WO2013161312A1 - Pyrrolopyridinone derivatives as ttx-s blockers - Google Patents

Pyrrolopyridinone derivatives as ttx-s blockers Download PDF

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Publication number
WO2013161312A1
WO2013161312A1 PCT/JP2013/002825 JP2013002825W WO2013161312A1 WO 2013161312 A1 WO2013161312 A1 WO 2013161312A1 JP 2013002825 W JP2013002825 W JP 2013002825W WO 2013161312 A1 WO2013161312 A1 WO 2013161312A1
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Prior art keywords
pyridin
dihydro
pyrrolo
oxo
ethyl
Prior art date
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PCT/JP2013/002825
Other languages
French (fr)
Inventor
Kiyoshi Kawamura
Mikio Morita
Tatsuya Yamagishi
Original Assignee
Raqualia Pharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US14/394,532 priority Critical patent/US9187475B2/en
Priority to IN2056MUN2014 priority patent/IN2014MN02056A/en
Priority to EP13782571.7A priority patent/EP2841435B1/en
Priority to MX2014012915A priority patent/MX360323B/en
Priority to RU2014147243A priority patent/RU2646754C2/en
Priority to JP2014551356A priority patent/JP6175672B2/en
Priority to KR1020147032850A priority patent/KR102090944B1/en
Priority to CN201380022248.1A priority patent/CN104520296B/en
Application filed by Raqualia Pharma Inc. filed Critical Raqualia Pharma Inc.
Priority to CA2871229A priority patent/CA2871229C/en
Priority to BR112014026283-7A priority patent/BR112014026283B1/en
Priority to ES13782571.7T priority patent/ES2645984T3/en
Publication of WO2013161312A1 publication Critical patent/WO2013161312A1/en
Priority to HK15104385.8A priority patent/HK1203940A1/en
Priority to HK15108099.6A priority patent/HK1207381A1/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • the present invention relates to the pyrrolopyridinone derivatives which are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.
  • the pyrrolopyridinone derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain. More particularly, the pyrrolopyridinone derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers.
  • TTX-S selective tetrodotoxin-sensitive
  • the invention is exemplified by reference to the inhibition of Na V1.3 or Na V1.7 channel as the TTX-S channels. They show the affinity for Na V1.3 or Na V1.7 channel which is significantly greater than their affinity for Na V1.5 channel as the tetrodotoxin-resistant (TTX-R) sodium channels.
  • the pyrrolopyridinone derivatives of the invention show good selectivity for the Na V1.3 or Na V1.7 channel as compared with Na V1.5 channel.
  • the rat Na V1.3 channel and the human Na V1.3 channel have been cloned in 1988, 1998, 2000 respectively (NPL 1, NPL 2, and NPL 3).
  • the Na V1.3 channel was formerly known as brain type III sodium channel.
  • Na V1.3 is present at relatively high levels in the nervous system of rat embryos but is barely detectable in adult rats.
  • Na V1.3 is up-regulated following axotomy in the Spinal Nerve Ligation (SNL), Chronic Constriction Injury (CCI), and diabetic neuropathy models (NPL 4, NPL 5, NPL 6, and NPL 7).
  • SNL Spinal Nerve Ligation
  • CCI Chronic Constriction Injury
  • NPL 4 diabetic neuropathy models
  • the up-regulation of Na V1.3 channel contributes to rapidly repriming sodium current in small dorsal root ganglion (DRG) neurons (NPL 3).
  • Na V1.3 sodium channel antagonist is useful to treat neuropathic pain conditions.
  • the Na v1.7 channel appears to be the best 'validated' pain target.
  • the most exciting findings with respect to Na v1.7 have come from human genetic studies.
  • Cox et al. (NPL 9) discovered SCN9A mutations that cause a loss of Na v1.7 function in three families from Pakistan. Their observations link loss of Na v1.7 function with a congenital inability to experience pain, adding to the evidence indicating Na v1.7 channel as an essential participant in human nociception.
  • Gain-of-function mutations have also been described that lead to enhanced pain, for example, Primary Erythermalgia in one case and Paroxysmal Extreme Pain Disorder in another.
  • a local anaesthetic lidocaine and a volatile anaesthetic halothane are known to act on both TTX-R and TTX-S sodium channels with poor selectivity and low potency (IC 50 values range from 50 microM to 10 mM). These anaesthetics at high systemic concentrations could cause devastating side effects, e.g., paralysis and cardiac arrest.
  • systemic administration of lidocaine at low concentrations is effective to treat chronic pain (NPL 10).
  • NPL 11 mechanical allodynic behavior
  • TTX-S subtypes of sodium channels play an important role in maintaining allodynic behaviors in an animal model of neuropathic pain.
  • the Na V1.5 channel is also a member of TTX-resistant sodium channels.
  • the Na V1.5 channel is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiac arrhythmias and conduction disorders.
  • TTX-S blockers that are useful as drugs.
  • Preferred compounds should bind potently to the TTX-S (Na V1.3 and/or Na V1.7 ) channels whilst showing little affinity for other sodium channels, particularly the Na V1.5 channel. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug exists in a physical form that is stable, non-hygroscopic and easily formulated.
  • the pyrrolopyridinone derivatives of the present invention are selective for the TTX-S channels over the Na V1.5 channel, leading to improvements in the side-effect profile.
  • the pyrrolopyridinone derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back, orofacial pain and chemo-induced pain.
  • Other conditions that may be treated with the pyrrolopyridinone derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck
  • the compounds showed activities against Na V1.3 or Na V1.7 channel. In addition they showed selectivity for the Na V1.3 or Na V1.7 channel as compared with Na V1.5 channel.
  • the compounds of the present invention can show less toxicity, good absorption and distribution, good solubility, less plasma protein binding, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.
  • This invention provides a compound represented by above formula (I) according to [1] or [2] wherein: k is 1; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  • Preferable compounds of this invention are represented by the following formula (II): wherein: A is aryl; R 1 is independently selected from the group consisting of; (1) hydrogen, (2) -O n -C 1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (3) -O n -C 3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (4) -O n -aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (5) -S-C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R 11
  • Preferable compounds of this invention are represented by the following formula (III): wherein: A is aryl; R 1 is independently selected from the group consisting of; (1) hydrogen, (2) -O n -C 1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (3) -O n -C 3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (4) -O n -aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (5) -S-C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R 11 , (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R 11 ;
  • Suitable individual compounds of the invention are: N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(1-
  • More suitable individual compounds of the invention are: N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2-tri
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [9], and a pharmaceutically acceptable carrier.
  • the present invention provides the pharmaceutical composition as described in [10], further comprising another pharmacologically active agent.
  • the present invention provides a method for the treatment of a condition or disorder in which TTX-S channel blockers are involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [9].
  • the present invention provides the method as described in [12], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic
  • the present invention provides a use of a compound described in any one of [1] to [9] or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which TTX-S channel blockers are involved.
  • the present invention provides the use as described in [14], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic
  • the present invention provides a compound described in any one of [1] to [9] or a prodrug or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which TTX-S channel blockers are involved.
  • the present invention provides a process for preparing a pharmaceutical composition comprising mixing a compound described in any one of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pyrrolopyridinone derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain. More particularly, the pyrrolopyridinone derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers.
  • TTX-S selective tetrodotoxin-sensitive
  • the invention is exemplified by reference to the inhibition of Na V1.3 or Na V1.7 channel as the TTX-S channels. They show the affinity for Na V1.3 or Na V1.7 channel which is significantly greater than their affinity for Na V1.5 channel as the tetrodotoxin-resistant (TTX-R) sodium channels.
  • the pyrrolopyridinone derivatives of the invention show good selectivity for the Na V1.3 or Na V1.7 channel as compared with Na V1.5 channel.
  • the pyrrolopyridinone derivatives of the present invention are selective for the TTX-S channels over the Na V1.5 channel, leading to improvements in the side-effect profile.
  • the pyrrolopyridinone derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back, orofacial pain and chemo-induced pain.
  • Other conditions that may be treated with the pyrrolopyridinone derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck
  • TTX-S channels examples include, but are not limited to, TTX-S channels related diseases.
  • the compounds of the present invention show the TTX-S channels blocking activity.
  • the compounds of the present invention can show less toxicity, good absorption and distribution, good solubility, less protein binding affinity other than TTX-S channels, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.
  • halogen or “halo” as used herein is intended to include fluoro, chloro, bromo and iodo.
  • 1-6 as in C 1-6 is defined to identify the number as having 1, 2, 3, 4, 5 or 6.
  • C 1-6 as in C 1-6 alkyl is defined to identify the alkyl group as having 1, 2, 3, 4, 5 or 6 carbons.
  • C 2-6 alkenyl is defined to identify the alkenyl group as having 2, 3, 4, 5 or 6 carbons.
  • a group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
  • alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • alkoxy means an -O-alkyl, but not limited to, methoxy, ethoxy, propoxy, or 2-propoxy, butoxy (including all isomeric forms), and the like.
  • alkylthio means a -S-alkyl, but not limited to, methylthio, ethylthio, and the like.
  • alkylamino means a -NH-alkyl, but not limited to, methylamino, ethylamino, propylamino, 2-propylamino, and the like.
  • alkenyl means a hydrocarbon radical having at least one double bond , which may be in a E- or a Z- arrangement, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
  • cycloalkyl means a mono- or bicyclic ring, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norboranyl, adamantyl groups, and the like.
  • alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • cycloalkylene means a mono- or bicyclic ring, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.
  • aryl means mono- or bi-carbocyclic or mono- or bi-heterocyclic ring which may contain 0 to 4 heteroatoms selected from O, N and S, but not limited to, phenyl, naphthyl, benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyr
  • heterocyclyl as used herein includes both unsaturated and saturated heterocyclic moieties; wherein the unsaturated heterocyclic moieties (i.e. "heteroaryl”) include benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolidinonyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imid
  • C 0 means direct bond
  • protecting group means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 2007).
  • treating includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
  • preventing or “to prevent” includes prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder ".
  • Compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g.
  • succinic maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases such as triethylamine.
  • prodrugs of the compounds of formula (I).
  • certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic or hydrolysis cleavage.
  • Such derivatives are referred to as "prodrugs”.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • animal includes a mammalian subject or a non-mammalian subject.
  • suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates.
  • rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs.
  • companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets.
  • Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas.
  • Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys.
  • suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish.
  • birds include chickens, turkeys, ducks, and geese.
  • the preferred mammalian subject is a human.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • Some examples of prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains an alcohol functionality (-OH), compounds wherein the hydroxy group is replaced with a moiety convertible in vivo into the hydroxy group.
  • Said moiety convertible in vivo into the hydroxy group means a moiety transformable in vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme, e.g.
  • an esterase examples of said moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo.
  • Preferred are the moieties replaced the hydrogen of hydroxy group with acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl; and (ii) where the compound of the formula (I) contains an amino group, a pyrrolopyridinone derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug.
  • a particularly preferred pyrrolopyridinone derivative as a prodrug is -NHCO(CH 2 ) 2 OCH 3 , -NHCOCH(NH 2 )CH 3 or the like.
  • Compounds of formula (I) and salts thereof may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
  • Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
  • compounds of formula (I) may be administered as prodrugs.
  • a "prodrug" of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo.
  • Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • compounds of formula (I) there may be one or more chiral carbon atoms.
  • compounds of formula (I) exist as stereoisomers.
  • the invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers, diastereoisomers and mixtures thereof, such as racemates.
  • the different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.
  • the invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 18 F, 123 I and 125 I.
  • Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 123 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • certain compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as increased metabolic stability, enhanced oral bioavailability or absorption, and/or decreased drug-drug interactions.
  • the compounds of formula (I), being Na V1.3 and/or Na v1.7 channel blockers, are potentially useful in the treatment of a range of disorders.
  • the treatment of pain, particularly chronic, inflammatory, neuropathic, nociceptive and visceral pain, is a preferred use.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review).
  • These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus.
  • the nociceptors are found on nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (non-myelinated).
  • A-delta fibers myelinated
  • C fibers non-myelinated.
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumor related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • GI gastrointestinal
  • BBD functional bowel disorder
  • IBD inflammatory bowel disease
  • GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
  • pain include: (i) pain resulting from musculo-skeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis; (ii) heart and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredema and skeletal muscle ischemia; (iii) head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and (vi) orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • musculo-skeletal disorders including myalgia, fibromyalgi
  • the invention also relates to therapeutic use of compounds of formula (I) as agents for treating or relieving the symptoms of neurodegenerative disorders.
  • neurodegenerative disorders include, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.
  • the present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia. Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular accident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also, included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia.
  • CVA cerebral vascular accident
  • vascular disorders may occur in a patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like.
  • Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from emboly, hyperfusion, and hypoxia.
  • the instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.
  • a skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.
  • TTX-S sodium channels have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
  • the compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with TTX-S sodium channels, including one or more of the following conditions or diseases: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression,
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
  • the total daily dose of the compounds of the invention is typically in the range 0.1 mg to 1000 mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 1 mg to 1000 mg, while an intravenous dose may only require from 0.1 mg to 100 mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in another embodiment about 1 mg to 100 mg per patient per day; and in another embodiment about 5 mg to 50 mg per patient per day; in yet another embodiment about 1 mg to 30 mg per patient per day.
  • Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.
  • the pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
  • Compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned.
  • the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is envisioned.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including about 200: 1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • a TTX-S sodium channels blocker may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders.
  • a TTX-S sodium channels blocker particularly a compound of formula (I), or a prodrug thereof or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nal
  • NSAID nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid, meloxicam
  • nabumetone naproxen
  • nimesulide nitroflurbiprofen
  • olsalazine oxaprozin
  • phenylbutazone piroxicam
  • sulfasalazine sulindac
  • tolmetin or zomepirac a nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an H1 antagonist having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; - a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex TM , a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate;
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g. alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino
  • a muscarinic antagonist e.g. oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • coal-tar analgesic in particular paracetamol
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion TM or sarizotan;
  • vanilloid receptor agonist e.g. resiniferatoxin
  • antagonist e.g. capsazepine
  • V1, V2, V3, V4, M8, M2, A1 a transient receptor potential cation channel subtype (V1, V2, V3, V4, M8, M2, A1) agonist or antagonist;
  • beta-adrenergic such as propranolol
  • corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-((1H-tetrazol-5-
  • mGluR1 metabotropic glutamate subtype 1 receptor
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan TM ), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[( ⁇ 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl ⁇ amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl ⁇ amino)ethyl]benzoic acid;
  • leukotriene B4 antagonist such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,
  • a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);
  • a sodium channel blocker such as lidocaine
  • a calcium channel blocker such as ziconotide, zonisamide, mibefradil
  • a 5-HT3 antagonist such as ondansetron
  • a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leukovolin, paclitaxel
  • CGRP calcitonin gene related peptide
  • BK1 and BK2 bradykinin
  • a voltage gated sodium dependent channel blocker Na v1.3 , Na v1.7 , Na v1.8
  • - a voltage dependent calcium channel blocker N-type, T-type
  • P2X ion channel type ATP receptor
  • ASIC1a, ASIC3 acid-sensing ion channel
  • Angiotensin AT2 antagonist - a Chemokine CCR2B receptor antagonist
  • - a sigma1 receptor agonist or antagonist a 5-HT3 antagonist, such as ondansetron
  • a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leukovolin, pac
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrate compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.
  • binding agents e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g.
  • lactose microcrystalline cellulose or calcium hydrogen phosphate
  • tabletting lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • acceptable wetting agents e.g. sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.
  • fluid unit dosage forms are prepared utilizing a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a preservative.
  • Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • Compounds of formula (I) or pharmaceutically acceptable salts may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of formula (I) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compounds formula (I) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
  • bases are likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here.
  • bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine
  • the reactions are normally and preferably effected in the presence of inert solvent.
  • solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.
  • Suitable solvents include, but not limited to: halogenated hydrocarbons, such as DCM, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, DMA, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as MeCN and benz
  • solvents including but not limited to DMF, DMA, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, MeCN, DCM, dichloroethane and chloroform are preferred.
  • Flash column chromatography is carried out using Merck silica gel 60 (230-400 mesh ASTM), Fuji Silysia Chromatorex TM (TM: trademark) DU3050 (Amino Type), Wako Wakogel C300-HG, Biotage silica KP-Sil, Yamazen Hi-FLASH column, YMC DispoPack-SIL, or Biotage amino bounded silica KP-NH.
  • the purification of compounds using HPLC is performed by the following apparatus and conditions.
  • Apparatus Waters MS-trigger AutoPurification TM system Column; Waters XTerra C18, 19X50 mm, 5 micrometer particle Condition A: MeOH or MeCN / 0.01 %(v/v) ammonia aqueous solution Condition B: MeOH or MeCN / 0.05 %(v/v) formic acid aqueous solution
  • ESI mass spectral data
  • the pyrrolopyridinone derivatives of the formula (I) include the compounds defined by the formula (II) and formula (III).
  • the compounds of the formula (II) and formula (III) can be also prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof.
  • pyrrolopyridinone derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof.
  • the present invention also encompasses any one or more of these processes for preparing the pyrrolopyridinone derivatives of formula (I), in addition to any novel intermediates used therein.
  • an intermediate of formula (VI) can be prepared in situ by N-alkylation with an alkylating reagent of formula (V) in the presence of a suitable base in an inert solvent.
  • suitable bases include, but not limited to, such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine, and N,N-diisopropylethylamine.
  • Suitable organic solvents include such as THF, 1,4-dioxane, DMF, MeCN, DMA, and toluene.
  • the reaction can be carried out at a temperature of from about -20 to 150 o C, more preferably from about 0 to 100 o C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours.
  • an intermediate of formula (VI) can be cyclized to form the compound of formula (I).
  • the compound of formula (I) can be prepared by the general synthetic route of Scheme B.
  • LG 2 is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride
  • Step B-a a compound of formula (I-a) can be prepared from a compound of formula (IV) and a compound of formula (V-a) as described in Step A-a and Step A-b.
  • a compound of formula (I-b) can be prepared by coupling of a compound of formula (I-a) with a suitable reagent of formula (VII) under coupling conditions in suitable organic solvents in the presence of a suitable transition metal catalyst and in the presence or absence of a base.
  • transition metal catalysts include: tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(ll) trifluoromethanesulfonate, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1'-bis(diphenylphosphino)ferroc
  • Preferred catalysts are tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride.
  • Suitable reagents (VII) include, but not limited to, carboximides such as acetamide, propionamide, isobutyramide and cyclopropanecarboxamide.
  • suitable organic solvents include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as MeOH and ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride; and diethylether; in the presence or absence of base such as tripotassium phosphate, sodium bicarbonate, sodium carbonate and potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent.
  • additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine.
  • the reaction can be carried out at a temperature of from about 50 to 200 o C, more preferably from about 80 to 150 o C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
  • the reaction can be carried out with microwave system.
  • the reaction can be carried out at a temperature in the range from about 100 to 200 o C, preferably in the range from about 120 to 180 o C.
  • Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.
  • a compound of formula (I-d) can be prepared from a compound of formula (I-a) and a compound of formula (VIII) by CO insertion reaction in suitable organic solvents in the presence of suitable transition metal catalyst in the presence or absence of a base under carbon monoxide atmosphere.
  • transition metal catalysts include: palladium metal, palladium-carbon, palladium(II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, and a catalyst produced in solution by adding a ligand into the reaction solution of these.
  • the ligand added into the reaction solution may be a phosphoric ligand such as 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, 2,2'-bis(diphenylphosphino)-1,1'-binaphthol, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, tri-o-toluylphosphine, triphenylphosphine, 2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl and 2,2- bis (diphenylphosphino)-1,1'-binaphthyl.
  • 1,1'-bis(diphenylphosphino)ferrocene bis(2-diphenylphosphinophenyl)ether
  • suitable organic solvents include: THF; 1,4-dioxane; DMF; DMA; MeCN; toluene; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride; and diethyl ether; in the presence or absence of base such as triethylamine, N,N-diisopropylethylamine, tripotassium phosphate, sodium bicarbonate, sodium carbonate and potassium carbonate.
  • This reaction can be carried out in the presence of a suitable additive agent.
  • additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine.
  • the reaction can be carried out at a temperature of from about 50 to 200 o C, more preferably from about 60 to 150 o C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
  • reaction can be carried out with microwave system.
  • the reaction can be carried out at a temperature in the range from about 100 to 200 o C, preferably in the range from about 120 to 180 o C.
  • Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.
  • a compound of formula (I-c) can be prepared from a compound of formula (I-a) and alcohol by CO insertion reaction as described in Step B-c.
  • the reaction can be carried out with other carbon monoxide sources such as phenyl formate / triethylamine and molybdenum hexacarbonyl.
  • a compound of formula (I-d) can be prepared from a compound of formula (I-c) and a compound of formula (VIII) in suitable solvents.
  • suitable solvents include: THF, 1,4-dioxane, DMF, MeCN, MeOH, EtOH, and water.
  • the reaction can be carried out at a temperature of from about 0 to 200 o C, more preferably from about 20 to 150 o C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
  • a compound of formula (IX) can be prepared by hydrolysis of the ester compound of formula (I-c).
  • the hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • Suitable solvents include, for example: water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO.
  • Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100 o C for from about 30 minutes to 24 hours.
  • a compound of formula (I-d) can be prepared from a compound of formula (IX) by amidation with a compound of formula (VIII) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60 o C for about 1 to 24 hours.
  • a suitable condensation agent such as HBTU and EDC-HOBT
  • a compound of formula (I-d) can be also prepared from a compound of formula (VIII) by amidation with an acid halide prepared from a compound of formula (IX) using thionyl chloride or oxalyl chloride, preferably under the presence of a base such as triethylamine, pyridine, and N,N-diisopropylethylamine in a suitable solvent such as DCM at a temperature of from about 5 to 40 o C for about 1 to 24 hours.
  • a base such as triethylamine, pyridine, and N,N-diisopropylethylamine
  • a suitable solvent such as DCM
  • a compound of formula (XI) can be prepared by hydrolysis of the ester compound of formula (X).
  • the hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • Suitable solvents include, for example: water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO.
  • Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100 o C for from about 30 minutes to 24 hours.
  • a compound of formula (XII) can be prepared from acid of the formula (XI) and N,O-dimethylhydroxylamine by amidation (Weinreb amide formation) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60 o C for about 1 to 24 hours.
  • a suitable condensation agent such as HBTU and EDC-HOBT
  • a compound of formula (XIII) can be prepared from compound of formula (XII) by the treatment with a suitable alkylmetal reagent in an inert solvent.
  • suitable alkylmetal reagent include, but not limited to, such as methyllitium, ethyllithium, methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide.
  • inert solvents include, but not limited to, such as THF, DME, and 1,4-dioxane.
  • the reaction can be carried out at a temperature of from about -40 to 100 o C, more preferably from about 0 to 50 o C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
  • a compound of formula (XIV) can be prepared as a single diastereomer from carbonyl compound of formula (XIII) and a chiral tert-butanesulfinamide by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
  • a compound name of formula (XIV) is described as an (R) or (S) isomer, which represents the configuration of a sulfur atom.
  • a compound of formula (IV-a) can be prepared as a single enantiomer from a compound of formula (XIV) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
  • a compound of formula (XVI) can be prepared from aldehyde of formula (XV) and chiral tert-butanesulfinamide by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
  • a compound of formula (XVII) can be prepared as a single diastereomer from chiral sulfinyl imine of formula (XVI) and alkylmetal reagent by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
  • a compound of formula (IV-a) can be prepared as a single enantiomer from a compound of formula (XVII) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
  • a compound of formula (IV-b) can be prepared by hydrogenation of a compound of formula (XVIII) under known hydrogenolysis conditions, for example, in the presence of a suitable metal catalyst under a hydrogen atmosphere, or in the presence of hydrogen sources such as formic acid and ammonium formate, in an inert solvent. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid.
  • a preferred metal catalyst is selected from, for example, nickel catalysts such as Raney nickel, Pd-C, palladiumhydroxide-carbon, platinum oxide, platinum-carbon, ruthenium-carbon, Fe, Zn, Sn, and SnCl 2 .
  • Suitable inert aqueous or non-aqueous organic solvents include, but not limited to, alcohols, such as methanol, ethanol and ammonic methanol; ethers, such as THF and 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane and chloroform; and acetic acid; or mixtures thereof.
  • the reaction can be carried out at a temperature in the range of from about 20 to 150 o C, preferably in the range of from about 20 to 80 o C. Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 30 minutes to 24 hours.
  • This reaction can be carried out under a hydrogen atmosphere at a pressure ranging from about 1 to 100 atms, preferably from about 1 to 5 atms.
  • a compound of formula (XIX) can be prepared by reduction of a compound of formula (X).
  • the reduction may be carried out in the presence of a suitable reducing reagent in an inert solvent or without solvent.
  • a preferred reducing agent is selected from, for example, but not limited to, such as sodium borohydride, lithium aluminum hydride, lithium borohydride, boran-complex, and diisobutylaluminium hydride.
  • Reaction temperatures are generally in the range of from about -78 to 100 o C, preferably in the range of from about -70 to 60 o C. Reaction times are, in general, from about 30 minute to a day.
  • suitable solvents include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as methanol and ethanol; and halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride.
  • a compound of formula (XX) can be prepared by alkylation (Mitsunobu reaction) using corresponding alcohol in organic solvent in the presence of azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-ter-butyl azodicarboxylate as a coupling reagent.
  • azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-ter-butyl azodicarboxylate
  • suitable organic solvents include such as THF, 1,4-dioxane, DMF, MeCN, and toluene.
  • the reaction can be carried out at a temperature of from about -20 to 180 o C, more preferably from about 0 to 120 o C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
  • a compound of formula (IV-b) can be prepared from a compound of formula (XX) by deprotection with reagents such as hydrazine in an inert solvent.
  • suitable solvents include such as water, methanol and ethanol.
  • the reaction can be carried out at a temperature in the range of from about 0 to 150 o C, preferably in the range of from about 50 to 100 o C. Reaction times are, in general, from about 10 minutes to 96 hours, preferably from about 30 minutes to 24 hours.
  • a compound of formula (XXI) can be prepared by sulfonylation or substitution with halogen of a compound of formula (XIX) under, for example, known sulfonylation condition or known halogenation conditions in an inert solvent.
  • the reaction can be carried out in the presence of a base in an inert solvent.
  • a preferred base is selected from, for example, but not limited to: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride and potassium hydride; and an amine such as TEA, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine and dimethylaminopyridine.
  • an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride and potassium hydride
  • an amine such as TEA, tributylamine,
  • Suitable inert aqueous or non-aqueous organic solvents include: alcohols, such as methanol and ethanol; ethers, such as THF and 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane and chloroform; and pyridine; and mixtures thereof.
  • the reaction can be carried out at a temperature in the range of from about -10 o C to 200 o C, preferably in the range of from about 20 to 100 o C.
  • Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 10 minutes to 24 hours.
  • halogen sources include such as thionyl chloride, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, phosphorous trichloride, phosphorous tribromide, carbontetrachloride, and carbontetrabromide.
  • the reaction can be carried out in the presence of reducing agent such as triphenylphosphine.
  • suitable organic solvents include such as THF, 1,4-dioxane, DCM, 1,2-dichloroethane, carbontetrachloride, toluene, and DMF.
  • a compound of formula (XXII) can be prepared from a compound of formula (XXI) by substitution reaction with azide group.
  • the reaction can be carried out with a suitable reagent in an inert solvent.
  • a preferred reagent is selected from, for example, lithium azide, sodium azide, potassium azide, and cesium azide.
  • Reaction temperatures are generally in the range of from about 20 to 150 o C, preferably in the range of from about 50 to 120 o C.
  • Reaction times are, in general, from about 30 minutes to 96 hours, preferably from about 1 hour to 24 hours.
  • suitable solvents include such as THF, 1,4-dioxane, DMF, MeCN, and DMSO.
  • Step E-g a compound of formula (IV-b) can be prepared from a compound of formula (XXII) by hydrogenation reaction by the method described in Step E-a above.
  • Step-2> 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) (Intermediate-1)
  • a mixture (suspension) of ethyl 3-(bromomethyl)-2-chloroisonicotinate (698 mg, 2.5 mmol, Step-1), 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (643 mg, 2.5 mmol, Amine-1, single enantiomer) and cesium carbonate (3.3 g, 10.0 mmol) in THF (20 mL) is heated at refluxed temperature overnight.
  • Step-1> methyl 3-(1-bromoethyl)-2-chloroisonicotinate (racemate)
  • the title compound is prepared in 71 % yield (1.9 g, colorless oil) from methyl 2-chloro-3-ethylisonicotinate (2.0 g, 9.8 mmol) in a similar manner to Step-1 of Intermediate-1.
  • Step-2> 4-chloro-3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate) (Intermediate-6)
  • the title compound is prepared in 20 % yield (41 mg, pale brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol, Step-1, racemate) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (146 mg, 0.53 mmol, Amine-3) in a similar manner to Intermediate-2.
  • (ESI) m/z: 386 (M+H) + , 384 (M-H) - .
  • Step-1> 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
  • ethyl 2-chloro-3-cyano-6-methylisonicotinate 1.0 g, 4.5 mmol
  • EtOH 14.8 mL
  • Raney nickel 100 mg, RANEY 2800 NICKEL
  • the reaction mixture is stirred at 60 o C under hydrogen atmosphere for 2 days. After cooling to rt, the reaction mixture is filtered through a pad of Celite TM .
  • Step-2> 4-chloro-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
  • Intermediate-40 A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt.
  • Step-1> methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
  • a mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (540 mg, 1.40 mmol, Intermediate-2, single enantiomer), palladium(II) acetate (190 mg, 0.84 mmol), 1,3-bis(diphenylphosphino)propane (115 mg, 0.28 mmol), and triethylamine (0.58 mL, 4.20 mmol) in DMF / MeOH (2.5:1, 14
  • the reaction mixture is cooled to rt and dilute with water.
  • the mixture is filtered through a pad of Celite TM and the filtrate is extracted with n-hexane / EtOAc (1:1) mixed solvent.
  • the combined extracts are washed with water, and brine.
  • the organic extract is dried over sodium sulfate, filtrate, and volatiles are removed.
  • the residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (1:1 to 1:4) to give 300 mg (52 % yield) of the title compound as brown amorphous solid.
  • Step-2> 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) (Intermediate-47)
  • a solution of methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate 300 mg, 0.73 mmol, Step-1, single enantiomer
  • THF 8.0 mL
  • 2 M aqueous sodium hydroxide 1.1 mL, 2.2 mmol
  • reaction mixture is neutralized by the addition of 2 M aqueous hydrochloric acid (1.1 mL, 2.2 mmol).
  • the mixture is extracted with DCM, and the organic layer is dried over sodium sulfate. After filtration, the filtrate, and volatiles are removed to give 297 mg (>99 % yield) of the title compound as white solid.
  • Step-1> methyl 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
  • the title compound is prepared in 79 % yield (236 mg, pale yellow solid) from 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.76 mmol, Intermediate-5, single enantiomer) in a similar manner to Step-1 of Intermediate-47.
  • Step-2> 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) (Intermediate-48)
  • the title compound is prepared in 88 % yield (200 mg, white solid) from methyl 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (236 mg, 0.60 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.
  • Step-1> N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide
  • the title compound is prepared in >99 % yield (200 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.42 mmol, Intermediate-4) in a similar manner to Example-1.
  • Step-2> 4-amino-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (Intermediate-49) To a solution of N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (200 mg, 0.54 mmol, Step-1) in THF (5.0 mL) is added aqueous hydrochloric acid (3.0 mL) at rt.
  • Step-1> 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile (single enantiomer)
  • the mixture is filtered through a pad of Celite TM .
  • the Celite TM pad is washed with water, and EtOAc.
  • the filtrate is washed with water, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (3:1) to give 160 mg (80 % yield) of the title compound as colorless oil.
  • Step-2> 4-(aminomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) (Intermediate-53)
  • the title compound is prepared in 77 % yield (110 mg, colorless oil) from 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile (150 mg, 0.39 mmol, Step-1, single enantiomer) in a similar manner to Step-5 of Amine-3.
  • Step-1> ethyl 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
  • a mixture of 4-chloro-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 200 mg, 0.49 mmol, Intermediate-9, single enantiomer
  • palladium(II) acetate 33 mg, 0.15 mmol, 1,3-bis(diphenylphosphino)propane (20 mg, 0.049 mmol)
  • triethylamine 150 mg, 1.5 mmol
  • the mixture is diluted with water, and filtered through a pad of Celite TM .
  • the Celite TM pad is washed with EtOAc / toluene (2:1) mixed solvent.
  • the filtrate is washed with water, brine, and dried over sodium sulfate.
  • the organic layer is filtered, and the filtrate is concentrated.
  • the residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (1:1 to 1:2) to give 160 mg (73 % yield) of the title compound as yellow solid.
  • the title compound is prepared in 100 % yield (150 mg, yellow solid) from ethyl 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (160 mg, 0.36 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.
  • MS (ESI) m/z: 416 (M+H) + .
  • Step-1> ethyl 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
  • the title compound is prepared in 67 % yield (440 mg, yellow solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (600 mg, 1.5 mmol, Intermediate-17, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
  • Step-2> 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
  • the title compound is prepared in 76 % yield (310 mg, pale brown solid) from ethyl 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (440 mg, 1.0 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.
  • Step-1> ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
  • the title compound is prepared in 58 % yield (390 mg, pale brown solid) from 4-chloro-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (620 mg, 1.7 mmol, Intermediate-41) in a similar manner to Step-1 of Intermediate-86.
  • Step-2> 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
  • the title compound is prepared in 97 % yield (350 mg, pale yellow solid) from ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (390 mg, 1.0 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
  • Step-1> ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
  • the title compound is prepared in 60 % yield (380 mg, pale brown solid) from 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (580 mg, 1.6 mmol, Intermediate-83) in a similar manner to Step-1 of Intermediate-86.
  • the title compound is prepared in 97 % yield (350 mg, pale yellow solid) from ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (390 mg, 1.0 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
  • Step-1> ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
  • the title compound is prepared in 60 % yield (560 mg, pale brown solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (850 mg, 2.3 mmol, Intermediate-3) in a similar manner to Step-1 of Intermediate-86.
  • Step-2> 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
  • the title compound is prepared in 87 % yield (450 mg, pale brown solid) from ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (550 mg, 1.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
  • Step-1> ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
  • the title compound is prepared in 59 % yield (320 mg, brown oil) from 4-chloro-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (500 mg, 1.3 mmol, Intermediate-24) in a similar manner to Step-1 of Intermediate-86.
  • Step-2> 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
  • the title compound is prepared in 100 % yield (300 mg, pale brown solid) from ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (320 mg, 0.75 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
  • Step-1> tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate
  • the title compound is prepared in 83 % yield (560 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and tert-butyl 4-(aminomethyl)-2-methylbenzoate (400 mg, 1.8 mmol) in a similar manner to Intermediate-2.
  • Step-2> phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
  • the title compound is prepared in 90 % yield (280 mg, brown oil) from tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (250 mg, 0.67 mmol, Step-1) and phenyl formate (160 mg, 1.3 mmol) in a similar manner to Intermediate-91.
  • Step-3> tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate
  • the title compound is prepared in >99 % yield (260 mg, pale brown solid) from phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (270 mg, 0.59 mmol, Step-2) and ethylamine (0.14 mL, 1.8 mmol, 70 % aqueous solution) in a similar manner to Example-435 (Method-G).
  • Step-4> 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoic acid hydrochloride
  • a solution of tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (260 mg, 0.64 mmol, Step-3) in 4 M hydrogen chloride in dioxane (20 mL) is stirred overnight at rt.
