutes. Then intermediate B-5, 2-chioro-5-(trifluoromethyl)pyridine (150 mg, 0.83 mmol) and sodium tert-butoxide (1 15 mg, 1.16 mmol) were added and the reaction mixture was stirred at 70 °C. After 15h the reaction mixture was filtered through a pad of celite and solvent was evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound of step A (192 mg, 65%). MS (ESI) mass caicd. for : C j 7H22F3N3O2, 357.2; m z found 358.2 [M+H]+. Ή NMR (500 MHz, Chloroform-d) 8.33 (s, I H), 7.61 - 7.49 (m, I H), 6.35 t d. 8.8 Hz, 1H), 5.06 (s, 1H), 4.29 (s, l l . 4.20 (s, IH), 4.03 - 3.91 (m, I H), 2.04 (dd, ./ 13.0, 7.6 Hz, IH), 1.89 - 1.79 (m, IH), 1.79 - 1.71 (m, IH), 1.59 - 1.37 (m, 12H).
Step B: (1 S,2R!4R)-N-(5-(trifluoromethyl)pyridiii-2-yi)-7-azabicyclo[2.2.1 jlieptan-2- amine. To the title compound of step A (319 mg, 0.89 mmol) in DCM (8.7 niL) was added 4M HCl in dtoxane (1.1 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na2C03 (aq) and extracted with DCM (2X). The combined organics were dried (Na2S04) to give the title compound of step B that was used without further purification.
Step C: (3-fluoro-2-(pyrimidin-2-yr)phenyl)((l S,2R,4R)-2-((5-(tri
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of step B (100 mg, 0.39 mmol) in DCM (3.9 mL) was added DIPEA (87 ,uL, 0.51 mmol) and intermediate A-2 (100 mg, 0.43 mmol). Then T3P (50% solution in DMF, 0.7 mL, 1.16 mmol) was added dropwise and the reaction heated at 45 °C for 12h. After allowing to cool to ri, DCM was added and the mixture washed with ¾Q then saturated NaHCCb (aq). The combined aq layers were extracted with DCM. The combined organic layers were dried ( aaSO^. Purification was performed using Agilent prep method X to give the title compound (61 mg, 34%), MS (ESI) mass calcd. for: C23H F4N5O, 457.2; m/z found 458.2 [ M · H | . H NMR (400 MHz, Chioroform-d) 8.88 (d, J = 4.9 Hz, 2H), 8.22 (s, 1H), 7.67 i d. 9.3 Hz, l ! . 7.43 - 7.28 (m, 3H), 7.24 - 7.12 (in, 2H), 6.19 (d, J = 8.8 Hz, H I ). 4.76 - 4.68 (m, 1H), 4.43 - 4.32 (m, 1H), 4.08 (d, J = 5.0 Hz, 1H), 2.16 (dd, J = 12.9, 8.1 Hz, 1H), 2.08 - 1.83 (m, 2H), 1.77 - 1.38 (m, 3H).
Example 280 (4-fluoro-2-(pyrimidm-2-yl)phen^
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000224_0001
Prepared analogous to Example 279 substitutmg intermediate A-2 with intermediate A- 25. MS (ESI) mass calcd. for : C73H19F4 5O, 457.2; mJz found 458.2 [M+H]\ JH NMR (400 MHz, Chloroform-d) 8.89 --- 8.76 (m, 2H), 8.36 (s, 0.2H), 8.26 - 8.19 (m, 0.8H), 8.05 - 7.91 (m, 0.4H), 7.70 (dd, J= 9.3, 2.7 Hz, 0.6H), 7.60 - 7.53 (m, 0.3H), 7.48 - 7.40 (m, 0.3H), 7.40 - 7.28 (m, 2.6H), 7.25 - 6.99 (m, 1.6H), 6.36 (d, J= 8.7 Hz, 0.2H), 5.96 (d, J= 8.8 Hz, 0.8H), 5.70 (s, 0.2H), 4.87 - 4.80 (m, 0.8H), 4.73 (d, J= 5.3 Hz, 0.2H), 4.38 (s, 0.8H), 4.17 (s, 0.2H), 4.06 - 4.00 (m, 0.8H), 4.00 - 3.94 (m, 0.2H), 2.21 (dd, J = 12.9, 8.0 Hz, 0.8H), 2.12 - 1.35 (m, 5.2H).
Example 281 (3-metliyl~2-(pyr-iniidin-2-yl)phenyl)(( 1 S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7-azabicyc1o[2.2.1 ]heptan-7-yl)methanone
Figure imgf000224_0002
Prepared analogous to Example 269 substituting intermediate A- 16 with intermediate A- 26. MS (ESI) mass calcd. for : ί¾Η2!Ρ3Ν60, 454.2; m/z found 455.3 [M+H]+. !H NMR (500 MHz, Chloroform-d) 8.89 - 8.85 (m, 2H), 8.70 (s, 1H), 8.44 - 8.32 (m, 2H), 7.34 - 7.23 (m, 3H), 7.21 - 7.15 (m, 4.77 - 4.68 (m, H), 4.43 - 4.33 (m, IH), 4.1 1 (d, 5.1 Hz, Hi), 2.36 (s, 3H), 2.19 (dd, J = 12.8, 7.9 Hz, 1H), 2.09 - 1.99 (m, H ), 1.94 - 1 .85 (m, Hi), 1.72 - 1.48 (m, 3H).
Example 282 (3-fluoro-2-(pyrimidin-2-yl)phenyl)(( 1 S,2R,4R)-2-(methyl(5- (trifluorometbyl)pyrazm-2-yl)amino^
Figure imgf000225_0001
The title compound of Example 238 (63 mg, 0.14 mmol) was dissolved in DMF (1 ,4 ml.) and then sodium ieri-butoxide ( 15 mg, 0.15 mmol) followed by iodomethane (9 iiL, 0.14 mmol) were added. After 15h at room temperature ihe reaciion mixture was diluted with EtOAc and water was added. The aqueous phase was extracted twice with EtOAc and the combined organic phases were dried over MgSO t, filtered and evaporated. Purification was performed using Agilent prep method X to give the title compound (40 mg, 62%). MS (ESI) mass calcd. for :
C23H20F4N6O, 472.2; m z found 473.2 [M+H]+. >H NMR (500 MHz, Chloroform-d) 8.81 (d, 4.9 Hz, 2H), 8.35 (s, 1 H), 8.02 (s, 1H), 7.55 - 7.46 (m, 1H), 7.34 - 7.20 (m, 3H), 4.81 - 4.73 (m, I I I !. 4.67 (d, ./ 4.3 Hz, I ! I t 4.17 - 4.08 (m, 3.05 (s, 3H), 2.12 (dd, ./ 12.8, 8.3 Hz, I I I I 1.98 - 1.44 (m, 5H). Example 283 (3-methyl-2-(oxazol-2-yl)phenyl)((^
yl)ainino)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone
Figure imgf000226_0001
Prepared analogous to Example 269 substituting intermediate A- 16 with intermediate A- 31. MS (ESI) mass calcd. for : C22H20F3N5O2, 443.2; m/z found 444.1 [M+H]+. !H NMR (400
MHz, Chloroform-d) 8.48 (s, 1H), 8.35 (s, 1 H), 7.88 - 7.78 (m, 1H), 7.68 (s, 0.4H), ϊ .Δ
(m, 3.6H), 7.15 (dd, J = 6.6, 2.2 Hz, 0.6H), 7.06 - 6.97 (m, 0.41 h. 4.84 - 4.78 (m, 0.6H), 4.73 - 4.67 (m, 0.4H), 4.33 (td, J = 8.4, 3.0 Hz, 0.4H), 4.24 (td, J = 8.2, 3.7 Hz, 0.6H), 4.04 - 3.98 (m, 0.4H), 3.97 - 3.89 (m, 0.6H), 2.47 (s, 1.7H), 2.37 (s, 1 .3H), 2.19 - 1.41 (m, 6H).
Example 284 (3-fluoro-2-(oxazol-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000226_0002
In a microwave vial was dissolved the title compound of Example 277 (30 mg, 0.06 mmol) and 2-(tributylstannyl)oxazole (15 μΐ-, 0.07 mmol) in DME (1 mL). The solution was degassed wit!i N2 for 5 minutes then Cui (1 mg, 0.0045 mmol) and Pd(PPh3)/.| (5 mg, 0.0045 mmol) were added. The reaction was purged with N2 and heated at 145 °C for 3h. The reaction was cooled to ri, filtered through a pad of celite and purified via prep HPLC to give the title compound (19 mg, 72%). MS (ESI) mass calcd. for :
Figure imgf000226_0003
447.1 ; m/z found 448.1
[M-i-Hf. 'rI NMR (500 MHz, Chloroform-d) 8.49 (s, 1H), 8.36 (s, 0.8H), 7.85 (s, 0.8H), 7.76 (s. 0.4H), 7.62 - 7.45 (m, 1H), 7.43 - 7.33 (m, 1H), 7.32 - 7.23 (m, 2H), 7.23 - 7.09 (m, 1 H), 4.91 - 4.85 (m, 0.4H), 4.78 (d, J = 5.4 Hz, 0.6H), 4.42 (id, J= 8.6, 2.8 Hz, 0.6H), 4.28 (td, J = 8.2, 3.6 Hz, 0.4H), 4.00 - 3.95 (m, 0.6H), 3.89 (d, J= 4.4 Hz, 0.4H), 2.23 - 1.44 (m, 6H).
Example 285 (±)-(3-fluoro-2-(pyrimidm-2-yl)ph^
yl)oxy)-7-azabicyc1o[2.2.1 ]heptan-7-yl)methanone
Figure imgf000227_0001
Step A: (±)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yi)oxy)-7- azabicyclo[2.2.1]heptane-7-carboxylate: To (±)-tert-butyl 2-hydroxy-7- azabicycio[2.2.1 ]heptane-7-carboxylate (exo) (52 mg, 0.25 mol) in DMF (5 mL) was added 60 wt% NaH (20 mg, 0.5 mmol) in one portion. The reaction was heated at 80 °C for 5 mm, then 2- chloro-5-(trifluoromethyl)pyrimidme (89.7 mg, 0.49 mmol) was added. After heating at 80 °C for 2 hours, water was added and the mixture extracted with DCM (3X). The combined organics were dried (Na2S04) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (20 mg, 23%). MS (ESI) mass calcd. for :
C] 6H20F3N3O3, 359.4; mJz found 260.1 [M-Bocf.
Step B: (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyi)(2~((5-(trifluoromeihyi)pyrim
yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7~yl)methanone: To (±)-tert-bufyl 2-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2. l]heptane-7-carboxylate (20 mg, 0.06 mrnoiO in DCM (2 mL) was added 2 mL (2M HCl in Et20) and stirred ai n for 3 h. The reaction mixture was concentrated and placed under high vacuum for 1 h. To the intermediate in DCM (2 mL) was added intermediate acid (A-2) (13.3 mg, 0,06 mmol), HOBt (1 3.7 mg, 0.101 mmol), EDCI (19.4 mg, 0.101 mmol) and DIPEA (26 n , 0.15 mmol). After stirring ai ri for 2 h, saturated NaHCOj (aq.) was added and the mixture was extracted with DCM (3 ). The combined organics were dried (Na2S04), and concentrated. Purification via silica gel chromatography (0- 100 % EtOAc in hexanes) gave the title compound (9 mg, 38 %). MS (ESI) mass calcd. for: C22H17F4N5O2, 459.1 ; m/z found 460.1 [M+Hf. !H NMR (500 MHz,
Chlorofonn-d) 8.88 (d, J = 4.9 Hz, 1H), 8.81 (d, J= 4.9 Hz, 1H), 8.74 (d, J = 12.6 Hz, 2H), 7.63 - 7.27 (m, 3H), 7.14 (t, J = 8.9 Hz, I H), 4.99 (dt, J = 8.3, 4.8 Hz, 1H), 4.87 - 4.66 (m, IH), 4.16 - 3.97 (m, 1H), 2.07 (d, J= 4.3 Hz, I H), 1.91 (d, J= 32.9 Hz, IH), 1.85 - 1.68 (m, 2H), 1.66 - 1 .60 (in, 1 H), 1.51 (dd, ./ 7.9, 4.8 Hz, 1H).
Example 286 (±)-(3-fluoro-2-(p rimidm-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidm-2 yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000228_0001
Step A: (±)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7- azabicyclo[2.2.1]heptane-7-carboxylate: To (±)-tert-butyl 2-hydroxy-7- azabieyclo[2.2.1]heptane-7-carboxy].ate (endo) (150 mg, 0.703 mol) in DMF (8 mL) was added 60 wt% NaH (56.3 mg, 1.41 mmoi) in one portion. The reaction was heated at 80 °C for 5 min, then 2-chloro-5-(trifluoroniethyl)pyriniidine (257 mg, 1 ,4 mmoi) was added. After heating at 80 °C for 2 hours, water was added and the mixture extracted with DCM (3X). The combined organics were dried (N 2S04) and concentrated. Purification via silica gel chromatography (0- 50% EtOAc in hexanes) gave the title compound (130 mg, 51 %). MS (ESI) mass calcd. for: C,6H2oF, ,03, 359.4; m/z found 260.1 [M-Bocf. IH NMR (400 MHz, Chloroform-d) 8.82 - 8.71 (m, 21 1 ). 5.28 (d, J = 10.0 Hz, I H), 4.59 (s, IH), 4.25 (s, IH), 2.43 (dddd, J = 13.1, 10.1 , 5.2, 2.8 Hz, IH), 2.18 - 2.04 (m, IH), 1.85 (dd, J - 7.8, 3.8 Hz, IH), 1.69 (s, IH), 1.59 (s, 2H), 1.47 (s, 9H).
Step B: (3-fluoro-2-(pyrimidm-2-yl)phenyl)((lR,2S,4S)-2-((5- (trifluorome1hyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone: To (±)-tert- butyi 2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1 ]heptane-7-carboxylate ( 143 mg, 0.398 mmoi) in DCM (3 mL) was added 2M HCi in Et20 (3 mL). After 3h at rt the reaction mixture was concentrated and placed under high vacuum for 1 h. To the intermediate in DCM (3 mL) was added carboxcylic acid (A-2) (95.5 mg, 0.438 mmol), HOBt (88.9 mg, 0.658 mmolO, EDCI (126.1 mg, 0.658 mmol) and DIPEA (170 μί.,, 0.987 mmol). After stirring at rt for 2 h, saturated NaHC03 (aq.) was added and the mixture was extracted with DCM (3X). The combined organics were dried ( aaSCu), and concentrated. Purification via silica gel chromatography (0- 100 % EtOAc in hexanes) gave the title compound (78.6 mg, 47%). MS (ESI) mass calcd. for : C22H17F4N5O2, 459.1 ; m/z found 460.1 [M+Hf. 1H NMR. (400 MHz, Chloroform-d) d 8.85 (t, J = 5.2 Hz, 1 1 1 ). 8.76 (d, J = 12.3 Hz, 2H), 7.47 (dd, J = 8.5, 5.4 Hz, 1H), 7.29 (td, J = 5.4, 4.9, 4.3 Hz, 3H), 5.58 - 5.40 (m, 1H), 5.30 (s, 1H), 5.09 - 4.92 (m, i l l s. 4.67 (s, 1H), 4.34 (s, 1H), 4.02 (s, I I I ) . 2.61 - 2.39 (m, 1H), 2.32 - 2.08 (m, 1 H), .90 (d, J = 13.7 Hz, 1H).
Example 287 (3-ethoxy-6-methylpyridm-2-yJ)((l S^
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000229_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-8.
MS (ESI) mass calcd. for 1 ( J h >l- ;\\C 421.2; m/z found 422.2 j M l i ! . Ή NMR (400 MHz, Chloroform-d) 8.31 (s, 0.2H), 8.24 (s, 0.81 1 ). 8.01 - 7.81 (m, 1.8H), 7.25 - 7.09 (m, 2H), 6.15 (d, J = 8.0 Hz, 0.2H), 5.01 - 4.93 (m, 0.8H), 4.87- 4.80 (m, 0.21 1 ). 4.32 - 4.24 (m, 0.2H), 4.18 - 4.02 (m, 2.8H), 3.95 (d, J = 4.6 Hz, 0.8H), 3.88 - 3.82 (m, 0.2H), 2.55 - 2.46 (m, 3H), 2.26 - 1.23 (m, 9H).
Example 288 (3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yi)((l S,2R,4R)-2-((5-(trifluoromethyi)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000230_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 27, MS (ESI) mass calcd. for : C19H17F3N3O, 430.1 ; m/z found 431.2 [M+H]+. Ή NMR (400 MHz, Chloroform-d) 8.65 (dd, J= 4.7, 1.5 Hz, 0.2H), 8.55 (dd, J= 4.8, 1.5 Hz, 0.8H), 8.39 - 8.32 (m, 0.4H), 8.29 - 8.18 (m, 1.6H), 7.97 - 7.86 (m, 2.2H), 7.70 (s, 0.8H), 7.56 (dd, ./ 8.3, 4.7 Hz, 0.2H), 7.50 (dd, J - 8.3, 4.7 Hz, 0.8H), 7.15 (d, J= 8.6 Hz, 0.8H), 6.12 (d, J= 8.6 Hz, 0.2H), 4.97 - 4.89 (m, 0.8H), 4.82 (d, J= 5.2 Hz, 0.2H), 4.29 (td, J= 7.9, 2.8 Hz, I H), 4.12 - 4.07 (m, 0.2H), 4.04 (d, J= 5.0 Hz, 0.8H), 2.27 - 1.43 (m, 6H). xample 289 (2-metlioxy-6-(pyrimid n-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifi^^
-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000230_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 28. MS (ESI) mass calcd. for : C23H2iF3N602, 470.2; m/z found 471.2[M+H]+. ¾ NMR (400 MHz, Chloroform-d) 8.89 - 8.71 (m, 2H), 8.53 - 8.14 (m, 1.5H), 7.99 - 7.76 (m, 0.5H), 7.60 - 7.29 (m, 3.7H), 7.23 - 6.99 (m, IH), 6.08 (d, ./ 8.9 Hz, 0.2H), 5.78 (d, J= 8.5 Hz, 0.1 H), 5.00 4.78 (m, IH), 4.46 - 4.35 (m, IH), 4.07 (s, 0.5H), 3.91 - 3.79 (m, 3.5H), 2.32■- 1.24 (m, 6H).
Example 290 (2-fluoro-6-(pyrimidm-2-yl)phenyl)((l S,2R,4R)-2~((5-(trifluoromethyl)pyrazm yl)amino)-7-azabicyclo[2.2. l]heptan-7-yl)methanone
Figure imgf000231_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-6. MS (EST) mass calcd. for : C22H18F4N6O, 458.1; m/z found 459.2 [M+H]+. Ή NMR (400 MHz, Chforoform-d) 8.89 - 8.72 (m, 2H), 8.38 - 8.16 (m, 2H), 7.78 (dd, J= 7.8, 1.1 Hz, Hi), 7.55 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 7.34 - 7.14 (m, 2H), 4.93 - 4.85 (m, 1H), 4.50 - 4.39 (m, 1H), 3.98 - 3.88 (m, 1H), 2.31 - 1.1 1 (m, 6H).
Example 291 (7-ethoxyquinolin-8-yl)((l S,2R,4 )-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000231_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-
29. MS (EST) mass calcd. for : C23H22F3N5O2, 457.2 m/z found 458.2 [M+H]+.
Example 292 (2-(l ,4-dimethyl-iH-pyrazol-5-yi)-6-methoxyphenyr)((lS,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000232_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 30. MS (ESI) mass calcd. for : C24H25F3N6O2, 486.2 m/z found 487.2 [M+H]+.
Example 293 (3-methyl-2-(pyridin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2- yl) amino) -7-azabicycio[2.2.1 ] eptan-7-yl)methanone
Figure imgf000232_0002
Prepared analogous to Example 284 substituting title compound of Example 2.77 with title compound of Example 276 and 2-(tributylstannyI)oxazofe with 2-(tributylstannyi)pyridine. MS (ESI) mass calcd. for : C24H22F3N5O, 453.2 m z found 454.2 [M+Hf. !H NMR (400 MHz: Chloroform-d) 8.72 - 8.66 (m, 1H), 8.45 (s, 0.5H), 8.39 (s, 1.5H), 7.86 - 7.75 (m, 1H), 7.52 - 7.44 (m, 1H), 7.38 - 7.20 (m, 4.2H), 7.18 - 7.12 (m, 0.8H), 4.72 - 4.65 (m, 0.8H), 4.49 - 4.45 (m, 0.2H), 4.32 (s, 0.8H), 4.03 - 3.95 (m, 1H), 3.88 - 3.83 (m, 0.2H), 2.26 (s, 2.2H), 2.23 (s, 0.8H), 2.16 ( dd. ./ 12.8, 7.9 Hz, 0.8H), 1.98 - 1.08 (m, 5.21 1 K Example 294 (3-fluoro-2-(2H- ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- (trifluoromeihyi)pyridin-2-yl)amino)-7-azabicyclo[2.2 ]heptan-7-yl)methanone
Figure imgf000233_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- i 6. MS (EST) mass calcd. for :
Figure imgf000233_0002
446.1 m/z found 447.2 [M+H] :H NMR (500 MHz, Chlorofonn-d) 8.33 (s, 0.2H), 8.23 (s, 0.8H), 7.96 (s, 1.55H), 7.91 (s, 0.45H), 7.57 - 7.48 (m, 0.4H), 7.44 - 7.29 (m, 2H), 7.30 - 7.21 (m, 1H), 7.21 - 7.13 (m, 0.8H), 6.72 (s, 0.6H), 6.36 - 6.25 (m, 1H), 5.34 (s, 0.2H), 4.78 - 4.69 (m, 0.8H), 4.61 (d, J= 5.2 Hz, 0.2H), 4.28 (s, 0.8H), 4.12 (s, 0.2H), 4.05 - 3.95 (m, 1H), 2.17 - 1 .41 (m, 6H). Example 295 (3-methyl-2-(2H- 1 ,2,3-triazo!-2-yl)phenyl)((i S,2R,4R)-2-((5-
(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000233_0003
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 24. MS (ESI) mass calcd. for : C22H2iF3N60, 442.1 m/z found 443.2 [M+H]+. ;H NMR (500 MHz, Chloroform-d) 8.32 (s, 0.2ΪΤ), 8.23 (s, 0.8F1), 7.90 (s, 1.55H), 7.85 (s, 0.45FT), 7.57 - 7.25 (m, 3.2! . 7.24 - 7.15 (m, 0.8FI), 6.93 (s, 0.8H), 6.38 - 6.27 (m, l ! . 5.22 (s, 0.2FI), 4.74 - 4.65 (m, 0.8H), 4.55 (d, J= 4.7 Hz, 0.2H), 4.28 (s, 0.8H), 4.09 (s, 0.2H), 4.03 - 3.95 (m, 1H), 2.20 (s, 3H), 2.13 - 1.38 (m, 6H). Example 296 (3-methyl-2-(oxazol-2-yl)phenyl)^
yl)amino)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone
Figure imgf000234_0001
Prepared analogous to Example 279 substituting mtemiediate A-2 with intermediate A- 31. MS (EST) mass calcd. for :
Figure imgf000234_0002
442.2 m/z found 443.2 [M+H]+. ¾ NMR (500 MHz, Chloroform-d) 8.19 (s, 1 H), 7.91 - 7.80 (m, 2H), 7.32 - 7.21 (m, 4H), 7.19 - 7.13 (m, 1H), 6.32 (d, J = 8.8 Hz, 1H), 4.79 - 4.72 (m, 1H), 4.36 - 4.28 (m, 1H), 3.93 (d, J = 4.6 Hz, 1H), 2.29 (s, 3H), 2.10 (dd, J = 12.9, 8.1 Hz, 1H), 2.00 - 1.85 (m, 2H), 1.76 - 1.64 (m, 2H), 1.55 - 1.46 (m, 1H).
Example 297 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((lR,2S,4S)-2-((5-(n,ifluoromethyl)pyTazin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000234_0003
Prepared analogous to Example 238 substituting intermediate B-5 with intermediate B-8. MS (ESI) mass calcd. for C22H;SF4N60, 458.2; m/z found 459.1 j V! · Π j . Ή NMR (500 MHz, Chloroform-d) 8.91 - 8.84 (m, 2H), 8.27 (s, 1H), 8.19 (s, 1H), 7.65 i d. ./ 1.4 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.24 - 7.16 (m, 2H), 4.77 - 4.68 (m, 1H), 4.43 - 4.33 (m, 1H), 4.07 (d, J= 5.1 Hz, 1H), 2.16 (dd, J = 13.0, 8.2 Hz, 1H), 2.10 - 1 .99 (m, !H), 1.98 - 1 .86 (m, I I I ). 1.78 - 1.65 (m, 2H), 1.58 - 1.48 (m, 1H). Example 298: (3-fluoro-2-(oxazoi-2-yl)phenyl)( l S,2R,4 )-2-((5-(trifluoroniethyl)pyridin-2- ]heptan-7-yl)meth.anone
Figure imgf000235_0001
Prepared analogous to Example 320 substituting 2-(tributylstannyl)pyridine with 2-
(tributylstannyl)oxazole. MS (ESI) mass calcd. for C22H1SF4 4O2, 446.1 ; m/z found 447.1 i \! H i . 'H NMR (CDCI3): 8.36 (s, 0.2H), 8.23 - 8.16 (m, 0.8H), 7.90 (s, 0.8H), 7.86 (s, 0.2H), 7.70 - 7.46 (m, 1.2H), 7.43 - 7.20 (m, 2.8H), 7.19 - 7.10 (m, 1.8H), 6.39 (d, J= 8.8 Hz, 0.2H), 6.20 (d, J= 8.8 Hz, 1H), 4.85■· 4.79 (m, 0.8H), 4.72 (d, J= 5.3 Hz, 0.2H), 4.39■■ 4.31 (m, 0.8H), 4.26 (s, 0.2H), 3.95 - 3.88 (m, IH), 2.14 (dd, J = 12.9, 8.2 Hz, 0.8H), 2.06 - 1.41 (m, 5.2H).
Example 299: (3-methyl-2-(pyriniidin-2-y{)phenyl)((l S,2R,4R)-2-((5-(trifluorometh^ yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000235_0002
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-
26. Analytical HPLC was obtained on a Agilent 1 00 Series using an Inertsil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 xnL/min (Temperature = 50 °C), R( = 1. 1 min (major rotamer) at 254 nm. Ή NMR (500 MHz, CDCI3, Compound present as a mixture of retainers (0.90:0.10), only major rotamer reported) δ 8.84 (d, J = 4.9 Hz, 2H), 8.22 (s, 1H), 7.82 (d, J = 9.3 Hz, I H), 7.33 (t, J= 5.0 Hz, IH), 7.29 - 7.27 (m, IH), 7.23 (t, J= 7.5 Hz, 1 H), 7.21 - 7.17 (in, i l l ). 6.21 (d, J= 8.7 Hz, I I I ;. 4.67 > \. 4.8 Hz, IH), 4.42 - 4.29 (m, 1H), 4.09 i d. ./ 5.0 Hz, IH), 2.31 (s, 3H), 2.12 (dd. ./ 12.9, 8.1 Hz, IH), 2.06■ 1.97 (m, IH), 1.93■· 1.85 (m, 1H), 1.73 - 1.65 (m, I H), 1.61 - 1.53 (m, I H), 1.53 - 1.45 (m, IH). Example 300: (3-chloro-2-(pyrimidin-2-yl)phe"nyl)(( 1 S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1 Jheptan-7-yl)niethanone
Figure imgf000236_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 58. Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 1.26 min (major rotamer) at 254 nm. Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.92:0.08), only major rotamer reported) δ 8.88 (d, J= 5.0 Hz, 2H), 8.26 (d, J= 9.1 Hz, IH), 8.18 (s, I H), 7.74 i d. ./ 1.4 Hz, IH), 7.49 (tkl. J 7.2, 2.1 Hz, IH), 7.41 i i../ 5.0 Hz, IH), 7.31■■ 7.29 (in, IH), 4.71■■ 4.65 (m, IH), 4.34 (td, J = 8.7, 3.8 Hz, IH), 4.05 (d, J= 5.1 Hz, IH), 2.13 (dd, J = 13.0, 8.1 Hz, I H), 2.09 - 2.00 (m, IH), 1.96 - 1.85 (m, IH), 1 .75 - 1.66 (m, IH), 1.61 - 1.56 (m, I H), 1.54 - 1.46 (m, I H).