  • 6-chloronicotinic acid 7.0 g, 44.4 mmol
  • 2,2,2-trifluoroethanol 6.40 mL, 89.0 mmol
  • sodium hydride 5.33 g, 133.0 mmol, 60 % in oil
  • DMA 400 mL
  • the reaction mixture is poured slowly into 2M hydrochloric acid (300 mL) and extracted with n-hexane / EtOAc (1:10, 500 mL).
  • 6-(2,2,2-trifluoroethoxy)nicotinic acid (10.4 g, 47.3 mmol, Step-1)
  • N,O-dimethylhydroxylamine hydrochloride (5.08 g, 52.1 mmol)
  • HOBT (9.59 g, 71.0 mmol
  • EDC (13.6 g, 71.0 mmol
  • triethylamine (26.4 mL, 189 mmol) in DMA (237 mL) is stirred at 60 o C for 16 hours.
  • the reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with EtOAc (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1) to give 6.54 g (52 % yield) of the title compound as colorless oil.
  • N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide 6.54 g, 24.8 mmol, Step-2
  • 1.06M methylmagnesium bromide 46.7 mL, 49.5 mmol
  • the reaction mixture is stirred at rt for 1.5 hours.
  • the reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with EtOAc (300 mL).
  • Step-4> (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
  • the reaction mixture is cooled to 0 o C, sodium borohydride (2.72 g, 72.0 mmol) is added there, and the mixture is stirred at the same temperature for 1 hour.
  • Saturated aqueous sodium hydrogen carbonate 50 mL is added to the reaction mixture, and the mixture is stirred for 10 minutes.
  • EtOAc 300 mL
  • the organic layer is washed with water (100 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo.
  • the title compound is prepared in >99 % yield (2.27 g, yellow oil) from 6-fluoro-5-methylnicotinic acid (1.5 g, 9.67 mmol) in a similar manner to Step-1 of Amine-1.
  • N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.64 mmol)
  • HBTU 5.50 g, 14.51 mmol
  • triethylamine 5.39 mL, 38.7 mmol
  • the reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with DCM (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1) to give 2.03 g (76 % yield) of the title compound as colorless oil.
  • the title compound is prepared in 86 % yield (1.47 g, white solid) from N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide (2.03 g, 7.31 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 79 % yield (1.70 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (1.47 g, 6.32 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 94 % yield (1.27 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.70 g, 5.01 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • a mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.08 g, 13.1 mmol, Step-1 of Amine-2), iodomethane (0.983 ml, 15.72 mmol) and potassium carbonate (5.43 g, 39.3 mmol) in DMA (40 ml) is stirred at rt for 2 hours.
  • the reaction mixture is poured into water (200 mL) and extracted with n-hexane / EtOAc (1:10, 500 mL).
  • Step-2> (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
  • methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate (0.80 g, 3.21 mmol, Step-1)
  • lithium aluminum hydride (0.11 g, 3.21 mmol) at 0 o C.
  • the resulting mixture is stirred at rt for 1 hour.
  • the reaction mixture is carefully quenched with 25 % aqueous ammonia solution at 0 o C.
  • the mixture is diluted with DCM (50 mL) and celite is added to the mixture.
  • a mixture of (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (0.70 g, 3.18 mmol, Step-2), and thionyl chloride (0.46 mL, 6.36 mmol) in DCM (10 mL) is stirred at rt for 1 hour.
  • the organic solvent is concentrated under reduced pressure and the residue is dried to give 0.75 g (>99 % yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.
  • a mixture of 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.75 g, 3.15 mmol, Step-3) and sodium azide (0.41 g, 6.29 mmol) in DMA (8 mL) is stirred at 90 o C for 2 hours.
  • the reaction mixture is poured into water (50 mL), and extracted with n-hexane / EtOAc (1:10, 50 mL).
  • the organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.77 g (>99 % yield) of the title compound as colorless oil. This material is used for the next reaction (Step-5) without further purification.
  • Step-5> (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride
  • a mixture of 5-(azidomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.77 g, 3.12 mmol, Step-4) and palladium 10 % on carbon (0.1 g) in methanol (20 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is crystallized from THF, methanol and n-hexane to give 0.37 g (46 % yield) of the title compound as white solid.
  • Amine-4 (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride ⁇ Step-1>:methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate
  • the title compound is prepared in 88 % yield (2.99 g, white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (3.19 g, 14.7 mmol, Step-1 of Amine-5) in a similar manner to Step-1 of Amine-3.
  • the title compound is prepared in >99 % yield (2.62 g, colorless oil) from methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate (2.99 g, 12.9 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in >99 % yield (2.89 g, colorless oil) from (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol (2.62 g, 12.9 mmol, Step-2) in a similar manner to Step-3 of Amine-3.
  • the title compound is prepared in 86 % yield (2.56 g, colorless oil) from 5-(chloromethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine (2.89 g, 12.9 mmol, Step-3) in a similar manner to Step-4 of Amine-3.
  • the title compound is prepared in 66 % yield (1.77 g, white solid) from 5-(azidomethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine (2.56 g, 11.2 mmol, Step-4) in a similar manner to Step-5 of Amine-3.
  • the title compound is prepared in 73 % yield (1.02 g, an off-white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol (1.06 g, 12.9 mmol) in a similar manner to Step-1 of Amine-1.
  • the title compound is prepared in 98 % yield (1.20 g, white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (1.02 g, 4.70 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in >99 % yield (0.99 g, white solid) from 6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide (1.20 g, 4.61 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 82 % yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 94 % yield (0.91 g, white solid) from (R)-N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.22 g, 3.80 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in 87 % yield (7.0 g, pale brown oil) from 6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (6.9 g, 27.0 mmol) and in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 94 % yield (5.6 g, brown oil) from N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (7.0 g, 24.0 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 76 % yield (6.0 g, pale brown oil) from 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (5.6 g, 22.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 93 % yield (5.1 g, white solid) from (R)-2-methyl-N-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (5.1 g, 16.8 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
  • Amine-7 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • a mixture of 2,6-dichloro-5-fluoronicotinic acid (1.0 g, 4.8 mmol), 2,2,2-trifluoroethanol (0.69 mL, 9.5 mmol) and sodium hydroxide (0.57 g, 14.3 mmol) in water (24 mL) is stirred at 80 o C for 40 hours. After cooling to 0 o C, the mixture is acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.05 g (80 % yield) of the title compound as white solid.
  • the title compound is prepared in 30 % yield (0.36 g, colorless oil) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (1.05 g, 3.83 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 75 % yield (0.23 g, colorless oil) from 2-chloro-5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.36 g, 1.14 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
  • a mixture of 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.23 g, 0.86 mmol, Step-3) and triethylamine (0.17 mL, 1.20 mmol) in ethanol (9 mL) is stirred at rt for 1 hour.
  • 10 % palladium on carbon (0.03 g, 0.28 mmol) is added to the mixture.
  • the mixture is stirred at rt under a balloon of hydrogen gas for 5 hours.
  • the title compound is prepared in 78 % yield (0.17 g, white solid) from 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.15 g, 0.65 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 94 % yield (0.13 g, white solid) from (R)-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.17 g, 0.50 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-8 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • the title compound is prepared in 54 % yield (2.88 g, white solid) from 5,6-dichloronicotinic acid (4.0 g, 20.8 mmol) in a similar manner to Step-1 of Amine-1.
  • the title compound is prepared in 94 % yield (2.2 g, white solid) from 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.0 g, 7.8 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in >99 % yield (1.71 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (1.91 g, 6.40 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 57 % yield (0.65 g, white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 85 % yield (0.45 g, white solid) from (R)-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.65 g, 1.81 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in >99 % yield (0.41 g, white solid) from 6-chloro-5-methoxynicotinic acid (0.35 g, 1.79 mmol) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 76 % yield (0.38 g, white solid) from 6-chloro-N,5-dimethoxy-N-methylnicotinamide (0.41 g, 1.79 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • reaction mixture is poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (30 mL). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1) to give 0.25 g (>99 % yield) of the title compound as white solid.
  • the title compound is prepared in 83 % yield (0.29 g, white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.25 g, 0.99 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 97 % yield (0.23 g, white solid) from (R)-N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.29 g, 0.82 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • Step-2> (R)-2-methyl-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)
  • the title compound is prepared in 76 % yield (0.73 g, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.65 g, 2.99 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 86 % yield (0.50 g, white solid) from (R)-2-methyl-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer) (0.73 g, 2.26 mmol, Step-2) in a similar manner to Step-5 of Amine-1.
  • Amine-11 (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine is commercially available.
  • Amine-12 (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride
  • the title compound is prepared in 83 % yield (4.12 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
  • Step-2> methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate Thionyl chloride (1.38 ml, 18.9 mmol) is added to a solution of 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (1.5 g, 6.31 mmol, Step-1) in methanol (100 ml) at 0 o C. Then the reaction mixture is refluxed with stirring for 2 hours. After removing solvent to give 1.57 g (>99 % yield) of the title compound as white solid.
  • Step-3> (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol
  • the title compound is prepared in 62 % yield (0.87 g, colorless oil) from methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate (1.57 g, 6.25 mmol, Step-2) in a similar manner to Step-2 of Amine-3.
  • Step-5> (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride Hydrazine monohydrate (0.53 mL, 10.8 mmol) is added to a solution of 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.27 g, 3.60 mmol, Step-4) in methanol (50 mL) and stirred for 20 hours at 50 o C. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mLx3).
  • Amine-13 (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine ⁇ Step-1>:methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate
  • Step-1> methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate
  • the title compound is prepared in 54 % yield (1.79 g, colorless oil) from methyl 6-chloro-2-methoxynicotinate (2.5 g, 12.4 mmol) in a similar manner to Step-3 of Amine-9.
  • Step-2> (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
  • the title compound is prepared in 74 % yield (1.19 g, white solid) from methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate (1.79 g, 5.02 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in 37 % yield (0.67 g, white solid) from (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.19 g, 5.02 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
  • Step-4> (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine Hydrazine monohydrate (0.13 mL, 2.74 mmol) is added to a solution of 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.83 mmol, Step-3) in methanol (20 mL) and stirred at 50 o C for 20 hours. The reaction mixture is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mLx3). The organic layer is dried over sodium sulfate.
  • the title compound is prepared in >99 % yield (550 mg, brown oil) from (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (500 mg, 2.1 mmol) in a similar manner to Step-3 of Amine-3.
  • the title compound is prepared in 50 % yield (280 mg, colorless oil) from 5-(chloromethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (540 mg, 2.1 mmol, Step-1) in a similar manner to Step-4 of Amine-3.
  • Step-3> (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride
  • Palladium 10 % on carbon (10 mg) is added to a stirred solution of 5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (110 mg, 2.1 mmol, Step-2) and 2M hydrochloric acid (0.2 mL) in methanol (3.5 mL).
  • the mixture is stirred at rt under hydrogen atmosphere (1 atm) for 4 hours.
  • the mixture is filtered through a pad of celite and washed with methanol.
  • the filtrate is concentrated in vacuo to give 110 mg (93 % yield) of the title compound as white solid.
  • Step-1> methyl 6-(3,3,3-trifluoropropoxy)nicotinate
  • the title compound is prepared in 47 % yield (1.37 g, colorless oil) from methyl 6-chloronicotinate (2.0 g, 11.7 mmol) and 3,3,3-trifluoropropan-1-ol instead of 2,2,2-trifluoroethanol in a similar manner to Step-3 of Amine-9.
  • methanol (30 mL) 2 M sodium hydroxide (5 mL)
  • 2 M sodium hydroxide 5 mL
  • the residue is dissolved in water (30 mL) and acidified with conc. hydrochloric acid (pH 2).
  • the resulting white precipitate is collected by filtration and dried to give 1.15 g (86 % yield) of the title compound as white solid.
  • the title compound is prepared in 74 % yield (0.97 g, colorless oil) from 6-(3,3,3-trifluoropropoxy)nicotinic acid (1.11 g, 4.72 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in >99 % yield (0.82 g, white solid) from N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide (0.97 g, 3.50 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 80 % yield (0.95 g, white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (0.82 g, 3.51 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (0.76 g, colorless gum) from (R)-2-methyl-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (0.94 g, 2.79 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-16 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • the title compound is prepared in 70 % yield (3.38 g, colorless oil) from 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (4.07 g, 3.60 mmol, Step-1 of Amine-12) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in >99 % yield (2.84 g, white solid) from 5-chloro-6-(2,2-difluoroethoxy)-N-methoxy-N-methylnicotinamide (3.38 g, 3.60 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 85 % yield (3.56 g, white solid) from 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (2.88 g, 12.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 87 % yield (2.49 g, white solid) from (R)-N-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (3.56 g, 10.5 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in >99 % yield (3.7 g, white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
  • the title compound is prepared in 83 % yield (960 mg, clear colorless oil) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (800 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in >99 % yield (820 mg, clear colorless oil) from N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (900 mg, 3.4 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 77 % yield (880 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (820 mg, 3.1 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (800 mg, an orange gum) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (880 mg, 32.4 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in 87 % yield (0.53 g, colorless oil) from N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.70 g, 2.65 mmol, Step-2 of Amine-1) and ethyl magnesium bromide instead of methyl magnesium bromide in a similar manner to Step-3 of Amine-1.
  • Step-2> (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)propane-2-sulfinamide (single diastereomer)
  • the title compound is prepared in 50 % yield (0.39 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one (0.54 g, 2.29 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (0.34 g, colorless oil) from (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)propane-2-sulfinamide (single diastereomer) (0.37 g, 1.81 mmol, Step-2) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in >99 % yield (2.40 g, colorless oil) from 6-chloropicolinic acid (1.18 g, 7.49 mmol) in a similar manner to Step-1 of Amine-1.
  • methyl iodide 3.39 mL, 54.3 mmol
  • potassium carbonate 4.50 g, 32.6 mmol
  • the reaction mixture is poured into water (100 mL) and extracted with n-hexane / EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), dried over sodium sulfate.
  • Step-3> (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
  • THF tetrahydrofuran
  • lithium aluminum hydride 0.096 g, 2.53 mmol
  • the resulting mixture is stirred at rt for 1 hour.
  • the reaction mixture is carefully quenched with 25 % aqueous ammonia solution at 0 o C.
  • the mixture is diluted with DCM (50 mL) and celite is added to the mixture.
  • 6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3)
  • thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL)
  • the organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99 % yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.
  • 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.35 g, 1.55 mmol, Step-4)
  • sodium azide (0.20 g, 3.10 mmol) in DMA (8 mL)
  • the reaction mixture is poured into water (50 mL), and extracted with n-hexane / EtOAc (1:10, 50 mL).
  • the organic layer is washed with water (50 mL) and dried over sodium sulfate.
  • Step-6> (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine
  • a mixture of 2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.44 g, 1.90 mmol, Step-5) and palladium 10 % on carbon (0.070 g) in methanol (12 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo.
  • ⁇ Step-1> methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate
  • sodium hydride 4.9 g, 120 mmol, 60 % in oil
  • DMA 100 mL
  • 2,2,3,3,3-pentafluoropropan-1-ol 8. mL, 82 mmol
  • a solution of methyl 6-chloronicotinate 7.0 g, 41 mmol
  • DMA 120 mL
  • the mixture is stirred for 30 minutes at rt.
  • the mixture is stirred at 90 o C for 2 hours.
  • the title compound is prepared in 62 % yield (6.8 g, an off-white solid, yield is based on methyl 6-chloronicotinate) from methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate (8.4 g, crude from Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in 51 % yield (3.6 g, brown oil) from 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid (6.0 g, 22.1 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 97 % yield (3.0 g, brown oil) from N-methoxy-N-methyl-6-(2,2,3,3,3-pentafluoropropoxy)nicotinamide (3.6 g, 11.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 78 % yield (3.2 g, an off-white solid) from 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone (3.0 g, 11.0 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 84 % yield (2.2 g, white solid) from (R)-2-methyl-N-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (3.2 g, 8.6 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in 92 % yield (2.9 g, clear colorless oil) from 2-chloro-6-hydroxynicotinic acid (1.8 g, 11 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in a similar manner to Step-1 of Amine-10.
  • THF 35 mL
  • sodium methoxide 1.58 g, 29.2 mmol
  • the mixture is poured into water and extracted with DCM (10 mLx3).
  • the combined organic layer is washed with water, brine, and dried over sodium sulfate.
  • the organic solvent is removed under reduced pressure.
  • the title compound is prepared in 91 % yield (270 mg, white solid) from methyl 6-(2,2-difluoroethoxy)-2-methoxynicotinate (320 mg, 1.3 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in >99 % yield (990 mg, clear colorless oil) from 6-(2,2-difluoroethoxy)-2-methoxynicotinic acid (910 mg, 4.5 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 69 % yield (650 mg, pale yellow oil) from 6-(2,2-difluoroethoxy)-N,2-dimethoxy-N-methylnicotinamide (980 mg, 3.6 mmol, Step-4) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 73 % yield (400 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone (380 mg, 1.6 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 96 % yield (350 mg, white solid) from (R)-N-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.3 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in 75 % yield (21.0 g, white solid) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (32.2 g, 118 mmol, Step-1 of Amine-7) in a similar manner to Step-4 of Amine-7.
  • the title compound is prepared in 55 % yield (1.74 g, white solid) from 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.0 g, 12.6 mmol, Step-1) in a similar manner to Step-2 of Amine-12.
  • Step-3> (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
  • the title compound is prepared in 93 % yield (1.43 g, colorless oil) from methyl 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate (1.74 g, 6.89 mmol, Step-2) in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in 99 % yield (2.24 g, white solid) from (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.44 g, 6.39 mmol, Step-3) in a similar manner to Step-4 of Amine-12.
  • Step-5> (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride
  • the title compound is prepared in 41 % yield (0.67 g, white solid) from 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (2.24 g, 6.33 mmol, Step-4) in a similar manner to Step-5 of Amine-12.
  • the title compound is prepared in 95 % yield (350 mg, white solid) from 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (350 mg, 1.4 mmol, Step-1 of Amine-8) in a similar manner to Step-1 of Amine-3.
  • the title compound is prepared in 78 % yield (210 mg, white solid) from methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 1.1 mmol, Step-1) and diisobutylalminium hydride (1.0 M in hexane, 2.4 mL, 2.4 mmol) instead of lithium aluminum hydride in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in 64 % yield (210 mg, white solid) from (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (211 mg, 0.87 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
  • Step-4> (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine Hydrazine monohydrate (0.04 mL, 0.84 mmol) is added to a solution of 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (210 mg, 0.56 mmol, Step-3) in methanol (10 mL) and stirred for 20 hours at 50 o C.
  • the title compound is prepared in >99 % yield (1.1 g, white solid) from 3-chloro-4-(2,2-difluoroethoxy)benzoic acid (900 mg, 3.8 mmol) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 95 % yield (860 mg, white solid) from 3-chloro-4-(2,2-difluoroethoxy)-N-methoxy-N-methylbenzamide (1.1 g, 3.9 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 62 % yield (780 mg, clear colorless oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (860 mg, 3.7 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 98 % yield (610 mg, white solid) from (R)-N-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (780 mg, 2.3 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in >99 % yield (2.40 g, colorless oil) from 6-chloropicolinic acid (1.18 g, 7.49 mmol) in a similar manner to Step-1 of Amine-1.
  • methyl iodide 3.39 mL, 54.3 mmol
  • potassium carbonate 4.50 g, 32.6 mmol
  • the reaction mixture is poured into water (100 mL) and extracted with n-hexane / EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo.
  • Step-3> (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
  • THF tetrahydrofuran
  • lithium aluminum hydride 0.096 g, 2.53 mmol
  • the resulting mixture is stirred at rt for 1 hour.
  • the reaction mixture is carefully quenched with 25 % aqueous ammonia solution at 0 o C.
  • the mixture is diluted with DCM (50 mL) and celite is added to the mixture.
  • 6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3)
  • thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL)
  • the organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99 % yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.
  • Sodium cyanide (0.823 g, 16.8 mmol) is added to a solution of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (2.0 g, 7.63 mmol, Step-4) in DMSO (38 mL) and stirred at rt for 20 hours.
  • the reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (60 mL) and extracted with EtOAc (100 mL).
  • the organic layer is washed with water (50 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo.
  • the title compound is prepared in >99 % yield (1.69 g, yellow oil) from 2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetonitrile (1.03 g, 4.76 mmol, Step-5) in a similar manner to Step-3 of Amine-14.
  • Step-1> methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate
  • methyl 4-hydroxy-3-methylbenzoate 1.5 g, 9.0 mmol
  • 2,2-difluoroethanol 0.90 g, 10.8 mmol
  • triphenylphosphine 3.6 g, 13.5 mmol
  • diethyl azodicarboxylate 4.9 mL, 10.8 mmol, 40 % solution in toluene
  • the title compound is prepared in >99 % yield (1.1 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (1.0 g, 4.3 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in 94 % yield (900 mg, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methylbenzoic acid (800 mg, 3.7 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 98 % yield (730 mg, pale yellow oil) from 4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide (900 mg, 3.4 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 47 % yield (520 mg, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone (750 mg, 3.5 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 96 % yield (390 mg, white solid) from (R)-N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (750 mg, 3.5 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in 98 % yield (1.2 g, white solid) from 3-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (1.0 g, 3.9 mmol) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in >99 % yield (1.2 g, a pale yellow solid) from 3-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide (1.2 g, 3.9 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 58 % yield (940 mg, clear colorless oil) from 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 62 % yield (470 mg, white solid) from (R)-N-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (940 mg, 2.6 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in >99 % yield (1.18 g, colorless oil) from 4-(1,1,2,2-tetrafluoroethoxy)benzoic acid (1.00 g, 4.2 mmol) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 83 % yield (0.82 g, yellow oil) from N-methoxy-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzamide (1.18 g, 4.2 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • Step-3> (R)-2-methyl-N-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)
  • the title compound is prepared in 80 % yield (0.95 g, white solid) from 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.82 g, 3.46 mmol, Step-2) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 83 % yield (0.63 g, white solid) from (R)-2-methyl-N-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (0.95 g, 2.77 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
  • Step-1> methyl 3-(2,2-difluoroethoxy)-5-methylbenzoate
  • the title compound is prepared in 75 % yield (1.88 g, pale yellow oil) from methyl 3-hydroxy-5-methylbenzoate (1.8 g, 10.8 mmol) in a similar manner to Step-1 of Amine-27.
  • the title compound is prepared in 96 % yield (0.98 g, white solid) from methyl 3-(2,2-difluoroethoxy)-5-methylbenzoate (1.08 g, 4.69 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in >99 % yield (1.02 g, colorless oil) from 3-(2,2-difluoroethoxy)-5-methylbenzoic acid (0.85 g, 3.93 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 97 % yield (0.85 g, colorless oil) from 3-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylbenzamide (1.06 g, 4.09 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • Step-5> (R)-N-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
  • the title compound is prepared in 77 % yield (0.85 g, colorless oil) from 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (1.06 g, 3.04 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 88 % yield (0.67 g, white solid) from (R)-N-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.97 g, 3.04 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • Step-1> methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate
  • the title compound is prepared in 80 % yield (2.17 g, white solid) from methyl 4-hydroxy-3-methoxybenzoate (2.0 g, 11.0 mmol) in a similar manner to Step-1 of Amine-27.
  • the title compound is prepared in 95 % yield (1.05 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate (1.17 g, 4.74 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in 86 % yield (0.97 g, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methoxybenzoic acid (0.95 g, 4.09 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 95 % yield (0.77 g, pale yellow oil) from 4-(2,2-difluoroethoxy)-N,3-dimethoxy-N-methylbenzamide (0.97 g, 3.51 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 97 % yield (1.09 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone (0.77 g, 3.35 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 78 % yield (0.68 g, white solid) from (R)-N-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.09 g, 3.25 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.
  • Step-1> (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanol
  • the title compound is prepared in >99 % yield (0.89 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate (1.00 g, 4.06 mmol, Step-1 of Amine-31) in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in >99 % yield (0.96 g, white solid) from (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanol (0.89 g, 4.06 mmol, Step-1) in a similar manner to Step-3 of Amine-3.
  • the title compound is prepared in 94 % yield (0.93 g, colorless oil) from 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene (0.96 g, 4.06 mmol, Step-2) in a similar manner to Step-4 of Amine-3.
  • Step-4> (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride
  • the title compound is prepared in 80 % yield (0.77 g, white solid) from 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene (0.93 g, 3.81 mmol, Step-3) in a similar manner to Step-3 of Amine-14.
  • Step-1> methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate
  • the title compound is prepared in 98 % yield (2.0 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (1.5 g, 8.0 mmol) in a similar manner to Step-1 of Amine-27.
  • Step-2> (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol
  • the title compound is prepared in >99 % yield (860 mg, clear colorless oil) from methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate (930 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in >99 % yield (930 mg, clear colorless oil) from (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol (860 mg, 3.8 mmol, Step-2) in a similar manner to Step-3 of Amine-3.
  • the title compound is prepared in 88 % yield (840 mg, clear colorless oil) from 2-chloro-4-(chloromethyl)-1-(2,2-difluoroethoxy)benzene (930 mg, 3.8 mmol, Step-3) in a similar manner to Step-4 of Amine-3.
  • the title compound is prepared in 96 % yield (780 mg, white solid) from 4-(azidomethyl)-2-chloro-1-(2,2-difluoroethoxy)benzene (790 mg, 3.2 mmol, Step-4) in a similar manner to Step-3 of Amine-14.
  • 4-hydroxy-3-methylbenzoic acid (10 g, 65.7 mmol) and cesium carbonate (64.2 g, 197 mmol) in DMF (150 mL) is added 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.6 g, 145 mmol) at 0 o C.
  • the mixture is stirred at 0 o C for 10 minutes then at rt for 2 days.
  • water (150 mL) and NaOH pellet (10g) are added, and the mixture is stirred for 20 hours at rt.
  • the mixture is diluted with water (100 mL).
  • aqueous phase is washed with ether (100 mLx2) and then acidified with conc. hydrochloric acid (pH 4) at 0 o C to give a white suspension.
  • the precipitate is collected by filtration, washed with water and n-hexane, and dried in vacuo at 50 o C to give 14.8 g (96 % yield) of the title compound as white solid.
  • Step-2> (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol
  • the title compound is prepared in 80 % yield (5.26 g, white solid) from 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (7.00 g, 29.9 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
  • the title compound is prepared in 80 % yield (6.68 g, white solid) from (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol (5.26 g, 23.9 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
  • Step-4> (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine
  • the title compound is prepared in >99 % yield (4.25 g, pale brown oil) from 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (6.68 g, 19.1 mmol, Step-3) in a similar manner to Step-4 of Amine-13.
  • the title compound is prepared in 68 % yield (480 mg, a pale brown solid) from 2-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (600 mg, 2.4 mmol) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in >99 % yield (400 mg, pale yellow oil) from 2-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide (470 mg, 1.6 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 72 % yield (390 mg, clear colorless oil) from 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 71 % yield (220 mg, white solid) from (R)-N-(1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (380 mg, 1.0 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
  • Amine-36 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • Step-1> methyl 6-fluoro-5-methylnicotinate
  • the title compound is prepared in 77 % yield (1.34 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.60 g, 10.3 mmol) in a similar manner to Step-1 of Amine-3.
  • sodium hydride 0.44 g, 21.1 mmol
  • 3,3,3-trifluoropropan-1-ol (1.61 g, 14.1 mmol) in THF (10 mL) is added at 0 o C , and stirred for 5 minutes.
  • methyl 6-fluoro-5-methylnicotinate (1.19 g, 7.04 mmol, Step-1) in THF (10 mL) is added dropwise to the reaction mixture and stirred at rt for 2 hours.
  • the reaction mixture is diluted with water (30 mL) and stirred overnight.
  • the title compound is prepared in >99 % yield (2.16 g, colorless oil) from 5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid (1.76 g, 7.06 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
  • the title compound is prepared in 90 % yield (1.63 g, colorless oil) from N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropoxy)nicotinamide (2.15 g, 7.36 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 65 % yield (1.50 g, colorless oil) from 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (1.63 g, 6.59 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (1.44 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.5 g, 4.26 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-37 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Amine-2)
  • Step-1> (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide
  • the title compound is prepared in 83 % yield (0.79 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.66 g, 2.81 mmol, Step-3 of Amine-2) and (S)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 88 % yield (0.56 g, white solid) from (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer; antipode of Amine-2) (0.79 g, 2.33 mmol, Step-2) in a similar manner to Step-5 of Amine-1.
  • Amine-38 (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (6-(4-Fluorophenoxy)pyridin-3-yl)methanamine (Amine-38) is commercially available.
  • Amine-39 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • a mixture of methyl 6-fluoro-5-methylnicotinate (2.40 g, 14.2 mmol, Step-1 of Amine-36), 4-fluorophenol (2.39 g, 21.3 mmol), and potassium carbonate (3.92 g, 28.4 mmol) in DMF (45 mL) is stirred at 90 o C for 3 hours. After cooling to rt, the mixture is filtered through a pad of Celite and rinsed with EtOAc (200 mL). The filtrate is washed with water (200 mL) and brine (200 mL), and the organic layer is dried over sodium sulfate.
  • the title compound is prepared in 91 % yield (2.98 g, white solid) from methyl 6-(4-fluorophenoxy)-5-methylnicotinate (3.46 g, 13.2 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in >99 % yield (3.00 g, colorless oilcolorless oil) from 6-(4-fluorophenoxy)-5-methylnicotinic acid (2.50 g, 10.1 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in 97 % yield (2.47 g, white solid) from 6-(4-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (3.00 g, 10.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 76 % yield (2.67 g, white solid) from 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.47 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (2.33 g, a pale brown solid) from (R)-N-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.67 g, 7.62 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • the title compound is prepared in >99 % yield (1.78 g, a pale brown oil) from 3-fluorophenol (994 mg, 8.87 mmol) in a similar manner to Step-1 of Amine-39.
  • the title compound is prepared in 99 % yield (1.66 g, white solid) from methyl 6-(3-fluorophenoxy)-5-methylnicotinate (1.78 g, 6.81 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in 70 % yield (1.37 g, white solid) from 6-(3-fluorophenoxy)-5-methylnicotinic acid (1.66 g, 6.71 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in 98 % yield (1.13 g, white solid) from 6-(3-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (1.37 g, 4.72 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 79 % yield (1.27 g, colorless amorphous) from 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (1.13 g, 4.61 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (838 mg, 6.91 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (1.19 g, an off-white solid) from (R)-N-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.27 g, 3.62 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-41 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • Step-1> methyl 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinate
  • the title compound is prepared in 96 % yield (1.78 g, white solid) from 6-(trifluoromethyl)pyridin-3-ol (1.45 g, 8.87 mmol) in a similar manner to Step-1 of Amine-39.
  • the title compound is prepared in 98 % yield (1.67 g, white solid) from methyl 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinate (1.78 g, 5.70 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in >99 % yield (2.14 g, white solid) from 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinic acid (1.67 g, 5.60 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in 91 % yield (1.69 g, white solid) from N-methoxy-N,5-dimethyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinamide (2.14 g, 6.27 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 73 % yield (1.67 g, colorless amorphous) from 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone (1.69 g, 5.70 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.56 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in 89 % yield (1.25 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.69 g, 4.20 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-42 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • the title compound is prepared in 86 % yield (2.83 g, white solid) from 4-fluorobenzenethiol (1.89 g, 14.8 mmol) in a similar manner to Step-1 of Amine-39.
  • the title compound is prepared in >99 % yield (2.71 g, white solid) from methyl 6-((4-fluorophenyl)thio)-5-methylnicotinate (2.83 g, 10.2 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in >99 % yield (3.16 g, colorless oil) from 6-((4-fluorophenyl)thio)-5-methylnicotinic acid (2.70 g, 10.3 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in >99 % yield (2.71 g, an off-white solid) from 6-((4-fluorophenyl)thio)-N-methoxy-N,5-dimethylnicotinamide (3.16 g, 10.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 74 % yield (2.82 g, white solid) from 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone (2.71 g, 10.4 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.89 g, 15.6 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (2.81 g, an off-white solid) from (R)-N-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.82 g, 7.69 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-43 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • the title compound is prepared in 90 % yield (2.22 g, white solid) from 4-chlorophenol (1.71 g, 13.3 mmol) in a similar manner to Step-1 of Amine-39.
  • the title compound is prepared in >99 % yield (2.11 g, white solid) from methyl 6-(4-chlorophenoxy)-5-methylnicotinate (2.22 g, 7.99 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in >99 % yield (2.50 g, colorless oil) from 6-(4-chlorophenoxy)-5-methylnicotinic acid (2.11 g, 8.00 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in 95 % yield (2.02 g, white solid) from 6-(4-chlorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (2.50 g, 8.15 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 83 % yield (2.36 g, white solid) from 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone (2.02 g, 7.72 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (2.17 g, an off-white solid) from (R)-N-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.36 g, 6.43 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Step-1> methyl 6-(3,4-difluorophenoxy)-5-methylnicotinate
  • the title compound is prepared in 91 % yield (2.26 g, white solid) from 3,4-difluorophenol (1.73 g, 13.3 mmol) in a similar manner to Step-1 of Amine-39.
  • the title compound is prepared in >99 % yield (2.21 g, white solid) from methyl 6-(3,4-difluorophenoxy)-5-methylnicotinate (2.26 g, 8.09 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in 95 % yield (2.44 g, yellows oil) from 6-(3,4-difluorophenoxy)-5-methylnicotinic acid (2.21 g, 8.33 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in 96 % yield (2.00 g, white solid) from 6-(3,4-difluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (2.44 g, 7.91 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 73 % yield (2.03 g, white solid) from 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.00 g, 7.60 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.38 g, 11.4 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (1.95 g, white solid) from (R)-N-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.03 g, 5.51 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-45 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
  • Step-1> methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate
  • the title compound is prepared in 80 % yield (904 mg, white solid) from methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate (1.19 g, 4.7 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
  • the title compound is prepared in 98 % yield (1.50 g, colorless oil) from 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid (1.30 g, 5.47 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in >99 % yield (1.30 g, a pale yellow solid) from 6-(4-chloro-1H-pyrazol-1-yl)-N-methoxy-N,5-dimethylnicotinamide (1.50 g, 5.34 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 57 % yield (1.08 g, colorless amorphous) from 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone (1.30 g, 5.52 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.00 g, 8.27 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (951 mg, white solid) from (R)-N-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.08 g, 3.17 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
  • Amine-46 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (single enantiomer)
  • a mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol, Step-1 of Amine-36) and 2,2,2-trifluoroethanamine (9.37 g, 95 mmol) in N-methylpyrrolidone (24 mL) is stirred at 220 o C for 2.5 hours under microwave irradiation.
  • the mixture is diluted with MeOH (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) is added to the mixture.
  • the title compound is prepared in >99 % yield (1.65 g, colorless oil) from 5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid (1.38 g, 5.89 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
  • the title compound is prepared in 92 % yield (1.27 g, a pale yellow solid) from N-methoxy-N,5-dimethyl-6-((2,2,2-trifluoroethyl)amino)nicotinamide (1.65 g, 5.95 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
  • the title compound is prepared in 95 % yield (1.76 g, pale yellow amorphous) from 1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (1.27 g, 5.47 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.33 g, 10.9 mmol) in a similar manner to Step-4 of Amine-1.
  • the title compound is prepared in >99 % yield (1.87 g, a off-white solid) from (R)-2-methyl-N-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.76 g, 5.22 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
  • Step-1> methyl 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinate
  • the title compound is prepared in 71 % yield (2.39 g, a off-white solid) from 4-(trifluoromethyl)-1H-pyrazole (1.93 g, 14.2 mmol) in a similar manner to Step-1 of Amine-45.

Abstract

The present invention relates to pyrrolopyridinone derivatives which have blocking activities of voltage gated sodium channels as the TTX-S channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.

Description

PYRROLOPYRIDINONE DERIVATIVES AS TTX-S BLOCKERS
The present invention relates to the pyrrolopyridinone derivatives which are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.
The pyrrolopyridinone derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.
More particularly, the pyrrolopyridinone derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers. In the discussion that follows, the invention is exemplified by reference to the inhibition of NaV1.3 or NaV1.7 channel as the TTX-S channels. They show the affinity for NaV1.3 or NaV1.7 channel which is significantly greater than their affinity for NaV1.5 channel as the tetrodotoxin-resistant (TTX-R) sodium channels. The pyrrolopyridinone derivatives of the invention show good selectivity for the NaV1.3 or NaV1.7 channel as compared with NaV1.5 channel.
The rat NaV1.3 channel and the human NaV1.3 channel have been cloned in 1988, 1998, 2000 respectively (NPL 1, NPL 2, and NPL 3). The NaV1.3 channel was formerly known as brain type III sodium channel. NaV1.3 is present at relatively high levels in the nervous system of rat embryos but is barely detectable in adult rats. NaV1.3 is up-regulated following axotomy in the Spinal Nerve Ligation (SNL), Chronic Constriction Injury (CCI), and diabetic neuropathy models (NPL 4, NPL 5, NPL 6, and NPL 7). The up-regulation of NaV1.3 channel contributes to rapidly repriming sodium current in small dorsal root ganglion (DRG) neurons (NPL 3). These observations suggest that NaV1.3 may make a key contribution to neuronal hyperexcitability.
In order to validate the contribution of NaV1.3 sodium channel in the pain states, specific antisense oligonucleotides (ASO) were used in animal pain models. NaV1.3 sodium channel ASO treatment significantly attenuated pain-related behaviors after CCI operation (NPL 8). These findings suggest that NaV1.3 sodium channel antagonist is useful to treat neuropathic pain conditions.
The Nav1.7 channel appears to be the best 'validated' pain target. The most exciting findings with respect to Nav1.7 have come from human genetic studies. Cox et al. (NPL 9) discovered SCN9A mutations that cause a loss of Nav1.7 function in three families from Pakistan. Their observations link loss of Nav1.7 function with a congenital inability to experience pain, adding to the evidence indicating Nav1.7 channel as an essential participant in human nociception.
By contrast, Gain-of-function mutations have also been described that lead to enhanced pain, for example, Primary Erythermalgia in one case and Paroxysmal Extreme Pain Disorder in another. These gain-of-function mutations in patients led to different types of gating changes in Nav1.7 sodium currents and, interestingly, different degrees of effectiveness of specific sodium channel blocking drugs. The implication from these findings is that a selective Nav1.7 blocker may be an effective treatment for pain in man.
A local anaesthetic lidocaine and a volatile anaesthetic halothane are known to act on both TTX-R and TTX-S sodium channels with poor selectivity and low potency (IC50 values range from 50 microM to 10 mM). These anaesthetics at high systemic concentrations could cause devastating side effects, e.g., paralysis and cardiac arrest. However, systemic administration of lidocaine at low concentrations is effective to treat chronic pain (NPL 10). In rats, application of a very low dose of TTX to the DRG of the injured segment of the L5 spinal nerve significantly reduces mechanical allodynic behavior (NPL 11). This suggests that TTX-S subtypes of sodium channels play an important role in maintaining allodynic behaviors in an animal model of neuropathic pain.
The NaV1.5 channel is also a member of TTX-resistant sodium channels. The NaV1.5 channel is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiac arrhythmias and conduction disorders.
{NPL 1} FEBS Lett. 228 (1), 187-194, 1988.
{NPL 2} J. Mol. Neurosci., 10 (1), 67-70, 1998.
{NPL 3} Eur. J. Neurosci. 12 (12), 4281-4289, 2000
{NPL 4} J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al.
{NPL 5} Ann Neurol 52, 786-792, 2002. M.J. Cranner et al.
{NPL 6} J Biol Chem 279, 29341-29350, 2004. S. Hong et al.
{NPL 7} Mol Brain Res 95, 153-161, 2001. C.H. Kim et al.
{NPL 8} J. Neurosci. 24, 4832-4839, 2004, Hains, B.C. et al.
{NPL 9} Nature 444, 894-898, 2006.
{NPL 10} Trends in Pharm. Sci 22, 27-31, 2001, Baker, M.D. et al.
{NPL 11} Brain Res 871, 98-103, 2000, Lyu, Y.S. et al.
It is an objective of the invention to provide new TTX-S blockers that are useful as drugs. Preferred compounds should bind potently to the TTX-S (NaV1.3 and/or NaV1.7) channels whilst showing little affinity for other sodium channels, particularly the NaV1.5 channel. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug exists in a physical form that is stable, non-hygroscopic and easily formulated.
In particular, the pyrrolopyridinone derivatives of the present invention are selective for the TTX-S channels over the NaV1.5 channel, leading to improvements in the side-effect profile.
The pyrrolopyridinone derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back, orofacial pain and chemo-induced pain.
Other conditions that may be treated with the pyrrolopyridinone derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, chemo-induced pain and combinations thereof.
The compounds showed activities against NaV1.3 or NaV1.7 channel. In addition they showed selectivity for the NaV1.3 or NaV1.7 channel as compared with NaV1.5 channel.
Just one isoindolinone derivative is disclosed in WO2012/058133. However the compound is not for sodium channel blocker but for phosphodiesterase 10 inhibitor. In addition, the said patent was disclosed on May 3, 2012, which was after the priority date, April 25, 2012, of the present invention.
With respect to other compounds disclosed in the art, the compounds of the present invention can show less toxicity, good absorption and distribution, good solubility, less plasma protein binding, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.
[1] This invention provides a compound of the following formula (I):
Figure JPOXMLDOC01-appb-C000001
 Wherein:
A is aryl;
B is selected from the group consisting of a chemical bond, -C1-6 alkylene-, -C1-6 alkylene-NR2-, -NR2-, and -(C=O)-;
C is selected from the group consisting of a chemical bond, -(C=O)-, and -NR2-;
R1 is independently selected from the group consisting of;
(1) hydrogen, (2) -On-C1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (3) -On-C3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (4) -On-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -S-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11; (7) -NH-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (8) -NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11;
R2 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) -On-phenyl or -On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) -On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R7, (9) -(C=O)-NR8R9, (10) -NR8R9, (11) -S(O)2-NR8R9, (12) -NR8-S(O)2R9, (13) -S(O)t-R9, where t is 0, 1 or 2, (14) -NR8(C=O)R9, (15) -CN, and (16) -NO2;
wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
p is 1, 2, 3, or 4; when p is two or more than two, R2 may be same or different;
R3 and R4 are independently hydrogen or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -O-C1-6 alkyl;
or R3 forms a 3 to 7 membered ring with R4 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
R5 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, and (5) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7;
wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
R5 may be substituted anywhere on the pyrrolopyridinone ring;
q is 1, 2 or 3; when q is two or more than two, R5 may be same or different;
R6 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, -NR8R9, heterocyclyl, aryl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
where the C1-6 alkyl, the C1-6 alkoxy, the C2-6 alkenyl, the C3-7 cycloalkyl, the heterocyclyl, the aryl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, -C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyl-C1-6 alkoxy, -CN, -NR8R9, -(C=O)-R8, -(C=O)-NR8R9, -NR8-(C=O)-R9, -NR8-(C=O)-NR9R10, -NR8-(C=O)-OR9, -NR8-S(O)2-R9, -NR8-S(O)2- NR9R10, and -S(O)2-R8; when B is -NR2- and C is -(C=O)-, R6 may form the 4-7 membered ring with R2 of -NR2;
R7 is selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O)m-Ol-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -Ol-(C1-3)perfluoroalkyl, (6) -(C=O)m-Ol-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (7) -(C=O)m-Ol-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R11, (8) -(C=O)m-Ol-phenyl or -(C=O)m-Ol-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R11, (9) -(C=O)m-Ol-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R11, (10) -(C=O)-NR8R9, (11) -NR8R9, (12) -S(O)2-NR8R9, (13) -S(O)t-R8, where t is 0, 1 or 2, (14) -CO2H, (15) -CN, and (16) -NO2;
wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of -Ol- or -(C=O)m-, and when l is 0 and m is 0, a chemical bond is present in the place of -(C=O)m-Ol-;
R8, R9, and R10 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
where the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the aryl, the heterocyclyl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, trifluoromethyl, and trifluoromethoxy;
or R8 form a 4 to 7 membered ring with R9 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
R11 is independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) -C1-6 alkyl, which is unsubstituted or substituted with one or more halogens, (5) -C3-6 cycloalkyl, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) -O(C=O)-C1-6 alkyl, (8) -NH-C1-6 alkyl, (9) phenyl, (10) heterocyclyl, (11) -CN, and (12) -Si(C1-6 alkyl)3;
k is 1 or 2;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[2] The compound as described in [1] wherein the compound is for the treatment of a condition or disorder in which TTX-S channel is involved.
[3] This invention provides a compound represented by above formula (I) according to [1] or [2] wherein:
k is 1;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[4] Preferable compounds of this invention are represented by the following formula (II):
Figure JPOXMLDOC01-appb-C000002
 wherein:
A is aryl;
R1 is independently selected from the group consisting of;
(1) hydrogen, (2) -On-C1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (3) -On-C3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (4) -On-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -S-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11; (7) -NH-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (8) -NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11;
R2 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) -On-phenyl or -On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) -On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R7, (9) -(C=O)-NR8R9, (10) -NR8R9, (11) -S(O)2-NR8R9, (12) -NR8-S(O)2R9, (13) -S(O)t-R9, where t is 0, 1 or 2, (14) -NR8(C=O)R9, (15) -CN, and (16) -NO2;
wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
p is 1, 2, 3, or 4; when p is two or more than two, R2 may be same or different;
R3 and R4 are independently hydrogen or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -O-C1-6 alkyl;
or R3 forms a 3 to 7 membered ring with R4 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
R5 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, and (5) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7;
wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
R5 may be substituted anywhere on the pyrrolopyridinone ring;
q is 1, 2 or 3; when q is two or more than two, R5 may be same or different;
R6 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, -NR8R9, heterocyclyl, aryl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
where the C1-6 alkyl, the C1-6 alkoxy, the C2-6 alkenyl, the C3-7 cycloalkyl, the heterocyclyl, the aryl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, -C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyl-C1-6 alkoxy, -CN, -NR8R9, -(C=O)-R8, -(C=O)-NR8R9, -NR8-(C=O)-R9, -NR8-(C=O)-NR9R10, -NR8-S(O)2-R9, -NR8-S(O)2- NR9R10, and -S(O)2-R8;
R7 is selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O)m-Ol-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -Ol-(C1-3)perfluoroalkyl, (6) -(C=O)m-Ol-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (7) -(C=O)m-Ol-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R11, (8) -(C=O)m-Ol-phenyl or -(C=O)m-Ol-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R11, (9) -(C=O)m-Ol-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R11, (10) -(C=O)-NR8R9, (11) -NR8R9, (12) -S(O)2-NR8R9, (13) -S(O)t-R8, where t is 0, 1 or 2, (14) -CO2H, (15) -CN, and (16) -NO2;
wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of -Ol- or -(C=O)m-, and when l is 0 and m is 0, a chemical bond is present in the place of -(C=O)m-Ol-;
R8, R9, and R10 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
where the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the aryl, the heterocyclyl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, trifluoromethyl, and trifluoromethoxy;
or R8 form a 4 to 7 membered ring with R9 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
R11 is independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) -C1-6 alkyl, which is unsubstituted or substituted with one or more halogens, (5) -C3-6 cycloalkyl, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) -O(C=O)-C1-6 alkyl, (8) -NH-C1-6 alkyl, (9) phenyl, (10) heterocyclyl, (11) -CN, and (12) -Si(C1-6 alkyl)3;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[5] Compounds described in [4] are further preferred wherein:
R2 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;
p is 1;
R3 is hydrogen;
R4 is hydrogen or methyl;
R6 is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl, heterocyclyl, or aryl
where the methyl, the ethyl, the isopropyl, the cyclopropyl, the heterocyclyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, and -CN;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[6] Preferable compounds of this invention are represented by the following formula (III):
Figure JPOXMLDOC01-appb-C000003
 wherein:
A is aryl;
R1 is independently selected from the group consisting of;
(1) hydrogen, (2) -On-C1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (3) -On-C3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (4) -On-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -S-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11; (7) -NH-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (8) -NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11;
R2 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) -On-phenyl or -On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) -On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R7, (9) -(C=O)-NR8R9, (10) -NR8R9, (11) -S(O)2-NR8R9, (12) -NR8-S(O)2R9, (13) -S(O)t-R9, where t is 0, 1 or 2, (14) -NR8(C=O)R9, (15) -CN, and (16) -NO2;
wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
p is 1, 2, 3, or 4; when p is two or more than two, R2 may be same or different;
R3 and R4 are independently hydrogen or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -O-C1-6 alkyl;
or R3 forms a 3 to 7 membered ring with R4 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
R5 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, and (5) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7;
wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
R5 may be substituted anywhere on the pyrrolopyridinone ring;
q is 1, 2 or 3; when q is two or more than two, R5 may be same or different;
R6 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, heterocyclyl, aryl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
where the C1-6 alkyl, the C1-6 alkoxy, the C2-6 alkenyl, the C3-7 cycloalkyl, the heterocyclyl, the aryl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, -C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyl-C1-6 alkoxy, -CN, -NR8R9, -(C=O)-R8, -(C=O)-NR8R9, -NR8-(C=O)-R9, -NR8-(C=O)-NR9R10, -NR8-(C=O)-OR9, -NR8-S(O)2-R9, -NR8-S(O)2- NR9R10, and -S(O)2-R8;
R7 is selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O)m-Ol-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -Ol-(C1-3)perfluoroalkyl, (6) -(C=O)m-Ol-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (7) -(C=O)m-Ol-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R11, (8) -(C=O)m-Ol-phenyl or -(C=O)m-Ol-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R11, (9) -(C=O)m-Ol-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R11, (10) -(C=O)-NR8R9, (11) -NR8R9, (12) -S(O)2-NR8R9, (13) -S(O)t-R8, where t is 0, 1 or 2, (14) -CO2H, (15) -CN, and (16) -NO2;
wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of -Ol- or -(C=O)m-, and when l is 0 and m is 0, a chemical bond is present in the place of -(C=O)m-Ol-;
R8, R9, and R10 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
where the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the aryl, the heterocyclyl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, trifluoromethyl, and trifluoromethoxy;
or R8 form a 4 to 7 membered ring with R9 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
R11 is independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) -C1-6 alkyl, which is unsubstituted or substituted with one or more halogens, (5) -C3-6 cycloalkyl, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) -O(C=O)-C1-6 alkyl, (8) -NH-C1-6 alkyl, (9) phenyl, (10) heterocyclyl, (11) -CN, and (12) -Si(C1-6 alkyl)3;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[7] Compounds described in [6] are further preferred wherein:
R2 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;
p is 1;
R3 is hydrogen;
R4 is hydrogen or methyl;
R6 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, or butyl
where the methyl, the ethyl, the isopropyl, the propyl, or the butyl is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, -O-C1-6 alkyl, -CN, and -NR8-(C=O)-R9 in which each of R8 and R9 has the same meaning as above [6];
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[8] Suitable individual compounds of the invention are:
N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide;
3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
2-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
ethyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
methyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
isopropyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
methyl (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
isopropyl (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide;
(5S)-3-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-isopropyloxazolidin-2-one;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide;
methyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
ethyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
isopropyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
methyl (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
ethyl (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,3-oxazinan-2-one;
N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
ethyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
methyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
isopropyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
3-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(3-methyl-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
3-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-isopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-isopropyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(dimethylamino)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide;
2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide;
5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide;
4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-phenylacetamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)picolinamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrazine-2-carboxamide;
3-cyano-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
N-((2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)acetamide;
N-(2-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-cyano-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
4-(3-isopropyl-2-oxoimidazolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
N-(2-(dimethylamino)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-morpholinoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
6-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-5-carboxamide;
N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-amino-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
2-amino-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
N-(2-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
2-amino-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
2-amino-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
2-amino-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
4-(isoxazol-3-ylamino)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(oxazol-2-ylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
2-amino-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
N-(2-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-3-carboxamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyridazine-3-carboxamide;
(2S)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
(2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isonicotinamide;
(2S)-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrrolidine-2-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(4-methoxypiperidin-1-yl)-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide;
N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide;
1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide;
(2S)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
(2R)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
(3R)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide;
1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-2-carboxamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide;
(3S)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide;
(2R)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide;
2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide;
(2S)-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
(S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxyacetamide;
2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
(S)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
(R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
4-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
2-acetamido-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
(S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
(2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
(R)-2-hydroxy-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
(2R)-N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
(S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
(2R)-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
(2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
(2R)-N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
(R)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
(R)-N-(2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
(S)-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
(2R)-N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
(R)-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
(R)-2-hydroxy-N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
(2R)-N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
(2R)-N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
(2R)-N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
(2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(cyanomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(cyanomethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxy-2-methylpropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxy-2-methylpropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-cyclopropyl-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((S)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-amino-2-oxoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-amino-2-oxoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(2-hydroxyethoxy)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((S)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(R)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(S)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-((S)-1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-amino-3-oxopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-amino-3-oxopropyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(S)-N-(1-hydroxypropan-2-yl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-methoxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(4-((cyclopropylmethyl)carbamoyl)-3-methylbenzyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(3-methyl-4-(phenylcarbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(3-methyl-4-((4-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-methyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(4-methyl-1H-imidazol-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-N-(3-(2-oxopyrrolidin-1-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((S)-1-(methylamino)-1-oxopropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((1H-imidazol-2-yl)methyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((5-methyl-6-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
and N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[9] More suitable individual compounds of the invention are:
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
ethyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
isopropyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide;
2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
(R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
(S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
(2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
(2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
(2R)-N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
(2R)-N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
(R)-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
(2R)-N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
(2R)-N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
(2R)-N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
(R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
and N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[10] The present invention provides a pharmaceutical composition comprising a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [9], and a pharmaceutically acceptable carrier.
[11] The present invention provides the pharmaceutical composition as described in [10], further comprising another pharmacologically active agent.
[12] The present invention provides a method for the treatment of a condition or disorder in which TTX-S channel blockers are involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [9].
[13] The present invention provides the method as described in [12], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain;
and combinations thereof.
[14] The present invention provides a use of a compound described in any one of [1] to [9] or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which TTX-S channel blockers are involved.
[15] The present invention provides the use as described in [14], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain;
and combinations thereof.
[16] The present invention provides a compound described in any one of [1] to [9] or a prodrug or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which TTX-S channel blockers are involved.
[17] The present invention provides a process for preparing a pharmaceutical composition comprising mixing a compound described in any one of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
The pyrrolopyridinone derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.
More particularly, the pyrrolopyridinone derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers. In the discussion that follows, the invention is exemplified by reference to the inhibition of NaV1.3 or NaV1.7 channel as the TTX-S channels.
They show the affinity for NaV1.3 or NaV1.7 channel which is significantly greater than their affinity for NaV1.5 channel as the tetrodotoxin-resistant (TTX-R) sodium channels.
The pyrrolopyridinone derivatives of the invention show good selectivity for the NaV1.3 or NaV1.7 channel as compared with NaV1.5 channel.
In particular, the pyrrolopyridinone derivatives of the present invention are selective for the TTX-S channels over the NaV1.5 channel, leading to improvements in the side-effect profile.
The pyrrolopyridinone derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back, orofacial pain and chemo-induced pain.
Other conditions that may be treated with the pyrrolopyridinone derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia and chemo-induced pain.
Examples of conditions or disorders mediated by TTX-S channels include, but are not limited to, TTX-S channels related diseases. The compounds of the present invention show the TTX-S channels blocking activity. The compounds of the present invention can show less toxicity, good absorption and distribution, good solubility, less protein binding affinity other than TTX-S channels, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.
As appreciated by those of skill in the art, "halogen" or "halo" as used herein is intended to include fluoro, chloro, bromo and iodo. Similarly, 1-6, as in C1-6 is defined to identify the number as having 1, 2, 3, 4, 5 or 6. According to the definition, for example, C1-6, as in C1-6 alkyl is defined to identify the alkyl group as having 1, 2, 3, 4, 5 or 6 carbons. Similarly, C2-6 alkenyl is defined to identify the alkenyl group as having 2, 3, 4, 5 or 6 carbons. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
The term "alkyl", as used herein, means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
The term "alkoxy", as used herein, means an -O-alkyl, but not limited to, methoxy, ethoxy, propoxy, or 2-propoxy, butoxy (including all isomeric forms), and the like.
The term "alkylthio", as used herein, means a -S-alkyl, but not limited to, methylthio,
ethylthio, and the like.
The term "alkylamino", as used herein, means a -NH-alkyl, but not limited to, methylamino, ethylamino, propylamino, 2-propylamino, and the like.
The term "alkenyl", as used herein, means a hydrocarbon radical having at least one double bond , which may be in a E- or a Z- arrangement, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
The term "cycloalkyl", as used herein, means a mono- or bicyclic ring, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norboranyl, adamantyl groups, and the like.
The term "alkylene", as used herein, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
The term "cycloalkylene", as used herein, means a mono- or bicyclic ring, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.
The term "aryl", as used herein, means mono- or bi-carbocyclic or mono- or bi-heterocyclic ring which may contain 0 to 4 heteroatoms selected from O, N and S, but not limited to, phenyl, naphthyl, benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, phthalazyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and N-oxides thereof.
The term "heterocyclyl" as used herein includes both unsaturated and saturated heterocyclic moieties; wherein the unsaturated heterocyclic moieties (i.e. "heteroaryl") include benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolidinonyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazinanonyl, oxazolidinonyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and N-oxides thereof; and wherein the saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, tetrahydropyrimidinonyl, triazolopyrimidyl, tetrahydrothienyl, pyrrolidinonyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4,5,6,7-tetrahydro-indazolyl, 5,6,7,8-tetrahydro-1,6-naphthyridyl;
and N-oxides thereof and S-oxides thereof.
The term "C0", as used herein, means direct bond.
The term "protecting group", as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 2007).
The terms "treating" or "treatment", as used herein, includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. As used herein, the term "preventing" or "to prevent" includes prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder ".
As used herein, the article "a" or "an" refers to both the singular and plural form of the object to which it refers unless indicated otherwise.
Included within the scope of the "compounds of the invention" are all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I).
Compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases such as triethylamine.
Also within the scope of the invention are so-called "prodrugs" of the compounds of formula (I). Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic or hydrolysis cleavage. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
The term "animal," as used herein, includes a mammalian subject or a non-mammalian subject. Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates. Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas. Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese. The preferred mammalian subject is a human.
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:
(i) where the compound of formula (I) contains an alcohol functionality (-OH), compounds wherein the hydroxy group is replaced with a moiety convertible in vivo into the hydroxy group. Said moiety convertible in vivo into the hydroxy group means a moiety transformable in vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme, e.g. an esterase. Examples of said moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo. Preferred are the moieties replaced the hydrogen of hydroxy group with acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl; and
(ii) where the compound of the formula (I) contains an amino group, a pyrrolopyridinone derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred pyrrolopyridinone derivative as a prodrug is -NHCO(CH2)2OCH3, -NHCOCH(NH2)CH3 or the like.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Compounds of formula (I) and salts thereof may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
Compounds of formula (I) may have polymorphs in crystalline form, which are within the scope of the present invention.
Additionally, compounds of formula (I) may be administered as prodrugs. As used herein, a "prodrug" of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
In certain of the compounds of formula (I), there may be one or more chiral carbon atoms. In such cases, compounds of formula (I) exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers, diastereoisomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.
Certain of the compounds herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.
The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 18F, 123I and 125I. Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography), and 123I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
With respect to other compounds disclosed in the art, certain compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as increased metabolic stability, enhanced oral bioavailability or absorption, and/or decreased drug-drug interactions.
The compounds of formula (I), being NaV1.3 and/or Nav1.7 channel blockers, are potentially useful in the treatment of a range of disorders. The treatment of pain, particularly chronic, inflammatory, neuropathic, nociceptive and visceral pain, is a preferred use.
Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitization in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a heightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviors which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibers associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).
Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumor related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.
Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.
Other types of pain include:
(i) pain resulting from musculo-skeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;
(ii) heart and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredema and skeletal muscle ischemia;
(iii) head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and
(vi) orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
Compounds of formula (I) are also expected to be useful in the treatment of multiple sclerosis.
The invention also relates to therapeutic use of compounds of formula (I) as agents for treating or relieving the symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia. Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular accident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also, included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia. These vascular disorders may occur in a patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like. Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from emboly, hyperfusion, and hypoxia. The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.
A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.
TTX-S sodium channels have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with TTX-S sodium channels, including one or more of the following conditions or diseases: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain.
The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 1 mg to 1000 mg, while an intravenous dose may only require from 0.1 mg to 100 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in another embodiment about 1 mg to 100 mg per patient per day; and in another embodiment about 5 mg to 50 mg per patient per day; in yet another embodiment about 1 mg to 30 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
Compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is envisioned. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including about 200: 1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
A TTX-S sodium channels blocker may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders. For example, a TTX-S sodium channels blocker, particularly a compound of formula (I), or a prodrug thereof or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from
- an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
- a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;
- a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
- a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
- an H1 antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
- a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
- a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
- an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDexTM, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;
- an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
- a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;
- an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate;
- a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);
- a muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium;
- a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
- a coal-tar analgesic, in particular paracetamol;
- a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, MiraxionTM or sarizotan;
- a vanilloid receptor agonist (e.g. resiniferatoxin) or antagonist (e.g. capsazepine);
- a transient receptor potential cation channel subtype (V1, V2, V3, V4, M8, M2, A1) agonist or antagonist;
- a beta-adrenergic such as propranolol;
- a local anaesthetic such as mexiletine;
- a corticosteroid such as dexamethasone;
- a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
- a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
- a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
-TramadolTM;
- a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;
- an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-((1H-tetrazol-5-yl)methyl)cycloheptyl]methylamine, (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;
- a cannabinoid;
- a metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;
- a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
- a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (VivalanTM), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
- a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
- an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3 pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;
- an acetylcholinesterase inhibitor such as donepezil;
- a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;
- a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,
- a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);
- a sodium channel blocker, such as lidocaine;
- a calcium channel blocker, such as ziconotide, zonisamide, mibefradil;
- a 5-HT3 antagonist, such as ondansetron;
- a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leukovolin, paclitaxel;
- a calcitonin gene related peptide (CGRP) antagonist;
- a bradykinin (BK1 and BK2) antagonist;
- a voltage gated sodium dependent channel blocker (Nav1.3, Nav1.7, Nav1.8);
- a voltage dependent calcium channel blocker (N-type, T-type);
- a P2X (ion channel type ATP receptor) antagonist;
- an acid-sensing ion channel (ASIC1a, ASIC3) antagonist;
- an Angiotensin AT2 antagonist;
- a Chemokine CCR2B receptor antagonist;
- a Cathepsin (B, S, K) inhibitor;
- a sigma1 receptor agonist or antagonist;
and the pharmaceutically acceptable salts and solvates thereof.
Such combinations offer significant advantages, including synergistic activity, in therapy.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrate compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavorings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.
For parenteral administration, fluid unit dosage forms are prepared utilizing a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a preservative.
Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
Compounds of formula (I) or pharmaceutically acceptable salts may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of formula (I) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For intranasal administration, compounds formula (I) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). The compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
General Synthesis
Throughout the instant application, the following abbreviations are used with the following meanings:
DCM Dichloromethane
DMF N,N-Dimethylformamide
DMA N,N-Dimethylacetamide
DME 1,2-Dimethoxyethane
DMSO Dimethyl sulfoxide
EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride
e.e. Enantiomeric Excess
ESI Electrospray Ionization
EtOAc Ethyl acetate
EtOH Ethanol
HOBT 1-Hydroxybenztriazole
HBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate
HPLC High-Performance Liquid Chromatography
LC Liquid Chromatography
LG Leaving Group
tR Retention Time
MeCN Acetonitrile
MeOH Methanol
MHz Megahertz
MS Mass Spectrometry
NMR Nuclear Magnetic Resonance
PG Protecting Group
rt Room Temperature
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
TLC Thin Layer Chromatography
UV Ultraviolet
The term of "base" is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, and colidine; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, triethylamine, diisopropylethylamine, DBU, DBN, DABCO, pyridine, lutidine, colidine, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, potassium phosphate, barium hydroxide, and cesium carbonate are preferred.
The reactions are normally and preferably effected in the presence of inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but not limited to: halogenated hydrocarbons, such as DCM, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, DMA, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as MeCN and benzonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO) and sulfolane; ketones, such as acetone and diethylketone. Of these solvents, including but not limited to DMF, DMA, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, MeCN, DCM, dichloroethane and chloroform are preferred.

Examples
The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations are carried out at room or ambient temperature, that is, in the range of about 18-25 oC; evaporation of solvent is carried out using a rotary evaporator under reduced pressure with a bath temperature of up to about 60 oC; reactions are monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; the structure and purity of all isolated compounds are assured by at least one of the following techniques: TLC (Merck silica gel 60 F254 precoated TLC plates or Merck NH2 F254 precoated HPTLC plates), mass spectrometry or NMR. Yields are given for illustrative purposes only. Flash column chromatography is carried out using Merck silica gel 60 (230-400 mesh ASTM), Fuji Silysia ChromatorexTM(TM: trademark) DU3050 (Amino Type), Wako Wakogel C300-HG, Biotage silica KP-Sil, Yamazen Hi-FLASH column, YMC DispoPack-SIL, or Biotage amino bounded silica KP-NH. The purification of compounds using HPLC (preparative LC-MS) is performed by the following apparatus and conditions.
Apparatus; Waters MS-trigger AutoPurificationTM system
Column; Waters XTerra C18, 19X50 mm, 5 micrometer particle
Condition A: MeOH or MeCN / 0.01 %(v/v) ammonia aqueous solution
Condition B: MeOH or MeCN / 0.05 %(v/v) formic acid aqueous solution
Low-resolution mass spectral data (ESI) are obtained by the following apparatus and conditions: Apparatus; Waters Alliance HPLC system on ZQ or ZMD mass spectrometer and UV detector. NMR data are determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated chloroform (99.8 % D) or dimethylsulfoxide (99.9 % D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc. Chemical symbols have their usual meanings; M (mol(s) per liter), L(liter(s)), mL (milliliter(s)), g (gram(s)), mg(milligram(s)), mol (moles), mmol (millimoles).
Each prepared compound is generally named by ChemBioDraw (Ultra, version 12.0, CambridgeSoft).
Conditions for determining HPLC retention time:
Method: QC1
Apparatus: Waters ACQUITY Ultra Performance LC with TUV Detector and ZQ mass spectrometer
Column: Waters ACQUITY C18, 2.1 x 100 mm, 1.7 micrometer particle size
Column Temperature: 60 oC
Flow rate: 0.7 mL/min
Run time: 3 min
UV detection: 210 nm
MS detection: ESI positive/negative mode
Mobile phases:
A1: 10 mM ammonium acetate
B1: MeCN
Gradient program:
Figure JPOXMLDOC01-appb-I000001
Method: QC2
Apparatus: Waters 2795 Alliance HPLC with ZQ2000 mass spectrometer and 2996 PDA Detector
Column: XBridge C18, 2.1 x 50 mm, 3.5 micrometer particle size
Column Temperature: 45 oC
Flow rate: 1.2 mL/min
Run time: 4.5 min
UV detection: 210-400 nm scan
MS detection: ESI positive/negative mode
Mobile phases:
A: Water
B: MeCN
C: 1 % aqueous HCOOH solution
D: 1 % aqueous NH3 solution
Gradient program:
The pyrrolopyridinone derivatives of the formula (I) include the compounds defined by the formula (II) and formula (III). Thus the compounds of the formula (II) and formula (III) can be also prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof.
All of the pyrrolopyridinone derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the pyrrolopyridinone derivatives of formula (I), in addition to any novel intermediates used therein.
In the following general methods, descriptors are as previously defined for the pyrrolopyridinone derivatives of the formula (I) unless otherwise stated.
<Scheme A>
Figure JPOXMLDOC01-appb-C000004
When LG is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step A-a, an intermediate of formula (VI) can be prepared in situ by N-alkylation with an alkylating reagent of formula (V) in the presence of a suitable base in an inert solvent. Examples of suitable bases include, but not limited to, such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine, and N,N-diisopropylethylamine. Examples of suitable organic solvents include such as THF, 1,4-dioxane, DMF, MeCN, DMA, and toluene. The reaction can be carried out at a temperature of from about -20 to 150 oC, more preferably from about 0 to 100 oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours. In genenal, an intermediate of formula (VI) can be cyclized to form the compound of formula (I).
<Scheme B>
Figure JPOXMLDOC01-appb-C000005
Alternatively, the compound of formula (I) can be prepared by the general synthetic route of Scheme B.
When LG2 is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step B-a, a compound of formula (I-a) can be prepared from a compound of formula (IV) and a compound of formula (V-a) as described in Step A-a and Step A-b.
In Step B-b, a compound of formula (I-b) can be prepared by coupling of a compound of formula (I-a) with a suitable reagent of formula (VII) under coupling conditions in suitable organic solvents in the presence of a suitable transition metal catalyst and in the presence or absence of a base. Examples of suitable transition metal catalysts include: tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(ll) trifluoromethanesulfonate, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride. Preferred catalysts are tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride. Examples of suitable reagents (VII) include, but not limited to, carboximides such as acetamide, propionamide, isobutyramide and cyclopropanecarboxamide. Examples of suitable organic solvents include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as MeOH and ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride; and diethylether; in the presence or absence of base such as tripotassium phosphate, sodium bicarbonate, sodium carbonate and potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine. The reaction can be carried out at a temperature of from about 50 to 200 oC, more preferably from about 80 to 150 oC. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200 oC, preferably in the range from about 120 to 180 oC. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.
When -B-C-R6 component of formula (I) is -(C=O)-NR2R6, in Step-B-c, a compound of formula (I-d) can be prepared from a compound of formula (I-a) and a compound of formula (VIII) by CO insertion reaction in suitable organic solvents in the presence of suitable transition metal catalyst in the presence or absence of a base under carbon monoxide atmosphere. Example of suitable transition metal catalysts include: palladium metal, palladium-carbon, palladium(II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, and a catalyst produced in solution by adding a ligand into the reaction solution of these. The ligand added into the reaction solution may be a phosphoric ligand such as 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, 2,2'-bis(diphenylphosphino)-1,1'-binaphthol, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, tri-o-toluylphosphine, triphenylphosphine, 2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl and 2,2- bis (diphenylphosphino)-1,1'-binaphthyl. Examples of suitable organic solvents include: THF; 1,4-dioxane; DMF; DMA; MeCN; toluene; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride; and diethyl ether; in the presence or absence of base such as triethylamine, N,N-diisopropylethylamine, tripotassium phosphate, sodium bicarbonate, sodium carbonate and potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine. The reaction can be carried out at a temperature of from about 50 to 200 oC, more preferably from about 60 to 150 oC. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. Instead of carbon monoxide, other carbon monoxide sources such as molybdenumhexacarbonyl and DMF/potassium tert-butoxide can be employed. In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200 oC, preferably in the range from about 120 to 180 oC. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.
In Step B-d, a compound of formula (I-c) can be prepared from a compound of formula (I-a) and alcohol by CO insertion reaction as described in Step B-c. Alternatively, the reaction can be carried out with other carbon monoxide sources such as phenyl formate / triethylamine and molybdenum hexacarbonyl.