Example 301 : ((1 S,2R,4R)-2-((5-bromopyridin-2-yi)araino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- ol-2-yl)phenyl)methanone
Figure imgf000236_0002
Example 302: ((lS,2R,4R)-2-((5-bromopyridin-2-yl)ainino)-7-azabicyclo[2.2.1]heptan-7-yl)(3- l)methanone
Figure imgf000237_0001
Prepared analogous to Example 305 substituting intermediate A- 16 with intermediate A- 31. MS (ESI): mass caicd. for C H> BrN.C 452.1 ; m ,··: found, 452.9 [M HI . H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) 87.96 (d, J= 2.5 Hz, IH), 7.85 (d, J = 0.9 Hz, IH), 7.28 - 7.26 (series ra, 2H), 7.25 - 7.22 (m, 1H), 7.19 (dd, J= 8.9, 2.5 Hz, 1H), 7.17 - 7.13 (m, IH), 6.23 {■±.! 9.0 Hz, 1H), 4.73 (t, J= 4.5 Hz, H), 4.24 - 4.14 (m, IH), 3.90 (d, J= 4.6 Hz, ill).2.29 is, 3H), 2,07 (dd, J- 12.8, 8.1 Hz, IH), 1.95 - 1.85 (series of m, 211). 1.70■· 1.60 (series of m, 2H), 1.52 - 1.44 (m, IH).
Example 303: ((1 S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- nyi)methanone
Figure imgf000237_0002
Prepared analogous to Example 305 substituting intermediate A- 16 with intermediate A-
2. MS (ESI): mass calcd. for C22H19BrFN50} 467.1; nv'z found, 468.1 ivl-lii . ¾ NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.87:0.13), only major rotaraer reported) δ 8.87 (d, .7-4.9 Hz, 2H), 8.00 (d, J= 2.5 Hz, IH), 7.40 - 7.31 (series of m, 2H), 7.24 7.20 (m, I in.7.19 - 7.14 (series of m, 2H), 6.10 (d, ./ 8.9 Hz, IH), 4.70 (t, ./ 4.9 Hz, ill). 4.28■· 4.19 (m, IH), 4.06 id../ 5.Ϊ Hz, IH), 2.13 (dd,,/- 12.9, 8.1 Hz, IH), 2.06 - 1.83 (series ofm, 2H), 1.73 - 1.46 (series ofm, 2H). *1H buried under solvent peak. Example 304: (( 1 S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- methy 1-2■ (pyrimidin-2 -yl)phenyl)methanone
Figure imgf000238_0001
Prepared analogous to Example 305 substituting intermediate A- 16 with intermediate A- 26, MS (ESI): mass calcd. for C .i >BrN.;0. 463.1 ; m/z found, 464.1 | V! - 1 1 - Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.88:0.12), only major rotamer reported) δ 8.82 (d, J 4.9 Hz, 21 1 ). 8.00 i d. ./ 2.5 Hz, Hi), 7.31 (t, ./ 4.9 Hz, 1H), 7.28 - 7.26 (m, 1H), 7.25■· 7.16 (m, 3H), 6.12 (d, J = 8.8 Hz, IH), 4.69■ 4.60 (m, IH), 4.23 - 4.17 (m, 1H), 4.06 (d, J = 5.1 Hz, I H), 2.30 (s, 3H), 2.09 (dd, J= 12.8, 8.1 Hz, 1H), 2.04 - 1.95 (m, IH), 1.92 - 1.82 (m, IH), 1.69 - 1.61 (m, I H), 1.58 - 1.42 (m, 2H).
Example 305: ((l S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3- fluoro-2~('2H-l ,2,3-triazol-2-yl)phenyl)methanone
Figure imgf000238_0002
Step A: (l S,2R,4R)-tert-butyl 2-((5-bromopyridin-2-yl)amino)-7- azabicyclo[2.2.1 jheptane-7-carboxyiate. In a microwave vial, 5-bromo-2-iodopyridine (133 mg,
0.47 mmol) was dissolved in TFIF (2.4 mL) and sodium tert-butoxide (91 mg, 0.94 mmof) was added followed by Xantphos (20 mg, 0.033mmol) and Pd2(dba) j (17 mg, 0.019 mmol). The solution was degassed with IS for 10 minutes then intermediate B-5 (100 mg, 0.47 mmol) was added. After 2. days at 90 °C the reaction mixture was filtered through a pad of celite and solvent was evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound of step A (87 mg, 50%). MS (ESI): mass calcd. for Ci6H22BrN30¾ 367.1 ; m/z found, 368.1 i vi - 1 1 : . ¾ NMR (500 MHz, CDCI3) δ 8.10 (d, J= 2.4 Hz, 1H), 7.44 (dd, J= 8.8, 2.5 Hz, IH), 6.25 (d, J= 8.8 Hz, IH), 4.70 (s, 1H), 4.27 (s, 1H), 4.21 - 4.14 (m, 1H), 3.90 - 3.81 (m, 1 H), 2.00 (dd, J= 13.0, 7.6 Hz, IH), 1.89 - 1.66 (m, 2H), 1 .57 - 1.34 (m, 12H).
Step B: ( 1 S,2 ,4R)-N-(5-bromopyridin-2-yl)-7-azabicyclo[2.2. ]heptan-2-amine.
Prepared analogous to Example 382 step B. MS (ESI): mass calcd. for CnHi4Br 3, 267,0; m/z found, 268.1 1 N t U 1 .
Step C: ((lS,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone. Prepared analogous to Example 382 step C substituting intermediate A-2 with intermediate A- 16. MS (ES ): mass calcd. for C^oHigBrFNeO, 456.1 ; m/z found, 457.1 ΓΜ+Η] ; . i i NMR (500 MHz, CDCU, Compound present as a mixture of rotamers (0.80:0.20), only major rotamer reported) δ 8.00 (d, J= 2.5 Hz, IH), 7.94 (s, 2H), 7.41■■ 7.33 (m, IH), 7.33■■ 7.22 (m, 2H), 7.16 (dt, J= 7.7, 1.1 Hz, IH), 6.20 (d, J= 8.7 Hz, IH), 4.77 - 4.67 (m, IH), 4.20 - 4.10 (m, IH), 3.97 (d, J= 4.9 Hz, IH), 2.10 (dd, J= 13.0, 8.1 Hz, IH), 1.98 - 1.80 (m, 2H), 1.70 - 1.54 (m, 2H), 1.52 - 1 .46 (m, IH).
Example 306: ((1 S,2R,4R)-2-((5-bromopyridin-2-yj.)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- 2-y])phenyi)methanone
Figure imgf000239_0001
Prepared analogous to Example 305 substituting iniermediaie A- 16 with intermediate A-
24. MS (ESI): mass calcd. for C2iH2iBrN60, 452.1 ; m/z found, 452.9 [M+H]+. Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.00 (d, J= 2.5 Hz, 1 H), 7.89 ( , 2H), 7.42 (d, ./ 4.3 Hz, IH), 7.36 - 7.31 (m, IH), 7.28 - 7.24 (series of m, 2H), 7.22 - 7.16 (m, IH), 6.24 (d, J= 8.9 Hz, IH), 4.67 (t J= 4.7 Hz, IH), 4.21 - 4.06 (m, IH), 3.95 (d, J= 5.1 Hz, IH), 2.20 (s, 3H), 2.07 (dd, J= 12.9, 8.0 Hz, IH), 1.98 - 1.90 (m, IH), 1.87 - 1.78 (m, I H), 1.66 - 1.60 (m, IH), 1.57 - 1.50 (m, I H), 1.50 - 1.43 (m, IH). Example 307: ((lS,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3- fluoro-2-(oxazoi-2-yl)phenyl)methanone
Figure imgf000240_0001
Example 308: ((1 S,2R,4R)-2-((5-broraopyrazia-2-yl)aimno)-7-azabicyclo[2.2. l]heptan-7-yi)(3- metbyl-2-(oxazol-2-yl)pbenyl)methanone
Figure imgf000240_0002
Prepared analogous to Example 3 i 1 substituting intermediate A- 16 with intermediate A- 31. MS (ESI): mass ealcd. for C2iH2oBrN502, 453.1 ; m/'z found, 453.9 [M+Hf , Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.04 - 7.93 (m, 1H), 7,88 (d, J= 1.4 Hz, HI), 7.86 (d, ./ 0.9 Hz, IH), 7.54 i d. ./ 1.4 Hz, HI), 7.29 (d, 7.5 Hz, IH), 7.29 - 7.22 (m, IH), 7.18■· 7.14 (m, IH), 4.75 (t, J= 4.6 Hz, IH), 4.17■■ 4.09 (m, IH), 3.90 (d, J= 4.7 Hz, IH), 2.28 (s, 3H), 2.08 (dd, J = 12.9, 8.1 Hz, IH), 1.99 - 1.85 (m, 2H), 1.73 - 1.63 (m, 2H), 1.53 - 1.45 (m, ΓΗ).
Example 309: ((lS,2R,4R)-2-((5-bromopyrazm-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3 fluoro-2-(pyrimidm-2-yl)phenyl)methanone
Figure imgf000241_0001
Prepared analogous Example 311 substituting intermediate A- 16 with intermediate A-2, MS (ESI): mass calcd. for C2iHi8BrF 60, 468.1; m/z found, 469.9 [M+Hf. lH NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) 88.86 i d../ 5.0 Hz, 2H), 7.94 (d, ,/ = 1.4 Hz, IH), 7.42 (d,J= 1.4 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.25 - 7.20 (m, lH), 7.19 - 7.15 (m, 1H), 4.76 - 4.66 (m, lH), 4.27 -4.16 (m, IH), 4.04 (d, J= 5.0 Hz, 1H), 2.14 (dd, J= 12.9, 8.1 Hz, IH), 2,07 - 1.99 (m, IH), 1.95 - 1.86 (m, 1H), 1.73 - 1.62 (series of m, 211;·.1.54 - 1.47 (m, IH). Example 310: ((1 S,2R,4R)-2-((5-bromopyrazm-2-yf)amino)-7-azabcyclo[2.2. l]heptan-7-yl)(3- henyl)methanone
Figure imgf000241_0002
Prepared analogous Example 311 substituting intermediate A- 16 with intermediate A-26. Analytical HPLC was obtained on a Agilent 1100 Series using an Inertsil ODS-3 column (3μιη, 50x3 mm), mobile phase of 5-99% AC in 0.05% TEA over 1.6 rain and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 1.24 mm (major rotamer) at 254 nm. !H NMR (500 MHz, CDCI3, Compound present as a mixtitre of rotamers) δ 8.83 id../ 4.0 Hz, 2H), 7.92 (d, J= 1.4 Hz, IH), 7.41 id../ 1.4 Hz, IH), 7.34 (t, J = 5.0 Hz, IH), 7.30 - 7.27 (m, IH), 7.24 (t, J= 7.5 Hz, IH), 7.21 - 7.17 (m, IH), 4.71 - 4.61 (ra, IH), 4.21 - 4.12 (m, IH), 4.06 (d, J= 5.0 Hz, IH), 2.28 (s, Ml).2.09 (dd, J= 12.9, 8.1 Hz, IH), 2.06 - 1.97 fm, IH), 1.93 - 1.84 (m, IH), 1.66 - 1.62 (m, IH), 1.61 - 1.54 (m, IH), 1.51 - 1.43 (m, IH). Example 31 1 : ((1 S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2. l]heptan-7-yl)(3- -yl)phenyl)ineihanone
Figure imgf000242_0001
Step A: (1 S,2R,4R)-tert-butyf 2-((5-bromopyrazin-2-yI)ammo)-7- azabicyclo[2.2.1]heptane-7-carboxylate. In a microwave vial was dissolved intermediate B-5 (830 mg, 3.91 mmol) in DMSO (8 mL). K2CQ3 (81 1 mg, 5.87 mmol) was added followed by 2,5-dibromopyrazine (1.12 g, 4.70 mmol). The vial was capped and the reaction mixture was heated to 100 °C for 1 6h. Then water and EtOAc were added and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO/i, filtered and evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (291 mg, 20%). MS (ESI): mass calcd. for Ci5H21BrN402, 368.1; m/z found, 370.9 [M+Fl . :H NMR (500 MHz, ( ΊΧΊ .) δ 8.07 (s, 1 H), 7.62 (s, IH), 4.95 (s, IH), 4.28 (s, 1H), 4.18 (s, IH), 3.95 - 3.81 (m, IH), 2.05 - 1.99 (m, IH), 1.89 - 1.70 (m, 2H), 1.57 - 1.37 (m, 12H).
Step B: (1 S,2R,4R)-N-(5-bromopyrazin-2-yl)-7-azabicyclo[2.2.1 ]heptan-2-amine.
Prepared analogous to Example 390 step B. MS (ESI): mass calcd. for CioKtaBrlNU, 268.0; m/z found, 270.9 | .YJ l i j .
Step C: ((lS,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- fluoro-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)metb.anone. Prepared analogous to Example 390 step C. MS (ESI): mass calcd. for CisHnBrFNyO, 457.1 ; m/z found, 459.8 [M+H . !H NMR (500 MHz, CDClj, Compound present as a mixture of retainers) δ 7.94 (s, 3H), 7.54 (d, J = 1.4 Hz, IH), 7.43 - 7.37 (m, I H), 7.32 - 7.27 (m, I H), 7.21 - 7.16 (m, IH), 4.72 (t, J= 4.8 Hz, IH), 4.19 - 4.08 (m, IH), 3.93 (d, J= 5.0 Hz, I H), 2.10 (dd, ./ 13.2, 8.2 Hz, IH), 1.99 - 1.79 (series of m, 3H), 1.63■ 1.54 (m, IH), 1.54 - 1.46 (m, IH).
Example 312: ((1 S,2R,4R)-2-((5-bromopyrazin-2-yf)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone
Figure imgf000243_0001
Prepared analogous to Example 31 1 substituting intermediate A- 16 with intermediate A- 24. MS (ESI): mass calcd. for ( ".>..,! l.:„Kr\ ·() . 453.1 ; m/z found, 453.9 [M+H]+. Ή NMR (500 MHz, CDCh, Compound present as a mixture of rotamers) 8 7.93 d, J= 1.4 Hz, 1H), 7.90 (s, 2H), 7.56 (d, ./ 1.4 Hz, I H), 7.36 - 7.32 (m, 1 H), 7.30 (t, ./ 7.6 Hz, IH), 7.23 - 7.18 (m, 1H), 4.68 (t, J - 4.7 Hz, IH), 4.14■ 4.07 (m, 1H), 3.94 i d. ./ 5.1 Hz, 1H), 2.19 (s, 3H), 2.10 - 2.04 (m, I H), 2.00 - 1.92 (m, I H), 1.90 - 1.80 (m, IH), 1 .64 - 1.42 ( series of m, 3H).
Example 313: ((1 S,2R,4R)-2-((5-bromopyrimidia-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7- -fluoro-2~(oxazol-2-yl)phenyl)meihanone
Figure imgf000243_0002
Example 314: (( S,2R,4R)-2-((5-bromopyrirnidm-2-yl)amino)-7-azabicyclo[2.2. l ]heptan-7- -methyl-2-(oxazol-2-yl)phenyl)methanone
Figure imgf000243_0003
Prepared analogous to Example 317 substituting intermediate A- 16 with intermediate A- 31. MS (ESI): mass calcd. for C2iH2oBrN5{¾, 453.1 ; m/z found, 453.9 [ M H I . Π N M R (500 MHz, CDClj, Compound present as a mixture of rotamers (0.55:0.45), only major rotamer reported) δ 8.16 (s, 2H), 7.80 (s, IH), 7.40 - 7.35 fm, IH), 7.31 (s, I i n. 7.26 - 7.22 (series of m, 2H), 4.80■■ 4.74 (m, IH), 4.67 (d, J = 5.3 Hz, IH), 4.1 1 ■■ 4.03 (m, 1H), 2.37 (s, 3H), 2.10 (dd, J = 12.9, 8.0 Hz, 1H), 1.88 - 1.68 ( series of m, 3H), 1.61 - 1.39 (series of m, 2H).
Example 315: ((l S,2R,4R)-2-((5-bromopyriinidm-2-yl)amino)-7-azabicyclo[2.2. l ]heptan-7- -fluoro-2~(pyrimidin-2~yi)phenyl)methanone
Figure imgf000244_0001
Prepared analogous to Example 317 subsiituting intermediate A- 16 with intermediate A- 2. MS (ESI): mass calcd. for C2jHj 8BrFN60, 468.1 ; m/z found, 470.8 ί Π f ]H NMR (500 MHz, CDCh, Compound present as a mixture of rotamers (0.80:0.20), only major rotamer reported) δ 8.88 i d. ./ 4.9 Hz, 2H), 8.18 (s, 2H), 7.41 - 7.35 (m, I H), 7.32 (t, ,/ 4.9 Hz, 1H), 7.25 · 7.19 (m, IH), 7.16 (dd, J = 7.6, 1.1 Hz, I I I ). 4.77■■ 4.71 (m, 1H), 4.28■■ 4.18 (m, 1H), 4.06 (d, J = 5.1 Hz, I H), 2.18 (dd, J = 12.9, 7.9 Hz, IH), 2.02 - 1 .79 (m, 2H), 1.56 - 1 .49 (m, IH). *2 H buried under water peak.
Example 316: ((l S,2R,4R)-2-((5-bromopyiimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7- -methyl-2-(pyrimidin-2-yl)phenyl)Tnetbanone
Figure imgf000244_0002
Prepared analogous to Example 317 substituting intermediate A- 16 with intermediate A- 26. Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 0.82 min (major rotamer) at 254 nm. Ή NMR (500 MHz, CDCI3, Compound present as a mixture of retainers) δ 8.86 (d, J- 4.9 Hz, 2H), 8.19 (s, 2H), 7.34 - 7.23 (series ofm, 3H), 7.20 - 7.16 (m, H i ). 4.69 U. ./ 4.6 Hz, IH), 4.27 - 4.17 (m, IH), 4.10■ 4.06 (m, IH), 2.35 (s, 3H), 2.16 (dd, ./ 12.8, 7.9 Hz, IH), 2.07 - 1.96 (m, I H), 1.90 - 1.80 (m, I H), 1.69 - 1.54 (series ofm, 2H), 1.54 - 1.46 (m, IH).
Example 317: ((lS,2 ,4R)~2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptaii-7- yl)(3-fluoro-2-( azol-2-yl)phenyl)methanone
Figure imgf000245_0001
Step A: (l S,2R,4R)-tert-butyl 2-((5-bromopyrimidin-2-yl)amino)-7- azahicyeJo[2.2, l]heptane-7-carboxylate. To a solution of intermediate B-5 (520 mg, 2.45 mmol) in DMA (8.2 mi.) was added DIPEA (0.84 mL, 4.90 mmol) followed by 2,5-dibromopyrimidine (661 mg, 2.69 mmol). The reaction mixture was heated at 120 °C for 30 minutes using microwave and was then diluted with water and EtOAc. The aqueous phase was extracted twice with EtOAc and the combined organic layers were washed with a saturated solution of NaCl, dried over MgS04, filtered and evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (651 mg, 72%). MS (ESI): mass calcd. for C <\ \ , Br\ .() . 368.1 ; m/z found, 370.9 [M+H]+. Ή NMR (500 MHz, CDCi3) δ 8.28 (s, 2H), 5.56 (s, IH), 4.29 (s, IH), 4.23 - 4.15 (m, IH), 3.99 - 3.91 (m, IH), 2.03 - 1.93 (m, IH), 1.87 - 1.63 (m, 2H), 1.62 - 1.32 fm, 12H).
Step B: (1 S,2R,4R)-I>J-(5-bromopyrimidin-2-yl)-7-azabicyclo[2.2.1 ]heptan-2-amine. To the title compound of step A (812 mg, 2.2 mmol) in DCM (1 1 mL) was added 4M HQ in dioxane (2.7 mL). After 16h, the reaction was concentrated, neutralized with 5% Na^CO, (aq) and extracted with DCM (2X). The combined organics were dried ( aaSC ) to give the title compound of step B that was used without further purification. MS (ESI): mass calcd. for C10H13BrN4, 268.0; m/z found, 270.9 [M+H .
Step C: (( 1 S,2R,4R)-2-((5-bromopyrimidin-2-yl)ammo)-7-azabicyclo[2.2.1 jheptan-7- yl)(3-fluoro-2~(2H-l ,2,3-triazol-2-yl)phenyl)nietlianone. To a solution of the title compound of step B (30 mg, 0.11 mmol) and intermediate A- 16 (25 mg, 0.12. mmol) in DCM (1.1 mL) was added DIPEA (0.12 mL, 0.67 mmol) followed by HATIJ (51 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 16h. Solvent was e vaporated and purification via prep HPLC gave the title compound (50 mg, 98%). MS (ESI): mass calcd. for CigHnB F /Q, 457.1 ; m/z found, 459.8 ΓΜ+Η] ; . ii NMR (500 MHz, CDC! 3, Compound present as a mixture of rotamers (0.57:0.43), only major rotamer reported) δ 8.20 (s, 2H), 7.92 (s, 2H), 7.37 - 7.31 (m, 1H), 7.30■ 7.27 (m, 1H), 7.21 - 7.15 (m, 1H), 4.74 (t, J= 4.8 Hz, 1H), 4.13 (td, J= 8.3, 3.2 Hz, IH), 3.95 (d, J=5.0Hz, 1H), 2.11 (dd,J= 13.0, 8.0 Hz, 1H), 1.88 - 1.73 (m, 2H), 1.65 - 1.59 (m, ill!.1.52 - 1.42 !m.2H). Example 318: ((lS,2R,4R)-2-((5-bromopyTimidin-2-y{)amino)-7-azabicyclo[2.2J]heptan-7- iazol-2-y3)phenyl)methanone
Figure imgf000246_0001
Prepared analogous to Example 317 substituting intermediate A- 16 with intermediate A- 24. MS (ESI): mass calcd. for C20H20BrN7O, 453.1; m/z found, 453.9 [M+H . ¾ NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.59:0.58), only major rotamer reported) δ 8.20 (s, 2H), 7.88 (s, 2H), 7.44■■ 7.42 (m, IH), 7.34■■ 7.28 (m, IH), 7.22 - 7.17 (m, 1H), 4.69 (t, J= 4.9 Hz, IH), 4.07 (dd, /= 8.2, 3.4 Hz, IH), 3.96 (d, J= 5.1 Hz, H), 2.22 (s, 3H), 2.10 (dd, J = 32.9, 8.0 Hz, IH), 1.93 - 1.85 (m, IH), 1.83 - 1.74 (m, IH), 3.64 - 1.53 (m, 111).1.47- 1.42 (m, IH). ixample 319: (3-methyl-2-^yridin-2-yl)phenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyridin- vl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000247_0001
Example 320: (3-fluoro-2-(pyridin-2-yl)phenyl)(( l S,2R,4 )-2-((5-(trifluoromethyl)pyridm-2^
]heptan-7-yi)meihanone
Figure imgf000247_0002
Step A: (3 -fluoro-2-iodophenyl)((l S,2R^4R)-2-((5-(trifluoromethyi)pyridin-2-yl)am
7-azabicyelo[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 279 substituting intermediate A-2 with 3-fluoro-2-iodobenzoic acid. MS (ESI): mass calcd. for
Figure imgf000247_0003
505.0; m/z found 506.0 j V! · Π j . 1 1 N .Y1 R (500 MHz, CDC13) δ 8.35 (s, 0.5H), 8.24 (s, 0.5H), 7.60■· 7.50 (m, 1H), 7.40■■ 7.33 (m, 0.6H), 7.14 - 7.02 (m, 1.4H), 6.98■■ 6.92 (m, 0.5H), 6.90 (d, J = 7.4 Hz, 0.5H), 6.47 - 6.37 (m, IH), 5.36 (s, 0.5H), 4.95 - 4.90 (m, 0.5H), 4.82 (d, J = 5.4 Hz, 0.5H), 4.76 (s, 0.5H), 4.28 - 4.20 (m, 0.5H), 3.99 (s, 0.5H), 3.80 - 3.75 (m, 0.5H), 3.73 (d, J = 4.3 Hz, 0.5H), 2.21 ■■ 2.1 1 (m, IH), 2.08■■ 1.44 (m, 5H).
Step B: (3-fluoro-2-(pyridin-2-y])phenyl)((l S,2R,4R)-2-((5-(mfluorometbyl)pyridin-2- y])ammo)~7-azahicycfo[2.2.1 ]heptan-7-yl)methanone. Prepared analogous to Example 260 Step B substituting 2-(tributylstamryl)oxazole with 2-(tributylstannyl)pyridine. MS (ESI): mass calcd. for C24H20F4N4O, 456.2; m/z found, 457.1 [M+H]+. Analytical HPLC was obtained on a Agilent 1 100 Series using a XBridge C18 column (5μηι, 100 x 4.6mm), mobile phase of 10- 1 00% ACN in 20 mM NH4OH over 8 min and then hold at 100% ACN for 3 min, at a flow rate of 1 mL/min (Temperature = 30 °C). Rt = 7.26 min (major rotamer) at 254 nm. Example 321 : (3-fluoro-2-(pyridin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrimidm-2- yl)ainino)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone
Figure imgf000248_0001
Example 32.2: (3-methyl-2-(pyridin-2-yi)pheny^
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000248_0002
Example 32.3: (3-fluoro-2-(pyridin-2-yl)phenyl)((2S)-2-((5-(lrifiuororaethyl)pyrazin- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000248_0003
Example 324: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyridm-2- yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000249_0001
Example 325: (2-inethoxy-6-(pyritnidm-2-yl)phenyi)((l S,2R,4R)-2-((5- 2-yl)oxy)-7-azabicyc]o[2.2.1]heptan-7-yl)methanone
Figure imgf000249_0002
Example 326: (5-fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5-
(triiluorometliyl)pyridin-2-yl)oxy)-7-aza.bicyclo[2.2.1]hepiaii-7-yl)ineihanone
Figure imgf000249_0003
Example 327: (4-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((lS,2R,4R)-2-((5- (trifluoronietliyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]hepiaii-7-yl)ineihanone
Figure imgf000249_0004
Example 328: (3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5-
(triiluoronietliyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]hepiaii-7-yl)ineihanone
Figure imgf000250_0001
Example 329: (5-fluoro-2-(pyrimidm-2-yl)phenyl)((l ^^
yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)raethanone
Figure imgf000250_0002
Example 330: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((l S,2 ,4R)-2-((5-(trifluoromethyl)pyridm-2- .1]heptan-7-yl)methanone
Figure imgf000250_0003
Example 331 : (2-(2H- 1 ,2,3-triazol-2-yl)pbenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyridm-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000250_0004
Example 332: (6-meihyi-3-(2H- 1 ,2,3 -triazol-2-yl)pyridin-2-yl)((l S,2R,4R)-2-((5- (trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2J]hq)tan-7-yl)inethanone
Figure imgf000251_0001
Exanipie 333 : (3-methyi-2-(oxazol-2-yi)phenyl)(( 1 S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)raethanone
Figure imgf000251_0002
Example 334: (3-methyl-2-(pyridm-2-yl)phenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyridm-2
.1]heptan-7-yl)methanone
Figure imgf000251_0003
Example 335: (2-(5-fluoropyrimidm-2-yf)phenyl)((l S,2R,4R)-2-((5-(tri
yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000251_0004
Example 336: (2-fluoro-6-(2H-l,2,3-triazol-2-y1)phenyl)((lS,2R,4R)-2-((5-
(trifluorome1hyl)pyridi"n-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000252_0001
Example 337: i -meth l -3-; 211- i J.3-ni l-2 ·\ i )p ^ίί·:· ·2· νΙ >(' 1S.2R.-IR >·2·ϋ5
(tri fluoromethyljpyri din-2-y 1) oxy)- 7 -azabicycl o [2..2.1 ] h eptan-7-yl)methanone
Figure imgf000252_0002
Example 338: (2-bromo-3-fluorophenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pjoidin-2-yl)oxy)-
7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000252_0003
Example 339: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyTazin-2- yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000252_0004
Example 340: (2-methoxy-6-(pyr-imidin-2-yi)phe"nyl)(( 1 S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2 ]heptan-7-yl)methanone
Figure imgf000253_0001
Example 341 : (5-fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)((lS,2R,4R)-2-((5- -y])oxy)-7-azabicyclo[2.2.1] eptan-7-yl)methanone
Figure imgf000253_0002
Example 342: (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)metha.none
Figure imgf000253_0003
Example 343 : (3-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- 2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)metha.none
Figure imgf000253_0004
Example 344: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyraz^ yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000254_0001
Example 345: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((lS,2R,4R)-2-((5-(irifluoromethyl)pyrazin- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)raethanone
Figure imgf000254_0002
Example 346: (2-(2H- 1 ,2,3- riazol-2-yi)phei yl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000254_0003
Example 347: (6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)((lS!2R,4R)-2-((5-
(trifluoromethyl)pyrazin-2-y3)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000254_0004
Exanipie 348: (3-methyi-2-(oxazol-2-yi)phenyl)( S,2R,4R)-2-((5-(trifluoromethyl)pyrazhi-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)raethanone
Figure imgf000255_0001
N
Example 349: (3-memyi-2-(pyridin-2-yl)phenyl)((lS,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2~ yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)raethanone
Figure imgf000255_0002
Example 350: (2-(5-fluoropyrimidin-2-yl)pheny{)((l S,2R,4R)-2-((5-(trifluoromethy{)pyrazin-2- .1]heptan-7-yl)methanone
Figure imgf000255_0003
Example 351 : (2-f!uoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((lS!2R,4R)-2-((5- 2-y3)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000255_0004
Example 352: (5-methyl- 3-(2H- 1 ,2,3 -triazol-2-yt)pyridin-2-yl)(( 1 S!2R,4R)-2-((5 - (trifluoromethyl)pyrazin-2-y3)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000256_0001
F
Example 353 : (2-bromo-3-fluorophenyl)(( 1 S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-
7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000256_0002
F !