In Step B-e, a compound of formula (I-d) can be prepared from a compound of formula (I-c) and a compound of formula (VIII) in suitable solvents. Examples of suitable solvents include: THF, 1,4-dioxane, DMF, MeCN, MeOH, EtOH, and water. The reaction can be carried out at a temperature of from about 0 to 200 oC, more preferably from about 20 to 150 oC. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
In Step B-f, a compound of formula (IX) can be prepared by hydrolysis of the ester compound of formula (I-c). The hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide and lithium hydroxide. Suitable solvents include, for example: water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO. Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100 oC for from about 30 minutes to 24 hours.
In Step B-g, a compound of formula (I-d) can be prepared from a compound of formula (IX) by amidation with a compound of formula (VIII) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60 oC for about 1 to 24 hours. In addition, a compound of formula (I-d) can be also prepared from a compound of formula (VIII) by amidation with an acid halide prepared from a compound of formula (IX) using thionyl chloride or oxalyl chloride, preferably under the presence of a base such as triethylamine, pyridine, and N,N-diisopropylethylamine in a suitable solvent such as DCM at a temperature of from about 5 to 40 oC for about 1 to 24 hours.
The key intermediate amines of formula (IV-a) and (IV-b) can be prepared by the following general synthetic route of Scheme C, D, and E.
<Scheme C>
Figure JPOXMLDOC01-appb-C000006
In Step C-a, a compound of formula (XI) can be prepared by hydrolysis of the ester compound of formula (X). The hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide and lithium hydroxide. Suitable solvents include, for example: water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO. Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100 oC for from about 30 minutes to 24 hours.
In Step C-b, a compound of formula (XII) can be prepared from acid of the formula (XI) and N,O-dimethylhydroxylamine by amidation (Weinreb amide formation) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60 oC for about 1 to 24 hours.
In Step C-c, a compound of formula (XIII) can be prepared from compound of formula (XII) by the treatment with a suitable alkylmetal reagent in an inert solvent. Examples of suitable alkylmetal reagent include, but not limited to, such as methyllitium, ethyllithium, methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide. Examples of inert solvents include, but not limited to, such as THF, DME, and 1,4-dioxane. The reaction can be carried out at a temperature of from about -40 to 100 oC, more preferably from about 0 to 50 oC. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
In Step C-d, a compound of formula (XIV) can be prepared as a single diastereomer from carbonyl compound of formula (XIII) and a chiral tert-butanesulfinamide by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004). In the following intermediate and example sections, a compound name of formula (XIV) is described as an (R) or (S) isomer, which represents the configuration of a sulfur atom.
In Step C-e, a compound of formula (IV-a) can be prepared as a single enantiomer from a compound of formula (XIV) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
<Scheme D>
Figure JPOXMLDOC01-appb-C000007
In Step D-a, a compound of formula (XVI) can be prepared from aldehyde of formula (XV) and chiral tert-butanesulfinamide by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
In Step D-b, a compound of formula (XVII) can be prepared as a single diastereomer from chiral sulfinyl imine of formula (XVI) and alkylmetal reagent by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
In Step D-c, a compound of formula (IV-a) can be prepared as a single enantiomer from a compound of formula (XVII) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).
<Scheme E>
Figure JPOXMLDOC01-appb-C000008
In Step E-a, a compound of formula (IV-b) can be prepared by hydrogenation of a compound of formula (XVIII) under known hydrogenolysis conditions, for example, in the presence of a suitable metal catalyst under a hydrogen atmosphere, or in the presence of hydrogen sources such as formic acid and ammonium formate, in an inert solvent. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is selected from, for example, nickel catalysts such as Raney nickel, Pd-C, palladiumhydroxide-carbon, platinum oxide, platinum-carbon, ruthenium-carbon, Fe, Zn, Sn, and SnCl2. Examples of suitable inert aqueous or non-aqueous organic solvents include, but not limited to, alcohols, such as methanol, ethanol and ammonic methanol; ethers, such as THF and 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane and chloroform; and acetic acid; or mixtures thereof. The reaction can be carried out at a temperature in the range of from about 20 to 150 oC, preferably in the range of from about 20 to 80 oC. Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 30 minutes to 24 hours. This reaction can be carried out under a hydrogen atmosphere at a pressure ranging from about 1 to 100 atms, preferably from about 1 to 5 atms.
In Step E-b, a compound of formula (XIX) can be prepared by reduction of a compound of formula (X). The reduction may be carried out in the presence of a suitable reducing reagent in an inert solvent or without solvent. A preferred reducing agent is selected from, for example, but not limited to, such as sodium borohydride, lithium aluminum hydride, lithium borohydride, boran-complex, and diisobutylaluminium hydride. Reaction temperatures are generally in the range of from about -78 to 100 oC, preferably in the range of from about -70 to 60 oC. Reaction times are, in general, from about 30 minute to a day. Examples of suitable solvents include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as methanol and ethanol; and halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride.
In Step E-c, a compound of formula (XX) can be prepared by alkylation (Mitsunobu reaction) using corresponding alcohol in organic solvent in the presence of azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-ter-butyl azodicarboxylate as a coupling reagent. Examples of suitable organic solvents include such as THF, 1,4-dioxane, DMF, MeCN, and toluene. The reaction can be carried out at a temperature of from about -20 to 180 oC, more preferably from about 0 to 120 oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.
In Step E-d, a compound of formula (IV-b) can be prepared from a compound of formula (XX) by deprotection with reagents such as hydrazine in an inert solvent. Example of suitable solvents include such as water, methanol and ethanol. The reaction can be carried out at a temperature in the range of from about 0 to 150 oC, preferably in the range of from about 50 to 100 oC. Reaction times are, in general, from about 10 minutes to 96 hours, preferably from about 30 minutes to 24 hours.
When LG is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step E-e, a compound of formula (XXI) can be prepared by sulfonylation or substitution with halogen of a compound of formula (XIX) under, for example, known sulfonylation condition or known halogenation conditions in an inert solvent.
In case of sulfonylation, the reaction can be carried out in the presence of a base in an inert solvent. A preferred base is selected from, for example, but not limited to: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride and potassium hydride; and an amine such as TEA, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine and dimethylaminopyridine. Examples of suitable inert aqueous or non-aqueous organic solvents include: alcohols, such as methanol and ethanol; ethers, such as THF and 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane and chloroform; and pyridine; and mixtures thereof. The reaction can be carried out at a temperature in the range of from about -10 oC to 200 oC, preferably in the range of from about 20 to 100 oC. Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 10 minutes to 24 hours.
In case of halogenation, examples of halogen sources include such as thionyl chloride, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, phosphorous trichloride, phosphorous tribromide, carbontetrachloride, and carbontetrabromide. In the halogenation reaction, the reaction can be carried out in the presence of reducing agent such as triphenylphosphine. Examples of suitable organic solvents include such as THF, 1,4-dioxane, DCM, 1,2-dichloroethane, carbontetrachloride, toluene, and DMF.
In Step E-f, a compound of formula (XXII) can be prepared from a compound of formula (XXI) by substitution reaction with azide group. The reaction can be carried out with a suitable reagent in an inert solvent. A preferred reagent is selected from, for example, lithium azide, sodium azide, potassium azide, and cesium azide. Reaction temperatures are generally in the range of from about 20 to 150 oC, preferably in the range of from about 50 to 120 oC. Reaction times are, in general, from about 30 minutes to 96 hours, preferably from about 1 hour to 24 hours. Examples of suitable solvents include such as THF, 1,4-dioxane, DMF, MeCN, and DMSO.
In Step E-g, a compound of formula (IV-b) can be prepared from a compound of formula (XXII) by hydrogenation reaction by the method described in Step E-a above.
All starting materials and intermediates in the following syntheses may be commercially available or obtained by the conventional methods known to those skilled in the art, otherwise noted in the intermediate synthesis part.
Intermediate synthesis part
Intermediates are prepared as follows.
Intermediate-1: 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
<Step-1>: Ethyl 3-(bromomethyl)-2-chloroisonicotinate
A mixture of ethyl 2-chloro-3-methylisonicotinate (4.0 g, 20.0 mmol), N-bromosuccinimide (3.7 g, 21.0 mmol), and dibenzoyl peroxide (0.49 g, 2.0 mmol) in carbon tetrachloride (50 mL) is heated at reflux temperature for 2 hours. After cooling to rt, the reaction mixture (suspension) is filtered through a pad of CeliteTM(Celite Corporation), and washed with carbon tetrachloride. The filtrate is concentrated to give clear yellow oil. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (10:1) to give 4.1 g (73 % yield) of the title compound as a clear yellow liquid.
Figure JPOXMLDOC01-appb-I000003
1H-NMR (300 MHz, CDCl3) delta 8.46 (1H, d, J = 5.1 Hz), 7.68 (1H, d, J = 5.1 Hz), 5.03 (2H, s), 4.46 (2H, q, J = 7.1 Hz), 1.45 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 278 (M+H) +.
<Step-2>: 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) (Intermediate-1)
A mixture (suspension) of ethyl 3-(bromomethyl)-2-chloroisonicotinate (698 mg, 2.5 mmol, Step-1), 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (643 mg, 2.5 mmol, Amine-1, single enantiomer) and cesium carbonate (3.3 g, 10.0 mmol) in THF (20 mL) is heated at refluxed temperature overnight. After cooling to rt, the reaction mixture is filtered through a pad of Celite TM, and washed with EtOAc. The filtrate is concentrated to give a brown suspension. The residue is purified by column chromatography on NH-gel eluting with n-hexane / EtOAc (4:1) to give 300 mg (32 % yield) of the title compound as clear brown oil.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.4 Hz), 8.19 (1H, d, J = 2.2 Hz), 7.71-7.65 (2H, m), 6.88 (1H, d, J = 8.8 Hz), 5.78 (1H, q, J = 7.1 Hz), 4.76 (2H, q, J = 8.6 Hz), 4.42 (1H, d, J = 18.3 Hz), 4.07 (1H, d, J = 17.6 Hz), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 372 (M+H) +, 370 (M-H) -.
Intermediate-2: 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 78 % yield (540 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1), 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (490 mg, 1.8 mmol, Amine-2, single enantiomer), and triethylamine (1.0 mL, 7.2 mmol) as a base in a similar manner to Step-2 of Intermediate-1.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.02 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.45 (1H, d, J = 2.2 Hz), 5.75 (1H, q, J = 7.4 Hz), 4.75 (2H, q, J = 8.8 Hz), 4.40 (1H, d, J = 18.3 Hz), 4.06 (1H, d, J = 18.3 Hz), 2.23 (3H, s),1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 386 (M+H) +, 384 (M-H) -.
Intermediate-3: 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 50 % yield (185 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (257 mg, 1.0 mmol, Amine-3) in a similar manner to Step-2 of Intermediate-1.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 7.96 (1H, d, J = 2.2 Hz), 7.72 (1H, d, J = 4.4 Hz), 7.44 (1H, d, J = 1.5 Hz), 4.81-4.72 (3H, m), 4.32 (2H, s) 2.21 (3H, s), MS (ESI) m/z: 372 (M+H) +, 370 (M+H) -.
Intermediate-4: 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 44 % yield (154 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (239 mg, 1.0 mmol, Amine-4) in a similar manner to Step-2 of Intermediate-1.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 7.96 (1H, s), 7.72 (1H, d, J = 4.4 Hz), 7.42 (1H, s), 6.14 (1H, tt, J = 55.3, 4.0 Hz), 4.74 (2H, s), 4.55 (2H, td, J = 13.3, 4.2 Hz), 4.32 (2H, s), 2.20 (3H, s), MS (ESI) m/z: 354 (M+H) +, 352 (M+H) -.
Intermediate-5: 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 48 % yield (178 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (253 mg, 1.0 mmol, Amine-5, single enantiomer) in a similar manner to Step-2 of Intermediate-1.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.01 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.42 (1H, d, J = 1.5 Hz), 6.14 (1H, tt, J = 55.7, 4.0 Hz), 5.74 (1H, q, J = 7.3 Hz), 4.54 (2H, td, J = 13.6, 4.1 Hz), 4.40 (1H, d, J = 17.6 Hz), 4.06 (1H, d, J = 17.6 Hz), 2.21 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 368 (M+H) +.
Intermediate-6: 4-chloro-3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)
<Step-1>: methyl 3-(1-bromoethyl)-2-chloroisonicotinate (racemate)
The title compound is prepared in 71 % yield (1.9 g, colorless oil) from methyl 2-chloro-3-ethylisonicotinate (2.0 g, 9.8 mmol) in a similar manner to Step-1 of Intermediate-1.
1H-NMR (300 MHz, CDCl3) delta 8.40 (1H, d, J = 5.1 Hz), 7.40 (1H, d, J = 4.4 Hz), 5.85 (1H, q, J = 7.3 Hz), 3.99 (3H, s), 2.13 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 278 (M+H) +.
<Step-2>: 4-chloro-3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate) (Intermediate-6)
The title compound is prepared in 20 % yield (41 mg, pale brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol, Step-1, racemate) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (146 mg, 0.53 mmol, Amine-3) in a similar manner to Intermediate-2.
(ESI) m/z: 386 (M+H) +, 384 (M-H) -.
Intermediate-7: 4-chloro-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 60 % yield (137 mg, pale yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol) and 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (164 mg, 0.57 mmol, Amine-6, single enantiomer), and sodium bicarbonate (240 mg, 2.3 mmol) as a base in a similar manner to Step-2 of Intermediate-1.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.20 (1H, d, J = 2.2 Hz), 7.70 (1H, d, J = 5.1 Hz), 7.66 (1H, dd, J = 8.8, 2.9 Hz), 6.85 (1H, d, J = 8.8 Hz), 6.19-5.74 (2H, m), 4.74 (2H, t, J = 12.5 Hz), 4.42 (1H, d, J = 17.6 Hz), 4.07 (1H, d, J = 18.3 Hz), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 404 (M+H) +, 402 (M+H) -.
Intermediate-8: 4-chloro-2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 47 % yield (104 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (156 mg, 0.57 mmol, Amine-7, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 7.97 (1H, s), 7.71 (1H, d, J = 5.1 Hz), 7.45 (1H, dd, J = 10.3, 1.5 Hz), 5.77 (1H, q, J = 7.1 Hz), 4.83 (2H, q, J = 8.3 Hz), 4.44 (1H, d, J = 17.6 Hz), 4.10 (1H, d, J = 18.3 Hz), 1.76 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 390 (M+H) +, 388 (M+H) -.
Intermediate-9: 4-chloro-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 63 % yield (146 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-8, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.09 (1H, d, J = 2.2 Hz), 7.73-7.70 (2H, m), 5.76 (1H, q, J = 7.3 Hz), 4.81 (2H, q, J = 8.3 Hz), 4.44 (1H, d, J = 17.6 Hz), 4.10 (1H, d, J = 17.6 Hz), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 406 (M+H) +, 404 (M+H) -.
Intermediate-10: 4-chloro-2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 61 % yield (140 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (163 mg, 0.57 mmol, Amine-9, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.4 Hz), 7.76 (1H, d, J = 1.5 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 2.2 Hz), 7.83 (2H, q, J = 8.5 Hz), 5.76 (1H, q, J = 7.3 Hz),4.25 (1H, d, J = 17.6 Hz), 4.08 (1H, d, J = 17.6 Hz), 3.85 (3H, s), 1.76 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 402 (M+H) +, 400 (M+H) -.
Intermediate-11: 4-chloro-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 62 % yield (131 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (124 mg, 0.57 mmol, Amine-10, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 7.70 (1H, d, J = 4.4 Hz), 7.35 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 6.6 Hz), 5.78 (1H, q, J = 7.1 Hz), 4.40-4.31 (3H, m), 4.01 (1H, d, J = 18.3 Hz), 1.72 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 371 (M+H) +, 369 (M-H) -.
Intermediate-12: 4-chloro-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 65 % yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (138 mg, 0.57 mmol, Amine-11) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.14 (1H, d, J = 2.2 Hz), 7.72 (1H, d, J = 5.1 Hz), 7.65 (1H, dd, J = 8.8, 2.2 Hz), 6.88 (1H, d, J = 8.8 Hz), 4.80-4.72 (4H, m), 4.33 (2H, s), MS (ESI) m/z: 358 (M+H) +, 356 (M-H) -.
Intermediate-13: 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 75 % yield (158 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (147 mg, 0.57 mmol, Amine-12) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 2.2 Hz), 7.73-7.69 (2H, m), 6.16 (1H, tt, J = 55.3, 4.4 Hz), 4.76 (2H, s), 4.60 (2H, td, J = 13.2, 4.4 Hz), 4.36 (2H, s), MS (ESI) m/z: 374 (M+H) +, 372 (M-H) -.
Intermediate-14: 4-chloro-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 80 % yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (155 mg, 0.57 mmol, Amine-13) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 7.69 (1H, d, J = 5.1 Hz), 7.61 (1H, d, J = 8.8 Hz), 6.43 (1H, d, J = 8.1 Hz), 4.79-4.70 (4H, m), 4.39 (2H, s), 3.99 (3H, s), MS (ESI) m/z: 388 (M+H) +.
Intermediate-15: 4-chloro-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 60 % yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride (156 mg, 0.57 mmol, Amine-14) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.15 (1H, d, J = 3.0 Hz), 7.72 (1H, d, J = 5.1 Hz), 7.65 (1H, dd, J = 8.4, 2.6 Hz), 6.85 (1H, d, J = 8.8 Hz), 5.60 (1H, tt, J = 52.7, 4.4 Hz), 4.78-4.70 (4H, m), 4.33 (2H, s), MS (ESI) m/z: 390 (M+H) +, 388 (M-H) -.
Intermediate-16: 4-chloro-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 47 % yield (102 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-15, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.19 (1H, d, J = 2.2 Hz), 7.70 (1H, d, J = 4.4 Hz), 7.61 (1H, dd, J = 8.8, 2.2 Hz), 6.76 (1H, d, J = 8.8 Hz), 5.76 (1H, q, J = 7.1 Hz), 4.55 (2H, t, J = 6.6 Hz), 4.41 (1H, d, J = 17.6 Hz), 4.07 (1H, d, J = 18.3 Hz), 2.69-2.54 (2H, m), 1.74 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 386 (M+H) +, 384 (M-H) -.
Intermediate-17: 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 71 % yield (157 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.8 Hz), 8.09 (1H, d, J = 1.8 Hz), 7.72-7.25 (2H, m), 6.15 (1H, tt, J = 55.3, 4.5 Hz), 5.75 (1H, q, J = 7.2 Hz), 4.59 (2H, td, J = 13.2, 4.4 Hz), 4.43 (1H, d, J = 17.9 Hz), 4.10 (1H, d, J = 17.9 Hz), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 388 (M+H) +, 386 (M-H) -.
Intermediate-18: 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 64 % yield (152 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (172 mg, 0.57 mmol, Amine-17, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.8 Hz), 8.03 (1H, s), 7.71 (1H, d, J = 4.8 Hz), 7.45 (1H, s), 5.99 (1H, tt, J = 53.1, 4.5 Hz), 5.75 (1H, q, J = 6.8 Hz), 4.74 (2H, td, J = 12.6, 1.5 Hz), 4.41 (1H, d, J = 18.3 Hz), 4.06 (1H, d, J = 18.0 Hz), 2.21 (3H, s), 1.73 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 418 (M+H) +, 416 (M-H) -.
Intermediate-19: 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 51 % yield (112 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (154 mg, 0.57 mmol, Amine-18, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.20 (1H, d, J = 2.2 Hz), 7.70-7.67 (2H, m), 6.88 (1H, d, J = 8.8 Hz), 5.47 (1H, t, J = 8.1 Hz), 4.75 (2H, q, J = 8.5 Hz), 4.37 (1H, d, J = 17.6 Hz), 4.07 (1H, d, J = 18.3 Hz), 2.22-2.10 (2H, m), 1.10 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 386 (M+H) +, 384 (M-H) -.
Intermediate-20: 4-chloro-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 60 % yield (31 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (38 mg, 0.14 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (35 mg, 0.14 mmol, Amine-19) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 7.73 (1H, d, J = 4.4 Hz), 7.65 (1H, t, J = 8.1 Hz), 6.98 (1H, d, J = 7.4 Hz), 6.80 (1H, d, J = 8.1 Hz), 4.85 (2H, s), 4.70 (2H, q, J = 8.5 Hz), 4.51 (2H,s), MS (ESI) m/z: 358 (M+H) +, 356 (M-H) -.
Intermediate-21: 4-chloro-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 56 % yield (133 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (174 mg, 0.57 mmol, Amine-20, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.20 (1H, d, J = 2.6 Hz), 7.71 (1H, d, J = 4.8 Hz), 7.67 (1H, dd, J = 8.8, 2.6 Hz), 8.73 (1H, d, J = 8.8 Hz), 5.78 (1H, q, J = 7.1 Hz), 4.83 (2H, td, J = 13.1, 1.1 Hz), 4.40 (1H, d, J = 17.9 Hz), 4.07 (1H, d, J = 18.0 Hz), 1.75 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 422 (M+H) +, 420 (M-H) -.
Intermediate-22: 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 91 % yield (198 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-21, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.54 (1H, d, J = 4.8 Hz), 7.69-7.66 (2H, m), 6.44 (1H, d, J = 8.0 Hz), 6.11 (1H, tt, J = 55.5, 4.2 Hz), 5.69 (1H, q, J = 7.1 Hz), 4.52 (2H, td, J = 13.4, 4.2 Hz), 4.40 (1H, d, J = 18.3 Hz), 4.09 (1H, d, J = 17.9 Hz), 3.90 (3H, s), 1.68 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 384 (M+H) +.
Intermediate-23: 4-chloro-2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 46 % yield (98 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-22) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 5.1 Hz), 7.93 (1H, s), 7.73 (1H, d, J = 5.1 Hz), 7.44 (1H, d, J = 10 Hz), 4.87-4.79 (4H, m), 4.37 (2H, s), MS (ESI) m/z: 376 (M+H) +, 374 (M-H) -.
Intermediate-24: 4-chloro-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 60 % yield (134 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-23) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 4.4 Hz), 8.15 (1H, s), 7.74-7.26 (2H, m), 4.86-4.77 (4H, m), 4.36 (2H, s), MS (ESI) m/z: 392 (M+H) +, 390 (M-H) -.
Intermediate-25: 4-chloro-2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in >99 % yield (340 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (214 mg, 0.81 mmol) and 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (200 mg, 0.74 mmol, Amine-24, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.4 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.26-7.23 (1H, m), 6.93 (1H, d, J = 8.8 Hz), 6.14 (1H, tt, J = 54.9, 4.0 Hz ), 5.74 (1H, q, J = 7.1 Hz), 4.38 (1H, d, J = 17.6 Hz), 4.24 (2H, td, J = 12.7, 4.2 Hz), 4.03 (1H, d, J = 19.8 Hz), 1.71 (3H, 1H, d, J = 7.3 Hz).
Intermediate-28: 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 65 % yield (136 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-27, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 7.70 (1H, d, J = 4.7 Hz), 7.21-7.17 (2H, m), 6.78 (1H, d, J = 8.1 Hz), 6.10 (1H, tt, J = 55.1, 4.0 Hz), 5.74 (1H, q, J = 7.1 Hz), 4.36 (1H, d, J = 18.3 Hz), 4.18 (2H, td, J = 13.2, 4.0 Hz), 4.02 (1H, d, J = 17.9 Hz), 2.23 (3H, s), 1.69 (3H, d, J = 6.9 Hz), MS (ESI) m/z: 367 (M+H) +, 365 (M-H) -.
Intermediate-29: 4-chloro-2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 55 % yield (127 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-28, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.8 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.43 (1H, d, J = 2.2 Hz), 7.28-7.24 (1H, m), 6.96 (1H, d, J = 8.4 Hz), 5.75 (1H, q, J = 7.2 Hz), 4.44-4.36 (3H, m), 4.04 (1H, d, J = 17.9 Hz), 1.71 (3H, d, J = 7.4 Hz), MS (ESI) m/z: 405 (M+H) +, 403 (M-H)-.
Intermediate-31: 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer; antipode of Intermediate-2)
The title compound is prepared in 62 % yield (135 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-37, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.01 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.45 (1H, d, J = 1.5 Hz), 5.75 (1H, q, J = 6.8 Hz), 4.76 (2H, q, J = 8.5 Hz), 4.41 (1H, d, J = 18.3 Hz), 4.06 (1H, d, J = 18.3 Hz), 2.23 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 386 (M+H) +, 384 (M-H) -.
Intermediate-32: 4-chloro-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 75 % yield (165 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-29, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.7 Hz), 7.71 (1H, d, J = 4.8 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 5.91 (1H, tt, J = 53.1, 2.8 Hz), 5.81 (1H, q, J = 7.1 Hz), 4.41 (1H, d, J = 17.9 Hz), 4.06 (1H, d, J = 17.9 Hz), 1.74 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 389 (M+H) +, 387 (M-H) -.
Intermediate-33: 4-chloro-2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 85 % yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-30, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 7.71 (1H, d, J = 4.7 Hz), 6.84 (1H, s), 6.75 (1H, s), 6.67 (1H, s), 6.07 (1H, tt, J = 54.9, 4.0 Hz), 5.73 (1H, q, J = 7.1 Hz), 4.38 (1H, d, J = 18.3 Hz), 4.16 (2H, td, J = 13.2, 3.7 Hz), 4.05 (1H, d, J = 17.9 Hz), 2.34 (3H, s), 1.69 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 367 (M+H) +, 365 (M-H) -.
Intermediate-34: 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 71 % yield (154 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-31, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 7.70 (1H, d, J = 5.1 Hz), 6.96-6.90 (3H, m), 6.12 (1H, tt, J = 54.9, 4.4 Hz), 5.75 (1H, q, J = 7.1 Hz), 4.37 (1H, d, J = 17.6 Hz), 4.22 (2H, td, J = 13.2, 4.4 Hz), 4.03 (1H, t, J = 18.3 Hz), 3.85 (3H, s), 1.71 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 383 (M+H) +, 381 (M-H) -.
Intermediate-35: 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 35 % yield (74 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride (144 mg, 0.57 mmol, Amine-32) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 7.72 (1H, d, J = 4.4 Hz), 6.92-6.85 (3H, m), 6.12 (1H, tt, J = 54.9, 4.4 Hz), 4.76 (2H, s), 4.32 (2H, s), 4.21 (2H, td, J = 13.2, 4.4 Hz), 3.85 (3H, s), MS (ESI) m/z: 369 (M+H) +, 367 (M-H) -.
Intermediate-36: 4-chloro-3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (diastereomer mixture)
The title compound is prepared in 12 % yield (40 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (262 mg, 0.94 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.85 mmol, Amine-2, single enantiomer) in a similar manner to Intermediate-2.
(ESI) m/z: 400 (M+H) +, 398 (M-H) -.
Intermediate-37: 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)
The title compound is prepared in 24 % yield (63 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (206 mg, 0.86 mmol, Amine-4) in a similar manner to Intermediate-2.
(ESI) m/z: 368 (M+H) +, 366 (M-H) -.
Intermediate-38: 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)
The title compound is prepared in 16 % yield (45 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (223 mg, 0.86 mmol, Amine-12) in a similar manner to Intermediate-2.
(ESI) m/z: 388 (M+H) +, 386 (M-H) -.
Intermediate-39: 4-chloro-2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 84 % yield (225 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol) and (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride (195 mg, 0.75 mmol, Amine-33) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 7.73 (1H, d, J = 4.4 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.21 (1H, dd, J = 8.0, 2.2 Hz), 6.93 (1H, d, J = 8.8 Hz), 6.14 (1H, tt, J = 54.9, 4.0 Hz ), 4.75 (2H, s), 4.32 (2H, s), 4.25 (2H, td, J = 12.8, 4.4 Hz), MS (ESI) m/z: 373 (M+H) +, 371 (M-H) -.
Intermediate-40: 4-chloro-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
<Step-1>: 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
To a solution of ethyl 2-chloro-3-cyano-6-methylisonicotinate (1.0 g, 4.5 mmol) in EtOH (14.8 mL) is added Raney nickel (100 mg, RANEY 2800 NICKEL),and the mixture is stirred at 60 oC under hydrogen atmosphere for 2 days. After cooling to rt, the reaction mixture is filtered through a pad of CeliteTM. The filtrate is concentrated, and the residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (1:1), and the collecting sample is recrystallized from THF / n-hexane to give 91 mg (11 % yield) of the title compound as white solid.
1H -NMR (300 MHz, DMSO-d6) delta 9.12 (1H, br s), 7.58 (1H, s), 4.41 (2H, s), 2.57 (3H, s), MS (ESI) m/z: 183 (M+H) +.
<Step-2>: 4-chloro-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate-40)
A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (2:1) to give 65 mg (34 % yield) of the title compound as colorless oil.
1H -NMR (300 MHz, CDCl3) delta 8.10 (1H, d, J = 2.2 Hz), 7.55 (1H, s), 7.43 (1H, d, J = 2.2 Hz), 4.80-4.72 (4H, m), 4.27 (2H, s), 2.66 (3H, s), 2.21 (3H, s), MS (ESI) m/z: 386 (M+H) +.
Intermediate-41: 4-chloro-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 99 % yield (460 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (353 mg, 1.38 mmol, Amine-34) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 7.72 (1H, d, J = 4.4 Hz), 7.14-7.12 (2H, m), 6.77 (1H, d, J = 8.8 Hz), 4.74 (2H, s), 4.39-4.30 (4H, m), 2.25 (3H, s), MS (ESI) m/z: 371 (M+H) +, 369 (M-H) -.
Intermediate-42: 4-chloro-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 97 % yield (467 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (373 mg, 1.38 mmol, Amine-69, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.20-7.18 (2H, m), 6.77 (1H, d, J = 8.8 Hz), 5.74 (1H, q, J = 7.1 Hz), 4.40-4.31 (3H, m), 4.02 (1H d, J = 18.3 Hz), 2.26 (3H, s), 1.70 (3H d, J = 7.3 Hz), MS (ESI) m/z: 385 (M+H) +, 383 (M-H) -.
Intermediate-43:
4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (diastereomer mixture)
The title compound is prepared in 24 % yield (134 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (399 mg, 1.6 mmol, Amine-5, single enantiomer) in a similar manner to Intermediate-2.
(ESI) m/z: 382 (M+H) +, 380 (M-H) -.
Intermediate-44: 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (diastereomer mixture)
The title compound is prepared in 17 % yield (100 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (431 mg, 1.6 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.
(ESI) m/z: 402 (M+H) +, 400 (M-H) -.
Intermediate-45: 4-chloro-3-methyl-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)
The title compound is prepared in 50 % yield (137 mg, brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (200 mg, 0.79 mmol, Amine-34) in a similar manner to Intermediate-2.
(ESI) m/z: 385 (M+H) +.
Intermediate-46: 4-chloro-2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 61 % yield (260 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.08 mmol) and 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (337 mg, 1.19 mmol, Amine-36, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.4 Hz), 8.02 (1H, s), 7.71 (1H, d, J = 5.1 Hz), 7.40 (1H, s), 5.74 (1H, q, J = 7.3 Hz), 4.56 (2H, t, J = 6.3 Hz), 4.40 (1H, d, J = 18.3 Hz), 4.07 (1H,d, J = 18.3 Hz), 2.70-2.55 (2H, m), 2.17 (3H, s), 1.73 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 400 (M+H) +, 398 (M-H) -.
Intermediate-47: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
<Step-1>: methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (540 mg, 1.40 mmol, Intermediate-2, single enantiomer), palladium(II) acetate (190 mg, 0.84 mmol), 1,3-bis(diphenylphosphino)propane (115 mg, 0.28 mmol), and triethylamine (0.58 mL, 4.20 mmol) in DMF / MeOH (2.5:1, 14 mL) is heated at 100 oC under carbon monoxide atmosphere for 18 hours. The reaction mixture is cooled to rt and dilute with water. The mixture is filtered through a pad of CeliteTM and the filtrate is extracted with n-hexane / EtOAc (1:1) mixed solvent. The combined extracts are washed with water, and brine. The organic extract is dried over sodium sulfate, filtrate, and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (1:1 to 1:4) to give 300 mg (52 % yield) of the title compound as brown amorphous solid.
1H -NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 4.4 Hz), 8.02 (1H, d, J = 1.5 Hz), 7.96 (1H, d, J = 5.1 Hz), 7.46 (1H, d, J = 1.5 Hz ), 5.77 (1H, q, J = 7.1 Hz), 4.85-4.71 (3H, m), 4.47 (1H, d, J = 19.2 Hz), 4.03 (3H, s), 2.21 (3H, s), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 410 (M+H) +, 408 (M-H) -.
<Step-2>: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) (Intermediate-47)
To a solution of methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (300 mg, 0.73 mmol, Step-1, single enantiomer) in THF (8.0 mL) is added 2 M aqueous sodium hydroxide (1.1 mL, 2.2 mmol) at rt, and the reaction mixture is stirred overnight at rt. The reaction mixture is neutralized by the addition of 2 M aqueous hydrochloric acid (1.1 mL, 2.2 mmol). The mixture is extracted with DCM, and the organic layer is dried over sodium sulfate. After filtration, the filtrate, and volatiles are removed to give 297 mg (>99 % yield) of the title compound as white solid.
1H -NMR (300 MHz, CDCl3) delta 8.80 (1H, d, J = 4.4 Hz), 8.06-8.02 (2H, m), 7.46 (1H, d, J = 1.5 Hz), 5.76 (1H, q, J = 7.1 Hz), 4.92 (1H, d, J = 19.8 Hz), 4.75 (2H, q, J = 8.5 Hz), 4.53 (1H, J = 19.8 Hz), 2.21 (3H, s), 1.75 (3H, d, J = 7.3 Hz), a signal due to COOH is not observed, MS (ESI) m/z: 396 (M+H) +, 394 (M-H) -.
Intermediate-48: 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
<Step-1>: methyl 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 79 % yield (236 mg, pale yellow solid) from 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.76 mmol, Intermediate-5, single enantiomer) in a similar manner to Step-1 of Intermediate-47.
1H -NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 4.4 Hz), 8.02 (1H, s), 7.96 (1H, d, J = 4.4 Hz), 7.43 (1H, s), 6.13 (1H, tt, J = 55.7, 4.4 Hz), 5.76 (1H, q, J = 6.6 Hz), 4.81 (1H, d, J = 19.8 Hz), 4.53 (2H, td, J = 13.9, 4.4 Hz), 4.46 (1H, d, J = 19.8 Hz), 4.03 (3H, s), 2.20 (3H, s), 1.74 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 392 (M+H) +, 390 (M-H) -.
<Step-2>: 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) (Intermediate-48)
The title compound is prepared in 88 % yield (200 mg, white solid) from methyl 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (236 mg, 0.60 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.
1H -NMR (300 MHz, DMSO-d6) delta 8.86 (1H, d, J = 5.1 Hz), 8.05 (1H, d, J = 2.2 Hz), 7.93 (1H, d, J = 4.4 Hz), 7.66 (1H, d, J = 1.5 Hz), 6.39 (1H, tt, J = 54.9, 3.7 Hz), 5.50 (1H, q, J = 6.8 Hz), 4.87 (1H, d, J = 19.1 Hz), 4.62-4.47 (3H, m), 2.16 (3H, s), 1.68 (3H, d, J = 7.3 Hz), a signal due to COOH is not observed, MS (ESI) m/z: 378 (M+H) +,376 (M-H) -.
Intermediate-49: 4-amino-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride
<Step-1>: N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide
The title compound is prepared in >99 % yield (200 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.42 mmol, Intermediate-4) in a similar manner to Example-1.
1H -NMR (300 MHz, CDCl3) delta 8.43 (1H, d, J = 4.4 Hz), 8.31 (1H, br s), 7.93 (1H, d, J = 2.2 Hz), 7.63 (1H, d, J = 5.1 Hz), 7.41 (1H, d, J = 1.5 Hz), 6.13 (1H, tt, J = 53.5, 4.4 Hz), 4.71 (2H, s), 4.57-4.52 (4H, m), 2.22 (3H, s), 2.17 (3H, s), MS (ESI) m/z: 377 (M+H) +, 375 (M-H)-.
<Step-2>: 4-amino-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (Intermediate-49)
To a solution of N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (200 mg, 0.54 mmol, Step-1) in THF (5.0 mL) is added aqueous hydrochloric acid (3.0 mL) at rt. The reaction mixture is stirred at 90 oC for 16 hours. The reaction mixture is concentrated to give 220 mg (>99 % yield) of the title compound as pale yellow solid.
1H -NMR (300 MHz, DMSO-d6) delta 8.64 (2H, br s), 8.07 (1H, d, J = 6.6 Hz), 7.98 (1H, s), 7.53 (1H, s), 7.09 (1H, d, J = 6.6 Hz), 6.37 (1H, tt, J = 54.9, 3.5 Hz), 4.69 (2H, s), 4.55 (2H, td, J = 15.0, 3.7 Hz), 4.35(2H, s), 2.13 (3H, s), MS (ESI) m/z: 335 (M+H) +, 333 (M-H) -.
Intermediate-50: 4-amino-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (64 mg, pale yellow solid) from N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (65 mg, 0.17 mmol, Example-35, single enantiomer) in a similar manner to Step-2 of Intermediate-49.
MS (ESI) m/z: 349 (M+H) +, 347 (M-H) -.
Intermediate-51: 4-amino-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (44 mg, pale yellow solid) from N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (44 mg, 0.10 mmol, Example-61, single enantiomer) in a similar manner to Step-2 of Intermediate-49.
MS (ESI) m/z: 387 (M+H) +, 385 (M-H) -.
Intermediate-52: 4-amino-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (127 mg, pale yellow solid) from N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (120 mg, 0.31 mmol, Example-126, single enantiomer) in a similar manner to Step-2 of Intermediate-49.
MS (ESI) m/z: 348 (M+H) +, 346 (M-H) -.
Intermediate-53: 4-(aminomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
<Step-1>: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile (single enantiomer)
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (200 mg, 0.52 mmol, Intermediate-2, single enantiomer), zinc cyanide (300 mg, 1.56 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.052 mmol) in DMF (5 mL) is heated at 150 oC for 30 min by microwave irradiation. The mixture is filtered through a pad of CeliteTM. The CeliteTM pad is washed with water, and EtOAc. The filtrate is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (3:1) to give 160 mg (80 % yield) of the title compound as colorless oil.
1H -NMR (300 MHz, CDCl3) delta 8.88 (1H, d, J = 5.1 Hz), 8.02 (1H, d, J = 2.2 Hz), 7.96 (1H, d, J = 4.7 Hz), 7.45 (1H, s), 5.76 (1H, q, J = 7.3 Hz), 4.77 (2H, q, J = 8.4 Hz), 4.61 (1H, d, J = 17.9Hz), 4.26 (1H, d, J = 17.9Hz), 2.24 (3H, s), 1.74 (3H, d, J = 7.3Hz), MS (ESI) m/z: 377 (M+H) +.
<Step-2>: 4-(aminomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) (Intermediate-53)
The title compound is prepared in 77 % yield (110 mg, colorless oil) from 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile (150 mg, 0.39 mmol, Step-1, single enantiomer) in a similar manner to Step-5 of Amine-3.
1H -NMR (300 MHz, CDCl3) delta 8.71 (1H, d, J = 5.1 Hz), 8.00 (1H, s), 7.65 (1H, d, J = 5.1 Hz), 7.44 (1H, s), 5.76 (1H, q, J = 7.3 Hz), 4.75 (2H, q, J = 8.8 Hz), 4.47 (1H, d, J = 17.6 Hz), 4.11 (1H, d, J = 17.6 Hz), 4.03 (2H, s), 2.21 (3H, s), 1.72 (3H, d, J = 7.0 Hz) (signal due to NH2 is not observed), MS (ESI) m/z: 381 (M+H) +.
Intermediate-54: 4-chloro-2-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 54 % yield (130 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (180 mg, 0.64 mmol, Step-1 of Intermediate-1) and (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (140 mg, 0.64 mmol, Amine-18) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.14 (1H, d, J = 2.2Hz), 7.73-7.67 (2H, m), 7.12-7.08 (4H, m), 6.92 (1H, d, J = 8.8 Hz), 4.78 (2H, s), 4.34 (2H, s), MS (ESI) m/z: 370 (M+H) +.
Intermediate-55: 4-chloro-2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 84 % yield (120 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (100 mg, 0.36 mmol, Step-1 of Intermediate-1) and 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (120 mg, 0.43 mmol, Amine-39, single enantiomer) in a similar manner to Intermediate-2.
MS (ESI) m/z: 398 (M+H) +.
Intermediate-56: 4-chloro-2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 50 % yield (140 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (240 mg, 0.86 mmol, Amine-40, single enantiomer) in a similar manner to Intermediate-2.
MS (ESI) m/z: 398 (M+H) +.
Intermediate-57: 4-chloro-2-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 50 % yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (290 mg, 0.86 mmol, Amine-41, single enantiomer) in a similar manner to Intermediate-2.
MS (ESI) m/z: 449 (M+H) +.
Intermediate-58: 4-chloro-2-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 48 % yield (290 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (410 mg, 1.6 mmol, Amine-42, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.22 (1H, d, J = 2.2 Hz), 7.69 (1H, d, J = 4.4 Hz), 7.51 (2H, dd, J = 9.5, 5.5 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.10 (2H, dd, J = 8.4, 8.4 Hz), 5.72 (1H, q, J = 7.1 Hz), 4.38 (1H, d, J = 17.6 Hz), 4.06 (1H, d, J = 18.3 Hz), 2.35 (3H, s), 1.70 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 414 (M+H) +.
Intermediate-59: 4-chloro-2-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 83 % yield (270 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-43, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.00 (1H, d, J = 1.5 Hz), 7.70 (1H, d, J = 5.1 Hz), 7.52 (1H, d, J = 2.2 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 5.74 (1H, q, J = 7.3 Hz), 4.40 (1H, d, J = 17.6 Hz), 4.08 (1H, d, J = 17.6 Hz), 2.34 (3H, s), 1.72 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 414 (M+H) +.
Intermediate-60: 4-chloro-2-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 57 % yield (190 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (220 mg, 0.79 mmol, Step-1 of Intermediate-1) and 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-44, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.00 (1H, d, J = 2.2 Hz), 7.70 (1H, d, J = 4.4 Hz), 7.53 (1H, d, J = 2.2 Hz), 7.17 (1H, dd, J = 19.1, 8.8 Hz), 7.02-6.96 (1H, m), 6.89-6.85 (1H, m), 5.75 (1H, q, J = 7.1 Hz), 4.36 (1H, d, J = 17.6 Hz), 4.09 (1H, d, J = 17.6 Hz), 2.33 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 416 (M+H) +.
Intermediate-61: 4-chloro-2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 59 % yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (200 mg, 0.72 mmol, Amine-45, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 8.34 (1H, d, J = 1.5 Hz), 8.24 (1H, s), 7.72 (1H, d, J = 5.1 Hz), 7.64 (2H, s), 5.84 (1H, q, J = 7.1 Hz), 4.46 (1H, d, J = 17.6 Hz), 4.12 (1H, d, J = 17.6 Hz), 2.58 (3H, s), 1.80 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 388 (M+H) +.
Intermediate-62: 4-chloro-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 62 % yield (220 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (260 mg, 0.93 mmol, Step-1 of Intermediate-1) and 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (250 mg, 0.93 mmol, Amine-46, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 8.07 (1H, s), 7.69 (1H, d, J = 5.1 Hz), 7.27 (1H, s), 5.69 (1H, q, J = 7.3 Hz), 4.42-4.20 (4H, m), 4.06 (1H, d, J = 17.6 Hz), 2.13 (3H, s), 1.70 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 385 (M+H) +.
Intermediate-63: 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (single enantiomer)
To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and pyridine (250 mg, 3.1 mmol) in DCM (5 mL) is added 2-chloroacetyl chloride (89 mg, 0.79 mmol) at rt. The mixture is stirred for 1 hour at rt, and the mixture is diluted with water. The mixture is extracted with DCM. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (3:1 to 1:1) to give 270 mg (96 % yield) of the title compound as pale brown solid.
1H -NMR (300 MHz, CDCl3) delta 8.79 (1H, br s), 8.50 (1H, d, J = 5.1 Hz), 8.00 (1H, s), 7.68 (1H, d, J = 5.1 Hz), 7.44 (1H, s), 5.74 (1H, q, J = 6.8 Hz), 4.78-4.68 (3H, m), 4.28-4.21 (3H, m), 3.61 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 443 (M+H) +.
Intermediate-64: 4-chloro-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 65 % yield (200 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (240 mg, 0.79 mmol, Amine-47, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 5.1 Hz), 8.54 (1H, s), 8.37 (1H, d, J = 2.2 Hz), 7.90 (1H, s), 7.73 (1H, d, J = 5.1 Hz), 7.69 (1H, d, J = 2.2 Hz), 5.85 (1H, q, J = 7.3 Hz), 4.47 (1H, d, J = 18.3 Hz), 4.13 (1H, d, J = 17.6 Hz), 2.58 (3H, s), 1.81 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 422 (M+H) +.
Intermediate-65: 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 75 % yield (210 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (230 mg, 0.86 mmol, Amine-48, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 7.68 (1H, d, J = 5.1 Hz), 7.37 (1H, s), 5.77 (1H, q, J = 7.1 Hz), 4.98-4.86 (2H, m), 4.61 (2H, s), 2.28 (3H, s), 1.86 (3H, d, J = 7.4 Hz), MS (ESI) m/z: 387 (M+H) +.
Intermediate-66: 4-chloro-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 78 % yield (320 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.1 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (330 mg, 1.1 mmol, Amine-49, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.54 (1H, d, J = 5.1 Hz), 8.11 (1H, s), 7.68 (1H, d, J = 4.4 Hz), 7.20 (1H, s), 5.69 (1H, q, J = 7.1 Hz), 4.54 (2H, s), 4.42 (2H, q, J = 8.1 Hz), 2.26 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 386 (M+H) +.
Intermediate-67: 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 51 % yield (170 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride (230 mg, 0.90 mmol, Amine-50) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.39 (1H, s), 5.01 (2H, s), 4.93 (1H, q, J = 8.3 Hz), 4.58 (2H, s), 2.28 (3H, s), MS (ESI) m/z: 373 (M+H) +.
Intermediate-68: 4-chloro-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 71 % yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (410 mg, 1.3 mmol, Amine-51) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 7.97 (1H, s), 7.72 (1H, d, J = 4.4 Hz), 7.44 (1H, s), 5.99 (1H, tt, J = 52.7, 4.4 Hz), 4.78-4.70 (4H, m), 4.32 (2H, s), 2.19 (3H, s), MS (ESI) m/z: 404 (M+H) +.
Intermediate-69: 4-chloro-2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 72 % yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride (410 mg, 1.3 mmol, Amine-52) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.08 (1H, s), 7.72 (1H, d, J = 5.1 Hz), 7.17 (1H, s), 6.11 (1H, tt, J = 54.6, 4.0 Hz), 4.86 (2H, s), 4.52 (2H, s), 4.27 (2H, td, J = 13.0, 3.9 Hz), 2.24 (3H, s), MS (ESI) m/z: 354 (M+H) +.
Intermediate-70: 4-chloro-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 71 % yield (520 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (600 mg, 2.2 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride (480 mg, 2.2 mmol, Amine-53) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 4.4 Hz), 8.31 (1H, d, J = 2.2 Hz), 8.23 (1H, d, J = 2.2 Hz), 7.75-7.74 (2H, m), 7.65 (1H, d, J = 1.5 Hz), 6.46 (1H, t, J = 2.2 Hz), 4.86 (2H, s), 4.38 (2H, s), 2.57 (3H, s), MS (ESI) m/z: 340 (M+H) +.
Intermediate-71: 4-chloro-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 84 % yield (300 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (250 mg, 0.90 mmol, Amine-54) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 7.73 (1H, d, J = 4.4 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.21 (1H, d, J = 8.0, 2.2 Hz), 6.96 (1H, d, J = 8.8 Hz), 4.76 (2H, s), 4.40 (2H, q, J = 8.1 Hz), 4.33 (2H, s), MS (ESI) m/z: 391 (M+H) +.
Intermediate-72: 4-chloro-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 80 % yield (300 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (270 mg, 0.96 mmol, Step-1 of Intermediate-1) and 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (260 mg, 0.96 mmol, Amine-55, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.54 (1H, d, J = 5.1 Hz), 7.99 (1H, s), 7.68 (1H, d, J = 4.4 Hz), 5.71 (1H, q, J = 7.1 Hz), 4.80-4.68 (2H, m), 4.62 (2H, s), 2.51 (3H, s), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 387 (M+H) +.
Intermediate-73: 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 64 % yield (340 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (374 mg, 1.4 mmol, Amine-56, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.02 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 4.4 Hz), 7.42 (1H, d, J = 1.5 Hz), 5.74 (1H, q, J = 7.1 Hz), 4.50 (2H, t, J = 11.7 Hz), 4.40 (1H, d, J = 17.6 Hz), 4.06 (1H, d, J = 17.6 Hz), 2.21 (3H, s), 1.80-1.68 (6H, m), MS (ESI) m/z: 382 (M+H) +.
Intermediate-74: 4-chloro-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 22 % yield (42 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (170 mg, 0.61 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (230 mg, 0.51 mmol, Amine-57) in a similar manner to Step-2 of Intermediate-1.
MS (ESI) m/z: 372 (M+H) +.
Intermediate-75: 4-chloro-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 65 % yield (120 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (130 mg, 0.48 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine hydrochloride (130 mg, 0.48 mmol, Amine-58) in a similar manner to Intermediate-2.
1H -NMR (270 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.08 (1H, s), 7.71 (1H, d, J = 5.4 Hz), 7.15 (1H, s), 4.85 (2H, s), 4.51 (2H, s), 4.29 (2H, t, J = 5.9 Hz), 2.75-2.57 (2H, m), 2.21 (3H, s), MS (ESI) m/z: 386 (M+H) +.
Intermediate-76: 4-chloro-2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 71 % yield (360 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (350 mg, 1.4 mmol, Amine-59, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.53 (1H, d, J = 4.4 Hz), 8.11 (1H, s), 7.67 (1H, d, J = 4.4 Hz), 7.21 (1H, s), 6.11 (1H, tt, J = 54.9 and 3.9 Hz), 5.68 (1H, q, J = 7.1 Hz), 1.98 (2H, s), 4.27 (2H, td, J = 13.0 and 3.9 Hz), 2.25 (3H, s), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 368 (M+H) +.
Intermediate-77: 4-chloro-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 53 % yield (420 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (580 mg, 1.8 mmol, Amine-60, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.10 (1H, d, J = 1.5 Hz), 7.72-7.70 (2H, m), 6.06 (1H, tt, J = 53.1, 4.8 Hz), 5.26 (1H, q, J = 7.1 Hz), 4.77 (2H, t, J = 12.1 Hz), 4.44 (1H, d, J = 17.6 Hz), 4.10 (1H, d, J = 17.6 Hz), 1.76 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 438 (M+H) +.
Intermediate-78: 4-chloro-2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 60 % yield (450 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (480 mg, 1.8 mmol, Amine-61, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 8.09 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 4.4 Hz), 7.68 (1H, d, J = 2.2 Hz), 5.75 (1H, q, J = 7.1 Hz), 4.61 (2H, t, J = 6.6 Hz), 4.43 (1H, d, J = 17.6 Hz), 4.10 (1H, d, J = 17.6 Hz), 2.74-2.59 (2H, m), 1.74 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 420 (M+H) +.
Intermediate-79: 4-chloro-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 63 % yield (400 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (470 mg, 1.7 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (460 mg, 1.6 mmol, Amine-62, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, DMSO-d6) delta 8.58 (1H, d, 5.1Hz), 8.24 (1H, s), 7.74 (1H, d, J = 5.1 Hz), 7.25 (1H, s), 5.48 (1H, q, J = 7.3 Hz), 4.71 (1H, d, J = 18.3 Hz), 4.50 (1H, d, J = 18.3 Hz), 4.31 (1H, t, J = 5.9 Hz), 2.88-2.70 (1H, m), 2.15 (3H, s), 1.64 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 400 (M+H) +.
Intermediate-80: 4-chloro-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 83 % yield (1200 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1000 mg, 3.6 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (1030 mg, 3.6 mmol, Amine-63, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 4.4 Hz), 8.08 (1H, d, J = 2.2 Hz), 7.72-7.69 (2H, m), 5.75 (1H, q, J = 7.3 Hz), 4.54 (2H, t, J = 11.7 Hz), 4.43 (1H, d, J = 17.6 Hz), 4.10 (1H, d, J = 18.3 Hz), 1.83-1.71 (6H, m), MS (ESI) m/z: 402 (M+H) +.
Intermediate-81: 4-chloro-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 89 % yield (560 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.6 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (440 mg, 1.6 mmol, Amine-64, single enantiomer) in a similar manner to Intermediate-2.
MS (ESI) m/z: 384 (M+H) +.
Intermediate-82: 4-chloro-2-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 44 % yield (240 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (370 mg, 1.3 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (450 mg, 1.3 mmol, Amine-65, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 5.1 Hz), 8.56 (1H, d, J = 1.5 Hz), 7.73-7.71 (2H, m), 5.81 (1H, q, J = 7.1 Hz), 4.90 (2H, s), 4.46 (1H, d, J = 17.6 Hz), 4.12 (1H, d, J = 17.6 Hz), 4.01 (2H, q, J = 8.6 Hz), 1.79 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 420 (M+H) +.
Intermediate-83: 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 92 % yield (580 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride (430 mg, 1.8 mmol, Amine-66) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.20-7.10 (2H, m), 6.79-6.74 (1H, m), 6.10 (1H, tt, J = 54.9 and 4.4 Hz), 4.73 (2H, s), 4.29 (2H, s), 4.18 (2H, td, J = 13.2 and 3.7Hz), 2.22 (3H, s), MS (ESI) m/z: 353 (M+H) +.
Intermediate-84: 4-chloro-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 84 % yield (560 mg, colorless solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride (460 mg, 1.8 mmol, Amine-67) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.01 (1H, s), 7.71 (1H, d, J = 5.1 Hz), 4.86 (2H, s), 4.75 (2H, q, J = 8.3 Hz), 4.59 (2H, s), 2.52 (3H, s)., MS (ESI) m/z: 373 (M+H) +.
Intermediate-85: 4-chloro-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 35 % yield (230 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (430 mg, 1.8 mmol, Amine-68, single enantiomer) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.36 (1H, d, J = 2.2 Hz), 8.23 (1H, d, J = 2.9 Hz), 7.75-7.65 (2H, m), 7.65 (1H, d, J = 1.4 Hz), 6.45 (1H, t, J = 2.2 Hz), 5.85 (1H, q, J = 7.1 Hz), 4.46 (1H, d, J = 17.6 Hz), 4.12 (1H, d, J = 18.3 Hz), 2.58 (3H, s), 1.80 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 354 (M+H) +.
Intermediate-86: 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
<Step-1>: ethyl 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
A mixture of 4-chloro-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (200 mg, 0.49 mmol, Intermediate-9, single enantiomer), palladium(II) acetate (33 mg, 0.15 mmol, 1,3-bis(diphenylphosphino)propane (20 mg, 0.049 mmol), and triethylamine (150 mg, 1.5 mmol) in DMF / EtOH (2:1, 14 mL) is heated at 100 oC overnight under carbon monoxide atmosphere. The mixture is diluted with water, and filtered through a pad of CeliteTM. The CeliteTM pad is washed with EtOAc / toluene (2:1) mixed solvent. The filtrate is washed with water, brine, and dried over sodium sulfate. The organic layer is filtered, and the filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (1:1 to 1:2) to give 160 mg (73 % yield) of the title compound as yellow solid.
1H -NMR (300 MHz, CDCl3) delta 8.94 (1H, d, J = 5.1 Hz), 8.10 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 4.4 Hz), 7.73 (1H, d, J = 1.5 Hz), 5.77 (1H, q, J = 7.3 Hz), 4.87-4.76 (3H, m), 4.55-4.46 (3H, m), 1.76 (3H, d, J = 7.4 Hz), 1.47 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 444 (M+H) +.
<Step-2>:
2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
The title compound is prepared in 100 % yield (150 mg, yellow solid) from ethyl 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (160 mg, 0.36 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.
MS (ESI) m/z: 416 (M+H) +.
Intermediate-87: 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
<Step-1>: ethyl 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 67 % yield (440 mg, yellow solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (600 mg, 1.5 mmol, Intermediate-17, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.94 (1H, d, J = 4.4 Hz), 8.09 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 5.1 Hz), 7.71 (1H, d, J = 2.2 Hz), 6.15 (1H, tt, J = 55.3 and 4.3 Hz), 5.77 (1H, q, J = 7.1 Hz), 4.84 (1H, d, J = 19.1 Hz), 4.64-4.46 (5H, m), 1.76 (3H, d, J = 7.3 Hz), 1.47 (3H, t, J = 7.4 Hz), MS (ESI) m/z: 426 (M+H) +.
<Step-2>: 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
The title compound is prepared in 76 % yield (310 mg, pale brown solid) from ethyl 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (440 mg, 1.0 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.
1H -NMR (300 MHz, CDCl3) delta 8.84 (1H, d, J = 5.1 Hz), 8.19 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 2.2 Hz), 7.90 (1H, d, J = 5.1 Hz), 6.40 (1H, tt, J = 54.2, 3.4 Hz), 5.52-5.44 (1H, m), 4.89 (1H, d, J = 19.0 Hz), 4.69-4.58 (3H, m), 1.69 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 398 (M+H) +.
Intermediate-88: 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
<Step-1>: ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 58 % yield (390 mg, pale brown solid) from 4-chloro-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (620 mg, 1.7 mmol, Intermediate-41) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.93 (1H, d, J = 5.1 Hz), 7.96 (1H, d, J = 5.1 Hz), 7.16-7.12 (2H, m), 6.75 (1H, d, J = 8.8 Hz), 4.76 (2H, s), 4.69 (2H, s), 4.49 (2H, q, J = 7.3 Hz), 4.34 (2H, q, J = 8.0 Hz), 2.24 (3H, s), 1.45 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 409 (M+H) +.
<Step-2>: 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
The title compound is prepared in 97 % yield (350 mg, pale yellow solid) from ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (390 mg, 1.0 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
1H -NMR (300 MHz, CDCl3) delta 8.85 (1H, d, J = 5.1 Hz), 7.92 (1H, d, J = 4.4 Hz), 7.18-7.14 (2H, s), 7.03-7.00 (1H, m), 4.76-4.64 (6H, m), 2.14 (3H, s), MS (ESI) m/z: 381 (M+H) +.
Intermediate-89: 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
<Step-1>: ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 60 % yield (380 mg, pale brown solid) from 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (580 mg, 1.6 mmol, Intermediate-83) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.93 (1H, d, J = 5.1 Hz), 7.96 (1H, d, J = 5.1 Hz), 7.16-7.12 (2H, m), 6.75 (1H, d, J = 8.8 Hz), 6.10 (1H, td, J = 54.9 and 4.4 Hz), 4.76 (2H, s), 4.69 (2H, s), 4.49 (2H, q, J = 6.6 Hz), 4.17 (2H, td, J = 13.2 and 4.4 Hz), 2.22 (3H, s), 1.45 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 391 (M+H) +.
<Step-2>: 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
The title compound is prepared in 97 % yield (350 mg, pale yellow solid) from ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (390 mg, 1.0 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
MS (ESI) m/z: 363 (M+H) +.
Intermediate-90: 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
<Step-1>: ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 60 % yield (560 mg, pale brown solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (850 mg, 2.3 mmol, Intermediate-3) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.94 (1H, d, J = 4.4 Hz), 7.97-7.55 (2H, m), 7.45 (1H, d, J = 2.2 Hz), 4.80-4.71 (6H, m), 4.54-4.47 (2H, q, J = 7.1 Hz), 2.20 (3H, s), 1.46 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 410 (M+H) +.
<Step-2>: 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
The title compound is prepared in 87 % yield (450 mg, pale brown solid) from ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (550 mg, 1.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
1H -NMR (300 MHz, DMSO-d6) delta 8.84 (1H, d, J = 5.1 Hz), 8.04 (1H, s), 7.91 (1H, d, J = 4.4 Hz), 7.60 (1H, d, J = 1.5 Hz), 4.98 (2H, q, J = 9.3 Hz), 4.73 (2H, s), 4.70 (2H, s) 2.14 (3H, s), MS (ESI) m/z: 382 (M+H) +.
Intermediate-91: phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer), phenyl formate (32 mg, 0.26 mmol, single enantiomer), palladium acetate (II) (0.87 mg, 0.039 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.0 mg, 0.016 mmol) in MeCN (1.0 mL) is heated at 80 oC overnight (T. Ueda et al, Org. Lett., 2012, 14, 3100-3103). The mixture is diluted with water, and extracted with EtOAc. The organic layer is dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (2:1 to 1:2) to give 45 mg (74 % yield) of the title compound as off white solid.
1H -NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 4.4 Hz), 8.03 (1H, d, J = 5.1 Hz), 8.00 (1H, s), 7.50-7.43 (3H, m), 7.34-7.20 (3H, m), 5.77 (1H, q, J = 6.6 Hz), 4.84 (1H, d, J = 19.8 Hz), 4.74 (2H, q, J = 8.8 Hz), 4.48 (1H, d, J = 19.8 Hz), 2.20 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 472 (M+H) +.
Intermediate-92: 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
<Step-1>: ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 59 % yield (320 mg, brown oil) from 4-chloro-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (500 mg, 1.3 mmol, Intermediate-24) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.96 (1H, d, J = 5.1 Hz), 8.06 (1H, d, J = 1.5 Hz), 7.97 (1H, d, J = 5.1 Hz), 7.73 (1H, d, J = 2.2 Hz), 4.86-4.75 (6H, m), 4.51 (2H, q, J = 7.1 Hz), 1.47 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 430 (M+H) +.
<Step-2>: 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid
The title compound is prepared in 100 % yield (300 mg, pale brown solid) from ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (320 mg, 0.75 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.
1H -NMR (300 MHz, CDCl3) delta 8.83 (1H, d, J = 4.4 Hz), 8.08-8.06 (2H, m), 7.73 (1H, d, J = 2.2 Hz), 4.86-4.77 (6H, m), MS (ESI) m/z: 402 (M+H) +.
Intermediate-93: ethyl 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 68 % yield (220 mg, colorless solid) from 4-chloro-2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (290 mg, 0.74 mmol, Intermediate-61, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.95 (1H, d, J = 5.1 Hz), 8.35 (1H, d, J = 2.2 Hz), 8.23 (1H, s), 7.97 (1H, d, J = 5.1 Hz), 7.66 (1H, d, J = 1.5 Hz), 7.64 (1H, s), 5.86 (1H, q, J = 7.1 Hz), 4.87 (1H, d, J = 19.0 Hz), 4.55-4.47 (3H, m), 2.56 (3H, s), 1.81 (3H, d, J = 7.3 Hz), 1.46 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 426 (M+H) +.
Intermediate-94: ethyl 2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 78 % yield (250 mg, pale brown solid) from 4-chloro-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.70 mmol, Intermediate-64, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H -NMR (300 MHz, CDCl3) delta 8.95 (1H, d, J = 5.1 Hz), 8.53 (1H, s), 8.38 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 5.1 Hz), 7.89 (1H, s), 7.70 (1H, d, J = 2.2 Hz), 5.97 (1H, q, J = 7.3 Hz), 4.88 (1H, d, J = 19.1 Hz), 4.56-4.47 (3H, m), 2.57 (3H, s), 1.83 (3H, d, J = 7.3 Hz), 1.47 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 460 (M+H) +.
Intermediate-95: phenyl 2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 63 % yield (120 mg, yellow oil) from 4-chloro-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-66, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 8.99 (1H, d, J = 5.1 Hz), 8.07 (1H, s), 8.01 (1H, d, J = 4.4 Hz), 7.50-7.45 (2H, m), 7.35-7.18 (4H, m), 5.72 (1H, q, J = 7.3 Hz), 4.96 (1H, d, J = 19.8 Hz), 4.88 (1H, d, J = 19.8 Hz), 4.39 (2H, q, J = 8.1 Hz), 2.25 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 472 (M+H) +.
Intermediate-96: phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 52 % yield (37 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (58 mg, 0.15 mmol, Intermediate-65, single enantiomer) and phenyl formate (37 mg, 0.30 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 5.1 Hz), 8.00 (1H, d, J = 5.1 Hz), 7.50-7.42 (2H, m), 7.36-7.20 (4H, m), 5.79 (1H, q, J = 7.3 Hz), 5.00 (1H, s), 4.98 (1H, s), 4.93-4.82 (2H, m), 2.27 (3H, s), 1.86 (3H, d, J = 7.4 Hz), MS (ESI) m/z: 473 (M+H) +.
Intermediate-97: phenyl 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 78 % yield (220 mg, yellow solid) from 4-chloro-2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-39) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 5.1 Hz), 8.05 (1H, d, J = 4.4 Hz), 7.48-7.42 (2H, m), 7.37-7.18 (7H, m), 6.89 (1H, d, J = 8.8 Hz), 6.13 (1H, tt, J = 54.9 and 3.4 Hz), 4.77 (1H, s), 4.73 (1H, s), 4.22 (2H, td, J = 13.2 and 4.4 Hz), MS (ESI) m/z: 459 (M+H) +.
Intermediate-98: phenyl 2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 77 % yield (210 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.57 mmol, Intermediate-62, single enantiomer) and phenyl formate (140 mg, 1.1 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.00 (1H, d, J = 4.4 Hz), 8.06 (1H, d, J = 2.2 Hz), 8.02 (1H, d, J = 4.4 Hz), 7.48-7.40 (2H, m), 7.34-7.20 (4H, m), 5.72 (1H, q, J = 7.4 Hz), 4.65 (1H, d, J = 19.8 Hz), 4.49 (1H, d, J = 19.8 Hz), 4.39 (1H, t, J = 5.8 Hz), 4.30-4.20 (2H, m), 2.10 (3H, s), 1.70 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 471 (M+H) +.
Intermediate-99: phenyl 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 49 % yield (180 mg, brown solid) from 4-chloro-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.76 mmol, Intermediate-71) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 5.1 Hz), 8.06 (1H, d, J = 4.4 Hz), 7.48-7.19 (7H, m), 6.94 (1H, d, J = 8.1 Hz), 4.78 (2H, s), 4.74 (2H, s), 4.39 (2H, q, J = 8.1 Hz), MS (ESI) m/z: 477 (M+H) +.
Intermediate-100: phenyl 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 87 % yield (300 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.79 mmol, Intermediate-4) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.02 (1H, d, J = 5.1 Hz), 8.05 (1H, d, J = 5.1 Hz), 7.94 (1H, d, J = 2.2 Hz), 7.48-7.43 (3H, m), 7.34-7.21 (3H, m), 6.12 (1H, tt, J = 55.3 and 4.0 Hz), 4.75 (2H, s), 4.73 (2H, s), 4.52 (2H, td, J = 13.6 and 4.2 Hz), 2.18 (3H, s), MS (ESI) m/z: 440 (M+H) +.
Intermediate-101: phenyl 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 77 % yield (220 mg, brown solid) from 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-13) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.04 (1H, d, J = 5.1 Hz), 8.05 (1H, d, J = 5.1 Hz), 8.03 (1H, d, J = 1.5 Hz), 7.48-7.43 (2H, m), 7.35-7.22 (4H, m), 6.15 (1H, tt, J = 55.3 and 4.2 Hz), 4.78 (2H, s), 4.76 (2H, s), 4.58 (2H, td, J = 13.4 and 4.1 Hz), MS (ESI) m/z: 460 (M+H) +.
Intermediate-102: phenyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 64 % yield (130 mg, colorless solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (170 mg, 0.46 mmol, Intermediate-67) and phenyl formate (110 mg, 0.91 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.48-7.22 (6H, m), 5.05 (2H, s), 4.98 (2H, s), 4.95-4.80 (2H, m), 2.27 (3H, s), MS (ESI) m/z: 459 (M+H) +.
Intermediate-103: phenyl 2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 76 % yield (250 mg, brown solid) from 4-chloro-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (270 mg, 0.72 mmol, Intermediate-84) and phenyl formate (180 mg, 1.4 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.02 (1H, d, J = 4.4 Hz), 8.04 (1H, d, J = 5.1 Hz), 8.00 (1H, s), 7.49-7.44 (2H, m), 7.35-7.25 (3H, m), 4.96 (2H, s), 4.89 (2H, s), 4.74 (2H, q, J = 8.3 Hz), 2.48 (3H, s).
Intermediate-104: phenyl 2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 73 % yield (90 mg, yellow oil) from 4-chloro-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-42, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.00 (1H, d, J = 4.4 Hz), 8.03 (1H, d, J = 4.4 Hz), 7.49-7.42 (2H, m), 7.28-7.15 (5H, m), 6.75 (1H, d, J = 8.8 Hz), 5.76 (1H, q, J = 7.4 Hz), 4.80 (1H, d, J = 19.1 Hz), 4.44 (1H, d, J = 19.8 Hz), 4.32 (2H, q, J = 8.0 Hz), 2.22 (3H, s), 1.69 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 471 (M+H) +.
Intermediate-105: phenyl 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 49 % yield (60 mg, yellow oil) from 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-28, single enantiomer) and phenyl formate (67 mg, 0.61 mmol) in a similar manner to Intermediate-91.
MS (ESI) m/z: 453 (M+H) +.
Intermediate-106: phenyl 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 59 % yield (50 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (70 mg, 0.17 mmol, Intermediate-29, single enantiomer) and phenyl formate (42 mg, 0.35 mmol) in a similar manner to Intermediate-91.
MS (ESI) m/z: 491 (M+H) +.
Intermediate-107: phenyl 2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 70 % yield (86 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-25, single enantiomer) and phenyl formate (63 mg, 0.52 mmol) in a similar manner to Intermediate-91.
MS (ESI) m/z: 473 (M+H) +.
Intermediate-108: phenyl 2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 71 % yield (220 mg, yellow oil) from 4-chloro-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-68) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
MS (ESI) m/z: 490 (M+H) +.
Intermediate-109: phenyl 2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 56 % yield (154 mg, brown solid) from 4-chloro-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.62 mmol, Intermediate-85, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 4.4 Hz), 8.35 (1H, d, J = 1.4 Hz), 8.21 (1H, d, J = 2.9 Hz), 8.05 (1H, d, J = 5.1 Hz), 7.73 (1H, s), 7.66 (1H, s), 7.45 (2H, t, J = 8.1 Hz), 7.34-7.22 (3H, m), 6.44 (1H, d, J = 1.5 Hz), 5.46 (1H, q, J = 7.1 Hz), 4.90 (1H, d, J = 19.1 Hz), 4.55 (1H, d, J = 19.1 Hz), 2.56 (3H, s), 1.80 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 440 (M+H) +.
Intermediate-110: phenyl 2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 71 % yield (130 mg, brown solid) from 4-chloro-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-74) and phenyl formate (99 mg, 0.81 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.02 (1H, d, J = 5.1 Hz), 8.06-8.04 (2H, m), 7.46 (2H, t, J = 8.1 Hz), 7.34-7.23 (3H, m), 7.17 (1H, s), 4.90 (2H, s), 4.89 (2H, s), 4.41 (2H, q, J = 7.8 Hz), 2.25 (3H, s), MS (ESI) m/z: 458 (M+H) +.