Example 354: (2-meth xy-6-(pyrimidm-2-yl)phenyi)(( 1 S.2li.4li }-2-( {5- 2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000256_0003
Example 355: (5-f!uoro-2-(2H- 1 ,2,3-triazol-2-yJ)phenyl)(( 1 S,2R,4R)-2-((5 - (trifiuorometliyl)pyrimidm-2~y^
Figure imgf000256_0004
Example 356: (4-meihyi-2-(2H- 1 ,2,3 -triazol-2-yl)phenyi)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicycio[2.2J]heptan-7-yl)raethanone
Figure imgf000257_0001
Example 357: (3-meihyi-2-(2H- 1 ,2,3 -triazol-2-yl)phenyi)((l S,2R,4 )-2-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyc{o[2.2J]heptan-7-yl)raethanone
Figure imgf000257_0002
Example 358: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyc{o[2.2J]heptan-7-yl)raethanone
Figure imgf000257_0003
N
F
Example 359: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5- in-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)inethaiione
Figure imgf000257_0004
Example 360: (2-(2H- 1 ,2 ,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrimidm-2- yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000258_0001
Example 361 : (6-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)((lS,2R,4R)-2-((5- 2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000258_0002
Example 362: (3-methyl-2-(oxazoj-2-yl)phenyl)((l S,2R,4R)-2-CC5-(trifluoromethyl)pyrimidm-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000258_0003
Example 363: (3-methyi-2-(pyTidin-2-yl)phenyl)((l S,2R,4R)-2~((5-(trifluoromeihyl)pyrimidm- -yi)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000258_0004
Example 364: (2-(5-fluoropyrimidin-2-yl)phenyl)(( l S,2R,4R^ 2-yl)oxy)-7-azabicyclo[2.2.1] eptan-7-yl)methanone
Figure imgf000259_0001
Example 365: (2 -fl uoro-6-(2H- 1,2,3 -triazol-2 - l)phenyl)(( 1 S,2R,4R)-2-((5- in-2-yl)oxy)-7-azabicyclo[2.2.1Jheptan-7-yl)methanone
Figure imgf000259_0002
Example 366: (5-methyl-3-(2H- 1 ,2,3-triazol-2-yl)pyridin-2-yl)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone
Figure imgf000259_0003
Example 367: (2-bromo-3-tluoropheriyl)((l S,2R,4R)-2-((5-(irifiuoromeihy yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone
Figure imgf000259_0004
Example 368: (4-fluoro-2-(2H- 1 ,2,3-triazol-2-yi)phenyl)(( 1 S,2R,4R)-2-((5- (trifluoromethyi)pyridin-2-yl)am^
Figure imgf000260_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 12. MS (ESI): mass calcd. for C2]H] SF4N60, 446.1 ; m/'z found, 447.1 [Μ+ΗΫ. ]H NMR (500 MHz, CDCh, Compound present as a mixture of rotamers (0.64:0.36), only major rotamer reported) δ 8.22 (s, IH), 7.91 i s, 2H), 7.57 (dd, J= 9.1 , 2.5 Hz, IH), 7.40 - 7.33 (m, 2H), 6.38 (d, ./ 8.7 Hz, i l l ). 6.05 (s, IH), 4.83 (t, ./ 4.5 Hz, i l l ;. 4.24 - 4.16 (m, Hi), 3.93 - 3.88 (m, IH), 2.22 - 2.10 (m, IH), 2.09 ■ 1.86 (m, 11 1 ) . 1.68 - 1.61 (m, 1.57■· 1.50 (m, IH).
Example 369: (5-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- (trMuoromethyl)pyridin-2-yl)amm^
Figure imgf000260_0002
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 10. MS (ESI): mass calcd. for
Figure imgf000260_0003
446.1 ; mix found, 446.9 [M+Hf. i NMR (400 MHz, CDCls, Compound present as a mixture of rotamers) δ 8.40 - 8.19 (m, IH), 7.99 - 7.73 (series of m, 3H), 7.58 - 7.31 (m, IH), 7.31 - 7.1 0 (series of m, 2H), 7.06 (dd, J= 7.9, 2.9 Hz, IH), 6.16 - 5.67 (series of m, I H), 4.90 - 4.68 (series of m, I H), 4.38 - 3.84 (series of m, I H), 2.20 - 1.40 (series of m, 6H). Example 370: (2-fluoro-6-(2H- 1 ,2,3-triazol-2-yl)phen !)(( 1 S,2R,4R)-2-((5- )amino)-7-azabicyclo[2.2 ]heptan-7-yl)methanone.
Figure imgf000261_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 11. MS (ESI): mass caicd. for C2]H] SF4N60, 446.1 ; m/z found, 446.9 [M+Hf. Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a How rate of 2.2 mL/min (Temperature = 50 °C). Rt :;; 1.27 min (major rotamer) at 254 run.
Example 371 : (5-fIuoro-2-(pyrimidin-2-yi)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyridm-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000261_0002
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-7. MS (ESI): mass caicd. for Q23H19F4N5O, 457.2; m/z found, 458.2 [M+H]+. !H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0,80:0.20), only major rotamer reported) δ 8.82 i d. ./ 4.9 Hz, 2H), 8.22 (s, l ! . 8.02 (dd, ,/ 8.6, 5.4 Hz, i l l ). 7.34 - 7.27 (m, 2H), 7.15 (dd, J= 8.3, 2.7 Hz, 1H), 7.04 (dd, J= 8.4, 2.7 Hz, 1H), 6.01 - 5.88 (m, 1 H), 4.84 (t, J = 4.5 Hz, IH), 4.37 (s, IH), 4.07 - 4.01 (m, 1H), 2.20 (dd, ./- 13.0, 8.1 Hz, I H), 2.00 - 1.89 (m, 2H), 1.80 - 1.51 (series of m, 3H). Example 372: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyridm-2- yl)ainino)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone.
Figure imgf000262_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-6. MS (ESI): mass calcd. for C23H19F4N50, 457.2; m/z found, 458.2 [M+H]\ ¾ NMR (500 MHz, CDCI3, Compound present as mixture of rotamers) δ 8.85 (d, J= 4.9 Hz, 2H), 8.22 (s, IH), 7.78 (d, J= 7.7 Hz, 1H), 7.66 (d, J = 9.8 Hz, 1H), 7.48 - 7.43 (m, IH), 7.37 (t, J= 4.9 Hz, 1H), 7.18 (t, J= 8.8 Hz, IH), 5.88 (d, J= 8.8 Hz, 1 H), 4.88 (t, ,/ - 4.9 Hz, 1 H), 4.49 - 4.36 (m, IH), 3.93 (d, J = 5.0 Hz, IH), 2.25 (dd, J= 12.9, 7.9 Hz, IH), 2.18 - 2.08 (m, IH), 2.03■· 1.93 (m, IH), 1.81 - 1.67 (m, 2H). *1H buried under solvent peak.
Example 373: (2-(pyrimidin-2-yl)pheny1)((l S,2R,4R)-2-((5-(trifluoromethy1)pyridin-2- ]heptan-7-yf)methanone.
Figure imgf000262_0002
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 59. MS (ESI): mass caicd. for C23H20F3N5O, 439.2; m/z found, 440.0 [Μ+ΗΫ. ]H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.82:0.18), only major rotamer reported) δ 8.83 (d, J= 4.9 Hz, 2H), 8.23 - 8.20 (m, IH), 7.97 (d, J= 7.7 Hz, IH), 7.50 - 7.45 (m, IH), 7.41 - 7.35 (m, 2H), 7.32 (t, ./ 4.9 Hz, IH), 5.94 (d, ./ 8.8 Hz, IH), 4.84 (t, ./ 4.5 Hz, IH), 4.46■■ 4.30 (m, IH), 4.06 (d, J= 4.6 Hz, IH), 2.20 (dd, J= 12.9, 8.0 Hz, IH), 1.99■■ 1.91 (m, 2H), 1.82. - 1.59 (m, 2H), 1.59 - 1.50 (m, I H). * 1 H buried under solvent peak. Example 374: (2-(5-fluoropyrimidin-2-yl)phenyi)((lS,2R^4 )-2-((5-(Mfluoromethyi)pyridin- ]heptan-7-yl)methanone.
Figure imgf000263_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-
55. MS (ESI): mass caicd. for
Figure imgf000263_0002
457.2; m/z found, 457.9 [Μ+ΗΫ. !H NMR (500 MHz, CDCls) δ 8.68 (s, 2H), 8.21 (s, 1H), 7.93 (d,J= 7.7 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.38 - 7.30 (m, 3H), 6.00 (d, J= 8.8 Hz, IH), 4.83 (t, J= 4.6 Hz, i 11 i.4.29 (s, IH), 4.05 (d, J= 4.611/ il-I), 2,18 idd. 13.0, 8.0 Hz, IH), 2.05 - 1.92 (m, 2H), 1.71 - 1.64 (m, 2H), 1.59 - 1.54 (m, IH).
Example 375: (3-fluoro-2-(5-fluoropyrimdin-2-yr)phenyl)((lS52R,4R)-2-((5- (trifluoromethyl)pyridin-2-yl)animo)-7-azabicyclo[2.2.1]heptaii-7-yl)methanone.
Figure imgf000263_0003
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-
57. MS (ESI): mass calcd. for C23Hi8F;N50, 475.1 ; m/z found, 475.9 [M+H]+. Ή NMR (400 MHz, CDCI3) δ 8.73 (s, 2H), 8.28 - 8.13 (m, IH), 7.38 - 7.31 (m, 2H), 7.18 - 7.14 (m, 2H), 6.19 (d, ,/ 8.8 Hz, ill).4.72 (t, ./ 4.9 Hz, IH), 4.38 - 4.26 (m, IH), 4.09 (d, ./ 5.0 Hz, ill).2.16 (dd,J= 12.9, 8.1 Hz, IH), 2.07 - 1.98 (m, IH), 1.95 - 1.86 (m, IH), 1.75 - 1.66 (m, IH), 1.66 - 1.57 (m, IH), 1.57 - 1.48 (m, IH). Example 376: (3-chloro-2-(pyrimidiR-2-yl)phenyi)((iS,2R,4R)- yl)ainino)-7-azabicyclo[2.2.1 ] eptan-7-yl)methanone.
Figure imgf000264_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A~
58. MS (ESI): mass caicd. for ( >:Π .,(ΊΙ·;Ν5().473.1; m/z found, 474.1 ivi-lii . ¾ M (500 MHz, CDCh, Compound present as a mixture of rotamers (0.92:0.08), only major rotamer reported) δ 8.88 (d, J= 5.0 Hz, 2H), 8.24 - 8.19 (m, 1H), 7.67 - 7.60 (m, IH), 7.45 (dd, J= 5.9, 3.3 Hz, HI), 7.39 (t, J- ---- 5.0 Hz, 1H), 7.32 (dd, J= 8.8, 2.5 Hz, IH), 7.27 id../ 2.6 Hz, 1H), 6.29 (d, J= 8.8 Hz, 1H), 4.66 (i, J= 5.1 Hz, 1H), 4.32 (td, J= 8.6, 3.7 Hz, IH), 4.06 (d, J= 4.9 Hz, IH), 2.11 (dd, J= 12.9, 8.2 Hz, IH), 2.05 - 1.97 (m, IH), 1.92 - 1.84 (in, 1H), 1.74 - 1.67 (m, 1H), 1.59 - 1.53 (m, IH), 1.53 - 1.46 (m, IH).
Example 377: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((lS,2R,4R)-2-(meth l(5- )amino)-7-azabicyelo[2.2J
Figure imgf000264_0002
To a solution of compound of Example 279 (19 mg, 0,042 mmol) in DMF (0.42 mL) was added sodium tei -butoxide (5 mg, 0.05 mmol) followed by iodomethane (2.7 μΕ, 0.044 mmol). The reaction mixture was stirred ai room temperature for 12 hour's. Solvent was evaporated and purification via prep HPLC gave the title compound (16 mg, 82%). MS (ESI): mass calcd. for C24H21F4N5O, 471.2; m/z found, 472.2 [M+H . :H MR (500 MHz, CDCL Compound present as a mixture of rotamers (0.82:0.18), only major rotamer reported) δ 8.80 (d, J--- 4.9 Hz, 2H), 8.37 (s, IH), 7.62 (dd, J= 9.1, 2.6 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.32 - 7.22 (series of m, 3H), 6.50 (d,J=9.1 Hz, 1H), 4.93 (dd, J= 8.3, 5.0 Hz, H), 4.63 (d,J=4.1 Hz, 1H), 4.08 (t,J=4.4 Hz, 1H), 2.93 (s, Ml).2.09 (dd, J= 12.7, 8.3 Hz, IH), 1.92 -1.81 (m, 211).1.70 - 1.60 (m, 2H), 1.54- 1.45 (m, IH).
Example 378: (5-methyl-2-(pyriniidin-2-y1)pyridin-3-yl)((lS,2R,4R)-2-((5- o)-7-azabicyclo[2.2.1]heptan-7-yl)methano"ne.
Figure imgf000265_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 66. MS (ESI): mass calcd. for€23Η21Ρ3 60, 454.2; m/z found, 455.2 [M+Hf. i NMR (400 MHz, CDC1;„ Compound present as a mixture of rotamers (0.81:0.19), only major rotamer reported) δ 8.89 (d, J= 4.9 Hz, 2H), 8.56 id../ 1.7 Hz, 1H), 8.26 - 8.20 (m, IH), 7.48■ 7.41 (m. IH), 7.39 (t, J= 4.9 Hz, 1H), 7.35 - 7.28 (m, 1H), 6.01 (d, J= 8.8 Hz, 1H), 4.84 (t, J= 4.4 Hz, IH), 4.33 (s, IH), 3.98 id. J= 4.6 Hz, If 112.31 (s, 3H), 2.20 (dd, J= 13.0, 8.1 Hz, IH), 2.00 - 1.88 (series of m, 2H), 1.79 - 1.50 (series of m, 3H).
Example 379: (6-methyl-3-(pyrimidiii-2-yl)pyridin-2-y{)((l S,2R,4R)-2-((5- o)-7-azabicyclo[2.2.1]heptaii-7-yl)methanone.
Figure imgf000265_0002
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 63. MS (EST): mass calcd. for uh i:;X,,0.454.2; m/z found, |M-fl| . I! NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.89:0.1 1 ), only major rotamer reported) δ 8.79 (d, J= 4.9 Hz, IH), 8.31 (d, J = 8.1 Hz, 1H), 8.28 ·■ 8.24 (m, IH), 7.40 (dd, J= 8.8, 2.5 Hz, 1H), 7.31 - 7.26 (series of m, 3H), 7.18 (d, J = 8.8 Hz, I H), 6.21 (d, J= 8.8 Hz, IH), 4.89 (†, J = 4.7 Hz, I H), 4.39 - 4.24 (m, I H), 4.08 i d. ./ 5.1 Hz, IH), 2.61 (s, 3H), 2.19 (dd, ./ - 13.0, 7.5 Hz, IH), 2, 1 1 - 1.93 (series of m, 2H), 1.87 - 1.55 (series of m, 3H).
Example 380: (5-methyl~3-(pyrimidin~2-yl)pyridin-2-yl)((
o)-7-azabicyclo[2.2.1]heptan-7-yl)methano"ne.
Figure imgf000266_0001
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-
67. MS (ESI): mass caicd. for C > :l h !; :N„0. 454.2; m/z found, 455.2 [Μ+ΗΫ. ]H NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.88:0.12), only major rotamer reported) 8 8.83 (d, J = 4.9 Hz, 2H), 8.40 (dd, J - 2.1 , 0.9 Hz, 1 H), 8.26 - 8.22 (m, 1 H), 8.16 (dd, /= 2.0, 0.9 Hz, IH), 7.36 (dd, J= 8.8, 2.5 Hz, IH), 7.32 (t, J = 4.9 Hz, IH), 7.28 (d, /= 9.4 Hz, IH), 6.14 (d, J = 8.8 Hz, IH), 4.86 (t, J= 4.8 Hz, IH), 4.34 - 4.25 (m, IH), 4.13 (d, J = 5.2 Hz, I H), 2.41 (s, 3H), 2.19 (dd, ./- 12.9, 7.7 Hz, IH), 2.12 - 2.05 (m, IH), 2.03 - 1.93 (m, IH), 1.81 - 1.73 (m, IH), 1.65 - 1.52 (m, 2H).
Example 381 : (3-(pyrimidin-2-yl)pyridin-2-y{)((l S,2R,4R)-2-((5-(trifluoromethyl)pyridin- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000266_0002
Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A- 64, MS (ESI): mass eaicd. for C22H19F, 60, 440.2; m/z found, 441.2 [M+H]+. !H NMR (400 MHz, CDCij, Compound present as a mixture of rotamers (0.87:0.13), only major rotamer reported) δ 8.83 (d, .7 - 4.9 Hz, 2H), 8.59 (dd, J= 4.8, 1.7 Hz, 1H), 8.39 (dd, J= 7.9, 1.7 Hz, 1H), 8.26 - 8.22 (m, 1 H), 7.43 (dd, J= 7.9, 4.8 Hz, 1H), 7.37 (dd, ./ 8.9, 2.5 Hz, IH), 7.33 (t, J = 4.9 Hz, IH), 7.23 (d, J= 9.4 Hz, IH), 6.15 (d, J = 8.8 Hz, IH), 4.88 (t, J= 4.9 Hz, IH), 4.35 - 4.26 (m, IH), 4.1 1 (d, J= 5.2 Hz, IH), 2.20 (dd, J= 13.0, 7.7 Hz, IH), 2.14 - 2.07 (m, IH), 2.04 - 1.91 (m, IH), 1.84 - 1.74 (m, IH), 1.66 - 1.53 fm, 2H). Example 382: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5-
(trifluoromethyf)pyridin^
Figure imgf000267_0001
Step A: (1 S,2R,4R)-tert-butyi 2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- azabieyclo[2.2.1]heptane-7-carboxy].ate. In a microwave vial was dissolved intermediate B-5 (1.6g, 7.3 mmol) in ACN (11 mL). 2,3-difluoro-5-(trifluorornethyl)pyridine (0.74 mL, 5.82 mmol) was added followed by Et¾N (1 mL, 7.28 mmol). The microwave vial was capped and the reaction mixture was heated to reflux for 16h. Solvent was evaporated and purification via silica gel chromatography (0-2.0% EtOAc in hexanes) gave the title compound (1 .7g, 94%). MS (ESI): mass calcd. for C17H2JF4N3O2, 375.2; nv'z found, 376.2 [M+H]+. Ή NMR (500 MHz, CDCI3): δ 8.15 (s, IH), 7.29 f dd, J= 10.8, 2.0 Hz, IH), 5.23 (s, Hi), 4.36 - 4.27 (m, IH), 4.27 - 4.21 (m, IH), 4.21 - 4.15 (m, IH), 2.08 (dd, J= 13.1 , 7.7 Hz, IH), 1.91 - 1 .80 (m, IH), 1.80 - 1.70 (m, IH), 1.63 - 1.48 (m, 2H), 1.43 (s, lOH).
Step B: (1 S,2R,4R)-N-(3-fluoro-5-(trifluoromethyl)pyridm-2-yl)-7- azabicyclo[2.2.1]heptan-2-amine. To the title compound of step A (135 mg, 0.36 mmoi) in DCM (3.6 mL) was added 4M HC1 in dioxane (0.9 mL). After 16h, the reaction was concentrated, neutralized with 5% a2C03 (aq) and extracted with DCM (2X). The combined orga ics were dried (Na2S04) to give the title compound of step B that was used without further purification. MS (ESI) mass calcd. for C12H13F4N3, 275.1 ; m/z found 276.0 [M-i-H]+. Step C: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5-
(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2 ]heptan-7-yl)methanone.
To the title compound of step B (98 mg, 0.36 mmol) in DCM (3,6 mL) was added DIPEA (0.08 mL, 0.46 mmol) and intermediate A-2 (93 mg, 0.43 mmol). Then T3P (50% solution in DMF, 0.64 mL, 1.07 mmol) was added dropwise and the reaction heated at 45 °C for 16h. Solvent was evaporated and purification via prep HPLC gave the title compound (133 mg, 79%). MS (ESI): mass calcd. for O d i · Ν ·ϋ. 475.1 ; m/z found, 476.1 i vi - U i . :H MR (500 MHz, CDCh, Compound present as a mixture of rotamers (0.83:0.17), major rotamer reported) 8 8.84 (d, J- 5.0 Hz, 2H), 8.05 (s, 1H), 7.59 (br s, 1H), 7.36 - 7.30 (m, 2H), 7.23■· 7.10 (m, 3H), 4.84■■ 4.71 (m, 1H), 4.56 - 4.49 (m, 1H), 4.02 (d, J= 4.8 Hz, 1H), 2.20 (dd, J = 12.8, 8.3 Hz, 1H), 2.01 - 1.84 (m, 2H), 1.83 - 1.68 (m, 2H), 1.57 - 1 .49 (m, 1H).
Example 383: (( 1 S,2R,4R)-2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- (3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.
Figure imgf000268_0001
Step A: ( 1 S,2R,4R)-tert-butyl 2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 382 step A substituting 2,3-difluoro-5-(trifluoromethyl)pyridme with 3-chj ro-2-fluoro-5-(trifluoromethy](pyri.dine). MS (ESI): mass calcd. for C17H21CIF3N3O2, 391.1 ; m ,··: found, 392.2 [ M 1 11 . 1 1 \ \ I R (500 MHz, CDCI3) δ 8.26 (s, 1H), 7.62 (s, 1H), 5.65 (s, 1H), 4.39 - 4.22 (m, 2H), 4.22 - 4.13 (m, 1H), 2.09 (dd, J= 13.1 , 7.7 Hz, 1H), 1 .90 - 1.81 (m, IH), 1.81 - 1.71 (m, 1H), 1.62 - 1 .49 (m, 2H), 1.44 (s, 10Ϊ-1).
Step B: (1 S,2R,4R)-N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-7- azabicyclo[2.2.1]heptan-2-amine. Prepared analogous to Example 382 step B. MS (ESI): mass calcd. for CJ2H13CIF3N3, 291.1 ; m/z found, 292.1 [M+H] ; .
Step C: (( I S,2R,4R)-2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptan-7-yl)(3-fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone. Prepared analogous to Example 382 step C substituting intermediate A-2 with intermediate A- 16. MS (ESI): mass calcd. for α,ίΗ 7αΡ4 60, 480.1; m/z found, 481.1 [M+H]+. Ή NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.64:0.36), only major rotamer reported) δ 8.16 (s, IH), 7.88 (s, 2H), 7.60 (d, J= 2.1 Hz, I H), 7.43 - 7.30 (m, I H), 7.25 - 7.2 ! (m, IH), 7.18 - 7.12 (m, IH), 4.77 (t, 4.5 Hz, I H), 4.29 - 4.19 (m, IH), 3.92 - 3.89 an. IH), 2, 13 (dd, ./ 13.1, 8.1 Hz, IH), 1.80■ 1.36 (series of m, 5H).
Example 384: (( 1 S,2R,4R)-2-((3-cUoro-5-(trifluoromemyl)pyri(Un-2-yl)amino)-7- azabicyclo[2.2 ]heptan-7-yl)(3-fluoiO-2-(pyriniidin-2-yl)phenyl)methanone.
Figure imgf000269_0001
Prepared analogous to Example 383 substituting intermediate A- 16 with A-2. MS (ESI): mass calcd. for C^HixC^NsO, 491.1; m/z found, 492.1 [M+H . 'H MR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.74:0.26), only major rotamer reported) δ 8.84 (d, J= 4.8 Hz, 2H), 8.17 (s, IH), 7.55 (d, J = 2.2 Hz, IH), 7.32■ 7.26 (series of m, 2H), 7.19 ·■ 7.12 (series of m, 2H), 4.77 (t, J= 4.6 Hz, IH), 4.46 - 4.31 (m, I H), 3.98 (d, J= 4.3 Hz, IH), 2.25 - 2.13 (m, IH), 1.93 - 1.63 (series of m, 4H), 1.59 - 1.35 (m, IH).
Example 385: ((1 S,2R,4R) -2-((3-chloro - 5-(trifluoromethyl)pyridin-2~yl)amino)■ 7- 2-(5-iluoropyrimidin-2-yl)phenyl)methanone.
Figure imgf000269_0002
Prepared analogous to Example 383 substituting intermediate A- 16 with A-55. MS (ESI) mass mass calcd. for O . I CIF .N.xO. 491.1 ; m/z found, 492.1 [M+H] \ Ή NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.72:0.28), only major rotamer reported) δ 8.63 (s, 2H), 8.17 - 8.12 (m, IH), 8.08 - 8.02 (m, 1H), 7.56 (s, i 1 1 i. 7.57 - 7.37 (series of m, 2H), 7.37 - 7.29 (m, IH), 4.93 ft, J= 4.5 Hz, I I I ;. 4.36 - 4.24 (m, 1H), 3.90 (d, ,/ 5.0 Hz, IH), 2.21 (dd, J= 13.0, 8.1 Hz, IH), 2.00 - 1.51 (series of m, 5H).
Example 386: ((l S,2R,4R)-2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)ammo)-7- )(2-(pyrimidin-2-yl)phenyi)methanone.
Figure imgf000270_0001
Prepared analogous to Example 383 substituting intermediate A- 16 with A- 59. MS (ESI) mass calcd. for C23H19CIF3N5O, 473.1; m/z found, 474.1 [M+H]+. 'H MR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.74:0.26), only major rotamer reported) δ 8.79 (d, /= 4.9 Hz, 2H), 8.15■· 8.10 (m, 2H), 7.54■■ 7.52 (m, IH), 7.46■■ 7.39 (m, IH), 7.37 ·■ 7.29 (m, 2H), 7.22 ( J = 4.9 Hz, I H), 4.93 (t, J = 5.1 Hz, IH), 4.42 - 4.24 (m, IH), 3.89 (d, J = 5.0 Hz, IH), 2.20 f ile!. ./ 12.9, 8.1 Hz, I H), 1.99 - 1.47 (series of m, 5H).
Example 387: ((l S,2R,4R)-2-((3-chloro-5-(trifluoromethyl)p
azabicyclo[2.2.1]heptan-7-yi)(3-(pyrimidin-2-yl)pyridin-2-yl)methanone.
Figure imgf000270_0002
Prepared analogous to Example 383 substituting intermediate A-16 with A-64. MS (ESI) mass calcd. for C22i½ClF3N60, 474.1 ; m/z found, 475.1 [M+H . !H NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.89:0.1 1 ), only major rotamer reported) δ 8.79 (d, J= 4.9 Hz, 2H), 8.64 (dd, J= 4.8, 1.7 Hz, 1H), 8.50 (dd, J = 7.9, 1.7 Hz, IH), 8.23■ 8.19 (m, 1H), 7.60 (d, J = 2.1 Hz, IH), 7.47 (dd, J= 7.9, 4.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, IH), 7.25 (t, J= 4.9 Hz, I H), 4.94 (t, J = 4.7 Hz, i l l }. 4.38 (td, ./ 7.6, 2.9 Hz, i l l }. 4.12 (d, J= 4.8 Hz, I H), 2.25 (dd, J= 12.9, 7.4 Hz, 1H), 2.16 - 1.98 (series of m, 2H), 1.89 - 1.79 (m, 1H), 1.66 - 1.56 (series of m, 2H).
Example 388: ((1 S,2R,4R)-2-((5-(dif!uoromethyl)pyridin-2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-l ,2,3-triazol-2-yl)phenyl)methaiione.