Intermediate-111: phenyl 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 68 % yield (200 mg, pale brown solid) from 4-chloro-2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (240 mg, 0.68 mmol, Intermediate-69) and phenyl formate (170 mg, 1.4 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 5.1 Hz), 8.05-8.04 (2H, m), 7.45 (2H, t, J = 7.7 Hz), 7.34-7.23 (3H, m), 7.15 (1H, s), 6.10 (1H, tt, J = 54.9 and 3.9 Hz), 4.89 (4H, m), 4.25 (2H, tt, J = 12.6 and 3.9 Hz), 2.23 (3H, s), MS (ESI) m/z: 440 (M+H) +.
Intermediate-112: phenyl 2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 75 % yield (240 mg, brown solid) from 4-chloro-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.74 mmol, Intermediate-70) and phenyl formate (180 mg, 1.5 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.04 (1H, d, J = 4.4 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.21 (1H, d, J = 2.2 Hz), 8.07 (1H, d, J = 5.1 Hz), 7.73 (1H, d, J = 1.5 Hz), 7.65 (1H, d, J = 2.2 Hz), 7.45 (2H, t, J = 8.1 Hz), 7.34-7.22 (3H, m), 6.44 (1H, d, J = 2.2 Hz), 4.87 (2H, s), 4.79 (2H, s), 2.55 (3H, s), MS (ESI) m/z: 426 (M+H) +.
Intermediate-113: phenyl 2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 71 % yield (130 mg, pale brown solid) from 4-chloro-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.39 mmol, Intermediate-72, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.00 (1H, d, J = 5.1 Hz), 8.02-8.00 (2H, m), 7.48 (2H, t, J = 7.7 Hz), 7.36-7.27 (3H, m), 5.74 (1H, q, J = 7.1 Hz), 5.01 (2H, s), 4.73 (2H, q, J = 8.3 Hz), 2.47 (3H, s), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 473 (M+H) +.
Intermediate-114: phenyl 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 76 % yield (93 mg, brown solid) from 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-73, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 4.4 Hz), 8.04-8.00 (2H, m), 7.48-7.21 (5H, m), 5.76 (1H, q, J = 6.8 Hz), 4.83 (1H, d, J = 19.8 Hz), 4.51-4.43 (4H, m), 2.19 (3H, s), 1.79-1.60 (6H, m), MS (ESI) m/z: 468 (M+H) +.
Intermediate-115: phenyl 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 41 % yield (30 mg, white solid) from 4-chloro-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (60 mg, 0.16 mmol, Intermediate-75) and phenyl formate (38 mg, 0.31 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 4.5 Hz), 8.06-8.03 (2H, m), 7.48-7.42 (2H, m), 7.34-7.22 (3H, m), 7.13 (1H, s), 4.89 (2H, s), 4.88 (2H, s), 4.27 (2H, t, J = 6.0 Hz), 2.72-2.60 (2H, m), 2.19 (3H, s), MS (ESI) m/z: 472 (M+H) +.
Intermediate-116: phenyl 2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in >99 % yield (310 mg, pale brown solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.60 mmol, Intermediate-18, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.02 (1H, d, J = 5.1 Hz), 8.04-8.14 (2H, m), 7.48-7.43 (3H, m), 7.35-7.21 (3H, m), 6.17-5.73 (2H, m), 4.84 (1H, d, J = 19.1 Hz), 4.71 (2H, t, J = 12.5 Hz), 4.48 (1H, d, J = 19.1 Hz), 2.18 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 504 (M+H) +.
Intermediate-117: phenyl 2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 74 % yield (91 mg, colorless solid) from 4-chloro-2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-76, single enantiomer) and phenyl formate (66 mg, 0.54 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 8.99 (1H, d, J = 4.4 Hz), 8.06 (1H, s), 8.01 (1H, d, J = 4.4 Hz), 7.46 (3H, t, J = 7.7 Hz), 7.35-7.24 (2H, m), 7.17 (1H, s), 6.09 (2H, tt, J = 54.6, 4.0 Hz), 4.97 (1H, d, J = 19.8 Hz), 4.87 (1H, d, J = 19.8 Hz), 4.24 (2H, td, J = 13.0, 3.9 Hz), 2.22 (3H, s), 1.73 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 454 (M+H) +.
Intermediate-118: phenyl 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 70 % yield (130 mg, brown oil) from 4-chloro-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.34 mmol, Intermediate-77, single enantiomer) and phenyl formate (84 mg, 0.69 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 4.4 Hz), 8.09 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.71 (1H, d, J = 2.2 Hz), 7.46 (2H, t, J = 7.7 Hz), 7.35-7.22 (3H, m), 6.05 (1H, tt, J = 53.1, 4.9 Hz), 5.78 (1H, q, J = 7.1 Hz), 4.93 (1H, d, J = 19.0 Hz), 4.75 (2H, t, J = 12.1 Hz), 4.52 (1H, d, J = 19.1 Hz), 1.75 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 524 (M+H) +.
Intermediate-119: ethyl 2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 72 % yield (250 mg, yellow solid) from 4-chloro-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (320 mg, 0.79 mmol, Intermediate-79, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
MS (ESI) m/z: 438 (M+H) +.
Intermediate-120: phenyl 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 74 % yield (230 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-80, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 4.4 Hz), 8.08 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.69 (1H, d, J = 2.2 Hz), 7.46 (2H, t, J = 7.7 Hz), 7.35-7.22 (3H, m), 5.77 (1H, q, J = 7.3 Hz), 4.86 (1H, q, J = 19.8 Hz), 4.56-4.48 (3H, m), 1.82-1.70 (6H, m), MS (ESI) m/z: 488 (M+H) +.
Intermediate-121: phenyl 2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 79 % yield (140 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.36 mmol, Intermediate-78, single enantiomer) and phenyl formate (87 mg, 0.71 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 5.1 Hz), 8.08 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 2.2 Hz), 7.46 (2H, t, J = 7.7 Hz), 7.35-7.22 (3H, m), 5.77 (1H, q, J = 7.1 Hz), 4.86 (1H, q, J = 19.1 Hz), 4.59 (2H, t, J = 6.6 Hz), 4.52 (1H, d, J = 19.8 Hz), 2.72-2.58 (2H, m), 1.74 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 506 (M+H) +.
Intermediate-122: ethyl 2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 97 % yield (480 mg, pale yellow solid) from 4-chloro-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (450 mg, 1.2 mmol, Intermediate-81, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
MS (ESI) m/z: 422 (M+H) +.
Intermediate-123: 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoic acid hydrochloride
<Step-1>: tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate
The title compound is prepared in 83 % yield (560 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and tert-butyl 4-(aminomethyl)-2-methylbenzoate (400 mg, 1.8 mmol) in a similar manner to Intermediate-2.
1H -NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 5.1 Hz), 8.20 (1H, d, J = 8.8 Hz), 7.73 (1H, d, J = 5.1 Hz), 7.17-7.15 (2H, m), 4.81 (2H, s), 4.30 (2H, s), 2.56 (3H, s), 1.59 (9H, s), MS (ESI) m/z: 371 (M-H) -.
<Step-2>: phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 90 % yield (280 mg, brown oil) from tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (250 mg, 0.67 mmol, Step-1) and phenyl formate (160 mg, 1.3 mmol) in a similar manner to Intermediate-91.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 4.4 Hz), 8.06 (1H, d, J = 5.1 Hz), 7.79 (1H, d, J = 8.0 Hz), 7.42 (2H, t, J = 8.1 Hz), 7.33-7.15 (5H, m), 4.82 (2H, s), 4.71 (2H, s), 2.53 (3H, s), 1.78 (9H, s), MS (ESI) m/z: 459 (M+H) +.
<Step-3>: tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate
The title compound is prepared in >99 % yield (260 mg, pale brown solid) from phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (270 mg, 0.59 mmol, Step-2) and ethylamine (0.14 mL, 1.8 mmol, 70 % aqueous solution) in a similar manner to Example-435 (Method-G).
1H -NMR (300 MHz, CDCl3) delta 8.71 (1H, d, J = 4.4 Hz), 8.01 (1H, t, J = 5.5 Hz), 7.91 (1H, d, J = 4.4 Hz), 7.78 (1H, t, J = 7.3 Hz), 7.18-7.16 (2H, m), 4.80 (2H, s), 4.79 (2H, s), 3.48 (2H, quintet, J = 6.8 Hz), 2.53 (3H, s), 1.58 (9H, s), 1.27 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 410 (M+H) +.
<Step-4>: 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoic acid hydrochloride
A solution of tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (260 mg, 0.64 mmol, Step-3) in 4 M hydrogen chloride in dioxane (20 mL) is stirred overnight at rt. The mixture is concentrated to give 220 mg (89 % yield) of the title compound as pale brown solid.
1H -NMR (300 MHz, CDCl3) delta 8.98 (1H, t, J = 5.9 Hz), 8.81 (1H, d, J = 4.4 Hz), 7.93 (1H, d, J = 5.1 Hz), 7.81 (1H, d, J = 8.0 Hz), 7.24-7.13 (3H, m), 6.85 (1H, d, J = 8.0 Hz), 4.80 (2H, s), 4.76 (2H, s), 3.57 (3H, s), 3.50-3.26 (2H, m), 1.11 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 354 (M+H) +.
Intermediate-124: 4-chloro-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 95% yield (1.39 g, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1.14 g, 4.09 mmol, Step-1 of Intermediate-1) and 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (994 mg, 4.09 mmol, Amine-70, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 4.8 Hz), 7.99 (1H, s), 7.70 (1H, d, J = 5.1 Hz), 7.35 (1H, s), 5.72 (1H, q, J = 7.0 Hz), 4.38 (1H, d, J = 18.0 Hz), 4.14 (2H, d, J = 7.0 Hz), 4.05 (1H, d, J = 18.0 Hz), 2.19 (3H, s), 1.70 (3H, d, J = 7.0 Hz), 1.30-1.23 (1H, m), 0.61-0.55 (2H, m), 0.36-0.31 (2H, m), MS (ESI) m/z: 358 (M+H) +.
Intermediate-125: 4-chloro-2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 92% yield (683 mg, colorless amorphous) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.80 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (240 mg, 0.86 mmol, Amine-71, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.45-7.40 (3H, m), 7.06 (2H, t, J = 8.8 Hz), 5.74 (1H, q, J = 7.1 Hz), 5.36 (2H, s), 4.40 (1H, d, J = 18.3 Hz), 4.07 (1H, d, J = 18.3 Hz), 2.21 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 410 (M-H)-.
Intermediate-126: 4-chloro-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 71% yield (490 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.65 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (500 mg, 1.65 mmol, Amine-72, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.60-8.49 (1H, m), 8.12 (1H, s), 7.75-7.64 (1H, m), 7.19 (1H, s), 6.03 (1H, tt, J = 53.1, 4.4 Hz), 5.69 (1H, q, J = 7.0 Hz), 4.61-4.35 (4H, m), 2.24 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 418 (M+H) +.
Intermediate-127: 4-chloro-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 73% yield (321 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (344 mg, 1.24 mmol, Step-1 of Intermediate-1) and 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (300 mg, 1.24 mmol, Amine-73, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.53 (1H, d, J = 5.1 Hz), 8.08 (1H, s), 7.68 (1H, d, J = 5.1 Hz), 7.13 (1H, s), 5.68 (1H, q, J = 7.3 Hz), 4.54-4.42 (2H, m), 3.89 (2H, d, J = 7.0 Hz), 2.23 (3H, s), 1.72 (3H, d, J = 7.0 Hz), 1.36-1.22 (1H, m), 0.70-0.57 (2H, m), 0.40-0.33 (2H, m), MS (ESI) m/z: 358 (M+H) +.
Intermediate-128: 4-chloro-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 35% yield (263 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (561 mg, 2.02 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (457 mg, 2.02 mmol, Amine-74, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 8.06 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 5.1 Hz), 7.65 (1H, d, J = 2.2 Hz), 5.74 (1H, q, J = 7.0 Hz), 4.47-3.97 (4H, m), 1.73 (3H, d, J = 7.3 Hz), 1.42-1.30 (1H, m), 0.70-0.54 (2H, m), 0.42-0.31 (2H, m), MS (ESI) m/z: 378 (M+H) +.
Intermediate-129: 4-chloro-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 59% yield (431 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (574 mg, 2.06 mmol, Step-1 of Intermediate-1) and 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (500 mg, 2.06 mmol, Amine-75, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.56 (1H, d, J = 5.3 Hz), 7.99 (1H, d, J = 2.2 Hz), 7.70 (1H, d, J = 5.3 Hz), 7.34 (1H, d, J = 2.2 Hz), 5.71 (1H, q, J = 6.9 Hz), 5.19 (1H, quintet, J = 7.5 Hz), 4.38 (1H, d, J = 17.7 Hz), 4.06 (1H, d, J = 17.7 Hz), 2.55-2.38 (2H, m), 2.22-2.05 (2H, m), 2.17 (3H, s), 1.90-1.55 (2H, m), 1.70 (3H, d, J = 7.4 Hz), MS (ESI) m/z: 358 (M+H) +.
Intermediate-130: 4-chloro-2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 82% yield (585 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (522 mg, 1.88 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (500 mg, 1.88 mmol, Amine-76, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.54 (1H, d, J = 5.1 Hz), 8.09 (1H, s), 7.68 (1H, d, J = 5.1 Hz), 7.18 (1H, s), 5.69 (1H, q, J = 7.3 Hz), 4.54 (2H, s), 4.18 (2H, t, J = 11.4 Hz), 2.24 (3H, s), 1.78 (3H, t, J = 18.7 Hz), 1.73 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 382 (M+H) +.
Intermediate-131: 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 74% yield (612 mg, orange oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (605 mg, 2.17 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (600 mg, 1.98 mmol, Amine-77, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 4.4 Hz), 7.36 (1H, s), 5.99 (1H, tt, J = 52.7, 4.4 Hz), 5.83-5.74 (1H, m), 4.92 (2H, t, J = 13.9 Hz), 4.61 (2H, s), 2.26 (3H, s), 1.86 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 419 (M+H) +.
Intermediate-132: 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 83% yield (712 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (687 mg, 2.47 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (600 mg, 2.24 mmol, Amine-78, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 5.1 Hz), 7.33 (1H, s), 5.80-5.73 (1H, m), 4.76-4.55 (4H, m), 2.27 (3H, s), 1.85 (3H, d, J = 6.6 Hz), 1.76 (3H, t, J = 18.3 Hz), MS (ESI) m/z: 383 (M+H) +.
Intermediate-133: 4-chloro-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 69% yield (527 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (516 mg, 1.85 mmol, Step-1 of Intermediate-1) and 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (550 mg, 1.85 mmol, Amine-79, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.53 (1H, d, J = 4.9 Hz), 8.15 (1H, s), 7.68 (1H, d, J = 4.9 Hz), 7.45-7.34 (2H, m), 7.17 (1H, s), 7.15-7.03 (2H, m), 5.69 (1H, q, J = 7.0 Hz), 5.11 (2H, s), 4.53 (2H, s), 2.24 (3H, s), 1.72 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 412 (M+H) +.
Intermediate-134: 4-chloro-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 71% yield (562 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (550 mg, 2.15 mmol, Step-1 of Intermediate-1) and 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (550 mg, 2.15 mmol, Amine-80, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (270 MHz, CDCl3) delta 8.56 (1H, d, J = 4.9 Hz), 7.71 (1H, d, J = 4.9 Hz), 7.28-7.14 (3H, m), 5.76 (1H, q, J = 6.9 Hz), 4.40 (1H, d, J = 18.1 Hz), 4.06 (1H, d, J = 18.1 Hz), 2.32 (3H, s), 1.72 (3H, d, J = 8.1 Hz) , MS (ESI) m/z: 371 (M+H) +.
Intermediate-135: 4-chloro-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 76% yield (437 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (419 mg, 1.51 mmol, Step-1 of Intermediate-1) and 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (400 mg, 1.51 mmol, Amine-81, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 5.1 Hz), 7.70 (1H, d, J = 5.1 Hz), 7.20-7.14 (2H, m), 6.77 (1H, d, J = 8.1 Hz), 5.74 (1H, q, J = 7.0 Hz), 4.36 (1H, d, J = 18.0 Hz), 4.10 (2H, t, J = 11.0 Hz), 4.01 (1H, d, J = 18.0 Hz), 2.24 (3H, s), 1.79 (3H, t, J = 19.1 Hz), 1.69 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 381 (M+H) +.
Intermediate-136: 4-chloro-2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 76% yield (228 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (212 mg, 0.76 mmol, Step-1 of Intermediate-1) and (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride (211 mg, 0.76 mmol, Amine-82) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.8 Hz), 8.12 (1H, d, J = 1.8 Hz), 7.72 (1H, d, J = 4.8 Hz), 7.40 (1H, d, J = 1.8 Hz), 4.74 (2H, s), 4.33 (2H, s), 3.31-3.26 (4H, m), 2.26 (3H, s), 2.19-2.05 (4H, m), MS (ESI) m/z: 393 (M+H) +.
Intermediate-137: 4-chloro-2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 60% yield (513 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (666 mg, 2.39 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (600 mg, 2.17 mmol, Amine-83, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 7.72 (1H, d, J = 5.1 Hz), 7.50 (1H, s), 7.32 (2H, s), 5.78 (1H, q, J = 7.3 Hz), 4.43 (1H, d, J = 17.6 Hz), 4.09 (1H, d, J = 17.6 Hz), 1.74 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 391 (M+H) +.
Intermediate-138: phenyl 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 45% yield (275 mg, white solid) from 4-chloro-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (492 mg, 1.37 mmol, Intermediate-124, single enantiomer) and phenyl formate (336 mg, 1.37 mmol) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, DMSO-d6) delta 8.95 (1H, d, J = 4.8 Hz), 8.02 (1H, d, J = 4.8 Hz), 7.98 (1H, d, J = 2.2 Hz), 7.57 (1H, d, J = 1.8 Hz), 7.50-7.45 (2H, m), 7.34-7.28 (3H, m), 5.48 (1H, q, J = 7.3 Hz), 4.92 (1H, d, J = 19.1 Hz), 4.53 (1H, d, J = 19.1 Hz), 4.08 (2H, d, J = 7.0 Hz), 2.11 (3H, s), 1.65 (3H, d, J = 7.3 Hz), 1.26-1.16 (1H, m), 0.53-0.47 (2H, m), 0.31-0.26 (2H, m), MS (ESI) m/z: 444 (M+H) +.
Intermediate-139: phenyl 2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 86% yield (287 mg, brown oil) from 4-chloro-2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (276 mg, 0.67 mmol, Intermediate-125, single enantiomer) and phenyl formate (164 mg, 1.34 mmol) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 4.4 Hz), 8.04-8.03 (2H, m), 7.48-7.40 (5H, m), 7.34-7.21 (3H, m), 7.04 (2H, t, J = 8.8 Hz), 5.76 (1H, q, J = 7.1 Hz), 5.34 (2H, s), 4.83 (1H, d, J = 19.8 Hz), 4.49 (1H, d, J = 19.8 Hz), 2.18 (3H, s), 1.72 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 498 (M+H)+.
Intermediate-140: ethyl 2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 83% yield (333 mg, pale yellow solid) from 4-chloro-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (370 mg, 0.89 mmol, Intermediate-126, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 5.0 Hz), 8.10 (1H, s), 7.93 (1H, d, J = 5.0 Hz), 7.19 (1H, s), 6.03 (1H, tt, J = 53.1, 4.4 Hz), 5.71 (1H, q, J = 7.3 Hz), 4.94 (1H, d, J = 19.8 Hz), 4.84 (1H, d, J = 19.8 Hz), 4.52 (2H, q, J = 7.3 Hz), 4.42 (2H, t, J = 11.6 Hz), 2.23 (3H, s), 1.76 (3H, d, J = 7.3 Hz), 1.48 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 456 (M+H) +.
Intermediate-141: ethyl 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 73% yield (167 mg, pale yellow solid) from 4-chloro-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (206 mg, 0.58 mmol, Intermediate-127, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.90 (1H, d, J = 4.8 Hz), 8.07 (1H, s), 7.93 (1H, d, J = 4.8 Hz), 7.13 (1H, s), 5.70 (1H, q, J = 7.0 Hz), 4.92 (1H, d, J = 19.8 Hz), 4.79 (1H, d, J = 19.8 Hz), 4.51 (2H, q, J = 7.0 Hz), 3.88 (2H, d, J = 7.0 Hz), 2.22 (3H, s), 1.74 (3H, d, J = 7.0 Hz), 1.47 (3H, t, J = 7.0 Hz), 1.35-1.17 (1H, m), 0.70-0.54 (2H, m), 0.42-0.33 (2H, m), MS (ESI) m/z: 396 (M+H) +.
Intermediate-142: ethyl 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 69% yield (125 mg, white amorphous) from 4-chloro-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (164 mg, 0.43 mmol, Intermediate-128, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.93 (1H, d, J = 4.8 Hz), 8.07 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 4.8 Hz), 7.65 (1H, d, J = 2.2 Hz), 5.76 (1H, q, J = 7.0 Hz), 4.82 (1H, d, J = 19.2 Hz), 4.50 (2H, q, J = 7.0 Hz), 4.49 (1H, d, J = 19.2 Hz), 4.21 (2H, d, J = 7.0 Hz), 1.74 (3H, d, J = 7.0 Hz), 1.47 (3H, t, J = 7.0 Hz), 1.38-1.23 (1H, m), 0.71-0.54 (2H, m), 0.42-0.31 (2H, m), MS (ESI) m/z: 416 (M+H) +.
Intermediate-143: ethyl 2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 84% yield (296 mg, pale yellow solid) from 4-chloro-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (317 mg, 0.89 mmol, Intermediate-129, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.92 (1H, d, J = 4.7 Hz), 8.00 (1H, d, J = 2.0 Hz), 7.95 (1H, d, J = 4.7 Hz), 7.36 (1H, d, J = 2.0 Hz), 5.73 (1H, q, J = 7.3 Hz), 5.18 (1H, quintet, J = 7.3 Hz), 4.79 (1H, d, J = 19.2 Hz), 4.49 (2H, q, J = 7.0 Hz), 4.46 (1H, d, J = 19.2 Hz), 2.53-2.36 (2H, m), 2.20-2.01 (2H, m), 2.15 (3H, s), 1.92-1.53 (2H, m), 1.72 (3H, d, J = 7.0 Hz), 1.46 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 396 (M+H) +.
Intermediate-144: ethyl 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 69% yield (352 mg, yellow solid) from 4-chloro-2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (465 mg, 1.22 mmol, Intermediate-130, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 5.1 Hz), 8.08 (1H, s), 7.93 (1H, d, J = 5.1 Hz), 7.17 (1H, s), 5.71 (1H, q, J = 7.0 Hz), 4.93 (1H, d, J = 19.4 Hz), 4.82 (1H, d, J = 19.4 Hz), 4.52 (2H, q, J = 7.0 Hz), 4.17 (2H, t, J = 11.4 Hz), 2.23 (3H, s), 1.78 (3H, t, J = 18.7 Hz), 1.75 (3H, d, J = 7.0 Hz), 1.47 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 420 (M+H) +.
Intermediate-145: phenyl 2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 81% yield (440 mg, brown solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (450 mg, 1.08 mmol, Intermediate-131, single enantiomer) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 4.4 Hz), 8.01 (1H, d, J = 5.1 Hz), 7.49-7.47 (2H, m), 7.44-7.22 (4H, m), 5.98 (1H, tt, J = 53.5, 3.7 Hz), 5.83-5.76 (1H, m), 5.04 (1H, d, J = 19.4 Hz), 4.96 (1H, d, J = 19.4 Hz), 4.90 (2H, t, J = 12.5 Hz), 2.25 (3H, s), 1.86 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 505 (M+H) +.
Intermediate-146: phenyl 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 69% yield (380 mg, pale yellow solid) from 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (450 mg, 1.18 mmol, Intermediate-132, single enantiomer) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.00 (1H, d, J =5.1 Hz), 8.00 (1H, d, J = 4.4 Hz), 7.49-7.44 (2H, m), 7.34-7.23 (4H, m), 5.78 (1H, q, J = 6.6 Hz), 5.04 (1H, d, J = 19.4 Hz), 4.96 (1H, d, J = 19.4 Hz), 4.64 (2H, t, J = 12.1 Hz), 2.25 (3H, s), 1.85 (3H, d, J = 7.3 Hz), 1.75 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 469 (M+H) +.
Intermediate-147: ethyl 2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in >99% yield (470 mg, pale yellow solid) from 4-chloro-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (407 mg, 0.99 mmol, Intermediate-133, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 4.7 Hz), 8.14 (1H, s), 7.93 (1H, d, J = 4.7 Hz), 7.51-7.33 (2H, m), 7.15 (1H, s), 7.13-7.03 (2H, m), 5.71 (1H, q, J = 7.0 Hz), 5.09 (2H, s), 4.92 (1H, d, J = 19.8 Hz), 4.80 (1H, d, J = 19.8 Hz), 4.51 (2H, q, J = 7.3 Hz), 2.23 (3H, s), 1.74 (3H, d, J = 7.3 Hz), 1.47 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 450 (M+H) +.
Intermediate-148: phenyl 2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 66% yield (202 mg, brown solid) from 4-chloro-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.67 mmol, Intermediate-134, single enantiomer) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.01 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.48-7.43 (2H, m), 7.35-7.18 (6H, m), 5.79 (1H, q, J = 7.3 Hz), 4.84 (1H, d, J = 19.1 Hz), 4.48 (1H, d, J = 19.0 Hz), 2.29 (3H, s), 1.71 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 457 (M+H) +.
Intermediate-149: ethyl 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 85% yield (309 mg, pale yellow solid) from 4-chloro-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (330 mg, 0.87 mmol, Intermediate-135, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 4.8 Hz), 7.95 (1H, d, J = 4.8 Hz), 7.23-7.17 (2H, m), 6.75 (1H, d, J = 7.7 Hz), 5.76 (1H, q, J = 7.0 Hz), 4.77 (1H, d, J = 19.4 Hz), 4.49 (2H, q, J = 7.0 Hz), 4.42 (1H, d, J = 19.4 Hz), 4.09 (2H, t, J = 11.0 Hz), 2.23 (3H, s), 1.78 (3H, t, J = 18.7 Hz), 1.71 (3H, d, J = 7.0 Hz), 1.45 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 419 (M+H) +.
Intermediate-150: phenyl 2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 64% yield (196 mg, orange solid) from 4-chloro-2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.64 mmol, Intermediate-137, single enantiomer) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.02 (1H, d, J = 4.4 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.49-7.44 (3H, m), 7.35-7.22 (5H, m), 5.79 (1H, q, J = 6.6 Hz), 4.86 (1H, d, J = 19.1 Hz), 4.50(1H, d, J = 19.8 Hz), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 477 (M+H) +.
Intermediate-151: ethyl 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 86% yield (141 mg, pale yellow solid) from 4-chloro-2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.38 mmol, Intermediate-136) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.94 (1H, d, J = 4.8 Hz), 8.13 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 4.8 Hz), 7.41 (1H, d, J = 1.8 Hz), 4.76 (2H, s), 4.72 (2H, s), 4.50 (2H, q, J = 7.3 Hz), 3.30-3.24 (4H, m), 2.25 (3H, s), 2.18-2.04 (4H, m), 1.46 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 431 (M+H) +.
Intermediate-152: 4-chloro-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 87% yield (742 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (644 mg, 2.31 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine (500 mg, 2.31 mmol, Amine-84) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.6 Hz), 7.96 (1H, s), 7.72 (1H, d, J = 4.6 Hz), 7.42 (1H, s), 4.74 (2H, s), 4.50 (2H, t, J = 11.9 Hz), 4.36 (2H, s), 2.21 (3H, s), 1.74 (3H, t, J = 18.4 Hz), MS (ESI) m/z: 368 (M+H) +.
Intermediate-153: phenyl 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 71% yield (400 mg, pale yellow solid) from 4-chloro-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (400 mg, 1.09 mmol, Intermediate-152) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.02 (1H, d, J = 5.3 Hz), 8.04 (1H, d, J = 5.3 Hz), 7.95 (1H, s), 7.5-7.2 (6H,m), 4.75 (2H, s), 4.73 (2H, s), 4.48 (2H, t, J = 11.9 Hz), 2.19 (3H, s), 1.73 (3H, t, J = 18.4 Hz), MS (ESI) m/z: 454 (M+H) +.
Intermediate-154: 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)
The title compound is prepared in >99% yield (414 mg, white solid) from phenyl 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer) (400 mg, 0.95 mmol, Intermediate-114) in a similar manner to Step-2 of Intermediate-47.
1H-NMR (300 MHz, DMSO-d6) delta 8.84 (1H, d, J = 4.8 Hz), 8.03 (1H, s), 7.90 (1H, d, J = 4.8 Hz), 7.65 (1H, s), 5.48 (1H, q, J = 7.0 Hz), 4.85 (1H, d, J = 19.1 Hz), 4.52 (2H, t, J = 12.8 Hz), 4.47 (1H, d, J = 19.1 Hz), 2.14 (3H, s), 1.78-1.65 (6H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 392 (M+H) +.
Intermediate-155: 4-chloro-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
The title compound is prepared in 59% yield (331 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (389 mg, 1.40 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (400 mg, 1.40 mmol, Amine-85, single enantiomer) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 4.8 Hz), 7.71 (1H, d, J = 4.8 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.25 (1H, dd, J = 8.4, 2.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 5.74 (1H, q, J = 7.0 Hz), 4.38 (1H, d, J = 17.9 Hz), 4.15 (2H, t, J = 11.0 Hz), 4.03 (1H, d, J = 17.9 Hz), 1.82 (3H, t, J = 18.7 Hz), 1.70 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 401 (M+H) +.
Intermediate-156: ethyl 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)
The title compound is prepared in 85% yield (219 mg, colorless oil) from 4-chloro-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (236 mg, 0.59 mmol, Intermediate-155, single enantiomer) in a similar manner to Step-1 of Intermediate-86.
1H-NMR (300 MHz, CDCl3) delta 8.93 (1H, d, J = 4.6 Hz), 7.95 (1H, d, J = 4.6 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.25 (1H, dd, J = 8.4, 2.2 Hz), 6.90 (1H, d, J = 8.4 Hz), 5.76 (1H, q, J = 7.3 Hz), 4.79 (1H, d, J = 19.4 Hz), 4.50 (2H, q, J = 7.0 Hz), 4.43 (1H, d, J = 19.4 Hz), 4.14 (2H, t, J = 11.0 Hz), 1.82 (3H, t, J = 18.7 Hz), 1.72 (3H, d, J = 7.3 Hz), 1.46 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 439 (M+H) +.
Intermediate-158: 4-chloro-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 77% yield (925 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (945 mg, 3.39 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine (730 mg, 3.08 mmol, Amine-86) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 2.2 Hz), 7.74-7.69 (2H, m), 4.76 (2H, s), 4.54 (2H, t, J = 11.7 Hz), 4.35 (2H, s), 1.77 (3H, t, J = 18.3 Hz), MS (ESI) m/z: 388 (M+H)+.
Intermediate-159: phenyl 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 68% yield (248 mg, orange oil) from 4-chloro-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.77 mmol, Intermediate-158) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 9.04 (1H, d, J = 5.1 Hz), 8.06-8.02 (2H, m), 7.69 (1H, d, J = 2.2 Hz), 7.48-7.43 (2H, m), 7.34-7.21 (3H, m), 4.78 (2H, s), 4.76 (2H, s), 4.53 (2H, t, J = 11.7 Hz), 1.76 (3H, t, J = 19.0 Hz), MS (ESI) m/z: 474 (M+H)+.
Intermediate-160: 4-chloro-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
The title compound is prepared in 81% yield (1.01 g, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (917 mg, 3.29 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (800 mg, 2.93 mmol, Amine-87) in a similar manner to Intermediate-2.
1H-NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 5.3 Hz), 8.06 (1H, d, J = 2.0 Hz), 7.75-7.70 (2H, m), 6.07 (1H, tt, J = 52.7, 2.9 Hz), 4.84-4.71 (4H, m), 4.36 (2H, s), MS (ESI) m/z: 424 (M+H)+.
Intermediate-161: ethyl 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate
The title compound is prepared in 90% yield (840 mg, colorless oil) from 4-chloro-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (858 mg, 2.02 mmol, Intermediate-160) in a similar manner to Intermediate-91.
1H-NMR (300 MHz, CDCl3) delta 8.95 (1H, d, J = 5.1 Hz), 8.07 (1H, s), 7.97 (1H, d, J = 5.1 Hz), 7.72 (1H, s), 6.07 (1H, tt, J = 53.5, 4.4 Hz), 4.81-4.73 (6H, m), 4.51 (2H, q, J = 7.3 Hz), 1.47 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 426 (M+H)+.
<Amine synthesis part>
Amine-1:1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:6-(2,2,2-trifluoroethoxy)nicotinic acid
A mixture of 6-chloronicotinic acid (7.0 g, 44.4 mmol), 2,2,2-trifluoroethanol (6.40 mL, 89.0 mmol) and sodium hydride (5.33 g, 133.0 mmol, 60 % in oil) in DMA (400 mL) is stirred at 90 oC for 21 hours. After cooling to rt, the reaction mixture is poured slowly into 2M hydrochloric acid (300 mL) and extracted with n-hexane / EtOAc (1:10, 500 mL). The organic layer is washed with 2 M hydrochloric acid (300 mLx2) and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure to give 7.64 g (78 % yield) of the title compound as colorless oil. This material is used for the next reaction (Step-2) without further purification.
MS (ESI) m/z: 222 (M+H) +.
<Step-2>:N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide
A mixture of 6-(2,2,2-trifluoroethoxy)nicotinic acid (10.4 g, 47.3 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (5.08 g, 52.1 mmol), HOBT (9.59 g, 71.0 mmol), EDC (13.6 g, 71.0 mmol) and triethylamine (26.4 mL, 189 mmol) in DMA (237 mL) is stirred at 60 oC for 16 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with EtOAc (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1) to give 6.54 g (52 % yield) of the title compound as colorless oil.
1H-NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 2.2 Hz), 8.05 (1H, dd, J = 8.8, 2.2 Hz), 6.88 (1H, d, J = 8.8 Hz), 4.80 (2H, q, J = 8.4 Hz), 3.57 (3H, s), 3.38 (3H, s), MS (ESI) m/z: 265 (M+H) +.
<Step-3>:1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone
To a stirred solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (6.54 g, 24.8 mmol, Step-2) in THF (80 mL) is added dropwise 1.06M methylmagnesium bromide (46.7 mL, 49.5 mmol) at 0 oC. The reaction mixture is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with EtOAc (300 mL). The organic layer is washed with water (100 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (1:1) to give 4.51 g (83 % yield) of the title compound as colorless oil.
1H-NMR (300 MHz, CDCl3) delta 8.75 (1H, dd, J = 2.6, 0.7 Hz), 8.23 (1H, dd, J = 8.4, 2.6 Hz), 6.93 (1H, dd, J = 8.4, 0.7 Hz), 4.85 (2H, q, J = 8.4 Hz), 2.59 (3H, s), MS (ESI) m/z: 220 (M+H) +.
<Step-4>:(R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
A mixture of 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (4.51 g, 20.58 mmol, Step-3), (R)-2-methylpropane-2-sulfinamide (3.74 g, 30.9 mmol) and tetraethyl orthotitanate (6.47 mL, 30.9 mmol) in THF (23 mL) is stirred at 70 oC for 17 hours. The reaction mixture is cooled to 0 oC, sodium borohydride (2.72 g, 72.0 mmol) is added there, and the mixture is stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate (50 mL) is added to the reaction mixture, and the mixture is stirred for 10 minutes. After filtration through a pad of celiteTM, the filtrate is extracted with EtOAc (300 mL). The organic layer is washed with water (100 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1 to 1:1) to give 6.25 g (94 % yield) of the title compound as colorless oil.
1H-NMR (300 MHz, CDCl3) delta 8.11 (1H, d, J = 2.2 Hz), 7.67 (1H, dd, J = 8.4, 2.2 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.76 (2H, q, J = 8.4 Hz), 4.61-4.50 (1H, m), 3.37 (1H, br s), 1.53 (3H, d, J = 7.0 Hz), 1.31 (9H, s), MS (ESI) m/z: 325 (M+H) +.
<Step-5>:1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
A solution of (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (6.15 g, 18.9 mmol, Step-4) in 8M hydrochloric acid in methanol (20 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated under reduced pressure. The residue is crystallized from n-hexane / EtOAc to give 4.40 g (90 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.63 (2H, br s), 8.34 (1H, d, J = 2.6 Hz), 8.03 (1H, dd, J = 8.8, 2.6 Hz), 7.07 (1H, d, J = 8.8 Hz), 5.02 (2H, q, J = 9.2 Hz), 4.53-4.42 (1H, m), 1.54 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 221 (M+H) +.
Figure JPOXMLDOC01-appb-I000004
Amine-2:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid
The title compound is prepared in >99 % yield (2.27 g, yellow oil) from 6-fluoro-5-methylnicotinic acid (1.5 g, 9.67 mmol) in a similar manner to Step-1 of Amine-1.
MS (ESI) m/z: 234 (M-H)-.
<Step-2>:N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide
A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.27 g, 9.67 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.64 mmol), HBTU (5.50 g, 14.51 mmol) and triethylamine (5.39 mL, 38.7 mmol) in DCM (30 mL) is stirred at rt for 1. 5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with DCM (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1) to give 2.03 g (76 % yield) of the title compound as colorless oil.
1H-NMR (300 MHz, CDCl3) delta = 8.43 (1H, d, J = 2.2 Hz), 7.86 (1H, m), 4.82 (2H, q, J = 8.4 Hz), 3.60 (3H, s), 3.38 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 279 (M+H) +.
<Step-3>:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone
The title compound is prepared in 86 % yield (1.47 g, white solid) from N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide (2.03 g, 7.31 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta = 8.59 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 2.2 Hz), 4.84 (2H, q, J = 8.4 Hz), 2.57 (3H, s), 2.27 (3H, s), MS (ESI) m/z: 234 (M+H) +.
<Step-4>:(R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 79 % yield (1.70 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (1.47 g, 6.32 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta = 7.94 (1H, d, J = 2.2 Hz), 7.45 (1H, d, J = 2.2 Hz), 4.76 (2H, q, J = 8.8 Hz), 4.56-4.43 (1H, m), 3.32 (1H, d, J = 2.6 Hz), 2.24 (3H, s), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 339 (M+H) +.
<Step-5>:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 94 % yield (1.27 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.70 g, 5.01 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta = 8.56 (2H, br s), 8.16 (1H, d, J = 2.0 Hz), 7.87 (1H, d, J = 2.0 Hz), 5.03 (2H, q, J = 9.2 Hz), 4.50-4.28 (1H, m), 2.20 (3H, s), 1.50 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 235 (M+H) +.
Amine-3:(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride
<Step-1>:methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate
A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.08 g, 13.1 mmol, Step-1 of Amine-2), iodomethane (0.983 ml, 15.72 mmol) and potassium carbonate (5.43 g, 39.3 mmol) in DMA (40 ml) is stirred at rt for 2 hours. The reaction mixture is poured into water (200 mL) and extracted with n-hexane / EtOAc (1:10, 500 mL). The organic layer is washed with 2M hydrochloric acid (300 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (5:1) to give 2.87 g (88 % yield) of the title compound as white solid.
MS (ESI) m/z: 250 (M+H) +.
<Step-2>:(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
To a stirred solution of methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate (0.80 g, 3.21 mmol, Step-1) in THF (10 mL) is added slowly lithium aluminum hydride (0.11 g, 3.21 mmol) at 0 oC. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25 % aqueous ammonia solution at 0 oC. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of Celite, and the filtrate is concentrated in vacuo to give 0.70 g (99 % yield) of the title compound as colorless oil. This material is used for the next reaction (Step-3) without further purification.
MS (ESI) m/z: 222 (M+H) +.
<Step-3>:5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine
A mixture of (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (0.70 g, 3.18 mmol, Step-2), and thionyl chloride (0.46 mL, 6.36 mmol) in DCM (10 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and the residue is dried to give 0.75 g (>99 % yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.
<Step-4>:5-(azidomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine
A mixture of 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.75 g, 3.15 mmol, Step-3) and sodium azide (0.41 g, 6.29 mmol) in DMA (8 mL) is stirred at 90 oC for 2 hours. The reaction mixture is poured into water (50 mL), and extracted with n-hexane / EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.77 g (>99 % yield) of the title compound as colorless oil. This material is used for the next reaction (Step-5) without further purification.
<Step-5>:(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride
A mixture of 5-(azidomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.77 g, 3.12 mmol, Step-4) and palladium 10 % on carbon (0.1 g) in methanol (20 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is crystallized from THF, methanol and n-hexane to give 0.37 g (46 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.41 (2H, br s), 8.12 (1H, d, J = 2.2 Hz), 7.80 (1H, d, J = 1.5 Hz), 5.02 (2H, q, J = 9.2 Hz), 3.96 (2H, s), 2.18 (3H, s), MS (ESI) m/z: 221 (M+H) +.
Amine-4:(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride
<Step-1>:methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate
The title compound is prepared in 88 % yield (2.99 g, white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (3.19 g, 14.7 mmol, Step-1 of Amine-5) in a similar manner to Step-1 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta = 8.64 (1H, d, J = 1.8 Hz), 8.03 (1H, d, J = 1.8 Hz), 6.15 (1H, tt, J = 55.8, 4.4 Hz), 4.61 (2H, td, J = 13.2, 4.4 Hz), 3.91 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 232 (M+H) +.
<Step-2>:(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol
The title compound is prepared in >99 % yield (2.62 g, colorless oil) from methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate (2.99 g, 12.9 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta = 7.92 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz), 6.14 (1H, tt, J = 55.8, 4.0 Hz), 4.62-4.49 (4H, m), 2.22 (3H, s), 1.80 (1H, t, J = 5.9 Hz), MS (ESI) m/z: 204 (M+H) +.
<Step-3>:5-(chloromethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine
The title compound is prepared in >99 % yield (2.89 g, colorless oil) from (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol (2.62 g, 12.9 mmol, Step-2) in a similar manner to Step-3 of Amine-3.
MS (ESI) m/z: 222 (M+H) +.
<Step-4>:5-(azidomethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine
The title compound is prepared in 86 % yield (2.56 g, colorless oil) from 5-(chloromethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine (2.89 g, 12.9 mmol, Step-3) in a similar manner to Step-4 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta = 7.91 (1H, d, J = 1.8 Hz), 7.42 (1H, br s), 6.15 (1H, tt, J = 55.8, 4.4 Hz), 4.56 (2H, td, J = 13.6, 4.4 Hz), 4.26 (2H, s), 2.24 (3H, s), MS (ESI) m/z: 229 (M+H) +.
<Step-5>:(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride
The title compound is prepared in 66 % yield (1.77 g, white solid) from 5-(azidomethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine (2.56 g, 11.2 mmol, Step-4) in a similar manner to Step-5 of Amine-3.
1H-NMR (300 MHz, DMSO-d6) delta = 8.40 (2H, br s), 8.11 (1H, d, J = 2.2 Hz), 7.77 (1H, d, J = 2.2 Hz), 6.40 (1H, tt, J = 54.7, 3.7 Hz), 4.60 (2H, td, J = 15.0, 3.7 Hz), 3.96 (2H, s), 2.18 (3H, s), MS (ESI) m/z: 203 (M+H) +.
Amine-5:1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:6-(2,2-difluoroethoxy)-5-methylnicotinic acid
The title compound is prepared in 73 % yield (1.02 g, an off-white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol (1.06 g, 12.9 mmol) in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 13.09 (1H, br s), 8.56 (1H, d, J = 2.2 Hz), 8.07 (1H, d, J = 2.2 Hz), 6.42 (1H, tt, J = 54.3, 3.7 Hz), 4.66 (2H, td, J = 14.7, 3.7 Hz), 2.21 (3H, s), MS (ESI) m/z: 218 (M+H) +.
<Step-2>:6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in 98 % yield (1.20 g, white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (1.02 g, 4.70 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.43 (1H, d, J = 2.2 Hz), 7.84 (1H, br s), 6.16 (1H, tt, J = 55.8, 4.4 Hz), 4.60 (2H, td, J = 13.2, 4.4 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 261 (M+H) +.
<Step-3>:1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (0.99 g, white solid) from 6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide (1.20 g, 4.61 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (270 MHz, CDCl3) delta 8.58 (1H, d, J = 2.0 Hz), 8.01-8.00 (1H, m), 6.16 (1H, tt, J = 55.4, 4.0 Hz), 4.63 (2H, td, J = 13.2, 4.0 Hz), 2.57 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 216 (M+H) +.
<Step-4>:(R)-N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 82 % yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.97 (1H, d, J = 2.2 Hz), 7.43 (1H, br s), 6.14 (1H, tt, J = 55.8, 4.4 Hz), 4.59-4.46 (3H, m), 3.32 (1H, br s), 2.22 (3H, s), 1.50 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 321 (M+H) +.
<Step-5>:1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 94 % yield (0.91 g, white solid) from (R)-N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.22 g, 3.80 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H-NMR (270 MHz, DMSO-d6) delta 8.58 (2H, br s), 8.13 (1H, d, J = 2.0 Hz), 7.82 (1H, br s), 6.40 (1H, tt, J = 54.7, 3.3 Hz), 4.60 (2H, td, J = 15.2, 3.3 Hz), 4.42-4.36 (1H, m), 2.19 (3H, s), 1.52 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 217 (M+H) +.
Figure JPOXMLDOC01-appb-I000005
Amine-6:1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide
The title compound is prepared in 87 % yield (7.0 g, pale brown oil) from 6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (6.9 g, 27.0 mmol) and in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, d, J = 2.2 Hz), 8.06 (1H, dd, J = 8.8, 2.2 Hz), 6.86 (1H, d, J = 8.1 Hz), 6.01 (1H, tt, J = 52.7, 4.4 Hz), 4.79 (2H, tt, J = 12.5, 1.5 Hz), 3.58 (3H, s), 3.38 (3H, s), MS (ESI) m/z: 297 (M+H) +.
<Step-2>:1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in 94 % yield (5.6 g, brown oil) from N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (7.0 g, 24.0 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.76 (1H, d, J = 2.2 Hz), 8.21 (1H, dd, J = 8.8, 2.9 Hz), 6.91 (1H, d, J = 8.8 Hz), 6.00 (1H, tt, J = 52.7, 4.4 Hz), 4.83 (2H, t, J = 13.2 Hz), 2.60 (3H, s), MS (ESI) m/z: 252 (M+H) +.
<Step-3>:(R)-2-methyl-N-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 76 % yield (6.0 g, pale brown oil) from 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (5.6 g, 22.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.13 (1H, d, J = 2.2 Hz), 7.66 (1H, dd, J = 8.8, 2.2 Hz), 6.83 (1H, d, J = 8.8 Hz), 6.01 (1H, tt, J = 53.5, 5.1 Hz), 4.74 (2H, t, J = 13.2 Hz), 4.60-4.50 (1H, m), 3.36 (1H, br), 1.52 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 357 (M+H) +.
<Step-4>:1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 93 % yield (5.1 g, white solid) from (R)-2-methyl-N-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (5.1 g, 16.8 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.62 (2H, br s), 8.33 (1H, d, J = 2.2 Hz), 8.01 (1H, dd, J = 8.6, 2.2 Hz), 7.03 (1H, d, J = 8.1 Hz), 6.68 (1H, tt, J = 51.3, 5.9 Hz), 4.88 (2H, t, J = 14.6 Hz), 4.50-4.30 (1H, m), 1.53 (3H, d, J = 6.6 Hz).
Amine-7:1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid
A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.0 g, 4.8 mmol), 2,2,2-trifluoroethanol (0.69 mL, 9.5 mmol) and sodium hydroxide (0.57 g, 14.3 mmol) in water (24 mL) is stirred at 80 oC for 40 hours. After cooling to 0 oC, the mixture is acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.05 g (80 % yield) of the title compound as white solid.
MS (ESI) m/z: 274 (M+H)+.
<Step-2>:2-chloro-5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide
The title compound is prepared in 30 % yield (0.36 g, colorless oil) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (1.05 g, 3.83 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.46 (1H, d, J = 8.4 Hz), 4.82 (2H, q, J = 8.1 Hz), 3.53 (3H, s), 3.36 (3H, s), MS (ESI) m/z: 317 (M+H) +.
<Step-3>:1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone
The title compound is prepared in 75 % yield (0.23 g, colorless oil) from 2-chloro-5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.36 g, 1.14 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.84 (1H, d, J = 9.2 Hz), 4.86 (2H, q, J = 8.1 Hz), 2.70 (3H, s).
<Step-4>:1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone
A mixture of 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.23 g, 0.86 mmol, Step-3) and triethylamine (0.17 mL, 1.20 mmol) in ethanol (9 mL) is stirred at rt for 1 hour. Then 10 % palladium on carbon (0.03 g, 0.28 mmol) is added to the mixture. The mixture is stirred at rt under a balloon of hydrogen gas for 5 hours. After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (5:1) to give 0.15 g (76 % yield) of the title compound as colorless oil.
1H-NMR (300 MHz, CDCl3) delta 8.51 (1H, d, J = 1.8 Hz), 7.94 (1H, dd, J = 10.3, 1.8 Hz), 4.89 (2H, q, J = 8.4 Hz), 2.59 (3H, s).
<Step-5>:(R)-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 78 % yield (0.17 g, white solid) from 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.15 g, 0.65 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.89 (1H, d, J = 2.2 Hz), 7.44 (1H, dd, J = 10.7, 2.2 Hz), 4.82 (2H, q, J = 8.4 Hz), 4.55 (1H, m), 1.52 (3H, d, J = 6.2 Hz), 1.23 (9H, s) (a signal due to NH is not observed), MS (ESI) m/z: 343 (M+H) +.
<Step-6>:1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 94 % yield (0.13 g, white solid) from (R)-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.17 g, 0.50 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.52 (2H, br s), 8.15 (1H, d, J = 1.8 Hz), 8.05 (1H, dd, J = 11.4, 1.8 Hz), 5.11 (2H, q, J = 8.8 Hz), 4.48 (1H, m), 1.51 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 239 (M+H) +.
Figure JPOXMLDOC01-appb-I000006
Amine-8:1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid
The title compound is prepared in 54 % yield (2.88 g, white solid) from 5,6-dichloronicotinic acid (4.0 g, 20.8 mmol) in a similar manner to Step-1 of Amine-1.
MS (ESI) m/z: 256 (M+H)+.
<Step-2>:5-chloro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide
The title compound is prepared in 94 % yield (2.2 g, white solid) from 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.0 g, 7.8 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.50 (1H, d, J = 1.8 Hz), 8.13 (1H, d, J = 1.8 Hz), 4.86 (2H, q, J = 8.4 Hz), 3.59 (3H, s), 3.38 (3H, s), MS (ESI) m/z: 299 (M+H) +.
<Step-3>:1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (1.71 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (1.91 g, 6.40 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
H-NMR (300 MHz, CDCl3) delta 8.63 (1H, d, J = 2.2 Hz), 8.27 (1H, d, J = 2.2 Hz), 4.90 (2H, q, J = 8.4 Hz), 2.60 (3H, s), MS (ESI) m/z: 254 (M+H) +.
<Step-4>:(R)-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 57 % yield (0.65 g, white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.02 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 2.2 Hz), 4.82 (2H, q, J = 8.4 Hz), 4.59-4.49 (1H, m), 3.36 (1H, d, J = 2.9 Hz), 1.53 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 359 (M+H) +.
<Step-5>:1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 85 % yield (0.45 g, white solid) from (R)-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.65 g, 1.81 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.49 (2H, br s), 8.28 (1H, d, J = 2.2 Hz), 8.23 (1H, d, J = 2.2 Hz), 5.10 (2H, q, J = 9.1 Hz), 4.54-4.43 (1H, m), 1.52 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 255 (M+H) +.
Figure JPOXMLDOC01-appb-I000007
Amine-9:1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:6-chloro-N,5-dimethoxy-N-methylnicotinamide
The title compound is prepared in >99 % yield (0.41 g, white solid) from 6-chloro-5-methoxynicotinic acid (0.35 g, 1.79 mmol) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta = 8.40 (1H, d, J = 1.8 Hz), 7.58 (1H, d, J = 1.8 Hz), 3.96 (3H, s), 3.59 (3H, s), 3.40 (3H, s), MS (ESI) m/z: 231 (M+H) +.
<Step-2>:1-(6-chloro-5-methoxypyridin-3-yl)ethanone
The title compound is prepared in 76 % yield (0.38 g, white solid) from 6-chloro-N,5-dimethoxy-N-methylnicotinamide (0.41 g, 1.79 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta = 8.54 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 1.8 Hz), 3.99 (3H, s), 2.65 (3H, s), MS (ESI) m/z: 186 (M+H) +.
<Step-3>:1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone
To a solution of potassium tert-butoxide (0.22 g, 1.97 mmol) in THF (7 mL) is added 2,2,2-trifluoroethanol (0.09 mL, 1.28 mmol), and the mixture is stirred at rt for 20 minutes. A solution of 1-(6-chloro-5-methoxypyridin-3-yl)ethanone (0.18 g, 0.99 mmol, Step-2) in THF (8 mL) is added dropwise to the mixture, and the resulting mixture is stirred at rt for 3.5 hours. The reaction mixture is poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (30 mL). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1) to give 0.25 g (>99 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta = 8.32 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 2.0 Hz), 4.90 (2H, q, J = 8.4 Hz), 3.94 (3H, s), 2.60 (3H, s), MS (ESI) m/z: 250 (M+H) +.
<Step-4>:(R)-N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 83 % yield (0.29 g, white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.25 g, 0.99 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta = 7.68 (1H, d, J = 1.8 Hz), 7.16 (1H, d, J = 1.8 Hz), 4.83 (2H, q, J = 8.4 Hz), 4.62-4.46 (1H, m), 3.90 (3H, s), 3.37 (1H, d, J = 2.9 Hz), 1.54 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 355 (M+H) +.
<Step-5>:1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 97 % yield (0.23 g, white solid) from (R)-N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.29 g, 0.82 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta = 8.41 (2H, br s), 7.81 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 1.8 Hz), 5.01 (2H, q, J = 9.1 Hz), 4.51-4.38 (1H, m), 3.86 (3H, s), 1.53 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 251 (M+H) +.
Amine-10:1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone
A mixture of 1-(4-hydroxyphenyl)ethanone (0.5 g, 3.67 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.58 mL, 4.04 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in DMF (10 mL) is stirred at rt for 2.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with EtOAc (30 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (10 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.65 g (81 % yield) of the title compound as white solid. This material is used for the next reaction (Step-2) without further purification.
1H-NMR (300 MHz, CDCl3) delta = 7.97 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 4.42 (2H, q, J = 7.7 Hz), 2.58 (3H, s), MS (ESI) m/z: 219 (M+H) +.
<Step-2>:(R)-2-methyl-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 76 % yield (0.73 g, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.65 g, 2.99 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta = 7.35-7.28 (2H, m), 6.96-6.88 (2H, m), 4.57-4.46 (1H, m), 4.35 (2H, q, J = 8.0 Hz), 3.32 (1H, br s), 1.49 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 324 (M+H) +.
<Step-3>:1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 86 % yield (0.50 g, white solid) from (R)-2-methyl-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer) (0.73 g, 2.26 mmol, Step-2) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta = 8.43 (2H, br s), 7.48 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz), 4.79 (2H, q, J = 8.8 Hz), 4.48-4.31 (1H, m), 1.49 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 220 (M+H) +.
Amine-11:(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine
(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine is commercially available.
Amine-12:(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride
<Step-1>:5-chloro-6-(2,2-difluoroethoxy)nicotinic acid
The title compound is prepared in 83 % yield (4.12 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 13.4 (1H, br s), 8.65 (1H, d, J = 1.8 Hz), 8.28 (1H, d, J = 1.8 Hz), 6.44 (1H, tt, J = 54.3, 3.3 Hz), 4.73 (2H, td, J = 15.0, 3.3 Hz), MS (ESI) m/z: 236 (M-H) -.
<Step-2>:methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate
Thionyl chloride (1.38 ml, 18.9 mmol) is added to a solution of 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (1.5 g, 6.31 mmol, Step-1) in methanol (100 ml) at 0 oC. Then the reaction mixture is refluxed with stirring for 2 hours. After removing solvent to give 1.57 g (>99 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.68 (1H, d, J = 2.2 Hz), 8.33 (1H, d, J = 2.2 Hz), 6.44 (1H, tt, J = 54.3, 3.3 Hz), 4.74 (2H, td, J = 14.7, 3.3 Hz), 3.86 (3H, s), MS (ESI) m/z: 252 (M+H) +.
<Step-3>:(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol
The title compound is prepared in 62 % yield (0.87 g, colorless oil) from methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate (1.57 g, 6.25 mmol, Step-2) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.99 (1H, d, J = 2.2 Hz), 7.74 (1H, d, J = 2.2 Hz), 6.16 (1H, tt, J = 55.4, 4.4 Hz), 4.65 (2H, d, J = 5.5 Hz), 4.60 (2H, td, J = 13.2, 4.0 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 224 (M+H) +.
<Step-4>:2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione
A mixture of (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol (0.87 g, 3.88 mmol, Step-3), phthalimide (0.63 g, 4.26 mmol), di-tert-butyl azodicarboxylate (2.11 mL, 4.65 mmol, ca. 2.2 mol/L in toluene) and triphenylphosphine (1.53 g, 5.81 mmol) in THF (26 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (10:1 to 3:1) to give 1.27 g (93 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.14-7.81 (6H, m), 6.38 (1H, tt, J = 54.7, 3.3 Hz), 4.75 (2H, s), 4.62 (2H, td, J = 15.0, 3.3 Hz), MS (ESI) m/z: 353 (M+H) +.
<Step-5>:(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride
Hydrazine monohydrate (0.53 mL, 10.8 mmol) is added to a solution of 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.27 g, 3.60 mmol, Step-4) in methanol (50 mL) and stirred for 20 hours at 50 oC. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mLx3). The organic layer is dried over sodium sulfate. After filtration, the organic layer is concentrated in vacuo. The residue is dissolved in EtOAc (10 mL), 4 M hydrogen chloride in EtOAc (5 mL) is added and stirred for 1 hour. After removal of the solvent, the residue is crystallized from EtOAc / n-hexane to give 0.85 g (91 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.43 (2H, br s), 8.24 (1H, d, J = 2.2 Hz), 8.16 (1H, d, J = 2.2 Hz), 6.14 (1H, tt, J = 54.3, 3.3 Hz), 4.67 (2H, td, J = 15.0, 3.3 Hz), 4.03 (2H, m), MS (ESI) m/z: 223 (M+H) +.
Amine-13:(2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine
<Step-1>:methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate
The title compound is prepared in 54 % yield (1.79 g, colorless oil) from methyl 6-chloro-2-methoxynicotinate (2.5 g, 12.4 mmol) in a similar manner to Step-3 of Amine-9.
1H-NMR (300 MHz, CDCl3) delta 8.21 (1H, d, J = 8.0 Hz), 6.47 (1H, d, J = 8.0 Hz), 4.79 (2H, q, J = 8.8 Hz), 4.07 (3H, s), 3.87 (3H, s), MS (ESI) m/z: 266 (M+H) +.
<Step-2>:(2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
The title compound is prepared in 74 % yield (1.19 g, white solid) from methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate (1.79 g, 5.02 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.54 (1H, d, J = 8.0 Hz), 6.41 (1H, d, J = 8.0 Hz), 4.72 (2H, q, J = 8.8 Hz), 4.59 (2H, s), 3.97 (3H, s), 2.10 (1H, br s), MS (ESI) m/z: 238 (M+H) +.
<Step-3>:2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 37 % yield (0.67 g, white solid) from (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.19 g, 5.02 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 7.87-7.84 (2H, m), 7.74-7.72 (2H, m), 7.53 (1H, d, J = 8.0 Hz), 6.37 (1H, d, J = 8.1 Hz), 4.80 (2H, s), 4.71 (2H, q, J = 8.8 Hz), 3.94 (3H, s), MS (ESI) m/z: 367 (M+H) +.
<Step-4>:(2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine
Hydrazine monohydrate (0.13 mL, 2.74 mmol) is added to a solution of 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.83 mmol, Step-3) in methanol (20 mL) and stirred at 50 oC for 20 hours. The reaction mixture is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mLx3). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.41 g (95 % yield) of the title compound as white solid. This material is used for the next reaction without further purification.
1H-NMR (300 MHz, CDCl3) delta 7.48(1H, d, J = 7.4 Hz), 6.38 (1H, d, J = 7.4 Hz), 4.74 (2H, q, J = 8.8 Hz), 3.95 (3H, s), 3.73 (2H, s), 1.46 (2H, br s).
Amine-14:(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride
<Step-1>:5-(chloromethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine
The title compound is prepared in >99 % yield (550 mg, brown oil) from (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (500 mg, 2.1 mmol) in a similar manner to Step-3 of Amine-3.
MS (ESI) m/z: 258 (M+H) +.
<Step-2>:5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine
The title compound is prepared in 50 % yield (280 mg, colorless oil) from 5-(chloromethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (540 mg, 2.1 mmol, Step-1) in a similar manner to Step-4 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 8.10 (1H, d, J = 2.9 Hz), 7.62 (1H, dd, J = 8.8, 2.9 Hz), 8.87 (1H, d, J = 8.0 Hz), 6.01 (1H, tt, J = 53.5, 5.1 Hz), 4.75 (2H, tt, J = 12.5, 1.5 Hz), 4.32 (2H, s), MS (ESI) m/z: 265 (M+H) +.
<Step-3>:(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride
Palladium 10 % on carbon (10 mg) is added to a stirred solution of 5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (110 mg, 2.1 mmol, Step-2) and 2M hydrochloric acid (0.2 mL) in methanol (3.5 mL). The mixture is stirred at rt under hydrogen atmosphere (1 atm) for 4 hours. The mixture is filtered through a pad of celite and washed with methanol. The filtrate is concentrated in vacuo to give 110 mg (93 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.39 (2H, br s), 8.31 (1H, d, J = 2.2 Hz), 7.96 (1H, dd, J = 8.8, 2.2 Hz), 7.02 (1H, d, J = 8.8 Hz), 6.68 (1H, tt, J = 52.0, 5.9 Hz), 4.88 (2H, t, J = 14.6 Hz), 4.01 (2H, s).
Amine-15:1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(3,3,3-trifluoropropoxy)nicotinate
The title compound is prepared in 47 % yield (1.37 g, colorless oil) from methyl 6-chloronicotinate (2.0 g, 11.7 mmol) and 3,3,3-trifluoropropan-1-ol instead of 2,2,2-trifluoroethanol in a similar manner to Step-3 of Amine-9.
MS (ESI) m/z: 250 (M+H) +.
<Step-2>:6-(3,3,3-trifluoropropoxy)nicotinic acid
To a solution of methyl 6-(3,3,3-trifluoropropoxy)nicotinate (1.37 g, 5.50 mmol, Step-1) in methanol (30 mL) is added 2 M sodium hydroxide (5 mL),and stirred for 2 hours at 60 oC. After removal of the solvent, the residue is dissolved in water (30 mL) and acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.15 g (86 % yield) of the title compound as white solid.
MS (ESI) m/z: 236 (M+H) +.
<Step-3>:N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide
The title compound is prepared in 74 % yield (0.97 g, colorless oil) from 6-(3,3,3-trifluoropropoxy)nicotinic acid (1.11 g, 4.72 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.61 (1H, d, J = 2.2 Hz), 8.00 (1H, dd, J = 8.8, 2.6 Hz), 6.77 (1H, d, J = 8.4 Hz), 4.59 (2H, t, J = 6.6 Hz), 3.57 (3H, s), 3.37 (3H, s), 2.70-2.55 (2H, m), MS (ESI) m/z: 279 (M+H) +.
<Step-4>:1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (0.82 g, white solid) from N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide (0.97 g, 3.50 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.76 (1H, d, J = 2.6 Hz), 8.16 (1H, dd, J = 8.8, 2.6 Hz), 6.81 (1H, d, J = 8.8 Hz), 4.62 (2H, t, J = 6.2 Hz), 2.70-2.55 (2H, m), 2.57 (3H, s), MS (ESI) m/z: 234 (M+H) +.
<Step-5>:(R)-2-methyl-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 80 % yield (0.95 g, white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (0.82 g, 3.51 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.10 (1H, d, J = 2.2 Hz), 7.60 (1H, dd, J = 8.8, 2.6 Hz), 6.75 (1H, d, J = 8.4 Hz), 4.53 (2H, t, J = 6.2 Hz), 4.6-4.45 (1H, m), 3.33 (1H, br s), 2.70-2.55 (2H, m), 1.51 (3H, d, J = 6.6 Hz),1.22 (9H, s), MS (ESI) m/z: 339 (M+H) +.
<Step-6>:1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (0.76 g, colorless gum) from (R)-2-methyl-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (0.94 g, 2.79 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.54 (2H, br s), 8.28 (1H, d, J = 2.2 Hz), 7.92 (1H, dd, J = 8.8, 2.2 Hz), 6.89 (1H, d, J = 8.8 Hz), 4.48 (2H, t, J = 5.7 Hz), 4.40 (1H, m), 2.78 (2H, m), 1.50 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 235 (M+H) +.
Amine-16:1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-chloro-6-(2,2-difluoroethoxy)-N-methoxy-N-methylnicotinamide
The title compound is prepared in 70 % yield (3.38 g, colorless oil) from 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (4.07 g, 3.60 mmol, Step-1 of Amine-12) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, DMSO-d6) delta 8.50 (1H, d, J = 1.8 Hz), 8.11 (1H, d, J = 1.8 Hz), 6.17 (1H, tt, J = 55.4, 4.0 Hz), 4.64 (2H, td, J = 13.2, 4.0 Hz), 4.68 (3H, s), 3.37 (3H, s), MS (ESI) m/z: 281 (M+H) +.
<Step-2>:1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (2.84 g, white solid) from 5-chloro-6-(2,2-difluoroethoxy)-N-methoxy-N-methylnicotinamide (3.38 g, 3.60 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.74 (1H, d, J = 2.3 Hz), 8.34 (1H, d, J = 2.3 Hz), 6.43 (1H, tt, J = 54.4, 3.3 Hz), 4.75 (2H, td, J = 14.8, 3.3 Hz), 2.57 (3H, s), MS (ESI) m/z: 236 (M+H) +.
<Step-3>:(R)-N-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 85 % yield (3.56 g, white solid) from 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (2.88 g, 12.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.00 (1H, d, J = 2.2 Hz), 7.68 (1H, d, J = 2.2 Hz), 6.15 (1H, tt, J = 55.8, 4.4 Hz), 4.58 (2H, td, J = 13.2, 4.4 Hz), 4.52 (1H, m), 3.37 (1H, br s), 1.51 (3H, d, J = 6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 341 (M+H) +.
<Step-4>:1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 87 % yield (2.49 g, white solid) from (R)-N-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (3.56 g, 10.5 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.57 (2H, br s), 8.27 (1H, d, J = 2.2 Hz), 8.20 (1H, d, J = 2.2 Hz), 6.41 (1H, tt, J = 54.3, 3.3 Hz), 4.67 (2H, td, J = 15.0, 3.7 Hz), 4.46 (1H, q, J = 6.6 Hz), 1.52 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 237 (M+H) +.
Amine-17:1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid
The title compound is prepared in >99 % yield (3.7 g, white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.74 (1H, d, J = 2.2 Hz), 8.09 (1H, d, J = 2.2 Hz), 6.00 (1H, tt, J = 52.7, 3.7 Hz), 4.84 (2H, t, J = 12.5 Hz), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 268 (M+H) +.
<Step-2>:N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide
The title compound is prepared in 83 % yield (960 mg, clear colorless oil) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (800 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.44 (1H, s), 7.86 (1H, s), 6.01 (1H, tt, J = 53.2, 4.4 Hz), 4.79 (2H, t, J = 12.5 Hz), 3.57 (3H, s), 3.37 (3H, s), 2.24 (3H, s), MS (ESI) m/z: 311 (M+H) +.
<Step-3>:1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (820 mg, clear colorless oil) from N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (900 mg, 3.4 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 1.8 Hz), 8.02 (1H, d, J = 1.8 Hz), 5.99 (1H, tt, J = 53.2, 4.4 Hz), 4.83 (2H, tt, J = 12.5, 1.5 Hz), 2.57 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 266 (M+H) +.
<Step-4>:(R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 77 % yield (880 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (820 mg, 3.1 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.94 (1H, d, J = 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 6.00 (1H, tt, J = 53.2, 4.4 Hz), 4.12 (2H, tt, J = 12.5, 1.5 Hz), 4.50 (1H, m), 2.21 (3H, s), 1.50 (3H, d, J = 6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 371 (M+H) +.
<Step-5>:1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine (single enantiomer)
The title compound is prepared in >99 % yield (800 mg, an orange gum) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (880 mg, 32.4 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.60 (2H, br s), 8.13 (1H, d, J = 2.2 Hz), 7.84 (1H, d, J = 2.2 Hz), 6.68 (1H, tt, J = 51.7, 5.5 Hz), 4.87 (2H, t, J = 13.9 Hz), 4.38 (1H, m), 2.18 (3H, s), 1.50 (3H, d, J = 6.6 Hz).
Amine-18:1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (single enantiomer)
<Step-1>:1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one
The title compound is prepared in 87 % yield (0.53 g, colorless oil) from N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.70 g, 2.65 mmol, Step-2 of Amine-1) and ethyl magnesium bromide instead of methyl magnesium bromide in a similar manner to Step-3 of Amine-1.
1H-NMR (270 MHz, CDCl3) delta 8.76 (1H, d, J = 2.0 Hz), 8.22 (1H, dd, J = 8.6, 2.3 Hz), 6.92 (1H, d, J = 8.6 Hz), 4.83 (2H, q, J = 8.6 Hz), 2.96 (2H, q, J = 7.3 Hz), 1.23 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 234 (M+H) +.
<Step-2>:(R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 50 % yield (0.39 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one (0.54 g, 2.29 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.07 (1H, d, J = 2.6 Hz), 7.62 (1H, dd, J = 8.4, 2.6 Hz), 6.86 (1H, d, J = 8.4 Hz), 4.74 (2H, q, J = 8.4 Hz), 4.26 (1H, m), 2.07 (1H, m), 1.72 (1H, m), 1.22 (9H, s), 0.82 (3H, t, J = 7.3 Hz) (a signal due to NH is not observed), MS (ESI) m/z: 339 (M+H) +.
<Step-3>:1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (0.34 g, colorless oil) from (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)propane-2-sulfinamide (single diastereomer) (0.37 g, 1.81 mmol, Step-2) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.62 (2H, br s), 8.30 (1H, d, J = 2.2 Hz), 7.99 (1H, dd, J = 8.8, 2.6 Hz), 7.07 (1H, d, J = 8.8 Hz), 5.00 (2H, q, J = 8.8 Hz), 4.17 (1H, m), 1.99 (1H, m), 1.85 (1H, m), 0.74 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 235 (M+H) +.
Figure JPOXMLDOC01-appb-I000008
Amine-19:(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine
<Step-1>:6-(2,2,2-trifluoroethoxy)picolinic acid
The title compound is prepared in >99 % yield (2.40 g, colorless oil) from 6-chloropicolinic acid (1.18 g, 7.49 mmol) in a similar manner to Step-1 of Amine-1.