Figure imgf000271_0001
Step A: (1 S,2R,4R.)-tert-buryi 2-((5-(diiluoromethyl)pyridin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. Prepared analogous to Example 279 step A substituting
2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-5-(difluoromethyl)pyridine. MS (ESI): mass calcd. for C17H23F2N3O2, 339.2; m/z found, 340.0 [M+Jfff. Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μτη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TEA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 0.601 min at 254 nm.
Step B: (lS,2R,4R)-N-(5-(o¾fluororaethyl)pyridin-2-yl)-7-azabicycio[2.2.1]heptan-2- amine. Prepared analogous to Example 279 step B. MS (ESI): mass calcd. for C12H15F2N3, 239.1 ; m/z found, 240.0 j \ ί · H j .
Step C: ((1 S,2R,4R)-2-(('5-(difluoromethyl)pyridin-2-yl)ainino)-7- azabicycio[2.2.1]hepten-7-yl)(3-fluoro-2-(2H-l ,2,3-triazol-2-yl)phenyi)methanone. Prepared analogous to Example 181 step C substituting intermediate A- 1 with intermediate A- 16. MS (ESI): mass calcd. for C^H^NeO, 428.2; m/z found, 429.0 [M+HJ ; . !H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.09 - 8.02 (m, IH), 7.95 (s, 2.H), 7.39 - 7.33 (m, 2H), 7.29 - 7.21 (m, I H), 7.16 (dt, ,/ = 7.6, 1 .2 Hz, IH), 6.48 (t, J- 56.3 Hz, IH), 6.32 id, J - ---- 8.8 Hz, IH), 4.77 - 4.69 On. I I I ). 4.30 - 4.22 (in, i l l ). 3.99 i d. J -- 4.9 Hz, I I I ·. 2.12 (dd, J = 13.0, 8.1 Hz, 1H), 1.98 - 1.81 (m, 2H), 1.72■■ 1.58 (m, 2H), 1.54■■ 1.47 (m, 1H).
Example 389: (( 1 S,2R,4R)-2-((5-(difluoromethyI)pyridin-2-yl)amino)-7- )(3-fluoro-2-(pyrimidin-2-yl)phenyl)methaiione.
Figure imgf000272_0001
Prepared analogous to Example 388 substituting intermediate A- 16 with intermediate A- 2. MS (ESI): mass calcd. for C23H20F3N5O, 439.2; m/z found, 439.9 [M+H . ¾ NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.89:0.1 1), only major rotamer reported) δ 8.87 (d, J = 5.0 Hz, 2H), 8.09 - 8.02 (m, 1H), 7.51 - 7.43 (m, lH), 7.37 (t, J= 5.0 Hz, 1H), 7.34 - 7.28 (m, H), 7.21 - 7.12 (m, 2H), 6.47 (t, J= 56.3 Hz, IH), 6.22 (d, J= 8.7 Hz, I TT), 4.78 - 4.65 (m, IH), 4.35 ftd, ./ === 8.7, 3.7 Hz, IH), 4.07 i d. ./ 4.9 I Iz. I H), 2.15 (dd, J = 12.9, 8.1 Hz, IH), 2.05 - 1.96 (m, IH), 1.95■· 1.85 (m, IH), 1.76■■ 1.67 (m, IH), 1.63■■ 1.61 (m, IH), 1.55 - 1 .46 (m, IH).
Example 390: 6-((( l S,2R,4R)-7 3--fiuoro-2-(2H ,2,3-triazol-2--yi)benzoyl)-7-- azabicycio[2.2.1]hepten-2-yl)amino)nicotinonitrile.
Figure imgf000272_0002
Step A: (l S,2R,4R)-tert-butyi 2-((5-cyanopyridin-2-yI)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxyiate. To a solution of intermediate B-5 (442 mg, 2.08 mmol) in DMA (7 mL) was added DIPEA (0.72 mL, 4.16 mmol) followed by 2-chloro-5-cyanopyridine
(324 mg, 2.29 mmol). The reaction mixture was heated at 120 °C for 90 minittes using microwave and was then diluted with water and EtOAc. The aqueous phase was extracted twice with EtOAc and the combined organic layers were washed with a saturated solution ofNaCl, dried over MgS04, filtered and evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (41 6 nig, 64%). MS (ESI): mass calcd. for
C17H22N4O2, 314.2; m/z found, 315.1 ; M · H ! . Ή NMR (500 MHz, CDCI3) δ 8.36 (d, J = 2.2 Hz, i i ! ). 7.58 - 7.49 (m, i l l ;. 6.35 (d, J 8.7 Hz, i l l ). 5.42 (s, i l l ). 4.29 (s, l i ! ). 4.24 - 4.15 (m, 1H), 3.99 (s, 1H), 2.09 - 1.98 (m, 1H), 1.90 - 1.68 (m, 2H), 1.62 - 1.34 (m, 12H).
Step B: 6-((lS,2R,4R)-7-azabicyclo[2.2.1]heptan-2-yiainino)mcotinonitriie. To the title compound of step A (416 nig, 1.32 mmol) in DCM (6.5 mL) was added 4M HC1 in dioxane (1.7 mL). After 16h, the reaction was concentrated, neutralized with 5% ?C03 (aq) and extracted with DCM (2X). The combined organics were dried ( a2S04) to give the title compound of step B that was used without further purification. MS (ESI): mass calcd. for C^HMN,^ 214.1 ; m/z found, 215.0 i \) H I .
Step C: 6-(((l S,2R,4R)-7-(3-fluoro-2-(2H- l,2,3-triazol-2-yl)benzoyl)-7- azabicyclo[2.2.1 ]heptan~2~yl)amino)nicotinonitri1e. 'TO a solution of the title compound of step B (30 mg, 0, 14 mmol) and intermediate A- 16 (32 mg, 0.15 mmol) in DCM (1 .4 mL) was added DIPEA (0.15 mL, 0.84 mmol) followed by HATU (64 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 1 6I1. Solvent was evaporated and purification via prep HPLC gave the title compound (44 mg, 78%). MS (ESI): mass calcd. for C2]H]gFN70, 403.2; m/z found, 404.0 [M+H] ". Ti NMR (500 MHz, CDCL, Compound present as a mixture of rotamers) δ 8.25 (d, J = 2.1 Hz, IH), 7.96 (s, 2H), 7.40 - 7.27 (series of m, 3H), 7.18 (dt, J = 7.7, 1.1 Hz, IH), 6.27 (d, J= 8.9 Hz, I H), 4.79 - 4.68 (m, I H), 4.39 - 4.24 (m, I H), 3.97 (d, J = 5.0 Hz, IH), 2.12 (dd, J = 13.1 , 8.2 Hz, I H), 2.00 - 1.83 (m, 2H), 1.73 - 1.64 (m, 2H), 1 .55 - 1.48 (m, IH).
Example 391 : 6-(((l S,2R,4R)-7-(3-methyl-2-(2H- 1 ,2!3-triazol-2-yl)benzoyl)-7- azabicyclo[2.2.1 ]heptan-2-yl)amino)nicotinonitrile.
Figure imgf000273_0001
Prepared analogous to Example 390 substituting intermediate A- 16 with A-24. MS (ESI): mass calcd. for C > >H > X ). 399.2; m/z found, 400.0 [M+H] ; . lH NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.81 :0.19), only major rotamer reported) δ 8.25 (d, J= 2.3 Hz, 1H), 7.90 is, 2H), 7.39 - 7.27 (series of m, 3H), 7.23 - 7.15 (m, 1H), 6.31 (d, J = 9.0 Hz, 1H), 4.68 (t, J= 4.8 Hz, 1H), 4.37 - 4.20 (m, 1H), 3.95 (d, J = 5. 1 Hz, 1H), 2.19 (s, 3H), 2.12 - 2.03 (m, 1 H), 1.99 - 1.94 (m, M Y). 1.89 - 1.77 (m, 1 H), 1 .66 - 1.61 (m, IH), 1 .61 - 1.52 (m, 1H), 1.52 - 1.39 (m, 1H).
Example 392: 6-(((l S,2R,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7-azabicyclo[2.2.1]heptan- -yl)amino)nicotmomtrile.
Figure imgf000274_0001
Prepared analogous to Example 390 substituting intermediate A- l 6 with A-2. MS (ESI): mass calcd. for C23H19FN60, 414.2; m/z found, 415.0 [M+H]+. ?H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.87 (d, J --- 5.0 Hz, 2H), 8.25 (d, J --- 2.2 Hz, 1H), 8.10■· 7.99 (m, 1H), 7.40 (t, J = 4.9 Hz, 1H), 7.38 ·■ 7.34 (m, 1H), 7.31 - 7.27 (m, IH), 7.22■ 7.20 (m, 1H), 7.19 - 7.15 (m, I H), 6.16 (d, J - 8.8 Hz, IH), 4.79 - 4.67 (m, IH), 4.48 - 4.30 (m, IH), 4.07 (d, ./ 5.0 Hz, i l l ). 2.15 (dd, J= 13.0, 8.2 Hz, IH), 2,07 - 2.00 fm, IH), 1.96 - 1 .88 (m, IH), 1.76■■ 1.68 (m, IH), 1.68 - 1.63 (m, IH), 1.56 · 1.48 (m, IH).
Example 393 : 6-(((l S,2R,4R)-7-(3-methyl-2-(pyrimidin-2-yl)benzoyl)-7- l)amino)mcotinonitrile.
Figure imgf000274_0002
Prepared analogous to Example 390 substituting intermediate A- 16 with A-26. MS (ESI): mass calcd. for ( ·■ :! i N,.(). 410.2; m/z found, 41 1.0 [M+H . Π NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.83 (d, / = 5.0 Hz, 2H), 8.25 (d, ./-== 2.3 Hz, IH), 7.35 (t, J= 5.0 Hz, I H), 7.32 - 7.21 (m, 3H), 7.21 - 7.18 (m, III), 6.17 fd, J= 8.8 Hz, I H i. 4.72 - 4.62 (m, 1H), 4.42 - 4.31 (m, I I I ). 4.07 i d. ./ 5.0 Hz, IH), 2.30 (s, 3H), 2.1 1 (dd, ,/ 12.9, 8.1 Hz, IH), 2.07 - 1.98 (ni, 1H), 1.95 - 1 .84 (m, 1H), 1.72 - 1.65 (m, 1H), 1.61 - 1.54 (m, H), 1.52 - 1.45 (m, 1 H).
Example 394: 6-(((lS,2R,4R)-7-(3-methyl-2-(oxazol-2-yl)benzoyl)-7-azabicyclo[2.2.1]heptan-2-
Figure imgf000275_0001
Prepared analogous to Example 390 substituting intermediate A- 1 6 with A-31. MS (ES ): mass calcd. for C23H2SN5O2, 399.2; m/z found, 400.0 | M 1 1 1 . I I NMR (500 MHz, CDC¾,
Compound present as a mixture of rotamers (0.89:0.1 1), only major rotamer reported) δ 8.22 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 0.9 Hz, IH), 7.32■■ 7.22 (series of m, 4H), 7.20 - 7.13 (m, IH), 6.29 (dd, J= 9.0, 0.8 Hz, IH), 4.79 - 4.70 (m, IH), 4.39 - 4.27 (m, I H), 3.91 (d, J = 4.8 Hz, IH), 2.28 (s, 3H), 2.09 (dd, J= 12.9, 8.2 Hz, IH), 2.00 - 1 .87 (m, 2H), 1.73 - 1.64 (m, 2H), 1.54 - 1.46 (m, IH).
Example 395 : (3-fluoro-2-(pyrimidin-2-yl)phenyl) ((l S,2R,4R)-(2- H)-((5- (trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyck)[2.2.1 ]heptan-7^
Figure imgf000275_0002
Step A: ( l S,4R)-(2-iH)-tert-butyl 2-(((benzyloxy)carbo"nyl)ainmo)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. To a solution of intermediate (+)-B-2 (640 mg, 1.9 mniol) in CD3OD (5.5 mL) was added 0.45M NaOCD3 in CD3OD (5.8 mL, 2.90 mniol). The reaction mixture was heated to reflux for 2 days and cooled to room temperature. IN KHSO4 was added and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over MgSQ4, filtered and evaporated. The material was used in the next step without any further purification. To a solution of the residue in CD3OD (9.6 niL) cooled to 0 °C was added 2M NaOH in D20 (3.9 mL, 7.7 mmol). The reaction mixture was stirred for 2h and was then acidified with IN KHSO4 until pH 2-3. The aqueous phase was extracted 3 times with DCM and the combined organic layers were dried over MgS04, filtered and evaporated. The material was used in the next step without any further purification. 'TO the residue in PhC¾ (4.8 mL) was added TEA (0.3 mL, 2, 1 mmol). After heating in an oil bath to 70 °C, DPPA (0.46 mL, 2.1 mmol) in PI1CH3 ( 1 mL) was added. After 2.5h, BnOH (0, 19 mL, 1.8 mmol) was added and the oil bath temperature increased to 90 °C. After an additional 1 8I1, the reaction was cooled to rt, diluted with EtOAc and washed with saturated NaHC(½ (aq). The aqueous layer was extracted with EtOAc (IX). The combined organics were washed with brine and dried (MgS04).
Purification via prep HPLC gave gave the title compound (380 mg, 57%) as a mixture of diastereoisomers (80/20). MS (ESI): mass caicd. for Ci9H25DN204, 347.2; m/z found, 348.2 [M+H] Reporting only the major diastereoisomer. !H NMR (500 MHz, CDCI3) δ 7.40 - 7.28 · η·. 5H), 5.22 - 4.91 (m, 3H), 4.22 (s, 1H), 4.14 - 4.06 (m, 1 H), 1.92 i d. J= 13.1 Hz, ill), 1.85 - 1.59 (m, 2H), 1.44 (d, J = 7.6 Hz, 12H).
Step B: ί I S.2li .4R }- (2-2H)-tert-butyI 2-((5-(trifluoromethyl)pyrazin-2-y3)amino)-7- azabicyclo[2.2.1 ]heptane-7-carboxylate. To intermediate of step A (380 mg, 1.1 mmol) in EtOH (6.5 mL) was added 10 wt% Pd/C wet Degussa (79 mg). The reaction was purged with N2 followed by H2, then allowed to proceed under an atmosphere of H2 (balloon). Upon
completion, the reaction was filtered and concentrated to give the unprotected amine. MS (ESI): mass calcd. for C1 1H1 DN2O2, 213.2; m/z found, 214.2 [M+H] 1. In a microwave vial was dissolved the residue in ACN (3,7 mL). 5-chIoro-2-trifluoromethylpyrazine (0.08 mL, 0.66 mmol) was added followed by I¾N (0.1 1 mL, 0.82 mmol). The microwave vial was capped and the reaction mixtitre was heated to reflux for 16h. Solvent was evaporated and purification via silica gel chromatography (0-30% EtOAc in hexanes) gave the title compound (1 19 mg, 60%). Only the desired diastereoisomer was isolated. MS (ESI): mass calcd. for Q6H2oDF3N402, 359.2; m/z found, 360.2 [M+H]+. Ή NMR (400 MHz, CDCI3) δ 8.32 (s, lH), 7.85 (s, I H), 5.38 (s, I H), 4.30 (s, HI), 4.21 (s, HI), 2.06 i d. ./ 13.0 Hz, IH), 1.95 - 1.68 (m, 2H), 1.66 - 1.35 (m, 12H).
Step C: (3-fluoro-2-(pyrhnidin-2-yl)phenyl) ((l S,2R,4R)-(2-2H)-((5- (txifjuoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of step B (1 19 mg, 0.33 mmol) in DCM (3.3 mL) was added 4M HC1 in dioxane (0.4 mL). After 16h, the reaction was concentrated, neutralized with 5% Na2C03 (aq) and extracted with DCM (2X). The combined organics were dried (Na2S04) to give the unprotected amine that was used without any further purification in the next step, MS (ESI): mass calcd, for
C11H12DF3N4, 259.1; m/z found, 260.2 [M+H]+. To the residue in DCM (3,3 mL) was added DIPEA (0.07 mL, 0.43 mmol) and intermediate A-2 (86 mg, 0.39 mmol). Then T3P (50% solution in DMF, 0.59 mL, 0.98 mmol) was added dropwise and the reaction heated at 45 °C for 16h. Solvent was evaporated and purification via prep HPLC gave the title compound (107 mg, 71%). MS (ESI): mass calcd. for C22H17DF4N6O, 459.2; m/z found, 460.2 [M+H]+. Ή NMR (500 MHz, CDC1¾, Compound present as a mixture of rotamers (0.93:0.07), only major rotamer reported) δ 8.88 (d, J = 5.0 Hz, 2H), 8.27 (s, 1H), 8.19 (s, 1H), 7.65 (d, J= 1.4 Hz, 1H), 7.42 - 7.36 (ffl, 2H), 7.25 - 7.17 (m, 2H), 4.77 - 4.72 (m, 1H), 4,07 (d, J = 5.1 Hz, 1H), 2.17 (d, J= 13.0 Hz, 1H), 2.09 - 2.02 (m, 1H), 1.98 - 1.89 (m, 1H), 1.75 - 1.71 (m, 1H), 1.69 - 1.64 (m, l H), 1.55 - 1.49 (m, M b.
Example 396: (4-methyl-3 2H-l,2,3-triazol-2-yl)pyridin-2-yl)((l S,2R,4R)-2-((5- (trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000277_0001
Example 397: (2-(5-fluoropyrimidin-2-yI)phenyl)(( lS,2R,4R)-2-((5-(trifluoromethyl)p yl)amino)-7-azabicyclo[2.2. l]heptan-7-yI)methanone.
Figure imgf000277_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 55. MS (ESI): mass calcd. for C22H18F4 60, 458.1 ; m/z found, 458.9 [M+H]+. ¾ NMR (500 MHz, CDCls) δ 8.69 (s, 2H), 8.15 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.48 - 7.31 (m, 4H), 4.86 - 4.77 (m, 1H), 4.29 (s, 1H), 4.09 - 3.90 (m, i 1 1 i. 2.19 - 1.50 (series of m, 6H).
Example 398: (3-fluoro-2-(5-fluoropyrimidin~2-yl)phenyl)((l S,2 ,4R)-2-((5-
(trifluoromethyl)pyrazin-2-yl)amm^^
Figure imgf000278_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 57. MS (ESI): mass calcd. for C22H17F5N6O, 476.1 ; m/z found, 476.9 [M+H]+. ¾ NMR (400 MHz, CDCI3) δ 8.73 (s, 2H), 8.19 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.64 (d, J= 1.5 Hz, 1H), 7.40 - 7.32 (m, IH), 7.20 - 7.17 (m, I H), 4.72 (t, J - 5.2 Hz, IH), 4.33 (td, J = 8.7, 3.6 Hz, iH), 4.07 (d. ,/ 5.0 Hz, i l l ). 2.16 fdd, J= 13.1, 8.1 Hz, IH), 2.10 - 1.97 fm, IH), 1.96 - 1.85 (m, IH), 1.77 - 1 .68 (m, IH), 1.65 - 1.58 (m, IH), 1.57 - 1.48 (m, I H).
Example 399: (2-(5-fluoropyrimidin-2-yl)-3-methylphenyl)(( i S,2R,4R)-2-((5- (trifluoromemyl)pyrazin-2-yl)a.niino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000278_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 56. Analytical HPLC was obtained on a Agilent 1 100 Series using an inertsil OT3S-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TEA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 1.38 min (major retainer) at 254 rim, U NMR (500 MHz, CDC13) δ 8.70 (s, 2H), 8.17 (s, 1H), 7.88 (d, .1 9.1 Hz, 1H), 7.63 (s, I H), 7.26 - 7.18 (m, 2H), 4.73 - 4.65 (m, 1H), 4.36 - 4.26 (m, ! ! ! }. 4.1 1 (d, J= 5.2 Hz, 1H), 2.26 (s, 3H), 2.13 (dd, J = 13.0, 8.1 Hz, H), 2.10 - 2.01 (m, I H), 1.95 - 1.86 (m, I H), 1.70 - 1.64 (m, IH), 1.60 - 1.55 (m, 1H), 1.54 - 1.45 (m, 1H).
Example 400: (2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000279_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 59. MS (ESI): mass calcd. for C22Hi9F3 60, 440.2; m/z found, 441.2 [M+Hf. !H NMR (500 MHz, CDC1;„ Compound present as a mixture of rotamers (0.88:0.12), only major rotamer reported) δ 8.84 (d, J= 4.9 Hz, 2H), 8.16 (s, IH), 7.99 - 7.92 (in, IH), 7.53 - 7.47 (m, IH), 7.45 7.32 (series of m, 4H), 4.85 (t, J= 4.8 Hz, IH), 4.46 - 4.33 (m, I H), 4.07 (d, J= 5.0 Hz, IH), 2.20 (dd, J= 13.0, 8.1 Hz, I H), 2.06 - 1.91 (m, 2H), 1.86 - 1.66 (m, 2H), 1.59 - 1.52 (m, IH).
Example 401 : (5-methyl-2-(2H- l ,2,3-triazol-2-yl)pyridin-3-yl)((l S,2R,4R)-2-((5- mino)-7-azabicyclo[2.2.1]heptan-7-yl)rnethanone.
Figure imgf000279_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 60. MS (ESI): mass calcd. for CaoH^FsNsO, 444.2; m/z found, 445.2 [M+H]\ Analytical HPLC was obtained on a Agilent 1 100 Series using an Inerisil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TF A over 1.6 min and then hold at 99% ACM for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt :;; 1.13 min (major rotamer) at 254 nm.
Example 402: (2-(2Ti- l ,2,3-triazof-2-yi)pyridin-3-y])((l S,2R,4R)-2-((5-(trifluorometliyl)pyrazin- 2-yl)amino)-7-azabicyclo [2.2.1 ]heptan-7-yl)methanone.
Figure imgf000280_0001
Prepared analogous to Example 238 substitutmg intermediate A-2 with intermediate A- 61. MS (ESI): mass calcd. for Ci9Hi7F3NsO, 430.1 ; m/z found, 431.1 [M+H]\ Analytical HPLC was obtained on a Agilent 1 100 Series using an Inerisil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TF A over 1.6 min and then hold at 99% ACM for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 CC). R, = 1.05 min (major rotamer) at 254 nm.
Example 403 : (6-methyi-3-(pyrimid n-2-yl)pyridm-2-yl)((l S,2R,4R)-2-((5- o)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000280_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 63. MS (ESI): mass calcd. for C22H20F3N7O, 455.2; m/z found, 456.2 ! M 1 1 1 . !H NMR (500 MHz, CDCI3, Compound present as a mixture of retainers, major rotamer reported) δ 8.80 (d, J= 4.9 Hz, 2H), 8.31 (d, J = 8.0 Hz, 1 H), 8.23 (s, 1 H), 7.82 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 1 .4 Hz, 1H), 7.30 (d, J = 1.2 Hz, I I I ). 7.30 - 7.28 (m, 1 H), 4.94 - 4.87 (m, I H), 4.35 - 4.25 (m, IE), 4.14 id, J - ---- 5.3 Hz, 1H), 2.61 (s, 3H), 2.20 (dd, ,/ 13.1 , 7.6 Hz, i l l ). 2.16 - 2.09 (m, 1H), 2.06 - 1.97 (m, 1H), 1.84 · 1.76 (m, IH), 1.63 - 1.58 (m, 2H).
Example 404: (5-methyl-2-(p Trimidm-2-yl)pyridin-3-yl)((l S,2R,4R)-2-((5- )-7-azab"icyclo[2.2.1 ]heptan-7-yl)rnethanone.
Figure imgf000281_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 66. MS (ESI): mass calcd. for C22H20F3N7O, 455.2; m/z found, 456.2 [M+H]+. ¾ NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.79:0.21 ), only major rotamer reported) δ 8.89 (d, ./ 4.9 Hz, 2H), 8.61 i d. ./ 2.1 Hz, 1H), 8.18 (s, S i n. 7.54 - 7.46 (m, 11 1 ). 7.41 (t, ,/ 4.9 Hz, 1H), 4.85 (t, J = 4.5 Hz, 1H), 4.39 (s, IH), 3.97 (d, ,/ 4.4 Hz, 1H), 2.37 (s, 3H), 2.22 (dd, J= 13.0, 8.0 Hz, IH), 2.07 - 1 .90 (m, 2H), 1.85 - 1.65 (m, 2H), 1.61 - 1.52 (m, IH). Example 405 : (5-raethyl-3-(pyriniidin-2-yl)pyridin-2-yi)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrazm^
Figure imgf000281_0002
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 67. MS (ESI): mass calcd. for C22H20F3N7O, 455.2; m/z found, 456.2 [M+H]+. !H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.90:0.10), only major rotamer reported) δ 8.83 i d. ./ .0 Hz, 2H), 8.43 ·■ 8.37 (m, IH), 8.21 (s, IH), 8.18 - 8.13 (m, IH), 7.93■ 7.85 (m, IH), 7.56 (s, IH), 7.34 (t, J = 4.9 Hz, I H), 4.93 - 4.84 (m, I H), 4.31 (td, J = 8.4, 3.0 Hz, Ιϊ-Ι), 4.19 (d, ./ 5.3 Hz, 2.40 (s, 3H), 2.20 (dd, ./ 13.1 , 7.8 Hz, 1H), 2, 17 - 2. 1 i l l ;. 2.03 - 1.94 (m, IH), 1.84 - 1.76 (m, 1H), 1.64 - 1.53 (series of m, 2H).
Example 406: (3-(pyrimidin-2-y1)pyridin-2-yl)((l S,2R,4R)-2-((5-(trifluoromethyl)p
]heptan-7-yl)methanone.
Figure imgf000282_0001
Prepared analogous to Example 238 substitutmg intermediate A- 2 with intermediate A- 64. MS (ESI): mass caicd. for C2iHlgF3N70, 441.2; m/z found, 442.2 ί \ 1 · Π ; . JH NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.91 :0.09), only major rotamer reported) δ 8.84 (d, J = 4.9 Hz, 2H), 8.58 (dd, /= 4.8, 1.7 Hz, 1H), 8.38 (dd, J= 7.9, 1.7 Hz,
I H), 8.21 (s, I H), 7.83 (d, J = 8.8 Hz, IH), 7.58 (s, IH), 7.44 (dd, ./ - 7.9, 4.8 Hz, I H), 7.34 (t, J = 4.9 Hz, IH), 4.90 (t, ./ 4.8 Hz, I H), 4.40 - 4.26 (m, I H), 4.16 (d, J= 5.3 Hz, IH), 2.21 (dd, J - 13.1 , 7.8 Hz, IH), 2.18■■ 2.1 1 (m, IH), 2.05 - 1.94 (m, IH), 1.87 ■ 1.78 (m, IH), 1.68 - 1.55 (m, 2H).
Example 407: [l,r~biphenyl]-2-yl((lS,2R,4R)~2-((5-(trifluoromethyl)pjTazin-2-yl)ainino)-7- azabicyclo[2.2.1 ]heptan-7-yl)rnethanone.
Figure imgf000282_0002
Prepared analogous to Example 238 substituting intermediate A-2 with 2- biphenylcarcoxylic acid. MS (ESI): mass calcd. for C24H21F3N4O, 438.2; m/z found, 438.9
[M+H]\ Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1 .6 min and then hold at 99% ACN for 0.4 mm, at a flow rate of 2.2 mL/min (Temperature 50 °C). Rt 1.46 min (major rotamer) at 254 run.
Example 408: (3-fluoro-2-(p oidm-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifiuorornemyl)pyrazin-2- ]heptan-7-yl)meihanone.
Figure imgf000283_0001
Prepared analogous to Example 260 substituting 2-(tributylstaimyl)oxazole with 2- (tributylstannyl)pyridine. MS (EST): mass calcd. for C23H19F N5O, 457.2; ml 7. found, 458.2 [M+H]"1". 'H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers, only major rotamer reported) δ 8.55 (d, J = 5.4 Hz, IH), 8.17 (s, 1H), 7.88 (td, J= 7.8, 1.8 Hz, IH), 7.68 (dd, J = 8.0, 3.2 Hz, I H), 7.59 (s, 1H), 7.43 - 7.38 (m, IH), 7.37 - 7.31 (m, IH), 7.20 - 7.14 (m, 11 1 ). 4.78 (t, J 4.9 Hz, i l l ). 4.53 - 4.42 (m, l i s }. 4.02 (d, ./ 4.9 Hz, IH), 2.19 (dd, ,/ 12.9, 8.1 Hz, IH), 2.1 1 - 1.86 (series of m, 2H), 1.81 - 1.68 (series of m, 2H), 1.58 · 1.49 (m, IH). Example 409: (3-methyl-2-(oxazol-2-yl)phenyl)^
yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000283_0002
Prepared analogous to Example 263 substituting 3-(tributylstannyl)pyridazine with 2- (tributyistannyl)oxazole. MS (ESI): mass calcd. tor C >i ! >.,1; ;N.;( 443.2; m/z found, 444.2 i \! I l l . \ I X W R (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.91 :0.09), only major rotamer reported) δ 8.14 (s, I H), 7.88 (d, J = 0.9 Hz, IH), 7.79 (d, J - 1.4 Hz, I H), 7.31 - 7.27 (m, 2H), 7.26 - 7.23 (m, I H), 7.20 - 7.13 (m, IH), 4.78 (i, J- 4.6 Hz, IH), 4.33 - 4. ί η·. 1H), 3.94 (d. ./ 4.9 Hz, H i ). 2.28 (s, 3H), 2.12 ! c!d. ./ 13.0, 8.2 Hz, 1H), 2.06 - 1 .88 (series of m, 2H), 1.77■■ 1.64 (series of m, 2H), 1.56 - 1.48 (m, 1H).
Example 410: (5-fluoro-2-(oxazol-2-yl)phenyl)((l S,2R,4R)-2-((5-( rifjuoromethyl)pyrazin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000284_0001
Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A- 69. MS (ESI): mass calcd. for
Figure imgf000284_0002
447.1 ; m/z found, 448.1 [M+H]+. Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.65:0.35), only major rotamer reported) δ 8.16 (s, IH), 7.86 - 7.79 (series of m, 2H), 7.37 - 7.30 (series of m, 2H), 7.19 - 7.09 (m, IH), 7.04 (dd, J= 8.2, 2.7 Hz, IH), 4.93 (t, J = 4.4 Hz, 1H), 4.37 - 4.30 (m, IH), 3.87■ 3.81 (m, IH), 2.19 (dd, J= 13.1 , 8.1 Hz, I H), 2.05 - 1.68 (series of m, 4H), 1.62 - 1 .43 (m, IH).
Example 41 1 : (2-fluoro-6-(oxazoI-2-yl)phenyl)((l S,2R,4R)~2-((5-(triiluoromemyl)pyrazin~2- ]heptan-7-yl)methanone.
Figure imgf000284_0003
Prepared analogous to Example 181 substituting intermediate A- 1 with intermediate A- 70. MS (ESI): mass calcd. for C21H17F4N5O2, 447.1 ; m/z found, 448.1 [M÷Hf . ¾ NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.16 (s, IH), 7.87 - 7.83 (series of m, 2H), 7.63 (d, J = 7.8 Hz, IH), 7.47 - 7.40 (m, IH), 7.36 (d, J= 0.8 Hz, IH), 7.19 (td, J= 8.6, 1.1 Hz, HI), 4.99 (t, J - ---- 5.0 Hz, l ! . 4.42 - 4.35 On. H i s. 3.76 (d, ./ 5.0 Hz, Hi), 2,21 uk!. ./ 13.1, 8.0 Hz, 1H), 2.12■■ 1.55 (series of m, 5H).
Example 412: (4-fluoro-2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)phenyl)((l S,2R,4R)-2-((5~
o)-7-azabicyclo[2.2.1]heptari-7-y
Figure imgf000285_0001
Prepared analogous to Example 238 substitutmg intermediate A-2 with intermediate A- 71. MS (ESI): mass calcd. for C2iHigF4N602, 462.1; m/z found, 463.1 [M+H]\ lB NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.50:0.50), both rotamers reported) δ 8.32 (s, 0.5H), 8.18 (s, 0.5H), 8.08 (d, J= 1.4 Hz, 0.5H), 7.83 (dd, J = 8.8, 2.7 Hz, 0.5H), 7.58 (dd, J= 8.5, 2.6 Hz, 0.5H), 7.54 (s, 0.5H), 7.52 - 7.37 (m, I H), 7.32 (td, J= 8.1, 2.6 Hz, 0.5H), 7.18 (td, ,/ 8.1, 2.6 Hz, 0.5H), 6.93 (s, 0.5H), 6.17 (d, J -- 8.3 Hz, 0.5H), 4.88 (t, J 4.5 Hz, 0.5H), 4.80 (d, J= 5.3 Hz, 0.5H), 4.39 - 4.21 (m, 1H), 3.91 (t, J= 4.7 Hz, 0.5H), 3.84 (d, J= 4.4 Hz, 0.5H), 2.50 (two s, 3H), 2.23 - 2.06 (m, 1H), 2.07 - 1.67 (series of m, 4H), 1.64 - 1.46 (series ofm, l l .
Example 413 : (2-chloro-6-methoxypyridin-3-yl)((l S,2R,4R)-2-((5-(trifSuoromethyl)pyrazin-2- -7-yl)methanone.
Figure imgf000285_0002
Prepared analogous to Example 181 substituting intermediate A-l with intermediate A-
65. MS (ESI): mass calcd. for C si i (1i .N.; ( . 427.1 ; m/z found, 427.9 ; M · i I ] . Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.35 - 8.12 (m, IH), 7.98 - 7.89 (m, IH), 7.71 ■ 7.48 (m, IH), 6.84■■ 6.35 (m, IH), 6.29■■ 5.68 (m, IH), 4.92■■ 4.73 (m, IH), 4.30■■ 3.73 (series of m, 5H), 2.24 - 2,05 (m, l l . 2.07 - 1.79 (tn, 11 1 ). 1.64 - 1.46 (in, 2H), 1.01 i d. ./ 6.6 Hz, 1H).
Example 414: (4-fjuoro-2-(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trif!uoromethyl)pyrimidm- ]heptan-7-yl)methanone.
Figure imgf000286_0001
Prepared analogous to Example 269 substituting intermediate A- 6 with intermediate A- 25. MS (EST): mass calcd. for C22H18F4N60, 458.1 ; m/z found, 459.2 [M+H]+. ]H NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.70:0.30), only major rotamer reported) δ 8.85 (d, J = 4.9 Hz, 2H), 8.50 (d, J= 2.6 Hz, 1H), 8.39 (s, 1H), 7.76 (dd, J = 9.5, 2.7 Hz, 1H), 7.35 (dd, J = 8.4, 5.4 Hz, 1H), 7.32 (t, J = 4.9 Hz, H), 7.10 (td, J= 8.2, 2.7 Hz, I H), 4.87 (E, J= 4.6 Hz, IH), 4.48 - 4.35 fm, IH), 4.04 (d, J = 4.5 Hz, I H), 2.24 (dd, ./ 12,9, 8.0 Hz, IH), 1.99■ 1.93 (series of m, 2H), 1.83 - 1.76 (m, IH), 1.72 ■ 1.65 (m, IH), 1.61 - 1.54 (m, IH). Example 415: (5-†luoro-2-(pyrimidm-2-yl)phenyl)((l S,2R,4R)-2-((5-(tri
-yl)amino)-7-azabicyclo [2.2.1 ]heptan-7-y l)methanone.
Figure imgf000286_0002
Prepared analogous to Example 269 substituting intermediate A-16 with intermediate A- 7. MS (ESI): mass calcd. for C22H] 8F4N60, 458.1 ; m z found, 459.1 | M 1 1 1 . Ή NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers (0.70:0.30), only major rotamer reported) δ 8.82 (d, J= 4.9 Hz, 2H), 8.50 (s, IH), 8.38 (s, I H), 8.06 (dd, J = 8.6, 5.4 Hz, IH), 7.28 (t, J= 4.9 Hz, I H), 7.21 - 7.15 (m, I H), 7.04 (dd, ./ - 8.4, 2.6 Hz, IH), 4.95 - 4.84 (m, IH), 4.48 - 4.28 ϋϋ. I H i. 4.1 1 - 4.05 (m, I I I ). 2.24 (dd, ./ 12.9, 7.9 Hz, i l l ). 2.10 - 1.89 ( series of m, 2H), 1.82 - 1.63 (series of m, 2H), 1.63■■ 1.54 (m, 1H).
Example 416: (2-fluoro-6-(pyrimidm-2-yl)phenyl)((l S,2R,4 )-2-((5-(trifiuoromethyl)pyrimidm- -yl)amino)-7-azabicyclo [2.2.1 ]heptan-7-yl)methanone.
Figure imgf000287_0001
Prepared analogous to Example 269 substituting intermediate A- 16 with intermediate A- 6. MS (ESI): mass calcd. for C22H18F4N6O, 458.1 ; m/z found, 459.2 [M+H]+. fH NMR (500 MHz, CDCI3, Compound present as a mixture of ro tamers) 8 8.86 i d. ./ 4.9 Hz, 2H), 8.55 (d, ,/ = 9.7 Hz, IH), 8.40 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.55 - 7.44 (m, 1H), 7.34 (t, J = 4.9 Hz,
1 H), 7.27 - 7.16 (m, I H), 4.92 ( J= 4.8 Hz, IH), 4.52 - 4.41 (m, 1H), 3.99 (d, J = 5.2 Hz, I H), 2.28 i dd. ./ 12.9, 7.8 Hz, IH), 2,20 - 2.1 1 fm, i l l ;. 2.04 - 1.94 (m, 1H), 1.83 - 1.77 (m, IH), 1.73■· 1.54 (series of m, 2H). Example 41 7: (2~(pyrimidin-2-yl)phenyl)((l S,2R,4R)-2-((5-(trifluoromethy1)pyrimidin-2- yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000287_0002
Prepared analogous to Example 269 substituting intermediate A-16 with intermediate A- 59. MS (ESI): mass calcd. for C22Hi9FjN60, 440.2; m/z found, 441 .2 [M+Hf. !H NMR (500 MHz, CDCI3, Compound present as a mixture of retainers (0.74:0.26), only major retainer reported) δ 8.84 (d, J= 4.9 Hz, 2H), 8.50 (s, IH), 8.38 (s, I H), 8.03 (dd, J = 7.7, 1.3 Hz, IH), 7.53 - 7.47 (m, I H), 7.45 - 7.39 (m, I H), 7.36 (dd, J= 7.4, 1.2 Hz, IH), 7.29 (t, J = 4.9 Hz, IH), 4.88 (t, ./ 4.6 Hz, H i !. 4.44 - 4.38 (m, i l l ). 4.07 (d, J= 4.5 Hz, I I I ;. 2.24 (dd, J 12.9, 7.9 Hz, 1H), 1.99■■ 1.96 (m, 1H), 1.84 - 1.76 (m, 1H), 1.73 - 1.65 (series of m, 2H), 1.60■■ 1.52 (m, 1H).
Example 418: (3-iluoro-2-(pyrimidin-2-yl)phenyl)(( l S,2R,4R)-2-((4-(trifluorom
2. l ]heptan-7-yl)methanone.
Figure imgf000288_0001
Step A: ( 18,2R,4R)-iert-butyi 2-((4-(trifluoromethyI)thiazol-2-yl)amino)-7- azabicyelo[2.2.1 ]beptane-7~carboxylate. To a solution of intermediate B-5 (107 mg, 0.50 mmol) in ACN (1 .7 mL) was added DTPEA (0.22 mL, 1.26 mmol) followed by 2-chloro-4- (trifluoromethyl)thiazoie (104 mg, 0.55 mmol). The reaction mixture was heated at 170 °C for 2.5h using microwave. Solvent was evaporated and purification via silica gel chromatography (0- 40% EtOAc in bexanes) gave the title compound (37 mg, 20%). MS (ESI): mass calcd. for C15H20F3N3O2S, 363. ! : m found, 364.0 | M H i . !H MR (500 MHz, CDCk) 8 6.91 (s, lH), 5.66 (s, I M i. 4.32 - 4.23 (m, 2H), 3.79 - 3.69 (m, 1 H), 2.08 - 2.00 (m, l H), 1.92 - 1.66 (m, 2H), 1.65 - 1.35 (m, 12H).
Step B: N-((l 8,2R,4R)~7~azabicyclo[2.2.1 jheptan-2-yl)-4-(trif!uoromethyl)thiazol-2- amine. To the title compound of step A (37 mg, 0.10 mmol) in DCM (1 mL) was added 4M HC1 in dioxane (0.26 mL). After 16h, the reaction was concentrated, neutralized with 5% N ^CC (aq) and extracted with DCM (2X). The combined organics were dried (NaaSO^ to give the title compound of step B that was used without further purification. MS (ESI): mass calcd. for
CI OH12FJNJS, 263.1 ; m/z found, 264.0 ! M ! i ; .
Step C: (3-fiuoro-2-(pyrimidin~2-yl)phenyl)((l S,2R,4R)-2-((4-(trifluoromethyl)iM yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of step B (27 mg, 0.1 0 mmol) in DCM (1 mL) was added DIPEA (0.04 mL, 0,21 mmol) and intermediate A-2 (25 mg, 0.1 1 mmol). Then T3P (50% solution in DMF, 0.19 mL, 0.31 mmol) was added drop wise and the reaction heated at 45 °C for 16h. Solvent was evaporated and purification via prep
HPLC gave the title compound (16 mg, 34%). MS (EST): mass calcd, for QiHnRjNsOS, 463.1 ; m/z found, 463.9 [M+H]+. Ή NMR (500 MHz, CDC13) δ 8.88 (d, J = 4.9 Hz, 2H), 7.45 - 7.40 (m, i l l !. 7.38 (t, J= 4.9 Hz, IH), 7.24 - 7.17 (in, 2H), 6.77 - 6.69 (m, i l l ). 4.70 ft, ./ 4.9, 1.2 Hz, IH), 4.22■ 4.16 (m, 2H), 2.16 (dd, J= 13.1, 8.0 Hz, IH), 2.10■■ 2.01 (m, IH), 1.96■■ 1.86 (m, IH), 1.76 - 1.57 (m, 21 1 ). 1.55 - 1.44 (m, I H). Example 419: (3-fluoro-2-(pyrimidin-2-yl)phenyl)(( 1 S,2R,4R)-2-((5-(trifluoromethy 1)- 1 ,3,4- t adiazol-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)niethanone.
Figure imgf000289_0001
Step A: ( S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)- 1 ,3,4-thiadiazol-2-yl)amino)-7- azab"icyclo[2.2.1]heptane-7-carboxylate. To a solution of intermediate B-5 (71 mg, 0,33 mmol) in ACN (0.85 mL) was added DIPEA (0.14 mL, 0.84 mmol) followed by 2-ch1oro-5-
(trifluoromethyl)- 1 ,3 ,4-thiadiazole (73 mg, 0,37 mmol). The reaction mixture was heated at 120 °C for 30 minutes using microwave. EtOAc was added and the organic phase was washed with a saturated solution of NaHCCh followed by a saturated solution of NaCl. The organic phase was dried over MgS04, filtered and evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (85 mg, 70%). Ή NMR (500 MHz, CDC13) δ 6.82 (s, IH), 4.38 - 4.22 (m, 2H), 3.96 - 3.82 (m, IH), 2.1 1 - 2.00 (m, i l l s. 1.92 - 1.79 (m, IH), 1.79 - 1 .66 (m, 2H), 1.43 (s, 1 IH). MS (ESI): mass calcd. for C14H19F3 4O2S, 364.1 ; nvz found, 365.0 i .Yi - i i ) .
Step B: N-( ( 1 S,2R,4R)-7-azabicyclo[2.2.1 ]heptan-2-yl)-5-(trifluoromethyl)- 1,3,4- thiadiazol-2-amine. To the title compound of step A (85 mg, 0.23 mmol) in DCM (2.3 mL) was added 4M HC1 in dioxane (0.30 mL). After 48h, the reaction was concentrated, neutralized with 5% Na2C(¾ (aq) and extracted with DCM (2X). The combined orga ics were dried (Na?SC>4) to give the title compound of step B ihai was used without further purification. MS (ESI): mass calcd. for C9HJ 1F3 4S, 264.1 ; m/z found, 265.0 [ V! - i l l .
Step C: (3-fluoro-2-(pyrimidin-2-y3)phenyl)((l S,2R,4R)-2-((5-(trifluoromethyl)-l,3,4- thiadiazol-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of step B (58 mg, 0.10 mmol) in DCM (2.2 mL) was added DIPEA (0.1 mL, 0.55 mmol) and intermediate A-2 (53 mg, 0.24 mmol). Then T3P (50% solution in DMF, 0.40 mL, 0.66 mmol) was added dropwise and the reaction heated at 45 °C for 16h. Solvent was evaporated and purification via prep HPLC gave the title compound (63 mg, 62%). MS (ESI): mass calcd. for C2oHi6F4N6OS, 464.1 ; m/z found, 464.9 [M+Hf , Ή NMR (500 MHz, CDC ) δ 8.94 (d, J = 9.3 Hz, IH), 8.87 (d, J- 5.0 Hz, 2H), 7.47 - 7.37 (m, 2H), 7.25 - 7.19 (m, 2H), 4.71 (td, J = 4.8, 1.2 Hz, ill), 4.33 - 4.18 (m, 2H), 2.17 (dd, ./ 13.3, 8.1 Hz, IH), 2.13 - 2.03 (m, I H), 1.98 - 1.85 (m, IH), 1.74■ 1.62 (m, 2H), 1.57■· 1.45 (m, IH).
Example 420: (( i S,2 ,4R)-2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- -methyl-3-(2H- l ,2,3-triazol-2-yl)pyridin-2-yl)methanone.
Figure imgf000290_0001
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 19. MS (ESI): mass calcd. for C21H19F4 7O, 461.2; m/z found, 462.2 ! M 1 1 1 . !H NMR (500 MHz, CDCI3) δ 8.39 (dd, J = 1.9, 0.8 Hz, IH), 8.12 - 8.08 (m, 2H), 7.86 (s, 2H), 7.26 - 7.22 (m, IH), 5.77 - 5.70 (m, IH), 4.97 - 4.91 (m, IH), 4.38 (td, J= 7.8, 3.0 Hz, IH), 4.09 - 4.05 (m, IH), 2.46 (s, M l ). 2.25 (dd, J - 13.0, 7.5 Hz, I H), 2.13 - 1.97 (m, 21 n. 1.88 - 1.80 (m, I H), 1.66 - 1.60 (m, 2.H).
Example 421 : (R/S)-(2-(2H~ 1 ,2,3-triazol-2-yl)phenyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)- -azabieyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000290_0002
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A- 1. MS (ESI): mass calcd. for C21H18F3 5O , 429.1 ; m/z found, 429.9 [M+Hf. Π N M R (400 MHz, CDClj) δ 8.32 - 8.25 (in, 1 H), 7.82 - 7.74 (m, 4H), 7.49 - 7.39 (m, 2H), 7.20 (td, J = 7.6, 1.2 Hz, 1H), 6.75 (d, J= 8.7 Hz, 1H), 4.97 (dd, J= 6.6, 2.5 Hz, 1H), 4.88 (t, J = 5.0 Hz, 1H), 3.89 (d, J = 5.3 Hz, 1H), 2.08 - 1 .94 (m, 2H), 1.87 - 1.75 (m, 1 H), 1.55 - 1.48 (m, I H), 1.47 - 1.40 (m, 1H), 1.36 - 1 .27 (m, 1H).
Example 422: (R/S) 3-methyl-2-(2H ,2,3-triazol-2-yi)phenyl)-2-((5-(trifiuoromethy
~y{)oxy)-7-azabicyclo[2.2.1 ]heptan-7~yl)methanor!e.
Figure imgf000291_0001
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A-
24. MS (EST): mass caicd. for C22H2oF3N502, 443.2; m/z found, 443.9 [M÷H]+ . Ή NMR (500 MHz, CDCI3, Compound present as a mixture of ro tamers) 8 8.43 - 8.28 (m, IH), 7.85 - 7.75 (series of m, 3H), 7.44■■ 7.27 (series of m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.86■■ 6.76 (m, 1H), 5.06 - 4.97 (m, IH), 4.76 - 4.63 (m, I H), 4.05 - 3.90 (m, I H), 2.21 - 2.12 (m, 3H), 2.04 - 1.98 (m, IH), 1 .98 - 1.92 ( in. IH), 1 .87 - 1.78 (m, IH), 1 .54 - 1 .44 (m, IH), 1.39 - 1 .31 (m, 11 1 ).
Example 423 : (R/'S)-(3-fluoro-2-(2H- 1 ,2,3 -triazol-2-yl)phenyi)-2-((5-(irifluoromeihyi)pyridin-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000291_0002
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A- 16. MS (ESI): mass caicd. for C21H17F4N5O2, 447. 1 ; m/z found, 448.1 [M+H]+. !H NMR (400 MHz, CDCI3) δ 8.42 ·■ 8.29 (m, IH), 7.91 - 7.82 (m, 2H), 7.79 (dd, J = 8.7, 2.5 Hz, IH), 7.41 - 7.19 (m, 3H), 6.84 - 6.75 (m, 1H), 5.07 - 4.96 (m, IH), 4.82 - 4.68 (m, 1H), 4.03 - 3.86 (m, IH), 2.08 - 1.91 (m, 2H), 1.77■ 1.47 (m, 111).1.44 - 1.31 (m, 2H),
Example 424: (R/S)-(3-fluoro-2-(lH- 1 ,2,3-triazol- 1 -yl)phenyl)-2-((5-(trifluorometh.yl)pyridin-2- eptan-7-yl)methanone.
Figure imgf000292_0001
Prepared analogous to Example 433 substituting intermediate A-55 with 3-fluoro-2-(lH- 1,2,3-triazol-l -yl)benzoic acid, obtained during the synthesis of intermediate A-16. MS (EST): mass calcd. for C21H17F4N5O2, 447.1; m/z found, 447.9 [M+H . 'rlNMR (400 MHz, CDC13) δ 8.36 - 8.32 (m, IH), 7.93 (t, J= 1.2 Hz, 1H), 7.84■■ 7.79 (m, 2H), 7.41■■ 7.27 (m, 3H), 6.88■■ 6.84 (m, H), 5.04 (dd, J = 6.9, 2.3 Hz, 1H), 4.69 (t, J= 5.1 Hz, 1H), 4.06 (d,J=5.6 Hz, 1H), 2.12 - 2.01 (m, 1H), 1.99 - 1.90 (m, 1H), 1.87 - 1.78 (m, 1H), 1.71 - 1.59 (m, III).1.41 l.i 8.4 Hz, 2H). Example 425: (R/S)-(2~ffuoro-6-(2ii-l,2,3-triazo^^
eptan-7-yl)methanone.
Figure imgf000292_0002
Prepared analogous to Example 433 substitutmg intermediate A-55 with intermediate A- 11. MS (ESI): mass calcd. for C2iH17F4N502, 447.1; mz found, 447.9 [M+H]+. IHNMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.47■ 8.24 (m, IH), 7.86■ 7.66 (series of m, 4H), 7.53 - 7.34 (m, IH), 7.20 - 6.94 (m, IH), 6.92 - 6.79 (m, IH), 5.19 - 4.90 (series of m, 2H), 3.95 - 3.77 (m, 1H), 2. 12 - 1.97 (series of m, 2 Π ). 1.96 - 1.56 (series of m, 11 1 ). 1.48 ·■ 1.26 (series of m, 2H).
Example 426: (R/S)-(2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)-2-((5-(trifluorornethyl)pyridin-2- eptan-7-yl)methanone.
Figure imgf000293_0001
Prepared analogous to Example 433 substituting mtermediate A-55 with mtermediate A- 61. MS (ESI): mass ealcd. for C2oH17F,N602, 430.1 ; m/z found, 430.9 [M+H]+. 5H NMR (400 MHz, CDCh) δ 8.55 (dd, J = 4.8, 1 .8 Hz, 1H), 8.34 - 8.25 (m, 1H), 7.89 - 7.84 (m, 3H), 7.78 (dd, J = 8.8, 2.5 Hz, 1 H), 7.21 (dd, J = 7.6, 4.8 Hz, IH), 6.73 (d, J = 8.7 Hz, 1 H), 4.99 (dd, J = 6.8, 2.4 Hz, IH), 4.91 (t, J= 4.8 Hz, IH), 3.88 (d, ,/ 5.3 Hz, IH), 2.08 i d. 6.9 Hz, IH), 2.04 - 2.00 (m, IH), 1.93 - 1.83 (m, IH), 1.57■· 1.44 (m, 2H), 1.39■■ 1.31 (m, IH).
Example 427: (R/S)-(6-methyl-2-(2H- 1 ,2,3-triazol-2-yf)pyridin-3-yl)-2-((5- )-7-azabicyclo[2.2. ]heptan-7-y l)methanone.
Figure imgf000293_0002
Prepared analogous to Example 433 substituting mtermediate A-55 with mtermediate A- 3. MS (ESI): mass calcd. for
Figure imgf000293_0003
Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a How rate of 2.2 mL/min (Temperature = 50 °C). ¾ :;; 1.29 min (major rotamer) at 254 run. Example 428: (R/S)-(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)-2-((5- xy)-7-aza.bicyclo[2.2.1]hepiaii-7-yl)ineihanone.
Figure imgf000294_0001
Prepared analogous to Example 433 substitutmg intermediate A-55 with intermediate A- 60. MS (ESI): mass calcd. for
Figure imgf000294_0002
444.2; mix found, 444.9 [M+H] !H NMR (400 MHz, CDC13) δ 8.35 - 8.32 (m, 1H), 8.32■■ 8.30 (m, 1H), 7.85 (s, 2H), 7.83■■ 7.77 (m, 1H), 7.63 7.57 (m, IH), 6.74 (d, J = 8.6 Hz, H), 4.96 (dd, J = 6.3, 3.0 Hz, 1H), 4.90 (t, J= 4.5 Hz, 1H), 3.91 (d, J- 5.3 Hz, 1H), 2.21 (s, 3H), 2.13 - 1.94 (m, 2H), 1.91 - 1.76 (m, I H), 1.55 - 1.27 (m,
Example 42.9: (R/S)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)-2-((5-(lxifiuoromethyl)pyridin-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000294_0003
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A-
2. MS (ESI): mass calcd. for
Figure imgf000294_0004
458.1; m z found, 458.9 [M+H], Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 CC). t = 1.37 min (major rotamer) at 254 nni. Example 430: (R'¾)-(4-iluoro-2-(pyrimidin-2-yl)phen^
7-yl)methanone.
Figure imgf000295_0001
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A- 25. MS (ESI): mass calcd. for C23H18F4N4O2, 458.1 ; m/z found, 458.9 [M+H]+. !H NMR (400 MHz, CDCh, Compound present as a mixture of rotamers, major rotamer reported) δ 8.76 - 8,74 (m, 2H), 8.34 - 8.28 (m, I ) i ;·. 7.85 (dd, .1 9.8, 2.6 Hz, i l l ). 7.80 - 7.75 (m, IH), 7.44 - 7.40 (m, 1H), 7.21 (t, J= 4.8 Hz, IH), 6.95 (td, J = 8.2, 2.7 Hz, IH), 6.75 (d, /= 8.7 Hz, IH), 5.00 (dd, J = 6.7, 2.4 Hz, IH), 4.88 (t, J= 4.8 Hz, IH), 3.95 (d, J = 5.5 Hz, IH), 2.08 - 1.99 (m, IH), 1.88 - 1.81 (m, IH), 1.68 - 1.58 (m, IH), 1.53 - 1 .45 (m, IH), 1.41 - 1.32 (m, I H), 0.86 - 0.81 (m, I H).
Example 431 : (R/S)-(2-fluoro-6-( yrimidm-2-yl)pte
yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000295_0002
Prepared analogous to Example 433 substituting intermediate A-55 with mtermediate A-
6. MS (ESI): mass calcd. for C23H18F4N4O2, 458.1 ; m/z found, 458.9 [M+H]+. Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μηι, 50 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 CC). Rt = 1.40 min (major rotamer) at 254 nm. Example 432: {^S)-(2-(pyrimidin-2-yl)phenyl)-2-((5-(tri^
methanone.
Figure imgf000296_0001
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A- 59. MS (ESI): mass calcd. for C23H19F3N4O2, 440. 1 ; m/z found, 441.1 [M+H]+. !H NMR (400 MHz, CDCI3) d 8.80 - 8.71 (m, 2H), 8.43 - 8.27 (m, IH), 8.21 - 8.09 (m, IH), 7.83 - 7.74 (m, il-I), 7.57 - 7.37 (m, 2H), 7.28 - 7.13 fm, 2H), 6.90 - 6.72 (m, IH), 5.12 - 4.86 (m, 11 1 ). 4.00 - 3.83 (m, IH), 2.14 - 1.77 (m, 3H), 1.74■■ 1.53 (m, IH), 1.53 ■■ 1.21 (m, 2H).
Example 433 : (R/S)-(2-(5-fluoropyrimidin-2-yl)ph^
tan-7-yl)methanone.
Figure imgf000296_0002
Step A. (R/S)-ie/t-Butyl 2-((5-(trifluoromethyl)pyridin-2~yl)oxy)-7- azabicycJo[2.2.1 ]heptane-7~carboxylate. To a solution of intermediate B- l l (1.35 g, 6.33 mmol) and 2-chloro-5-(trifiuoromethyl)p rridme (1.35 g, 7.44 mmol) in DMF (20 mL) at rt was added NaH (310 mg, 7.75 mmol) and the mixture stirred ai rt overnight. The reaciion was diluted with water (200 mL) and extracted with EtOAc (3x50 mL). The combined organies were dried over Na2S04, filtered and the solvent removed. Purification via silica gel chromatography (80g redisep, 0- 100 % EiOAc in hexaries) provided 1.68 g of the title compound as a waxy solid. Ή NMR (400 MHz, CD<¾) δ 8.42 (s, IH), 7.76 (dd, J - 8.8, 2.6 Hz, IH), 6.77 (d, J - 8.7 Hz, IH), 5.03 (dd, J = 6.9, 2.6 Hz, Hi), 4.45 - 4.24 (m, 2H), 2.02 - 1.95 (m, 1H), 1.95 - 1.67 (in, 3H), 1.50 ■■ 1.31 (m, 1 1H).
Step B. R/S)-2-((5-(trifluoromethyl)pyridm-2-yl)oxy)-7-azabicyc]o[2.2. ]heptane. To a solution of (R/S)-teri-Butyl 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1 Jheptane- 7-earhoxyiate from step A ( 1.35g, 3.77 mmol) in DCM (20 mL) was added TFA (5 mL). This solution was stirred at rt for ~4h. The solvent was the removed and the residue was then partitioned between 2M Na2C03 (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2x20 mL). The combined organics were dried over Na2SG4, filtered and the solvent removed to reveal 0.98g of ihe title compound. The material was utilized as is. Ή NMR (400 MHz, CDC13) δ 8.42 (dt, J = 2.0, 1.1 Hz, 1H), 7.75 (dd, J = 8.7, 2.5 Hz, I H), 6.78 (d, J - 8.7 Hz, I H), 5.05 (dd, J - 6.7, 2.1 Hz, 1 H), 3.73 (q, J - 4.9 Hz, 2H), 2.01 ukl. J 13.3, 6.7 Hz, i l l ). 1.96 - 1.88 (m, i l l ). 1.74 - 1.55 (m, 3H), 1.40 - 1.22 (m, 2H).
Step C. (R/S)-(2-(5 - fluoropyrimidm-2-yl)phenyl)-2-((5-(trifluoromethyl)pyridin-2- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To a 20 mL screw cap vial were added intermediate A-55 (60 mg, 0.27 mmol), (R/S)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7- azab"icyclo[2.2.1]heptane from step B (56 mg, 0.217 mmol), HOBt (40mg, 0.29 mmol), and EDC1 (75 mg, 0.39 mmol). DMF (2 mL) and TEA (50 uL) were then added and vial capped and stirred at rt. overnight. The resulting reddish mixture was diluted with water (2.5 mL) and extracted with EtOAc (3x 10 mL) and the organic layers combined and the solvent removed. Purification via silica gel chromatography (0-100 % EtOAc in hexanes) provided 80.4 mg of the title compound. Ή NMR exhibits a mixture of rotamers, MS (ESI): mass calcd. for C23H1S-F4N4O2, 458.1; m/z found, 459.2 [M+H]+. Ή NMR (500 MHz, CDCI3) δ 8.65 - 8.56 (m, 2H), 8.45 - 8.28 (m, H), 8.15 - 8.03 (m, I H), 7.85 - 7.75 (m, IH), 7.56 - 7.37 (m, 2.5H), 7.25 - 7.22 (m, 0.5H), 6.89 - 6.75 (m, IH), 5.13 - 4.99 (m, I H), 4.97 - 4.85 (m, IH), 4.03 - 3.84 (m, IH), 2.15■ 1.93 (m, 2H), 1.92 - 1.66 (m, 2H), 1.55 - 1.21 (m, 2.H).
Example 434: (R/S)- (3-fluoro-2-(5-fluoropyrimidm-2-yl)phenyl)-2-((5-(trifiuoromethyl)pyridm- 2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000298_0001
Prepared analogous to Example 433 substituting nitermediate A-55 with intermediate A- 57. MS (ESI): mass calcd. for C23H17F5 4O2, 476.1 ; m/z found, 476.9 i \) 1 11 . ¾ NMR (400 MHz, CDCI3, Compound present as a mixture of retainers, major rotamer reported) δ 8.66 (s, 2H), 8.38 - 8.32 (m, 1H), 7.80 (dt, J= 8.8, 2.6 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.19 (m, H), 7.18 - 7.11 (m, IH), 6.84 (d, J = 8.7 Hz, IH), 5.09 - 4.98 (m, IH), 4.76 (d, J= 5.4 Hz, I H), 4.72 ft, ./ = 4.4 Hz, IH), 4.12 (d, J--- 5.5 Hz, IH), 3.97 (t, J= 4.7 Hz, 1H), 2.1 1 - 1 .32 i ns. 4H).
Example 435: (R/S)-(3-methyl-2-(oxazol-2-yl)phenyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)- -azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000298_0002
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A- 31. MS (ESI): mass calcd. for C23H20F3 3O3, 443.1 ; m z found, 443.9 [M+Hf. 'H MR (400 MHz, CDCI3, Compound present as a mixture of retainers, major rotamer reported) δ 8.32■■ 8,26 (m, IH), 7.78 - 7.73 (m, 2H), 7.39 - 7.19 (m, 3H), 7.18 (d, J= 7.6 Hz, IH), 6.76 (d, J = 8.7 Hz, IH), 4.98 (dd, J= 6.6, 2.6 Hz, IH), 4.76 (t, J= 4.5 Hz, I H), 3.93 (d, J= 5.0 Hz, IH), 2.39 (s, 3H), 2.07 - 1.28 (m, 6H).
Example 436: (WS)-(3-fluoro-2-(oxazol-2-yl)phenyl)-2-((5-(trifluoromeihyi)pyridin-2-yl)oxy)- 7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000299_0001
Prepared analogous to Example 433 substituting intermediate A-55 with intermediate A-
68, MS (ESI): mass calcd, for C22H17F4N303, 447, 1 ; m/z found, 448.9 [M÷H] . Ή NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers (0.69:0.31 ), major rotamer reported) δ 8.34 - 8.27 (m, 1H), 7.78 - 7.74 (m, 2H), 7.30 - 7.22 (m, 3H), 7.18 - 7.09 (m, IH), 6.73 (d, J ------
8.6 Hz, IH), 4.98 (dd, J= 6.8, 2.5 Hz, IH), 4.85 · ! . ./ 4.7 Hz, IH), 3.89 (d, J= 5.6 Hz, 1H), 2.1 1 - 1 .20 (m, 6H).
Example 437: (R/S)-(3-memyl-2-(2H-l,2,3-triazol-2-yi)phenyl)-2-((6-(trifluoromethyl)pyridin- -yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone.
Figure imgf000299_0002
Prepared analogous to Example 433 substituting 2-cUoro-5-(trifluoromethyl)pyridine with 5-fluoro-2-(trifluoromethyl)pyriduie and intermediate A-55 with intermediate A~24.
MS (ESI): mass calcd. for C22H20F3N5O2, 443,2; m/z found, 444,9 [M+Hf . lH NMR (500 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.33 - 8.25 (m, IH), 7.85 - 7.72 (m, 2H), 7.64 ·■ 7.54 (m, IH), 7.44■ 7.27 (series of m, 3H), 7.23 ·■ 7.12 (m, IH), 4.82 - 4.66 (m, IH), 4.44■ 4.35 (m, IH), 4.06 - 3.95 (m, IH), 2.16 (s, 3H), 2.06 - 1.92 ( series of m, 21 1 ). 1.91 - 1.75 (m, IH), 1.56 - 1.22 (series of m, 3H). Example 438: (Ry'S)-(3-fluoro-2-(2H- 1,2,3 -triazol-2 -yl)phenyi)-2-((6-(irifluoromethyi)pyridin- yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)raethanone.
Figure imgf000300_0001
Prepared analogous to Example 437 substituting intermediate A-24 with intermediate A- 16, MS (ES ): mass calcd. for C21H17F4N5O2, 447.1 ; m/z found, 447.9 [M+H]+. !H NMR (500 MHz, CDCl;,, Compound present as a mixture of rotamers) δ 8.33 - 8.23 (m, 1H), 7,89 - 7.78 (m, 11 1 ). 7.66 - 7.55 (m, 1 H), 7.42 - 7.27 (series of m, 3H), 7.25 - 7.09 (m, 1 H), 4.84 - 4.71 (m, 1H), 4.46■· 4.37 (m, 1H), 3.98 i d. ./ 5.5 Hz, 1H), 2.09 ■ 1.56 (series of m, 4H), 1.48 - 1.26 (series of m, 2H),
Example 439: (R/S)- (2-fluoro-6-(2H~ 1 ,2,3 -triazol-2-yl)phenyI)-2-((6-(trifluoromeihyI)pyridin-3- eptan-7-yl)methanone.
Figure imgf000300_0002
Prepared analogous to Example 437 substituting intermediate A-24 with intermediate A- 1 1. MS (ESI): mass calcd. for C21H17F4N5O2, 447.1 ; m/z found, 448.9 [M+H]+. Analytical HPLC was obtained on a Agilent 1 100 Series using a XBridge C 1 8 column (5 μτη, 100 x 4.6mm), mobile phase of 10- 100% ACN in 20 mM NH4OH over 8 min and then hold at 100% ACN for 3 min, at a flow rate of 1 mL/min (Temperature = 30 °C). Rt = 1.29 min (major rotamer) at 254 Example 440: (R/S)-2-((5-bromopyridin-2-yl)oxy)-7-azabicyclo[2.2.1 jheptan- - 1 ,2,3-triazoi-2-yl)phenyl)methanone.
Figure imgf000301_0001
Step A: (R/S)-Benzyf 7-azabicyclo[2.2.1 ]hept-5-ene-7-carboxylate. To a solution of (R/S)-benz l 2-bromo-7-azabicyclo[2.2.1 ]heptane-7-carbox late (2.96g, 9.5 mmol; J. Org.
Chem, 2007, 72, 8656) in THF (65 mL) under N2 was added 16.5 mL of tBuOK 1M solution in THF. This mixture was stirred at rt. and slowly a suspension forms (~2h) and reaction monitored by LC/MS. Upon completion the mixture was diluted with saturated NH4CI (20 mL) solution and water then extracted with EtOAc (3x50 mL). The combined organics were washed with brine and dried over Na2S04 then solvent concentrated to give 1.34g the title compound that was utilized without purification. MS (EST) mass calcd. for: Ci4Hj5N02, 229, 1 ; m/z found 230.1 I I - 1 11
Step B: (R/S)-Benzyl 2-hydroxy-7-azabicyelo[2.2.1 ]heptane-7-carboxylate.
To a solution of (R/'SVBenzyl 7-azabicycio[2.2.1 ]hept-5-ene-7-carboxylate (1 g, 4.36 mmol) from step A in THF (25 mL), cooled to 0 °C, was added 1 M BIT3 in THF (9.6 mL) drop-wise and the solution was allowed to warm to rt. After 3 h the reaction mixture was cooled in an ice bath and the excess borane quenched with water (2.38 mL), followed by addition of 4M NaOH (2.38 mL), and the drop-wise addition of H202 (50% by weight, 2.38 mL), The reaction was then removed from the ice bath and wanned to 40 °C for 2 h. The mixture was then cooled to rt. and solid K2CO3 (1.0 g) added. THF was removed under vacuum and the reaction diluied with water (100 mL) and extracted with DCM (3X). The combined organics were washed with water, dried with Na2S04, filtered and concentrated. Purification via silica gel chromatography (0-3 % 2M NH3 in MeOH/DCM) provided 0.9g of the title compound. MS (ESI) mass calcd. for :
C14H17NO3, 247.1 ; m/z found 248.1 [M+H]+ !H NMR (400 MHz, CDCI3) δ 7.46 - 7.18 (m, 5H), 5.09 (s, 2H), 4.31 (t, J = 4.7 Hz, 1H), 4.19 (d, J - 5.1 Hz, 1H), 3.86 (ddd, J = 6.7, 4.6, 1.8 Hz, IH), 1 .78 (dd, J = 13.1, 6.8 Hz, 1H), 1.72 - 1.54 (m, 3H), 1 .22 (dt, J = 10.2, 2.4 Hz, 2H).
Step C: (R/S)-7-azabicyclo[2.2.1]heptan-2-ol. A solution of (R/S)-benzyl 2-hydroxy-7- azabicyelo[2.2.1]heptane-7-carboxylate (504 mg, 2.038 mmol) from step B in MeOH (20 mL) was charged with 10% Pd/C (217 mg, 0.204 mmol) and then stirred at ri under an atmosphere of hydrogen. Upon completion the reaction was filtered through a bed of celite and concentrated to give 180 mg of the title compound that was utilized without purification. MS (ESI) mass calcd. for : CV,! i NO. 1 13; m/z found 1 14.10 ; ! i i
Step D. (3-fluoro-2-(2H- >2,3-triazol-2-yl)phenyl)((R/S)-2-hydroxy-7- azabicyclo[2.2.1]heptan-7-yl)methanone. To a 20 mL screw cap vial was added intermediate A- 16 (400 mg, 1.9 mmoi), (R/S)-7-azabieyclo[2.2.1]heptan-2-o] from step C (198 mg, 1.75 mmol), HOBt (425mg, 3.14 mmol), and EDCI (600 mg, 3.13 mmol). DMF (10 mL) and TEA (0.7 mL) were then added and the vial was capped and stirred at rt overnight. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3x20 mL) and the organic layers combined and the solvent removed. Purification via silica gel chromatography (40g redisep, 0- 100 % EtOAc in hexanes) provided 160 mg of the title compound as a white solid. MS (ESI) mass calcd. for : C .-J i ..FX -C 302.3; m/z found 303.1 I l i ! .
Step E. ( S)-2-((5-bromopyridm-2-yl)oxy)-7-azabicyclo[2 ]heptan-7-yl)(3-f!uoro-2- (2H- 1 ,2,3-triazol-2-yl)phenyl)methanone. To a solution of (3-fluoro-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)((R/''S)-2-hydroxy-7-azabicyclo[2.2.1]heptan-7-yl)methanone from step D (26.7 mg, 0.08 mmol) and 5-bromo~2~fJuoropyridine in DMF (2 mL) at rt was added NaH (8 mg, 0.2 mmol) in a single portion. The mixture was stirred overnight then diluted with water (20 mL) and extracted with EtOAc (3x10 mL). The organic layers were combined and the solvent removed. Purification via silica gel chromatography (0-100 % EtOAc in hexanes) provided 35.7 mg of the title compound as a light tan solid. MS (ESI): mass calcd. for C^HnBrF sC , 457.1 ; m/z found, 458.0 [M+H]+. Ή NMR (400 MHz, CDC13) d 8.17 - 8.05 (m, ITT), 7.89 - 7.78 (m, 2I-I), 7.65 (dd, J = 8.7, 2.6 Hz, 1H), 7.39 - 7.20 fm, 3Ii), 6.66 - 6.58 (m, I H i. 4.95 - 4.86 (tn, 1H), 4.79 .. 4,66 (m, 1H), 3.98■ 3.85 (m, 1H), 2.03 - 1.89 (m, 2H), 1.73■· 1.45 (m, 2H), 1.41■■ 1.29 (m, 21 n.
Example 441 : (R/S)-2-((5-bromopyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)(3-fluoro- 2-(2H- 1 ,2,3-triazol-2.-yl)plienyl)methanone.
Figure imgf000303_0001
Prepared analogous to Example 440 substituting 5-bromo-2-fluoropyridme with 5- bromo-2-chioropyrimidine. MS (EST): mass calcd. for CigHigBrFNgC^, 458, 1 ; m/z found, 459.0 ! ¾ · ! ! ! . 1 1 X.vi R (500 MHz, CDCI3) δ 8.54 - 8.47 (m, 2H), 7.91 - 7.83 (m, 2H), 7.49 - 7.45 (m, 1H), 7.39■ 7.31 (m, IH), 7.26■· 7.20 (m, 1H), 4.89■■ 4.81 (m, 1H), 4.74■■ 4.70 (m, 1H), 4.01■■ 3.89 (m, 1H), 2.05 - 2.00 (m, I H), 2.00 - 1.69 (m, 3H), 1.46 - 1.28 (m, 2H).
Example 442: (R/S)-(3-fluoro-2-(2H- 1 ,2,3-ttiazol-2-yl)phenyl)-2-(quinoxalin-2-yloxy)-7- l)methanone.
Figure imgf000303_0002
Prepared analogous to Example 440 substituting 5-bromo-2-fluoropyridtne with 2- chloroquinoxaline. MS (ESI): mass calcd, for C23H19FN6O2, 430.2; m/z found, 431.1 i vi - l i i . Π NMR (500 MHz, CDCI3) δ 8.47 - 8.40 (m, IH), 8.07 - 7.99 (m, IH), 7.91 - 7.82 (m, 2H), 7.81 - 7.72 (m, IH), 7.70 - 7.63 (m, I H), 7.61 - 7.55 (m, IE), 7.42 - 7.33 (m, 1H), 7.33 - 7.27 (m, IH), 7.19 - 7.1 1 (m, IH), 5.21 - 5.12 (m, IH), 4.94 - 4.73 (m, I H), 4.08 - 3.93 (m, IH), 2.15 - 2.01 (m, 2H), 1.78■■ 1.53 (m, 2H), 1.49 ·■ 1.35 (m, 2H).
Example 443: (R/S)-2-((5-bromo-2-chloropyridiri-3-yl)oxy)-7-azabicyclo[2
fluoro-2~(2H-l ,2,3-triazol-2-yl)phenyl)niethanone.
Figure imgf000304_0001
Prepared analogous to Example 440 substituting 5-bromo-2-fluoropyridme with 5- bromo-2-chloro-3-fluoropyridine. MS (ESI): mass calcd. for C2oHi6BrClFN502, 491 .0; m/z found, 491.8 i \) H i . IH NMR (400 MHz, CDC13, Compound present as a mixture of ro tamers) δ 8.10 (d, J - 2.0 Hz, IH), 7.86 (s, 2H), 7.67 (dt, J - 7.7, 1.2 Hz, IH), 7.48■■ 7.39 (m, IH), 7.39 ·■ 7.28 (m, I H), 7.10 (d, J = 2.0 Hz, I H), 4.84 - 4.76 (m, IH), 4.41 - 4.31 (m, IH), 4.17 - 4.08 (m, IH), 2.14 - 2.07 (m, IH), 2.04 - 1 .79 (m, 2H), 1.77 - 1 .61 (m, I T ), 1.48 - 1.29 (m, 21 n.
Example 444: (R/S)-(3-memyl-2-(2H- l ,2,3-triazol-2-yI)phenyl)-2-((5-(trifluoromethyl)pyrazin- -yl)oxy)-7-azabicyclo[2.2.1 ]lieptan-7-yl)methanone.
Figure imgf000304_0002
Prepared analogous to Example 445 substituting nitermediate A- 1 6 with intermediate A- 24. MS (ESI): mass calcd. for C iH^NeO?, 444.2; m/z found, 444.9 i \) 1 1 1 . ¾ NMR (400 MHz, CDCI3, Compound present as a mixture of retainers) δ 8.45 - 8.32. (m, IH), 8.30 ■ 8.19 (m, IH), 7.86 - 7.76 (m, 2H), 7.47 - 7.17 (series of m, 3H), 5.04 - 4.94 (series of m, I H), 4.79 - 4.67 (series of m, I H), 4.04 - 3.93 (m, IH), 2.16 (two s, M l ). 2.07 - 1 .96 (series of m, IH), 1 .90 - 1.76 (series of m, 2H), 1.55 - 1.30 (series of m, 3H). Example 445: (R/S)-(3-fiuoro-2-(2H-l ,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazm-2- eptan-7-yl)methanone.
Figure imgf000305_0001
Step A: (R/S)-tert-buty3 2-((5-(trifluoromemyl)pyrazin-2-y3)oxy)-7- azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-l 1 (43 mg, 0.203 mol) in DMF (5 mL) was added NaH (1 1 mg, 0.26 mmol, 60% dispersion in mineral oil) in one portion, and ihe reaction mixture was heated at 80 °C for 5 minutes. Then, 2-chloro-5-(trifluoromethyl)pyrazixie (59 mg, 0.325 mmol) was added. After heating at 80 °C overnight, water was added and the mixture extracted with DCM (3X). The combined organics were dried (Na^SC ) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (30 mg, 41%). MS (ESI) mass calcd. for C (1i i ;N ;();. 359.2; m/z found 304.1
Figure imgf000305_0002
Step B: (R/S)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1] eptane. To the title compound of step A (30 mg, 0.106 mmol) in DCM (2 mL) was added 2M HQ in Et20 (2 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and placed under high vacuum for 1 h to give the title compound of step B. MS (ESI) mass calcd. for C11H12F3N3O, 259.1; m/z found 2.60.1 i V! · ! i |
Step C: (R/S)-(3-fluoro-2-(2H- 1 ,2,3-triazol-2-y3)phenyr)(-2-((5-(trifluoromethyI)pyrazin- 2-yl)oxy)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanone. To the title compound of step B (30 mg, 0.101 mmol) in DCM (5 mL) was added intermediate A- 16 (23 mg, 0.112 mmol), ΗΟΒΐ (23 mg, 0.168 mmol), EDCI (32 mg, 0.168 mmol) and DIPEA (43 μΐ,, 0.252 mmol). After stirring at room temperature for 2 h, saturated NaHC(¾ (aq.) was added and the mixture was extracted with DCM (3X). The combined organics were dried (Na2S04), filtered and concentrated. Purification via silica gel chromatography (0- 100 % EtOAc in hexanes) gave the title compound (29 mg, 64 %). MS (ESI): mass calcd. for CaoH^NeOa, 448.1 ; m/z found, 448.9 [M+H]+. ¾ NMR (400 MHz, CDCI3, Compound present as a mixture of rotamers) δ 8.48 - 8.21 (series of m, 2IT), 7.95 - 7.78 (m, 2H), 7.59 - 7.18 (series of m, 3H), 5.09 - 4.95 (m, 1H), 4.85 - 4.71 (m, 1 H), 3.96 (d, J - ---- 5.2 Hz, 1H), 2, 1 1 - 1.94 (series of m, 2H), 1.90 - 1.61 (series of m, 1 H), 1.56 - 1.47 (series of m, 1H), 1.43■■ 1.29 (series of m, 2H).
Example 446: (R/S)-(6-methyl-2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)(2-((5- -7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000306_0001
Prepared analogous to Example 445 substituting intermediate A- 16 with intermediate A- 3. MS (ESI): mass calcd. for ¾οΗ18Ρ3Ν7ί¾, 445.1 ; m/z found, 445.9 [Μ+Η . ]H NMR (400 MHz, CDCh, Compound present as a mixture of rotamers) δ 8.31 (series of three s, 2H), 7.93 - 7.83 (m, 2H), 7.83 - 7.70 (m, I H), 7.36 - 7.04 (m, IH), 5.10 - 4.86 (series ofm, 2H), 3.91 - 3.78 (m, IH), 2.65 (two s, 3H), 2.14 - 1.65 (series of m, 3H), 1.54■■ 1.27 (series of m, 3H).
Example 447: (R/S)-(3-iluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(tri
eptan-7-yl)methanone.
Figure imgf000306_0002
Prepared analogous to Example 445 substituting intermediate A- 16 with intermediate A-
2. MS (ESI): mass calcd. for C22H17F4N5O2, 459.1 ; m/z found, 459.9 [M+H]". !H NMR (400
MHz, CDCI3, Compound present as a mixture of rotamers) 8 8.85 - 8.79 (m, 2H), 8.49 - 8.31 (m,
IH), 8.30 - 8.17 (m, I H), 7.53 - 7.27 (series ofm, 3H), 7.26 - 7.11 (m, IH), 5.06 - 4.97 (m, I H), 4.83 - 4.69 (m, IH), 4.10 - 4.01 (m, IH), 2.06 - 2.00 (m, IH), 1.94 - 1.71 (m, IH), 1.69 - 1.31
(series of m, 4H). Example 448: (2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5- )amino)-7-azabicyclo[2.2 ]heptan-7-yl)methanone.
Figure imgf000307_0001
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A-1. MS (ESI): mass calcd. for GnHuRNA 446.1; m/z found, 447.2 [M+H]\ Agilent 1 100 Series using an Inerisii ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/'min (T'emperature = 50 °C). R, = 1.39 min at 254 nm. Example 449: (3-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5- )arnino)-7-azabicyclo[2.2.1 jheptan-7-yl)methanone.
Figure imgf000307_0002
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 16. MS (ESI): mass calcd. for C21H17F5N60, 464.1 ; m/z found, 465.2 [M+H]+. !H NMR (500 MHz, CDClj) δ 8.15 (s, 0.4H), 8.06 (s, 0.6H), 7.91 (s, 2H), 7.57 - 7.48 (m, 0.4H), 7.43 - 7.12 (m, 3.6H), 6.48 (s, 0.6H), 5.12 - 5.04 (m, 0.4H), 4.78 (t, J= 4.5 Hz, 0.6H), 4.62 (d, J - 5.2 Hz, 0.4H), 4.40 (s, 0.6H), 4.31 (td, J= 8.0, 3.3 Hz, 0.4H), 4.01 - 3.91 (m, I H), 2.21 - 2.13 (m, 0.6! U. 2.09 - 2.01 (m, 0.4H), 1.96 - 1.41 (m, 5H). Example 450: ((lS,2R,4R)-2-((3-fluoro-5-(ttifluoromethyl)pyridm-2-yl)ammo)-7- azabicyclo[2.2.1 ]heptan-7-yl)(3-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyi)methanone.
Figure imgf000308_0001
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 24. MS (EST): mass calcd. for C22l¾oF4N60, 460.2; m/z found, 461.2 [M+H]+. ]H NMR (500 MHz, CDClj) δ 8.14 (s, 0.3H), 8.06 (s, 0.7H), 7.89 - 7.82 (m, 2H), 7.46 - 7.41 (m, 0.7H), 7.36 - 7.24 (m, 2H), 7.23 - 7.16 (m, L3H), 6.84 (s, 0.7H), 5.00 - 4.93 (m, 0.3H), 4.76 - 4.70 (m, 0.7H), 4.55 (d, J = 5.2 Hz, 0.3H), 4.40 (s, 0.7H), 4.30 - 4.22 (m, 0.3H), 3.99 - 3.92 (m, 1H), 2.22 (s, 2H), 2.19 (s, I H), 2.15 (dd, ,/- 12.9, 8.2 Hz, 0.7F1), 2.03 (dd, J= 13.1 , 8.0 Hz, 0.3H), 1.97 - 1.55 (m, 4H), 1.53 - 1.46 (m, 0.7H), 1.46 - 1.39 (m, 0.3H). Example 451 : ((1 S,2R,4R)-2-((3-fluoro-5-(trifluoromethyr)pyrid n-2-y3)ammo)-7- 6-methyl-3-(2H-i,2,3-triazol-2-yl)pyridm-2-yl)methanone.
Figure imgf000308_0002
Prepared analogous to Example 382 substitutmg intermediate A-2 with intermediate A- 21. MS (ESI): mass calcd. for C21H19F4N70, 461.2; m/z found, 462.2 | \ ! · Π ; . JH NMR (500 MHz, CDC13) δ 8.23 - 8.17 (m, 0.4H), 8.14 - 8.08 (m, 1.6H), 7.87 (s, 0.4H), 7.84 (s, 1.6H), 7.39 - 7.30 (m, 1.2H), 7.24 (dd, J= 10.9, 2.0 Hz, 0.8H), 6.69 (d, J = 8.0 Hz, 0.8H), 5.78 (d, J = 8.8 Hz, 0.2H), 4.94 - 4.90 (m, 0.81 i s. 4.79 (d, J= 5.3 Hz, 0.2H), 4.48 (td, J= 8.3, 3.2 Hz, 0.21 i ). 4.39 (id, ,/ 7.9, 2,9 Hz, O.Hi I i. 4.08 - 4.03 fm, 0.8H), 4.02 - 3.98 (m, 0.2H), 2,64 (s, 0.6H), 2.59 (s, 2.4H), 2.27 - 2.19 (m, 0.8H), 2, 12 - 1.92 (m, 2.2H), 1.86■- 1.56 (m, 2.8H), 1.50 - 1.42 (m, 0.2H). Example 452: ((l S,2R,4R)-2-((3-fluoro-5-(trifluorom
-methyl-2~(2H-l,2,3-triazol-2-yl)pyridin-3-yl)methanone.
Figure imgf000309_0001
Prepared analogous to Example 382 substituting iniermediaEe A-2 with intermediate A-3. MS (ESI): mass calcd. for
Figure imgf000309_0002
461.2; m z found, 462.2 [M+H . Analytical HPLC was obtained on a Agilent 1 100 Series using a XBridge CI 8 column (5μηι, 100 x 4.6mm), mobile phase of 10- 100% ACN in 20 mM NH4OH over 8 min and then hold at 100% ACN for 3 rain, at a flow rate of 1 mL/min (Temperature = 30 °C). R; = 6.59 min at 254 nm.
Example 453 : ((1 S,2R,4R)-2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)a.mino)-7- azabicycio[2.2.1 ]heptan-7-yl)(5-methy{-2-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-y{)methanone.
Figure imgf000309_0003
Prepared analogous to Example 382. substituting intermediate A-2 with intermediate A- 60. MS (ESI): mass calcd. for C21H19F4N7O, 461.2; m/z found, 462.2 [M+H]+. Analytical HPLC was obtained on a Agilent 1 100 Series using a XBridge C 18 column (5 μτη, 100 x 4.6mm), mobile phase of 10-100% ACN in 20 mM NH4OH over 8 min and then hold at 100% ACN for 3 min, at a flow rate of 1 mL/min (Temperature = 30 °C). Rt = 6.60 min at 254 nm.
Example 454: (3-fluoro-2-(oxazol-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5- (trifluoromemyI)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000310_0001
Prepared analogous to Example 382. substituting intermediate A-2 with intermediate A- 68, MS (ESI): mass calcd, for C22H17F5N4O2, 464, 1 ; m/z found, 465.2 [M+H]+. Ή NMR (500 MHz, CDCI3) δ 8.18 (s, 0.4H), 8.03 (s, 0.6H), 7.85 - 7.81 (m, lH), 7.53 - 7.46 (m, 0.4H), 7.41 - 7.27 i n:. 2.6! . 7.23 - 7.09 (m, 2.4 Π ). 6.05 (d, J= 8.6 Hz, 0.6H), 4.91 - 4.87 (m, 0.6H), 4.73 (d, J = 5.3 Hz, 0.4H), 4.49 - 4.43 (m, 1H), 3.91 - 3.87 (m, 0.4H), 3.85 (d, J= 4.8 Hz, 0.6H), 2.23 - 2.16 (m, 0.6H), 2.06 - 2.00 (m, 0 M i ). 1.99 - 1 .82 (m, 2.6H), 1.81 - 1.65 (m, ! . ·! ! ! ). 1.59 - 1 .52 (m, 0.6H), 1.49 - 1.42 (m, 0.4H). Example 455 : ((l S,2R,4R)-2-((3-fluoro-5-(trffiuorom
Figure imgf000310_0002
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 66. MS (EST): mass calcd. for C23l¾F4N60, 472.2; m/z found, 473.2 [M+H]+. Analytical HPLC was obtained on a Agilent 1 100 Series using a XBridge C 18 column (5μηι, 100 x 4.6mm), mobile phase of 10- 100% AC in 20 mM NH4OH over 8 min and then hold at 100% ACN for 3 rain, at a flow rate of 1 mL/niin (Temperature = 30 °C). R* = 6.08 min at 254 nm.
Example 456: ((i S,2R,4R)-2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- azabieyclo[2,2.1 ]heptan~7-yJ)(6~methyl-3-(pyrimidin-2-yl)pyridin-2~y
Figure imgf000311_0001
Prepared analogous to Example 382 substituting isitersiiediate A-2 with intermediate A- 63. MS (ESI): mass calcd. for C23H20F4NA 472.2; m/z found, 473.2 [M+Hf. !H NMR (500 MHz, CDCI3) δ 8.77 (d, 4.9 Hz, 2H), 8.36 (d, J= 8.0 Hz, H ), 8.09 (s, Hi), 7.31 - 7.22 (m, 2H), 7.19 (dd, ,/ 1 1.0, 2.0 Hz, H I ). 7.07 i d. ./ 8.4 Hz, IH), 4.95 - 4.90 (m, l i b. 4.46 - 4.40 (m, 1H), 4.08 (d, J = 5.1 Hz, I H), 2.59 (s, 3H), 2.24 (dd, J = 13.0, 7.6 Hz, 1H), 2.14 - 2.01 (m, 2H), 1 .88 - 1.81 (m, IH), 1.66 - 1.57 (m, 2H).
Example 457: ((l S,2 ,4R)-2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- methyl-3-(pyrimidin-2-yf)pyridin-2-yl)methanone.
Figure imgf000311_0002
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 67. MS (ESI): mass calcd. for ( J i ^F N^O. 472.2; m/z found, 473.2 [M+Hf. ]H NMR (500 MHz, CDCI3) δ 8.79 (d, J= 4.9 Hz, 2H), 8.44 (dd, J = 2.0, 0.9 Hz, IH), 8.26 (dd, J= 2.1, 0.9 Hz, IH), 8.09 (s, I H), 7.72 (d, J= 8.2 Hz, IH), 7.30 - 7.24 (m, IH), 7.19 (dd, J = 1 1.0, 2.0 Hz, IH), 4.95 - 4.90 (m, I H), 4.46 - 4.39 (m, IH), 4.12 (d, J= 5.3 Hz, I H), 2.44 (s, 3H), 2.29 - 2.22 (m, Hi), 2.16 - 2.06 (m, IH), 2.04 - 1.96 (m, I H), 1.90 - 1.82 (m, IH), 1.68 - 1.55 (m, 2H).
Example 458: ((l S,2R,4R)-2-((3-fluoro-5-(lxifluororaethyl)pyridin-2-yl)araino)-7- azabicyclo[2.2.1 ]heptan-7-yl)(3-(pyrimidin-2-yI)pyridin-2-yl)methanone.
Figure imgf000312_0001
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 64. MS (ESI): mass caicd. for C22H1gF4N60, 458.1 ; m ,··: found, 459.2 ! M H j . ¾ NMR (500 MHz, CDC13) δ 8.80 (d, J = 4.9 Hz, 1 1 1 ) . 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 8.48 (dd, J = 7.9, 1.7 Hz\ IH), 8.08 (s, 1H), 7.66 (d, J = 8.4 Hz, I H), 7.46 (dd, J = 8.0, 4.8 Hz, 1H), 7.28 (t, J = 4.9 Hz, IH), 7.19 (dd, J = 1 1.0, 2.0 Hz, 1H), 4.96 - 4.91 (m, IH), 4.47 - 4.41 (m, I I I ). 4.1 1 (d, ./ 5.2 Hz, I H), 2.27 i dd. 12.9, 7.5 Hz, 1H), 2.12 i ckid. ./ 14.0, 8.7, 4.3 Hz, IH), 2.06 - 1.97 (m, IH), 1.91 - 1.83 (m, IH), 1.68 - 1.59 (m, 11 1 ). Example 459: ((l S,2R,4R)-2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- )(2~fluoro-6-(pyrimiditi-2-yl)phenyl)methanone.
Figure imgf000312_0002
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A-6. MS (ESI): mass caicd. for C23H18F5N5O, 475.1 ; m/z found, 476.2 [M+Hf. Agilent 1 100 Series using an Inertsil ODS-3 column (3μτη, 50 x 3 mm), mobile phase of 5-99% ACN in 0,05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 niL/min (Temperature = 50 °C). R ; = 1.41 min at 254 nm.
Example 460: ((1 S,2R,4R)-2-((3-†luoro-5-(trifluoromethyi)pyridin-2-y1)amino)-7- azabicyclo[2.2.1 ]heptan-7-yl)(2-(5-fluoropyrimidin-2-yl)phenyl)methanone.
Figure imgf000313_0001
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 55. MS (ESI): mass calcd. for CajHjgFsNsO, 475.1 ; m/z found, 476.2 [M+Hf. !H NMR (500 MHz, CDC13) δ 8.65 (s, 1.6H), 8.60 (s, 0.4H), 8.18 (s, 0.2H), 8.1 1 (dd, J = 7.6, 1.4 Hz, 0.2H), 8.06 - 7.99 (m, 1.6H), 7.58 - 7.42 (m, 1 .8H), 7.41 - 7.30 (m, 2.2H), 7.1 1 (d, J = 10.9 Hz, 0.8H), 5.49 (d, J= 7.9 Hz, 0.2H), 4.93 - 4.87 (m, 0.8H), 4.75 (d, J= 5.3 Hz, 0.2H), 4.50 (s, 0.8H), 4.42 - 4.36 (m, 0.2H), 4.03 - 3.97 (m, 1H), 2.25 (dd, J = 12.9, 8.2 Hz, 0.8H), 2.1 1 i dd. 12.8, 7.7 Hz, 0.2H), 2.00 - 1 .89 (m, 1.6H), 1.88 - 1.78 (m, 0.4H), 1.74 - 1.53 (m, 2.8H), 1.48 - 1.40 (m, 0.2H).
Example 461 : ((l S,2 ,4R)-2-((3-fluoro-5-(trifluoromethyl)pyridm-2-yl)a.mino)-7- 2-( yrimidm-2-yl)pheiiyl)methanone.
Figure imgf000313_0002
Prepared analogous to Example 382. substituting intermediate A-2 with intermediate A- 59. MS (ESI): mass calcd. for C23H19F4N5O, 457.2; m/z found, 458.2 [M+H]+. Agilent 1 100 Series using an Inertsil ODS-3 column (3μηι, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 1 ,38 min at 254 nm. Example 462: ((1 S52R,4R)-2-((3-fluoro-5-(trifluoromethyr)pyridin-2-y3)arrjino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrirnidin-2-yi)phenyl)methanone.
Figure imgf000314_0001
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 26. 'H NMR (500 MHz, CDC13) δ 8.80 (d, J= 4.9 Hz, 2H), 8.05 (s, IH), 7.97 (s, IH), 7.32 - 7.15 (m, 4H), 7.10 (dd, ./ 1 1.1 , 2.0 Hz, IH), 4.76 - 4.70 (m, I H), 4.57 - 4.49 (m, I H), 4.03 (d, J= 4.9 Hz, IH), 2.33 (s, 3H), 2.17 (dd, J= 12.7, 8.3 Hz, IH), 2.04 - 1.94 (m, IH), 1.94 - 1.82 (ni, IH), 1.77 - 1 .68 (m, 2H), 1.54 - 1 .46 (m, IH). Agilent 1 100 Series using an Inertsil ODS-3 column (3μιπ, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). Rt = 1.42 min at 254 nm.
Example 463 : (3-fluoro-2-(5-fiuoropyrimidm-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2J]heptan-7-yl)meth
Figure imgf000314_0002
Prepared analogous to Example 382 substituting intermediate A-2 with intermediate A- 57. MS (ESI): mass calcd. for C23H17F6N5O, 493.1 ; m/z found, 494.1 [M+Hf. !H NMR (500 MHz, CDCI3) δ 8.69 (s, 2H), 8.06 (s, IH), 7.39 - 7.32 (m, IH), 7.24 - 7.07 (m, 4H), 4.80 - 4.75 (ni, IH), 4.56 - 4.48 (m, IH), 4.04 (d, J = 4.9 Hz, IH), 2.21 (dd, J= 12.9, 8.2 Hz, IH), 2.01 - 1.94 (m, I H), 1.94 - 1.86 (m, IH), 1.79 - 1.69 (m, 2H), 1 .58 - 1.50 (m, IH). Example 464: ((l S,2R,4R)-2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-7- (3-methyl-2~(pyrimidin-2~yi)phenyl)methanone.
Figure imgf000315_0001
Example: 465: ((l S,2R,4R)-2-((3-cWoro-5-(trif!uoromethyl)pyridin-2-yl)amino)-7- azabicyclo[2.2J]heptan-7-yl)(3-fluoro^
Figure imgf000315_0002
Example 466: (( 1 S,2R,4R)-2-((3-chloro-5-(trifluorometh l)pyridin-2-yl)ammo)-7- )(2~fluoro-6-(pyriinidin-2-yl)phenyl)methanone.
Figure imgf000315_0003
Example 467: ((1 S,2R,4R)-2-((3-ch1oro-5-(trifluoromethy{)pyridin-2-yl)ainino)-7- azabicyclo[2.2.1 ]heptan-7-yl)(5-methy3-2-(pyrimidin-2-yi)pyridin-3-yl)methanoi e.
Figure imgf000316_0001
Example 468: ((l S,2R,4R)-2-((3-chloro-5-(trifiuoromethyl)pyridin-2-yl)ammo)-7- -methyl-3-(pyrimidin-2-yl)pyridin-2-yi)meihanone.
Figure imgf000316_0002
Example 469: ((1 S,2R R)-2-({3-eh1oro-5-(triftuQrom
-methyl-3-(pyrimidin-2-yi)pyridin-2-yl)methanoi e.
Figure imgf000316_0003
Example 470: (2-(2H- l,2,3-triazol-2-yl)phenyl)(( 1 S,2R,4R)-2-((3-chloro-5- (trifluoromethyl)pyridin-2-yl)amino)-7-azab"icyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000317_0001
Example 471 : ((1 S,2R,4R)-2-((3-chloro-5-(trifluorom
azabicyclo[2.2J ]heptan-7-yl)(3-methy^
Figure imgf000317_0002
Example 472: ((lS,2R,4R)-2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)ainino)-7-
Figure imgf000317_0003
Example 473: ((l S,2R,4R)-2-((3-chloro-5-(trifluoromethyl)py'ridin-2-yl)amino)-7- azabicyclo[2.2.1 ]heptan-7-yl)(6-methyl-2-(2H- 1 ,2>3-triazol-2-yl)pyridin-3-yl)methanone.
Figure imgf000318_0001
Example 474 : (( 1 S,2R,4R) -2-((3-chloro - 5-(trifluoromethyl)pyridin-2~yl)amino)■ 7- azabicyclo[2.2.1 ]heptan-7-yi)(5-metb.yl-2-(2H- 1 ,2,3-lriazol-2-y{)pyridin-3-yl)raethanone.
Figure imgf000318_0002
Example 475 : (( 1 S,2R,4R)~2-((3-chloro-5-(irifluoromeihyl)pyridin-2-yl)amino)-7- azabicyc{o[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone.
Figure imgf000318_0003
Example 476: (3-fluoro-2-(pyrimidin-2-yi)phen^
yl)amino)-7-azabicyclo [2.2.1 ] -(3 -2H,2H)-heptan-7-yl)methanone
Figure imgf000319_0001
Example 477: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((lS,2R,4R)-(2-'!H)-((5- amino)-7-azabicyclo[2.2.1]-(3- H,"H)-heptan-7-yl)methanone
Figure imgf000319_0002
Example 478: ((l S,2R,4R)-2-((3-fluoro-5-(trifluoromethy3)p ridm-2-yl)amino)-7- azabicyclo[2.2J]heptan-7-yl)(4-methyl-3-(pyrimidin-2-yl)pyridtn-2-yl)meth
Figure imgf000319_0003
Example 479: (4-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 1 S,2R,4R)-2-((5- (trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2. l]heptan-7-yl)met anone.
Figure imgf000320_0001
Example 480: (4-methyl-3-(p>oimidin-2-yl)pyridin-2-yl)(( 1 S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-^^
Figure imgf000320_0002
Example 481 : (4-methyl- 3 -(pyrimidin-2-yl)pyridin-2-yl)((l S,2R,4R) -2-((5- (Wfluororaethyl)pyrimidin-2-y^^
Figure imgf000320_0003
Example 482: (4-methyl-3-(2H- l ,2,3-triazol-2-yl)pyridin-2-yl)((l S,2R,4R)-2-((5- )a.mino)-7-azabicyclo[2.2.1]hepian-7-yl)meihanone.
Figure imgf000321_0001
Example 483: (3-fluoro-4-melhyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((3-fluoro-5- (trifluoronietliyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yi)methanone.
Figure imgf000321_0002
Example 484: (4,5-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,2R!4R)-2-((3-fluoro
(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2J]heptan-7-yl)m
Figure imgf000321_0003
Example 485: ((l S,2R,4R)-2-((3-fluoro-5-(trifluoiOmethyl)pyrid"in-2-yl)a.mino)-7- azabicyclo[2.2. Ϊ .]heptan-7-yl)(3-fluoro-6-methyl-2-(pyrimidin-2-yl)phenyl)methanone.
Figure imgf000322_0001
Example 486: (3-fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- (trifluorometlxyl)pyraziir-2-yl)a^
Figure imgf000322_0002
Example 487: (4,5-dimethyl-3-(pyrimidin-2-yl)pyridm-2-yl)((l S,2R,4R)-2-((5- )a.mino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.
Figure imgf000322_0003
Example 488: (3-fluoro-6-methyl-2-(pyrimM
(trifluoromethyl)pyrazin-2-y3)ammo)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanoi e.
Figure imgf000323_0001
Example 489: (3-fluoro-4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((l S,2R,4R)-2-((5- amino)-7-azabicyclo[2.2.1]heptan-7-yi)methanone.
Figure imgf000323_0002
Example 490 : (4,5-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 1 S,2R,4R)-2-((5 - (trifluoromethyl)pyridin-2-yl)amm^
Figure imgf000323_0003
Example 491 : (3 -fluoro-6-methyl-2-(pyrimidin-2-yl)phenyi)((l S,2R,4R)-2-((5- (trifluoromethyl)pyridin-2-yl)ammo)-7-azabicyclo[2.2. l]heptan-7-yl)met anone.
Figure imgf000324_0001
Example 492: (3-fluoro-4-methyl-2-(pyrimid^
)ammo)-7-azabicyclo[2.2.1 ]heptan-7-yl)methanoi e.
Figure imgf000324_0002
Example 493 : (3 -fluoro-4-methyl-2-(pyrimidin-2-yl)phenyi)((l S,2R,4 )-2-((5- ammo)-7-azabicyclo[2.2. l]heptan-7-yl)met anone
Figure imgf000324_0003
Example 494: (3-fluoro-5-methyl-2-(pyrimidin-2-yl)phenyi)((l S,2R,4R)-2-((5- (triiluoronietliyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1 ]heptan-7-yi)methanone.
Figure imgf000325_0001
Example 495: (3-fluoro-5-methyl-2-(pyrimidin-2-yl)phenyi)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2 ]heptan-7-yl)methanone.
Figure imgf000325_0002
Assays:
The in vitro affinity of the compounds of the invention for the rat/hitman orexin 1 and human orexin 2 receptors was determined by competitive radioligand binding using [3H] (l-(5- (2-fli iro-plienyl)-2-methyl hiazo]-4-yf)- i-((S)-2-(5-phenyl-(1
pyrrolidm-l-yl)-methanone)(Langmead et al., 2004) and [3HJEMPA (n-ethyl-2[96-methoxy- pyridin-3-yl)-(toluene-2-sulfonyl)-ainiiio]-N^yridin-3-ylmethyl acetamide), respectively (Langmead et al, 2004, British Journal of Pharmacology 141 :340-346; Malherbe et al., 2004, British Journal of Pharmacology 156: 1326-41 ).
The in vitro functional antagonism of the compounds on the hitman orexin 1 and orexin 2 receptors was determined using fluorometric imaging plate reader (FL1PR) based calcium assays.
Data are analyzed using pc-Sandy macro and graphed on Graphpad Pris 5. For analysis, each concentration point is averaged from triplicate values and the averaged values are plotted on Graphpad Prism. The IC50 is determined by applying the following equation
(GraphPad Prism 5.0, SanDiego) for one site competition where X=log (concentration) and
Y-specific binding. Top denotes the total [¾]- ( l-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)- i -((S)-2-(5-phenyl-(l ,3,4)oxadiazol-2- rmethyl)-pyrrolidin- 1 -yl)-methanone) binding, bottom denotes the nonspecific [¾]- ( 1 -(5-(2-fluoro-phenyi)-2-metb.yl-thiazol-4-yi)- 1 -((S)-2-(5-phenyl- (1 ,3,4)oxadiazoi-2-ylmethy3)-pyrrolidin- 1 -yl)-methanone) binding. Graphpad Prism calculates
Ki value from IC50 and the pre-determined Kd values for ( l -(5-(2-fluoro-phenyl)-2- m6thyl-ihiazol-4-yi)- l-((S)-2-(5-p^^
methanone) and [3HJ-EMPA. The Ki for each compound is then uploaded into 3DX. Each run comprises individual compounds in triplicate. The data in Table 1 and Table 2 represent averages from between 2-20 runs. Rat and human orexin 1 receptor radioligand binding studies
Human Embry onic Kidney 293 ceils (HEK293) stably expressing rat orexin 1 receptor (Genebank accession number NM_001525) or Chinese ovary cells (CHO) stably expressing human orexin I receptor (Genebank accession number NM_001526) were grown to confluency in DMEM (Hyclone, cat # SH30022), 10% FBS, IX Pen/Strep, IX sodium pyruvate, 10 mM HEPES, 600 ^sg/mL G418 and DMEM/F12 (Gibco, Cat #11039), 10%FBS, IX Pen/Strep, 600 μg/mL G418 media, respectively on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phoshpate Buffered Saline IX with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2.K xG, 5 min at 4 °C), the supernatant was aspirated and the pellets frozen and stored at -800C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #1 1836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and homogenized for 45 sec prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using 1 i ί I - (l -(5-(2-fjuoro-phenyl)-2-metbyl-thiazol-4-yl)-l -((S)-2-(5-phenyi-(l,3,4)oxadiazol- 2-ylmeihyl)-pyrrolidin- 1 -yl)-methanone) (Moraveck Corporation, specific activity = 35.3
Ci/mmol), diluted to a 10 nM concentration in PBS (4 nM final). Compounds were solubiiized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μΜ). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 iiM almorexant. The total volume of each reaction is 200 ΐ, (20 μί., of diluted compounds, 80 μΐ,, of [3Hj- (1 -(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)- 1 -((S)-2-(5-phenyl-(l,3,4)oxadiazol-2- ylmethyl)-pyrrolidin-l-yl)-methanone) diluted in PBS and 100 of the cell suspension).
Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55 °C oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
IC50 values (i.e. concentration of unlabelied compound required to compete for 50% of specific binding to the radioligand) was calculated using the GraphPad Prism software
(GrapliPad Prism Software inc., San Diego, CA) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as Ki = IC5o/i i+C/Kd), where C is concentration of radioligand and Kd = 4 nM for rat orexin 1 receptor and 6 nM for human orexin 1 receptor.
Human orexin 2 receptor radioligand binding studies
HEK293 stably expressing hitman orexin 2 receptor (Genebank accession number NM_001 26) were grown to eonflueney in DMEM (Hyclone, eat # SH30022) , 10%FBS, IX Pen/Strep, IX NaPymvate, 10 mM HEPES, 600 ug/'ml G418 media on 150 cm' tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phoshpate Buffered Saline IX with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K xG, 5 min at 40 °C), the supernatant was aspirated and the pellets frozen and stored at -800 °C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #1 1836145001 ) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and homogenized for 45 sec just prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3HJ-EMPA (Moraveck Corporation, specific activity = 29.6 Ci/mmol), diluted to a 5 nM concentration in PBS (2 nM final concentration). Compounds were soiubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentration (from 0.1 nM to 10 μΜ). The final concentration of DMSO in the reactions is equal to or less than 0.1 %. Total and nonspecific binding was determined in the absence and presence of 10 μΜ almorexant. The total volume of each reaction is 2.00 μΕ (20 μί_ of diluted compounds, 80 μ.Ε of [3HJ-EMPA diluted in PBS and 100 μΐ. of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the ceil harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55 °C oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard). IC50 values (i.e. concentration of unlabelled compound required to compete for 50% of specific binding to the radioligand) was calculated using the GraphPad Prism software
(GraphPad Prism Software Inc., San Diego, CA) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as Ki = ICso (l+CKd), where C is concentration of radioligand and Kd = 2 nM.
Human orexin 1 receptor Ca2÷ mobilization assay
CFiQ cells stably transfected with the human orexin 1 receptor (Genebank accession number NM 001526) were grown to confluency in DMEM/F12, 10% FBS, IX pen-strep, 400 .ug/mi G418. Cells were seeded on to 384-well Packard viewplates at a density of 10,000 cells/well and incubated overnight at 370C, 5% C02. The cells were dye-loaded with BD Calcium Assay kit (BD, cat # 640178) in HBSS (Gibco, cat# 14025-092) with 2.5 mM probenecid and incubated at 37 °C, 5% C02 for 45 min. Cells were pre -incubated with compounds (diluted in DMEM F-12) for 15-30 minutes before agonist (orexin A, 10 nM) stimulation. Ligand-induced Ca2 f release was measured using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA). Functional responses were measured as peak fluorescence intensity minus basal. The concentration of agonist that produced a half- maximal response is represented by the EC50 value. Antagonistic potency values were converted to apparent pKB values using a modified Cheng-Prusoff correction. Apparent pKB = - log IC50/ 1 -'-[cone agonisi/ECso] .
Human orexin 2 receptor C--.il mobilization assay
PFSK-1 cells endogenously expressing the human orexin 2 receptor were grown to confluency in RPMI1640 (Hyclone, cai# 30027.02), 10% FBS, IX pen-strep. Cells were seeded on to 384- well Packard viewplates at a density of 5,000 cells/well and incubated overnight at 370C, 5% C02. The cells were dye-loaded with BD Calcium Assay kit (BD, cat # 640178) in HBSS (Gibco, cat# 14025-092) with 2.5 mM probenecid and incubated at 37 °C, 5% C02 for 45 min. Cells were pre-incubated with compounds (diluted in DMEM/F-12) for 15-30 minutes before agonist (orexin B, 100 nM) stimulation, Ligand-induced Ca4' release was measured using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA).
Functional responses were measured as peak fluorescence intensity minus basal. The concentration of agonist that produced a half-maximal response is represented by the EC50 value. Antagonistic potency values were converted to apparent pKB values using a modified Cheng- Prusoff correction. Apparent pKB = - log ICjo/l+[conc agonist/EC50j. Preferred compounds of the invention are set forth in Table 1 below . Orexin receptor activity of certain compounds of the invention is also set forth in Table 1 below
Table I
Figure imgf000329_0001
an -7 -
- -
- - -
an -7■
an -7 - ,2,3-
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
an ·■
-
-
-.' ) - 7 - an- ,2,3- an -7 -
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
- - 7 - id in -
- 7 - -
1 ,2,3- - -7 -
1 )pyridi n- -7 -
6-
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
-( oxazo 1-2 -
- -
an-7 -
din-2- ] hep tan- 7■
-
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
1 arni no) - - ] hep tan- 7■ - ] hep tan- 7■
Figure imgf000365_0001
-7■■
] iiep tan- 7■
Figure imgf000366_0001
216 99 71 475 (±)-(2-(2H-l,2,3-triazoi-2- yl)phenyl)(2-((5- chlorobenzo[d]oxazol-2- y!)amino)-7- azabicy clo [ 2.2.1 ]heptan - 7 -
N yl)tnet anone
CI
217 59 40 770 (i)-(2-((5-bromopyriclin-2- y!)amino)-7- azabicyclo[2.2.1 ]heptan-7- yl)(6-methyl-3-(pyrimidia- 2-yl)pyridia-2- N yl)niethanone
218 2.700 6700 (±)-(2-((5-bromopyriditi-2- yi)ainino)-7- azabicyclop. 2 1 ]heptan-7- yl)(3-fluoro-2- methoxypheiiyl)met anone
N
219 257 1700 (±) -(2 -((5 - bromopyridin-2 - yl)amino)-7- azab icyc lo [2.2.1 ]hept an- 7 - yi)(3-ethoxy-6- methylpyridin-2- yl)methanone
220 38 26 1100 (i)-(2 -(( 5 -bromopyri din -2-
^ If yi)amino)-7- azabicy clo f 2..2 , 1 "jheptan - 7 - yl)(6-methyl-3-(2H-l ,2,3- irl azo 1■■ 2 -y 1 )pyridin- 2■ N yl)tnetbanone
Figure imgf000368_0001
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0001
1■
,2,3- - - 7 -
Figure imgf000372_0001
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
- . 11
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
7■
-
- - 2 - 7 -
an - 7■
Figure imgf000379_0001
-
- - epi a.n-7 -
-7 -
Figure imgf000380_0001
Figure imgf000381_0001
jhepian- 7■ -7 - - - 7 -
Figure imgf000382_0001
2■■
] hep tan- 7 -
- 2 - an- 7 -
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
344 (5-fluoro-2-(pyrimidiit-2- vl)phenvl)(( l S,2R,4R)-2- ('(5-
(tri fl uoromcihy ! ) pyrazin■■ 2■■ yl)oxy)-7-
F N
azab i cy c i o [ 2.2.1 ] hep tan- 7■ yljmethanone
F
345 ( 2 -fluoro -6 - (pyrim idin-2 - vl)phenyD(( ί S,2R,4R)-2- ((5- f .0 (triiluoromethyl)pyrazia-2- yl)oxy)-7-
F azabicyclop. 2 1 ]heptan-7- yl!methanone
F
346 (2-(2H-l ,2,3-triazol-2-
\ // vljpheny Π(( i S,2R,4R)-2 - ((5-
(trifluoromethyl)pyrazin-2- yl)oxy)-7- N azabicyclo[2.2.1 ]heptan-7- yl)met anone
F
347 (6-methy3-3-(2H-l,2,3- v / triazoi - 2 -y l)py ridin-2 - y!)((l S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2- yl)oxy)-7- azabicyclo[2.2.1 ]heptan-7- yl)methanone
F
348 (3 -methy 1- 2- (oxazol-2■ yl)pbenyl)((l S,2R,4R)-2- i(5-
(trifluorometlty 1) pyrazin - 2 - yl)oxy)-7- azab icyc lo [2.2.1 ]hept an- 7 - yljmethanone
F 349 ( 3 -me thy! - 2 -(pyridin - 2 - y[)p envi)(( l S,2R,4R)-2- ('(5-
(tri i! uoromcihy ! ) pyrazin■■ 2■■ yl)oxy)-7-
N
azab i cy c i o [ 2.2.1 ] hep tan- 7■ yljmethanone
F F
350 (2 -( 5 -fmoropyrimidiri-2 - vl)phenyD(( ί S,2R,4R)-2- ((5-
(triiluoromethyl)pyrazia-2- yl)oxy)-7-
N azabicyclop. 7, 1 ]heptan-7- yljmethatione
F
351 (2-fiuoro-6-(2H- 1 ,2,3- // triazol-2- vl)phenyi¼(iS,2R,4R)-2- ((5-
(trifluoromethyl)pyrazin-2- N yl)oxy)-7- azabicyclo[2.2.1 ]heptan-7- y3)metlianone
F F
352 (5-rnethyI-3-(2H-l ,2,3- triazoi-2-yl)pyridin -2 - yl)((lS,2R,4R.)-2-((5- ( tri fl uoromeihy! )pyrazin - 2 - yl)oxy)-7-
N
azab i cy c i o [ 2.2.1 ] !iep tan- 7 - yljmethanone
F
353 F (2-brome-3- wBr fluorophenyl)((l S,2R,4R)- f -O 2-((5-
(trifluoromethyl)pyrazia-2-
N
yl)oxy)-7- azabicyclo[2.2.1 ]heptan-7- yl)methanone
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
In another embodiment, preferred compounds of the invention are set forth m Table 2 below. Orexin receptor activity from further testing of certain compounds of the invention is set forth in Table 2 below . Table 2
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
yljmetlianone
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000472_0001
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Figure imgf000477_0001
Figure imgf000478_0001
Figure imgf000479_0001
Figure imgf000480_0001
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0001
Figure imgf000488_0001

Claims

What is Claimed:
1.
Figure imgf000489_0001
or an enantiomer or diastereomer therof;
or a pharmaceutically acceptable salt thereof;
wherein
ring A is phenyl, naphthaleny!, pyridyi, quinoliny!, isoquinoiinyl, imidazopyridyi,
furanyl, thiazoiyl, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl;
Rj is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyi, pyrimidinyl, pyrazinvi, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrroiidinyl, thiophenyl, morpholirryl, or dialkylamino, wherein phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyi, pyrimidinyl, pyrazinvi, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrroiidinyl, thiophenyl, or morpholinyl is optionally substituted with up to two substituents selected from halo and alkyl;
R? is H, alkyl, alkoxy, hydroxyalkylene, or halo;
Z is NH, N-alkyl, or O;
R5 is pyridyi, pyrimidinyl, pyrazinyl, pyridazinyl, qumazolinyi, quinoxalinyl, pyrazolyl, thiazoiyl, thiadiazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cyano, alky! carboxyiate, alkoxy, and halo; and n is 0 or 1.
The compound of claim 1 , wherein Z is NR . The compound of claim 1 , wherein Z. is N-alkyl. The compound of claim 3, wherein Z is N-CH3. The compound of claim 1 , wherein Z is O.
6. The compound of any one of claims 1 to 5, wherem ring A is furanyi, thiazolyl, isoxazoiyi, pyrazolyl, or imidazothiazolyi,
7. The compound of any one of claims 1 to 5, wherein ring A is phenyl or naphthalenyl.
8. The compound of any one of claims 1 to 5, wherem ring A is pyridyl, quinoiinyl, isoquinolinyl, imidazopyridyl, benzimidazoiyi, or indazolyl.
9. The compound of any one claims 1 to 8, wherein ¾ is alkyl.
10. The compound of any one of claims 1 to 8, wherem Ri is alkoxy.
1 1. The compound of claim 10, wrherein alkoxy is haloalkoxy.
12. The compound of any one of claims 1 to 8, wherein R; is hydroxyalkylene or OH.
13. The compound of any one of claims 1 to 8, wherein R is halo.
14. The compound of any one of claims 1 to 8, wherein Rj is phenyl.
15. The compound of claim 14, wherem phenyl is halo-phenyl.
16. The compound of any one of claims 1 to 8, wherein Rj is triazolyl, oxazolyl, or isoxazoiyi.
17. The compound of claim 16, wherem oxazolyl is methyl-oxazolyl.
18. The compound of claim 16, wherein isoxazoiyi is methyl-isoxazolyl.
19. The compound of any one of claims 1 to 8, wherein R; is pyridyl.
20. The compound of claim 19, wherein pyridyl is metbyl-pyridyl.
21. The compound of any one of claims 1 to 8, wherein R; is pyrimidinyl, pyrazinyl, or pyridazinyi.
22. The compound of any one of claims 1 to 8, wherein R is piperazinyl, morpholinyl, pyrrolidinyl, or dialkyamino.
23. The compound of any one of claims 1 to 8, wherein R; is pyrazolyl, oxadiazolyl, or thiophenyl.
24. The compound of claim 23, wherem pyrazolyl is methyl-pyrazolyl or dimethyl-pyrazolyl.
25. The compound of claim 23, wherein oxadiazolyl is methyl-oxadiazoiyl.
26. The compound of any one of claims 1 to 25, wherein I¾ is H.
27. The compound of any one of claims 1 to 25, wherein R.2 is alkyl.
28. The compound of any one of claims 1 to 25, wherein R? is alkoxy.
29. The compound of any one of claims 1 to 25, wherein R2 is hydroxyaikylene.
30. The compound of any one of claims 1 to 25, wherein R? is halo.
31. The compound of any one of the preceding claims, wherein R5 is pyridyi, pyrimidinyl, pyrazinyi, or pyridazinyl optionally substituted with a one or two subsiituenis independently selected from the group consisting of alkyl, alkoxy, or halo.
32. The compound of claim 31, wherein alkyl is trihaloalkyi.
33. The compound of claim 32, wherem 5 is pyridyi substituted with trifluoromethyl.
34. The compound of claim 32, wherein R5 is pyrimidinyl substituted with trifluoromethyl.
35. The compound of claim 32, wherem R5 is pyrazinyi substituted with trifluoromethyl.
36. The compound of claim 32, wherein R5 is pyridazinyl substituted with trifluoromethyl.
37. The compound of any one of claims 1 to 30, wherein R5 is quinazolinyl or quinoxalinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo.
38. The compound of claim 37, wherein alkyl is trihaloalkyi.
39. The compound of claim 38, wherem R5 is quinazolinyl substituted with trifluoromethyl.
40. The compound of claim 38, wherein R5 is quinoxalinyl substituted with trifluoromethyl.
41. The compound of any one of claims 1 to 30, wherein R5 is pyrazolyl, benzoxazolyl, imidazopyrazinyf, or triazolopyrazinyl optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo.
42. The compound of claim 41, wherem pyrazolyl is methyl-pyrazolyl.
43. The compound of claim 41 , wherein alkyl is trilialoalkyl.
44. The compound of claim 43, wherein R5 is pyrazolyl substituted with trifiuoromethyl.
45. The compound of claim 43, wherein R5 is benzoxazolyl substituted with trifiuoromethyl. 46. The compound of claim 43 wherein R5 is imidazopyrazinyi subsiituted with
trifiuoromethyl.
47. The compound of claim 43, wherein R5 is triazolopyrazinyl substituted with
trifiuoromethyl.
48. The compound of any one of the preceding claims, wherein n is 0. 49. The compound of any one of claims 1 to 47, wherein n is 1.
50. A compound selected from the group consisting of
Figure imgf000492_0001
Figure imgf000493_0001
tan- 7 - - ',
1 ,2.3 - 7 - -
Figure imgf000494_0001
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Figure imgf000498_0001
Figure imgf000499_0001
Figure imgf000500_0001
Figure imgf000501_0001
Figure imgf000502_0001
Figure imgf000503_0001
Figure imgf000504_0001
Figure imgf000505_0001
Figure imgf000506_0001
Figure imgf000507_0001
Figure imgf000508_0001
Figure imgf000509_0001
Figure imgf000510_0001
Figure imgf000511_0001
Figure imgf000512_0001
Figure imgf000513_0001
Figure imgf000514_0001
140 (±)-(6-methyl-2-( 1 H- 1,2,3- triazol - 1 -yl)pyridin-3- yl){2- (( 6 -methylpyri din-2 - yl)oxy)methyl)-7- azabicyclo[2,2.1 ]hep1:an-7- yijraeihanoiie
141 (- )-(2-(3-methyl-l,2,4- o y-- oxadiazoi-5-yl)pheiiyl)(2- (((6 -methylpyridin-2 - yl)oxy)methyl)-7- azabicyclo [2.2.1 jlieptan -7 - yl)methaiiorie
142 (±) 3-n.uoro-2-(2H- ,3-
FT ^ // triazol-2-yl)pheny])(2-(((6- methylpyridin-2- f i o yl)oxy)melhy])-7- azabicyclo[2,2.1 ]heptan-7- yl)methanone
143 (±)-(6-meihyl-2-(2H-l ,2,3- triazo! - 2 -y 1 )py rid i ts■· 3■· yl)(2-(((6- (tri"fluoromeihy])pyridin-2- y!)oxy)methyl)-7- azabicy clo j 2.2. i ] hep tan■ 7■ yi)srieihatione
F
144 (:t)-(6-iiiethyl-2-(! H- 2,3- triazo! - 1 -y 1 )py rid i ts■· 3■· yl)(2-(((6- (trifluoromeihyl)pyridin-2- yl)oxy)methyl)-7 - azabicyclo \ 2.2. i ] heptan- 7 - yljmeihanone
F
145 (- )-(2-(3-methyl-l,2,4- o - -- oxadiazol-5-yl)phenyi)(2- (((6-
(triflu oromeiliyl)pyridiii-2 - yl)oxy)methyl)~7~ azabicyclo[2.2.1]heptan-7- yljmetlianone
F
Figure imgf000516_0001
Figure imgf000517_0001
Figure imgf000518_0001
Figure imgf000519_0001
Figure imgf000520_0001
Figure imgf000521_0001
Figure imgf000522_0001
Figure imgf000523_0001
Figure imgf000524_0001
Figure imgf000525_0001
Figure imgf000526_0001
Figure imgf000527_0001
Figure imgf000528_0001
Figure imgf000529_0001
Figure imgf000530_0001
l)( 2 - tan- 7 -
,2,3- tan- 7 -
7 -
- -7 -
Figure imgf000531_0001
Figure imgf000532_0001
Figure imgf000533_0001
Figure imgf000534_0001
Figure imgf000535_0001
Figure imgf000536_0001
Figure imgf000537_0001
tan- 7 - -
-4 - 7 -
in-2-
Figure imgf000538_0001
Figure imgf000539_0001
Figure imgf000540_0001
Figure imgf000541_0001
Figure imgf000542_0001
Figure imgf000543_0001
8 - -7 tan - 7 -
Figure imgf000544_0001
- 7 - -
din- tan
Figure imgf000545_0001
tan- 7 - - i no) -
Figure imgf000546_0001
.2,3- t h anone )amino ) -
heptan-
Figure imgf000547_0001
Figure imgf000548_0001
Figure imgf000549_0001
Figure imgf000550_0001
Figure imgf000551_0001
Figure imgf000552_0001
Figure imgf000553_0001
Figure imgf000554_0001
Figure imgf000555_0001
Figure imgf000556_0001
Figure imgf000557_0001
Figure imgf000558_0001
Figure imgf000559_0001
7 - - 2 - -7 -
tan - 7 -
Figure imgf000560_0001
Figure imgf000561_0001
Figure imgf000562_0001
(3-fluoro-2-(pyrimidin-2-
382
yI)pheny3)((lS,2R,4R)-2-
((3-fluoro-5- (trifluoromethy l)p yridin -2 - y])amino)-7- azabicyclo[2.2.1]heptan-7- ylYmethanone
383 ((iS,2R,4R)-2-((3-chloiO- 5 -(trif luoro met hy Dpyridin■■
2-y])amino)-7- azabicyclo [2.2. ί ] heptan- 7 - yl)(3-fiuoro-2-(2H-l ,2,3- triazC'3-2- yl)phetiyl)rnethanone
384 (( 1 S,2R,4R)-2 -((3 -chloro- 5-(1:ri i]uoromeihy!)pyridin-
2-yl)amino)-7- azabicyclo[2,2. i ]heptan-7- yl)(3-iluoro-2-(pyrimidin- 2 -yl)pheny3 )methanone
Figure imgf000563_0001
385 i(lS,2R,4R)-2-((3<:h!oro- 5 -(tri :iluoromeihyi)pyri din-
2-yl)amino)-7- azabicyclo[2,2.I ]hep1:an-7- yl)(2-(5-fluoropyrimidin-2- yl)phenyl)methanone 386 (( 1 S,2R,4R)-2-((3-chloro- 5-(trifluorome1iiyl)pyridiii-
2-yl)atnitio)-7- azabicyclo [2.2.1 jlieptan - 7 - yl)(2-(pyrimidin-2- y 1 )phenyl )rnethancme
387 (( 1 S,2R,4R)-2-((3-chloro- 5-(trifluoromeinyl)pyridin-
2-yl)atmtio)-7- azabicyclo [2.2.1 jlieptan -7 - yl)(3-(pyrimidin-2- yl)pyridin-2-yl)methanone
388 ((lS,2R,4R)-2-((5- (clifluoromet yl)pyridin-2- yl)amino)-7- azabicyc3o[2.2.1 ]heptan-7- yl)(3-iluoro-2-(2H-i,2,3-
Figure imgf000564_0001
triazol-2- yl )pi seny 1 )me tb anone
389 ((lS,2R,4R)-2-((5- (diiluoromet.hyl)pyridm-2- yl)amino)-7- azabicy clo [ 2.2.1 ] hep tan - 7 - yl)(3-fluoro-2-(pyrimidin- 2-yl)phetiyl)raethar]one 390 6-(((l S,2R,4R)-7-(3- fluoro-2-(2H-l,2,3-triazol-
2-yl)benzoyl)-7- azabicyclo[2.2.1]heptan-2- yl)arnino)isicoiitionl1xile
3Qi 6-((("lS,2R,4R)-7-(3- methyl -2 2 H-l ,2,3 -triazo!■·
2~yI)benzoyl)-7- azabicyclo[2,2. i ]heptan-2- yl)amino)nicotinonitrile
392 6-(((tS,2R,4R)-7-(3- fluoro-2-(pyrimidin-2- yl)benzoyl)-7- azabicyclo[2.2.1]heptan-2- y3)amiiio)nicotinonitri3e
393 6-(((l S,2R,4R)-7-(3- methy3-2-(pyrimidin-2- y])benzoyl)-7- azabicyc3o[2.2.1 ]heptan-2- yl)arnino)isicoiitionl1xile
394 6-(((lS,2R,4R)-7-(3- methyl-2-(oxazol-2- yl)benzoyl)-7- azabicyclo[2.2.1]heptan-2- yl)amit]o)mcotinot]itrile
Figure imgf000565_0001
Figure imgf000566_0001
R,4R)- 7 - 7 -
Figure imgf000567_0001
Figure imgf000568_0001
Figure imgf000569_0001
Figure imgf000570_0001
Figure imgf000571_0001
Figure imgf000572_0001
H-
Figure imgf000573_0001
tan■
-2 - -2 -
Figure imgf000574_0001
Figure imgf000575_0001
-7 -
)■ - 7 -
- tan- 7 -
Figure imgf000576_0001
Figure imgf000577_0001
- 7 - in-2- 7 -
Figure imgf000578_0001
(2-(2H-l,2,3-triazol-2-
448 yl)phenyl)((lS,2R,4R)-2-
((3-fluoro-5- (trifluoromethyl)pyridin-2- y!)amlno)-7- azabicyclo[2,2.I ]hep1:an-7- yi)methaii ne
449 (3-fliioro-2 -(21-1-1 ,2,3- iriazol-2- yI)pheny3)((lS,2R,4R)-2-
((3-fluoro-5- (trifluoromethy l)p yridin -2 - y!)amlno)-7- azabicycIo[2.2.iJheptaii-7- ylYmethanone
45U ((1 S,2R,4R)-2-((3-fluoro- 5-(trifluorotnethyl)pyriditi-
2-yl)amino)-7- azabicy clo j 2.2. Ϊ ] hep tan■ 7■ yI)(3-methyl-2-(2H-L2,3- triazC'3-2- yl )phenyl (rnethanotie
((IS,2R,4R)-2-((3-fluoro- 5 -(trif luoro met hy l)pyriditi■■
2-yl)amino)-7- azabicyclo [2.2. ί ] heptaii- 7 - yl)(6-methyi-3-(2H-l,2,3- triazol-2-yi)pyridin-2- yl)meihatione (( 1 S,2R,4R)-2-((3-fiuoro- 5-(trifluorome1iiyl)pyridiii-
2-yl)atnitio)-7- azabicyclo [2.2.1 jlieptan - 7 - yl)(6-rnetby!-2-(2H-l,2,3- triazol-2-yi)pyridin-3- yi)methaii ne
(( 1 S,2R,4R)-2-((3-fiuoro- 5-(trifluoromeinyl)pyridin-
2-yl)atnitio)-7- azabicyclo [2.2.1 jlieptan -7■ yl)(5-rnetby!-2-(2H-l,2,3- triazol-2-yi)pyridin-3- yi)methaii ne
454 (3-fluoro-2-(oxazol-2- yl)phenyl)((lS,2R,4R)-2-
((3-fluoro5- (trifluoronieihyl)p>Tidin-2- yl)amino)-7- azabicyclo[2,2.I ]hep1:an-7- yi)methaii ne
455 ((1 S,2R,4R)-2-((3-fluoro- 5-(trifluorotnethyl)pyriditi-
2-yl)amino)-7- azabicy clo [ 2.2.1 ] hep tan - 7 - yl)(5-metkyl-2-(pyrimidin- 2-yl)pyridin-3- yBmethanone
Figure imgf000580_0001
456 ((lS^R,4R)-2-((3-iluoro- 5 -(tri :fluoromeihyl)pyri din-
2-yl)amino)-7- azabicyclo[2,2.I ]hep1:an-7- y3)(6-methyl-3-(pyrimidin- 2-yl)pyriditi-2- yljmetlianone (( 1 S,2R,4R)-2-((3-fluorc- 5-(trifluorome1iiyl)pyridiii-
2-yL)amin )--7- azabicyclo [2.2.1 jlieptan - 7 - yl)(5 -me thy i -3 -(pyrirniditi- 2-yl)pyridin-2- yi)methaii ne
458 (( 1 S,2R,4R)-2 -((3 - fluoro- 5-(tri"fluoromeihy])pyridin-
2-yl)amino)-7- azabicyclo[2,2. i ]heptan-7- yl)(3-(p>Timidin-2- yl)pyridin-2-y3)rnethanone
459 ((IS,2R,4R)-2-((3-fluoro- 5-(trifluoromethyl)pyridin-
2-y])amino)-7- azabicyclo [2.2. ί ] heptaii- 7 - yi)(2-fiuoro-6-(pyritnidm- 2-yl)phenyl)methanone
460 (( 1 S,2R,4R)-2-((3-fluorc- 5-(trifluoromeihyl)pyridin-
2-yl)atnitio)-7- azabicyclo [2.2.1 jlieptan -7 - y])(2-(5-fluoropyrirnidin-2- yl)phenyl)methanone
Figure imgf000581_0001
Figure imgf000582_0001
Figure imgf000583_0001
Figure imgf000584_0001
-7 -
Figure imgf000585_0001
478 (( 1 S,2R,4R)-2-((3-fiuoro- 5-(trifluorome1iiyl)pyridiii-
2-yL)amin )--7- azabicyclo [2.2.1 jlieptan - 7 - yl)(4 - me thy i -3 -(pyrirniditi- 2-yl)pyridin-2- yi)methaii ne
479 (4-metbyl-3-(pyrinxidin- yl)pyridin-2- yl)((lS,2R,4R)-2-((5- (trifluoromethyl)pyriditi- yl)amino)-7- azabicy clo j 2.2. Ϊ ] hep tan■ yljmetlianone
480 (4-meth l-3-(pyrimidin- yl)pyridin-2- yl)((iS,2R,4R)-2-((5- (irifiuoromethy!)pyrazin- yl)amino)-7- azabicyclo[2,2. i jheptan- ylVrieihatione
481 (4-methyl-3 -(pyrimidin-2 - yl)pyrldiis-2- y])((lS,2R,4R)-2-((5- (trifluorometky3)pyrimidin-
2-y])amino)-7-
Figure imgf000586_0001
azabicyclo [2.2. ί ] heptaii- 7 - ylYmethanone 482 (4-methyl-3-(2H-l,2,3- triazol-2-yl)p ridin-2- y])((l S,2R,4R)-2-((5- (trifiuoromethyl)pyrazin-2- y])amlno)-7- azabicyclo[2,2.I jheptaii-7- yi)methaii ne
51. A pharmaceutical composition comprising a therapeutically effective amount of a
compound according to any one of the preceding claims and at least one
pharmaceutically acceptable excipient. 52. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 50.
53. The method of claim 52, wherein the disease, disorder, or medical condition mediated by orexin receptor activity is a disorder of the sleep-wake cy cle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleep disorder secondary to neurological disorders, mania, depression, manic depression, schizophrenia, a pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesit or a condition related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility , sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse. 54. The method of claim 53 wherein the disease, disorder, or medical condition is mood disorders, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse..
55. A compound of Formula LA:
Figure imgf000588_0001
wherein
X is C¾, N, or NR6;
Y is CR'/, Ν, or NR7;
Rf, is H, alkyl, alkoxy, OH, halo, triazolyl, oxazolyl, oxadiazoiyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyi, or thiophenyl, wherein triazolyl, oxazolyl, oxadiazoiyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyi, or thiophenyl is optionally substituted with up to two substituents selected from halo and alkyl;
R? is H, alkyl, alkoxy, or halo;
j is H, alkyl, alkoxy, hydroxyalkyiene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazoiyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyi, oxadiazoiyi, pyrrolidinyl, thiophenyl, morpholinyl, or dialkvlamino, wherem phenyl, triazolyl, oxazolyl, isoxazoiyi, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyi, oxadiazoiyi, pyrrolidinyl, thiophenyl, or morpholinyl is optionally substituted with up to two substituents selected from halo and alkyl;
R4 is H, alkyl, alkoxy, or halo;
or
e and R7, together with the atoms to which they are attached, form a 5- or 6- membered heteroaryl ring optionally substituted with alkyl; or
R3 and R4, together with the atoms to which (hey are attached, form a 6- membered aryl or 6-membered heteroaryl ring; or
R and R4, together with the atoms to which they are attached, form a 6- membered aryl or 6-membered heteroaryl ring;
Z is NH, N-alkyl, or O; R-5 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyi, quinoxalinyl, pvrazolyl, thiazoiyi, thiadiazolyl, benzoxazoiyi, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyi, cyano, aikyl carboxylate, alkoxy, and halo; and n is 0 or 1.
56. The compound of claim 54, wherein X is C¾ and Y is CR7.
57. The compound of claim 54, wherein X is CRe and Y is N.
58. The compound of claim 54, wherein X is N and Y is CR?.
59. The compound of any one of claims 55 to 57, wherein Rf, is H.
60. The compound of any one of claims 55 to 57, wherein R^ is alk l, alkoxy, OH, or halo.
61. The compound of any one of claims 55 to 57, wherein ¾ is triazolyl, oxazolyl,
oxadiazolyl, pvrazolyl, or thiophenyl.
62. The compound of claim 61, wherein oxazoly l is methyl-oxazolyl.
63. The compound of claim 61, wherein pyrazolyl is methyl-pyrazolyl or dimethyl-pyrazolyl.
64. The compound of claim 61, wherein oxadiazolyl is methyl-oxadiazolyl.
65. The compound of any one of claims 54 to 57, wherein Rg is pyridyl.
66. The compound of claim 65, wherein pyridyl is methyl-pyridyi.
67. The compound of any one of claims 55 to 57, wherein R$ is pyrimidinyl, pyrazinyl, or pyridazinyl.
68. The compound of any one of claims 55, 56, or 58, wherein R7 is H.
69. The compound of any one of claims 55, 56, or 58, wherein R7 is alkyl, alkoxy, or halo.
70. The compound of claim 69, wherein alkoxy is haloalkoxy.
71. The compound of claim 55, wherein X is N¾ and Y is CR?.
72. The compound of claim 55, wherein X is C & and Y is NR7.
73. The compound of claim 47 or 48, wherein ¾ and R7, together with the atoms to which they are attached, form a 5-membered heteroarvl ring optionally substiiuted with alkyi.
74. The compound of claim 71 or 72, wherein g and R?, together with the atoms to which they are attached, form a 6-membered heteroaiyl ring optionally substituted with alkyl.
75. The compound of any one of claims 55, 56 or 58 to 67, wherein R7 and R4, together with the atoms to which they are attached, form a 6-membered aryi ring.
76. The compound of any one of claims 55, 56, or 58 to 67, wherein R7 and R4, together with the atoms to which they are attached, form a 6-membered heteroarvl ring.
77. The compound according to any one of claims 55 to 76, wherein R3 is H.
78. The compound according to any one of claims 55 to 76, wherein 3 is aikyl, alkoxy, hydroxyalkylene, OH, halo, or phenyl.
79. The compound of claim 78, wherein alkoxy is haioaikoxy.
80. The compound according to any one of claims 55 to 76, wherein 3 is triazoiyi, oxazoiyi, isoxazo!yi, oxadiazolyl, pyridyl, or pyrazolyl.
81. The compound of claim 80, wherein oxazoiyi is methyl-oxazolyl.
82. The compound of claim 80, wherein isoxazolyl is methyl-isoxazoiyi.
83. The compound of claim 80, wherein pyridyl is methyl-pyridyi.
84. The compound of claim 80, wherein pyrazolyl is methyl-pyrazolyl or dimethyl-pyrazolyl.
85. The compound of claim 80, wherein oxadiazolyl is methyl-oxadiazolyl.
86. The compound according to any one of claims 55 to 76, wherein R3 is pyrimidinyl,
pyrazinyi, or pyridazinyl.
87. The compound according to any one of claims 55 to 76, wherein R3 is piperazmyl,
pyrazolyl, pyrrolidinyl, thiophenyi, morpholinyl, or dialkylamino.
88. The compound of any one of claims 55 to 87, wherein R is H.
89. The compound of any one of claims 55 to 87, wherein R4 is alkyl, alkoxy, or halo.
90. The compound according to any one of claims 55 to 74, wherein R3 and R4, together with the atoms to which they are attached, form a 6-nienibered aryl ring.
91. The compound according to any one of claims 55 to 74, wherein R3 and R4, together with the atoms to which they are attached, form a 6-membered heieroaryl ring.
92. A compound of claim 55 selected from the following
Figure imgf000591_0001
Figure imgf000592_0001
Figure imgf000593_0001
93. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 55 to 92. and at least one pharmaceutically acceptable excipient.
94. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, comprising administering to the subject an effective amount of a compound according to any one of claims 55 to 92.
95. The method of claim 94, wherein the disease, disorder, or medical condition mediated by orexin receptor activity is a disorder of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleep disorder secondary to neurological disorders, mania, depression, manic depression, schizophrenia, a pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesit or a condition related to overweight or obesity, insulin resistance, type Π diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorders, attention deficii disorders, cognitive deficiencies, or substance abuse.
96. The method of claim 94 wherein the disease, disorder, or medical condition is mood disorders, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse..
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