MS (ESI) m/z: 222 (M+H) +.
<Step-2>:Methyl 6-(2,2,2-trifluoroethoxy)picolinate
A mixture of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.40 g, 10.9 mmol, Step-1), methyl iodide (3.39 mL, 54.3 mmol) and potassium carbonate (4.50 g, 32.6 mmol) in DMA (54 mL) is stirred at rt for 4 hours. The reaction mixture is poured into water (100 mL) and extracted with n-hexane / EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (5:1) to give 1.14 g (45 % yield) of the title compound as colorless oil.
1H-NMR (270 MHz, CDCl3) delta 7.82-7.74 (2H, m), 7.06 (1H, dd, J = 7.3, 2.0 Hz), 4.86 (2H, q, J = 8.6 Hz), 3.96 (3H, s), MS (ESI) m/z: 236 (M+H) +.
<Step-3>:(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
To a stirred solution of methyl 6-(2,2,2-trifluoroethoxy)picolinate (0.40 g, 1.69 mmol, Step-2) in THF (17 mL) is added slowly lithium aluminum hydride (0.096 g, 2.53 mmol) at 0 oC. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25 % aqueous ammonia solution at 0 oC. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of celite, and the filtrate is concentrated in vacuo to give 0.32 g (92 % yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.
MS (ESI) m/z: 208 (M+H) +.
<Step-4>:2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine
A mixture of (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3), and thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99 % yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.
MS (ESI) m/z: 226 (M+H) +.
<Step-5>:2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine
A mixture of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.35 g, 1.55 mmol, Step-4) and sodium azide (0.20 g, 3.10 mmol) in DMA (8 mL) is stirred 90 oC for 1 hour. The reaction mixture is poured into water (50 mL), and extracted with n-hexane / EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.44 g (>99 % yield) of the title compound as colorless oil. This material is used for the next reaction (Step-6) without further purification.
MS (ESI) m/z: 233 (M+H) +.
<Step-6>:(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine
A mixture of 2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.44 g, 1.90 mmol, Step-5) and palladium 10 % on carbon (0.070 g) in methanol (12 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondEluteTM SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure to give 0.27 g (68 % yield) of the title compound as dark brown oil.
MS (ESI) m/z: 207 (M+H) +.
Amine-20:1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate
To a stirred suspension of sodium hydride (4.9 g, 120 mmol, 60 % in oil) in DMA (100 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (8.1 mL, 82 mmol) at 0 oC. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (7.0 g, 41 mmol) in DMA (120 mL) is added dropwise at 0 oC, and the mixture is stirred for 30 minutes at rt. Then, the mixture is stirred at 90 oC for 2 hours. After cooled to rt, 2M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane / EtOAc (1:2, 200 mL). The organic layer is washed with water, brine, and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give 8.4 g of the title compound as crude product (include 2,2,3,3,3-pentafluoropropyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate as a byproduct). The residue is used for the next reaction (Step-2) without further purification.
MS (ESI) m/z: 286 (M+H) +.
<Step-2>:6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid
The title compound is prepared in 62 % yield (6.8 g, an off-white solid, yield is based on methyl 6-chloronicotinate) from methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate (8.4 g, crude from Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 8.90 (1H, d, J = 2.2 Hz), 8.29 (1H, dd, J = 8.8, 2.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 4.93 (2H, t, J = 11.7 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 270 (M-H) -.
<Step-3>:N-methoxy-N-methyl-6-(2,2,3,3,3-pentafluoropropoxy)nicotinamide
The title compound is prepared in 51 % yield (3.6 g, brown oil) from 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid (6.0 g, 22.1 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.61 (1H, d, J = 2.2 Hz), 8.06 (1H, dd, J = 8.8, 2.2 Hz), 6.89 (1H, d, J = 8.8 Hz), 4.89 (2H, t, J = 11.7 Hz), 3.57 (3H, s), 3.39 (3H, s), MS (ESI) m/z: 315 (M+H) +.
<Step-4>:1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in 97 % yield (3.0 g, brown oil) from N-methoxy-N-methyl-6-(2,2,3,3,3-pentafluoropropoxy)nicotinamide (3.6 g, 11.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.76 (1H, d, J = 2.2 Hz), 8.22 (1H, dd, J = 8.8, 2.2 Hz), 6.93 (1H, d, J = 8.8 Hz), 4.92 (2H, t, J = 13.9 Hz), 2.60 (3H, s), MS (ESI) m/z: 270 (M+H) +.
<Step-5>:(R)-2-methyl-N-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 78 % yield (3.2 g, an off-white solid) from 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone (3.0 g, 11.0 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.12 (1H, d, J = 2.2 Hz), 7.66 (1H, dd, J = 8.8, 2.2 Hz), 6.85 (1H, d, J = 8.8 Hz), 4.83 (2H, t, J = 13.2 Hz), 4.58-4.50 (1H, m), 3.36 (1H, br), 1.52 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 375 (M+H) +.
<Step-6>:1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 84 % yield (2.2 g, white solid) from (R)-2-methyl-N-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (3.2 g, 8.6 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.71 (2H, br s), 8.36 (1H, d, J = 2.2 Hz), 8.05 (1H, dd, J = 8.8, 2.2 Hz), 7.06 (1H, d, J = 8.0 Hz), 5.13 (2H, t, J = 13.2 Hz), 4.50-4.40 (1H, m), 1.54 (3H, d, J = 6.6 Hz).
Amine-21:1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate
The title compound is prepared in 92 % yield (2.9 g, clear colorless oil) from 2-chloro-6-hydroxynicotinic acid (1.8 g, 11 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in a similar manner to Step-1 of Amine-10.
1H-NMR (300 MHz, CDCl3) delta 8.23 (1H, d, J = 8.0 Hz), 6.84 (1H, d, J = 8.8 Hz), 6.32-5.88 (2H, m), 4.66-4.46 (4H, m).
MS (ESI) m/z: 302 (M+H)+.
<Step-2>:methyl 6-(2,2-difluoroethoxy)-2-methoxynicotinate
To a stirred solution of 2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate (2.9 g, 9.8 mmol, Step-1) in THF (35 mL) is added sodium methoxide (1.58 g, 29.2 mmol) at 0 oC. Then the mixture is stirred at rt for 15 hours. The mixture is poured into water and extracted with DCM (10 mLx3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1 to 1:4) to give 615 mg (26 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 8.19 (1H, d, J = 8.0 Hz), 6.42 (1H, d, J = 8.1 Hz), 6.12 (1H, tt, J = 54.9, 3.7 Hz), 4.58 (2H, td, J = 13.2, 4.4 Hz), 4.04 (3H, s), 3.87 (3H, s), MS (ESI) m/z: 248 (M+H)+.
<Step-3>:6-(2,2-difluoroethoxy)-2-methoxynicotinic acid
The title compound is prepared in 91 % yield (270 mg, white solid) from methyl 6-(2,2-difluoroethoxy)-2-methoxynicotinate (320 mg, 1.3 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 8.39 (1H, d, J = 8.8 Hz), 6.59 (1H, d, J = 8.0 Hz), 6.12 (1H, tt, J = 54.9, 3.7 Hz), 4.60 (2H, td, J = 13.2, 4.4 Hz), 4.17 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 234 (M+H)+.
<Step-4>:6-(2,2-difluoroethoxy)-N,2-dimethoxy-N-methylnicotinamide
The title compound is prepared in >99 % yield (990 mg, clear colorless oil) from 6-(2,2-difluoroethoxy)-2-methoxynicotinic acid (910 mg, 4.5 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
MS (ESI) m/z: 277 (M+H)+.
<Step-5>:1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone
The title compound is prepared in 69 % yield (650 mg, pale yellow oil) from 6-(2,2-difluoroethoxy)-N,2-dimethoxy-N-methylnicotinamide (980 mg, 3.6 mmol, Step-4) in a similar manner to Step-3 of Amine-1.
1H-NMR (270 MHz, CDCl3) delta 8.18 (1H, d, J = 8.6 Hz), 6.54 (1H, d, J = 8.6 Hz), 6.12 (1H, tt, J = 55.4, 4.0 Hz), 4.59 (2H, td, J = 13.8, 4.6 Hz), 4.04 (3H, s), 2.59 (3H, s), MS (ESI) m/z: 232 (M+H)+.
<Step-6>:(R)-N-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 73 % yield (400 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone (380 mg, 1.6 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.52 (1H, d, J = 8.1 Hz), 6.37 (1H, d, J = 8.1 Hz), 6.12 (1H, tt, J = 55.7, 4.4 Hz), 4.63 (1H, quintet, J = 6.6 Hz), 4.51 (2H, td, J = 13.9, 4.4 Hz), 3.92 (3H, s), 3.74 (1H, d, J = 5.9 Hz), 1.46 (3H, d, J = 7.3 Hz), 1.21 (9H, s), MS (ESI) m/z: 337 (M+H)+.
<Step-7>:1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanaminehydrochloride (single enantiomer)
The title compound is prepared in 96 % yield (350 mg, white solid) from (R)-N-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.3 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.36 (2H, br s), 7.86 (1H, d, J = 8.1 Hz), 6.57 (1H, d, J = 8.1 Hz), 6.42 (1H, tt, J = 54.9, 3.7 Hz), 4.59 (2H, td, J = 14.6, 2.9 Hz), 4.52-4.40 (1H, br), 3.93 (3H, s), 1.46 (3H, d, J = 6.6 Hz).
MS (ESI) m/z: positive ion of a fragment signal 216 is observed.
Amine-22:(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride
<Step-1>:5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid
The title compound is prepared in 75 % yield (21.0 g, white solid) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (32.2 g, 118 mmol, Step-1 of Amine-7) in a similar manner to Step-4 of Amine-7.
1H-NMR (300 MHz, DMSO-d6) delta 13.40 (1H, br), 8.55 (1H, d, J = 1.8 Hz), 8.13 (1H, dd, J = 10.3, 1.8 Hz), 5.16 (2H, q, J = 9.2 Hz), MS (ESI) m/z: 238 (M-H) -.
<Step-2>:methyl 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate
The title compound is prepared in 55 % yield (1.74 g, white solid) from 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.0 g, 12.6 mmol, Step-1) in a similar manner to Step-2 of Amine-12.
1H-NMR (300 MHz, DMSO-d6) delta 8.58 (1H, d, J = 1.8 Hz), 8.20 (1H, dd, J = 10.3, 1.8 Hz), 5.16 (2H, q, J = 8.8 Hz), 3.87 (3H, s).
<Step-3>:(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
The title compound is prepared in 93 % yield (1.43 g, colorless oil) from methyl 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate (1.74 g, 6.89 mmol, Step-2) in a similar manner to Step-2 of Amine-3.
MS (ESI) m/z: 226 (M+H) +.
<Step-4>:2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 99 % yield (2.24 g, white solid) from (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.44 g, 6.39 mmol, Step-3) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, DMSO-d6) delta 8.03 (1H, d, J = 1.8 Hz), 7.90-7.82 (4H, m), 7.76 (1H, dd, J = 11.0, 1.8 Hz), 5.06 (2H, q, J = 9.2 Hz), 4.77 (2H, s), MS (ESI) m/z: 355 (M+H) +.
<Step-5>:(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride
The title compound is prepared in 41 % yield (0.67 g, white solid) from 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (2.24 g, 6.33 mmol, Step-4) in a similar manner to Step-5 of Amine-12.
1H-NMR (300 MHz, DMSO-d6) delta 8.56 (2H, br s), 8.14 (1H, d, J = 1.8 Hz), 8.04 (1H, dd, J = 11.3, 1.8 Hz), 5.11 (2H, q, J = 9.2 Hz), 4.04 (2H, d, J = 5.5 Hz), MS (ESI) m/z: 225 (M+H) +.
Amine-23:(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine
<Step-1>:methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate
The title compound is prepared in 95 % yield (350 mg, white solid) from 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (350 mg, 1.4 mmol, Step-1 of Amine-8) in a similar manner to Step-1 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 8.68 (1H, d, J = 1.5 Hz), 8.29 (1H, d, J = 1.5 Hz), 4.88 (2H, q, J = 8.1 Hz), 3.94 (3H, s).
<Step-2>:(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
The title compound is prepared in 78 % yield (210 mg, white solid) from methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 1.1 mmol, Step-1) and diisobutylalminium hydride (1.0 M in hexane, 2.4 mL, 2.4 mmol) instead of lithium aluminum hydride in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 8.00 (1H, d, J = 2.2 Hz), 7.76 (1H, d, J = 2.2 Hz), 4.82 (2H, q, J = 8.8 Hz), 4.66 (2H, s), MS (ESI) m/z: 242 (M+H) +.
<Step-3>:2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 64 % yield (210 mg, white solid) from (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (211 mg, 0.87 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 8.15 (1H, s), 7.90-7.80 (3H, m), 7.75-7.70 (2H, m), 4.79 (2H, q, J = 8.1 Hz), 4.78 (2H, s), MS (ESI) m/z: 371 (M+H) +.
<Step-4>:(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine
Hydrazine monohydrate (0.04 mL, 0.84 mmol) is added to a solution of 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (210 mg, 0.56 mmol, Step-3) in methanol (10 mL) and stirred for 20 hours at 50 oC. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mLx3) and dried over sodium sulfate, and concentrated in vacuo to give 0.15 g (>99 % yield) of the title compound as colorless oil. This material is used for the next reaction without further purification.
1H-NMR (300 MHz, CDCl3) delta 7.96 (1H, s), 7.75 (1H, s), 4.81 (2H, q, J = 8.8 Hz), 3.84 (2H, s), 1.38 (2H, br), MS (ESI) m/z: 241 (M+H) +.
Amine-24:1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:3-chloro-4-(2,2-difluoroethoxy)-N-methoxy-N-methylbenzamide
The title compound is prepared in >99 % yield (1.1 g, white solid) from 3-chloro-4-(2,2-difluoroethoxy)benzoic acid (900 mg, 3.8 mmol) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.84 (1H, d, J = 2.2 Hz), 7.67 (1H, dd, J = 8.8, 2.2 Hz), 6.93 (1H, d, J = 8.8 Hz), 6.17 (1H, tt, J = 54.2, 3.7 Hz), 4.28 (2H, td, J = 12.5, 3.7 Hz), 3.56 (3H, s), 3.36 (3H, s), MS (ESI) m/z: 280 (M+H) +.
<Step-2>:1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone
The title compound is prepared in 95 % yield (860 mg, white solid) from 3-chloro-4-(2,2-difluoroethoxy)-N-methoxy-N-methylbenzamide (1.1 g, 3.9 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.02 (1H, d, J = 2.2 Hz), 7.87 (1H, dd, J = 8.8, 2.2 Hz), 6.97 (1H, d, J = 8.8 Hz), 6.18 (1H, tt, J = 54.9, 4.4 Hz), 4.31 (2H, td, J = 12.5, 4.4 Hz), 2.57 (3H, s).
<Step-3>:(R)-N-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 62 % yield (780 mg, clear colorless oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (860 mg, 3.7 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.38 (1H, d, J = 2.2 Hz), 7.22 (1H, dd, J = 8.4, 2.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.14 (1H, tt, J = 55.0, 4.0 Hz), 4.53-4.43 (1H, m), 4.23 (2H, td, J = 12.8, 4.0 Hz), 3.34 (1H, br s), 1.48 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 340 (M+H) +.
<Step-4>:1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 98 % yield (610 mg, white solid) from (R)-N-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (780 mg, 2.3 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.46 (2H, br s), 7.65 (1H, d, J = 2.2 Hz), 7.46 (1H, dd, J = 8.4, 2.2 Hz), 7.28 (1H, d, J, = 8.4 Hz), 6.41 (1H, tt, J = 54.3, 3.3 Hz), 4.43 (2H, td, J = 14.7, 3.3 Hz), 4.37 (1H, m), 1.47 (3H, d, J = 7.0 Hz).
Amine-26:2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride
<Step-1>:6-(2,2,2-trifluoroethoxy)picolinic acid
The title compound is prepared in >99 % yield (2.40 g, colorless oil) from 6-chloropicolinic acid (1.18 g, 7.49 mmol) in a similar manner to Step-1 of Amine-1.
MS (ESI) m/z: 222 (M+H) +.
<Step-2>:methyl 6-(2,2,2-trifluoroethoxy)picolinate
A mixture of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.40 g, 10.9 mmol, Step-1), methyl iodide (3.39 mL, 54.3 mmol) and potassium carbonate (4.50 g, 32.6 mmol) in DMA (54 mL) is stirred at rt for 4 hours. The reaction mixture is poured into water (100 mL) and extracted with n-hexane / EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (5:1) to give 1.14 g (45 % yield) of the title compound as colorless oil.
1H-NMR (270 MHz, CDCl3) delta 7.82-7.74 (2H, m), 7.06 (1H, dd, J = 7.3, 2.0 Hz), 4.86 (2H, q, J = 8.6 Hz), 3.96 (3H, s), MS (ESI) m/z: 236 (M+H) +.
<Step-3>:(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
To a stirred solution of methyl 6-(2,2,2-trifluoroethoxy)picolinate (0.40 g, 1.69 mmol, Step-2) in THF (17 mL) is added slowly lithium aluminum hydride (0.096 g, 2.53 mmol) at 0 oC. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25 % aqueous ammonia solution at 0 oC. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of celite, and the filtrate is concentrated in vacuo to give 0.32 g (92 % yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.
MS (ESI) m/z: 208 (M+H) +.
<Step-4>:2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine
A mixture of (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3), and thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99 % yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.
MS (ESI) m/z: 226 (M+H) +.
<Step-5>:2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetonitrile
Sodium cyanide (0.823 g, 16.8 mmol) is added to a solution of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (2.0 g, 7.63 mmol, Step-4) in DMSO (38 mL) and stirred at rt for 20 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (60 mL) and extracted with EtOAc (100 mL). The organic layer is washed with water (50 mLx2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on amine gel eluting with n-hexane / EtOAc (3:1) to give 1.13 g (69 % yield) of the title compound as yellow oil.
MS (ESI) m/z: 217 (M+H) +.
<Step-6>:2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride
The title compound is prepared in >99 % yield (1.69 g, yellow oil) from 2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetonitrile (1.03 g, 4.76 mmol, Step-5) in a similar manner to Step-3 of Amine-14.
MS (ESI) m/z: 221 (M+H) +.
Amine-27:1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate
To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40 % solution in toluene) at 0 oC. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60 oC for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (18:1) to give 1.9 g (90 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 7.90-7.85 (2H, m), 6.79 (1H, d, J = 8.8 Hz), 6.13 (1H, tt, J = 54.9, 4.4 Hz), 4.24 (2H, td, J = 12.5, 3.7 Hz), 3.89 (3H, s), 2.27 (3H, s).
<Step-2>:4-(2,2-difluoroethoxy)-3-methylbenzoic acid
The title compound is prepared in >99 % yield (1.1 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (1.0 g, 4.3 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 7.97-7.90 (2H, m), 6.83 (1H, d, J = 8.1 Hz), 6.14 (1H, tt, J = 54.9, 4.4 Hz), 4.26 (2H, td, J = 12.5, 4.4 Hz), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 215 (M-H) -.
<Step-3>:4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide
The title compound is prepared in 94 % yield (900 mg, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methylbenzoic acid (800 mg, 3.7 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.60-7.50 (2H, m), 6.78 (1H, d, J = 8.0 Hz), 6.13 (1H, tt, J = 54.9, 4.4 Hz), 4.23 (2H, td, J = 12.4, 3.7 Hz), 3.56 (3H, s), 3.35 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 260 (M+H) +.
<Step-4>:1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone
The title compound is prepared in 98 % yield (730 mg, pale yellow oil) from 4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide (900 mg, 3.4 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.84-7.80 (2H, m), 6.81 (1H, d, J = 8.0 Hz), 6.14 (1H, tt, J = 54.9, 3.7 Hz), 4.25 (2H, td, J = 12.5, 3.7 Hz), 2.82 (3H, s), 2.28 (3H, s), MS (ESI) m/z: 215 (M+H) +.
<Step-5>:(R)-N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 47 % yield (520 mg, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone (750 mg, 3.5 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.14 (2H, br), 6.75 (1H, d, J = 8.8 Hz), 6.10 (1H, tt, J = 54.9, 4.4 Hz), 4.50-4.40 (1H, m), 4.17 (2H, td, J = 13.2, 4.4 Hz), 3.33 (1H, br s), 2.24 (3H, s), 1.47 (3H, d, J = 6.6 Hz), 1.23 (9H, s).
<Step-6>:1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 96 % yield (390 mg, white solid) from (R)-N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (750 mg, 3.5 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.23 (2H, br s), 7.31-7.25 (2H, m), 7.06 (1H, d, J = 8.8 Hz), 6.40 (1H, tt, J = 54.2, 2.9 Hz), 4.33 (2H, td, J = 14.7, 3.7 Hz), 2.18 (3H, s), 1.47 (3H, d, J = 6.6 Hz) (a signal due to CHNH2 (benzylic proton) is not observed).
Amine-28:1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:3-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide
The title compound is prepared in 98 % yield (1.2 g, white solid) from 3-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (1.0 g, 3.9 mmol) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.85 (1H, d, J = 2.2 Hz), 7.67 (1H, dd, J = 8.8, 2.2 Hz), 6.96 (1H, d, J = 8.1 Hz), 4.47 (2H, q, J = 7.3 Hz), 3.56 (3H, s), 3.36 (3H, s), MS (ESI) m/z: 298 (M+H) +.
<Step-2>:1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone
The title compound is prepared in >99 % yield (1.2 g, a pale yellow solid) from 3-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide (1.2 g, 3.9 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.03 (1H, d, J = 2.2 Hz), 7.87 (1H, dd, J = 8.8, 2.2 Hz), 6.99 (1H, d, J =8.0 Hz), 4.49 (2H, q, J = 8.1 Hz), 2.58 (3H, s).
<Step-3>:(R)-N-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 58 % yield (940 mg, clear colorless oil) from 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.39 (1H, d, J = 2.2 Hz), 7.22 (1H, dd, J = 8.8, 2.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 4.53-4.45 (1H, m), 4.39 (2H, q, J = 8.0 Hz), 3.35 (1H, br), 1.49 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 358 (M+H) +.
<Step-4>:1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 62 % yield (470 mg, white solid) from (R)-N-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (940 mg, 2.6 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.31 (2H, br s), 7.65 (1H, s), 7.46 (1H, d, J = 8.1 Hz), 7.34 (1H, d, J = 8.1 Hz), 4.90 (2H, q, J = 8.8 Hz), 4.45-4.30 (1H, m), 1.47 (3H, d, J = 6.6 Hz)
Amine-29:1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:N-methoxy-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzamide
The title compound is prepared in >99 % yield (1.18 g, colorless oil) from 4-(1,1,2,2-tetrafluoroethoxy)benzoic acid (1.00 g, 4.2 mmol) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.77-7.73 (2H, m), 7.26-7.24 (2H, m), 5.92 (1H, tt, J = 52.8, 2.9 Hz), 3.55 (3H, s), 3.37 (3H, s), MS (ESI) m/z: 282 (M+H) +.
<Step-2>:1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone
The title compound is prepared in 83 % yield (0.82 g, yellow oil) from N-methoxy-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzamide (1.18 g, 4.2 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.03-7.99 (2H, m), 7.32-7.29 (2H, m), 5.94 (1H, tt, J = 52.8, 2.9 Hz), 2.61 (3H, s), MS (ESI) m/z: 237 (M+H) +.
<Step-3>: (R)-2-methyl-N-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 80 % yield (0.95 g, white solid) from 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.82 g, 3.46 mmol, Step-2) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.39-7.35 (2H, m), 7.21-7.17 (2H, m), 5.91 (1H, tt, J = 52.8, 2.9 Hz), 4.60-4.52 (1H, m), 3.39 (1H, br s), 1.51 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 342 (M+H) +.
<Step-4>:1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 83 % yield (0.63 g, white solid) from (R)-2-methyl-N-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (0.95 g, 2.77 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.55 (2H, br s), 7.64 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 6.83 (1H, tt, J = 52.1, 2.9 Hz), 4.49-4.41 (1H, m), 1.52 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 221 is observed.
Amine-30:1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 3-(2,2-difluoroethoxy)-5-methylbenzoate
The title compound is prepared in 75 % yield (1.88 g, pale yellow oil) from methyl 3-hydroxy-5-methylbenzoate (1.8 g, 10.8 mmol) in a similar manner to Step-1 of Amine-27.
1H-NMR (300 MHz, CDCl3) delta 7.53 (1H, s), 7.36 (1H, s), 6.96 (1H, s), 6.09 (1H, tt, J = 55.0, 4.0 Hz), 4.21 (2H, td, J = 12.8, 4.0 Hz), 3.91 (3H, s), 2.38 (3H, s)
<Step-2>:3-(2,2-difluoroethoxy)-5-methylbenzoic acid
The title compound is prepared in 96 % yield (0.98 g, white solid) from methyl 3-(2,2-difluoroethoxy)-5-methylbenzoate (1.08 g, 4.69 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 7.60 (1H, s), 7.42 (1H, s), 7.01 (1H, s), 6.10 (1H, tt, J = 55.0, 4.0 Hz), 4.23 (2H, td, J = 12.8, 4.0 Hz), 2.40 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 215 (M-H) -.
<Step-3>:3-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylbenzamide
The title compound is prepared in >99 % yield (1.02 g, colorless oil) from 3-(2,2-difluoroethoxy)-5-methylbenzoic acid (0.85 g, 3.93 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.12 (1H, s), 7.00 (1H, s), 6.84 (1H, s), 6.08 (1H, tt, J = 55.0, 4.0 Hz), 4.19 (2H, td, J = 12.8, 4.0 Hz), 3.57 (3H, s), 3.34 (3H, s), 2.36 (3H, s), MS (ESI) m/z: 260 (M+H) +.
<Step-4>:1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone
The title compound is prepared in 97 % yield (0.85 g, colorless oil) from 3-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylbenzamide (1.06 g, 4.09 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.42 (1H, s), 7.29 (1H, s), 6.97 (1H, s), 6.09 (1H, tt, J = 55.0, 4.0 Hz), 4.22 (2H, td, J = 12.8, 4.0 Hz), 2.58 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 215 (M+H) +.
<Step-5>:(R)-N-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 77 % yield (0.85 g, colorless oil) from 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (1.06 g, 3.04 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 6.80 (1H, s), 6.73 (1H, s), 6.54 (1H, s), 6.08 (1H, tt, J = 55.0, 4.0 Hz), 4.47 (1H, m), 4.17 (2H, td, J = 12.8, 4.0 Hz), 3.38 (1H, br s), 2.33 (3H, s), 1.48 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 320 (M+H) +.
<Step-6>:1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 88 % yield (0.67 g, white solid) from (R)-N-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.97 g, 3.04 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.36 (2H, br s), 7.00 (1H, s), 6.92 (1H, s), 6.85 (1H, s), 6.39 (1H, tt, J = 54.2, 3.7 Hz), 4.31 (1H, m), 4.29 (2H, td, J = 14.7, 3.7 Hz), 2.29 (3H, s), 1.46 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 199 is observed.
Amine-31:1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate
The title compound is prepared in 80 % yield (2.17 g, white solid) from methyl 4-hydroxy-3-methoxybenzoate (2.0 g, 11.0 mmol) in a similar manner to Step-1 of Amine-27.
1H-NMR (300 MHz, CDCl3) delta 7.66 (1H, dd, J = 8.4, 2.2 Hz), 7.58 (1H, d, J = 2.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.16 (1H, tt, J = 55.0, 4.4 Hz), 4.28 (2H, td, J = 13.2, 4.4 Hz), 3.93 (3H, s), 3.91 (3H, s).
<Step-2>:4-(2,2-difluoroethoxy)-3-methoxybenzoic acid
The title compound is prepared in 95 % yield (1.05 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate (1.17 g, 4.74 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 7.53 (1H, dd, J = 8.4, 1.8 Hz), 7.46 (1H, d, J = 1.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 6.39 (1H, tt, J = 54.3, 3.7 Hz), 4.35 (2H, td, J = 14.7, 3.7 Hz), 3.80 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 231 (M-H)-.
<Step-3>:4-(2,2-difluoroethoxy)-N,3-dimethoxy-N-methylbenzamide
The title compound is prepared in 86 % yield (0.97 g, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methoxybenzoic acid (0.95 g, 4.09 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.37-7.33 (2H, m), 6.90 (1H, d, J = 8.1 Hz), 6.15 (1H, tt, J = 55.0, 4.0 Hz), 4.27 (2H, td, J = 13.2, 4.0 Hz), 3.90 (3H, s), 3.57 (3H, s), 3.37 (3H, s), MS (ESI) m/z: 276 (M+H)+.
<Step-4>:1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone
The title compound is prepared in 95 % yield (0.77 g, pale yellow oil) from 4-(2,2-difluoroethoxy)-N,3-dimethoxy-N-methylbenzamide (0.97 g, 3.51 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.58-7.51 (2H, m), 6.94-6.90 (1H, m), 6.16 (1H, tt, J = 55.4, 4.0 Hz), 4.29 (2H, td, J = 12.8, 4.0 Hz), 3.93 (3H, s), 2.58 (3H, s), MS (ESI) m/z: 231 (M+H) +.
<Step-5>:(R)-N-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 97 % yield (1.09 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone (0.77 g, 3.35 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 6.94-6.86 (3H, m), 6.12 (1H, tt, J = 55.1, 4.4 Hz), 4.55-4.46 (1H, m), 4.21 (2H, td, J = 13.2, 4.4 Hz), 3.88 (3H, s), 3.38 (1H, br s), 1.50 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 336 (M+H)+.
<Step-6>:1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 78 % yield (0.68 g, white solid) from (R)-N-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.09 g, 3.25 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.53 (2H, br s), 7.29 (1H, br s), 7.05-6.97 (2H, m), 6.35 (1H, tt, J = 55.0, 3.7 Hz), 4.36-4.18 (3H, m), 3.46 (3H, s), 1.49 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 232 (M+H)+.
Amine-32:(4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride
<Step-1>:(4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanol
The title compound is prepared in >99 % yield (0.89 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate (1.00 g, 4.06 mmol, Step-1 of Amine-31) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 6.97-6.86 (3H, m), 6.12 (1H, tt, J = 55.0, 4.4 Hz), 4.64 (2H, d, J = 5.9 Hz), 4.22 (2H, td, J = 13.2, 4.4 Hz), 3.89 (3H, s), 1.67 (1H, t, J = 5.9 Hz).
<Step-2>:4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene
The title compound is prepared in >99 % yield (0.96 g, white solid) from (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanol (0.89 g, 4.06 mmol, Step-1) in a similar manner to Step-3 of Amine-3.
<Step-3>:4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene
The title compound is prepared in 94 % yield (0.93 g, colorless oil) from 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene (0.96 g, 4.06 mmol, Step-2) in a similar manner to Step-4 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 6.89-6.83 (3H, m), 6.13 (1H, tt, J = 55.0 Hz, 4.4 Hz), 4.29-4.18 (4H, m), 3.89 (3H, s).
<Step-4>:(4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride
The title compound is prepared in 80 % yield (0.77 g, white solid) from 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene (0.93 g, 3.81 mmol, Step-3) in a similar manner to Step-3 of Amine-14.
1H-NMR (300 MHz, DMSO-d6) delta 8.36 (2H, br s), 7.25 (1H, s), 7.07-6.97 (2H, m), 6.38 (1H, tt, J = 54.3, 3.7 Hz), 4.28 (2H, td, J = 13.9, 3.7 Hz), 4.00-3.90 (2H, m), 3.80 (3H, s).
Amine-33:(3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride
<Step-1>:methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate
The title compound is prepared in 98 % yield (2.0 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (1.5 g, 8.0 mmol) in a similar manner to Step-1 of Amine-27.
1H-NMR (300 MHz, CDCl3) delta 8.09 (1H, d, J = 2.2 Hz), 7.94 (1H, dd, J = 8.8, 2.2 Hz), 6.94 (1H, d, J = 8.0 Hz), 6.18 (1H, tt, J = 54.9, 4.4 Hz), 4.30 (2H, td, J = 12.5, 4.4 Hz), 3.91 (3H, s).
<Step-2>:(3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol
The title compound is prepared in >99 % yield (860 mg, clear colorless oil) from methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate (930 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.42 (1H, d, J = 2.2 Hz), 7.22 (1H, dd, J = 8.1, 2.2 Hz), 6.93 (1H, d, J = 8.8 Hz), 6.15 (1H, tt, J = 54.9, 4.4 Hz), 4.63 (2H, d, J = 5.1 Hz), 4.24 (2H, td, J = 12.8, 4.4 Hz), 1.75-1.65 (1H, m).
<Step-3>:2-chloro-4-(chloromethyl)-1-(2,2-difluoroethoxy)benzene
The title compound is prepared in >99 % yield (930 mg, clear colorless oil) from (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol (860 mg, 3.8 mmol, Step-2) in a similar manner to Step-3 of Amine-3.
MS (ESI) m/z: negative ion of an adduct signal (+HCO2 - ) 285 is observed.
<Step-4>:4-(azidomethyl)-2-chloro-1-(2,2-difluoroethoxy)benzene
The title compound is prepared in 88 % yield (840 mg, clear colorless oil) from 2-chloro-4-(chloromethyl)-1-(2,2-difluoroethoxy)benzene (930 mg, 3.8 mmol, Step-3) in a similar manner to Step-4 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.37 (1H, d, J = 2.2 Hz), 7.19 (1H, dd, J = 8.0, 2.2 Hz), 6.93 (1H, d, J = 8.8 Hz), 6.15 (1H, tt, J = 51.3, 4.4 Hz), 4.28 (2H, s), 4.24 (2H, td, J = 13.2, 3.2 Hz).
<Step-5>:(3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride
The title compound is prepared in 96 % yield (780 mg, white solid) from 4-(azidomethyl)-2-chloro-1-(2,2-difluoroethoxy)benzene (790 mg, 3.2 mmol, Step-4) in a similar manner to Step-3 of Amine-14.
1H-NMR (300 MHz, DMSO-d6) delta 8.26 (2H, br s), 7.63 (1H, s), 7.43 (1H, J = 8.8 Hz), 7.28 (1H, d, J = 8.8 Hz), 6.42 (1H, tt, J = 54.2, 4.4 Hz), 4.44 (2H, td, J = 14.6, 3.7 Hz), 3.98 (2H, s).
MS (ESI) m/z: positive ion of a fragment signal 205 is observed.
Amine-34:(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride
<Step-1>:3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid
To a stirred solution of 4-hydroxy-3-methylbenzoic acid (10 g, 65.7 mmol) and cesium carbonate (64.2 g, 197 mmol) in DMF (150 mL) is added 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.6 g, 145 mmol) at 0 oC. The mixture is stirred at 0 oC for 10 minutes then at rt for 2 days. To the mixture, water (150 mL) and NaOH pellet (10g) are added, and the mixture is stirred for 20 hours at rt. The mixture is diluted with water (100 mL). The aqueous phase is washed with ether (100 mLx2) and then acidified with conc. hydrochloric acid (pH 4) at 0 oC to give a white suspension. The precipitate is collected by filtration, washed with water and n-hexane, and dried in vacuo at 50 oC to give 14.8 g (96 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 7.98-7.90 (2H, m), 6.83 (1H, d, J = 8.0 Hz), 4.43 (2H, q, J = 7.3 Hz), 2.31 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 233 (M-H) -.
<Step-2>:(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol
The title compound is prepared in 80 % yield (5.26 g, white solid) from 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (7.00 g, 29.9 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.19-7.16 (2H, m), 6.78 (1H, d, J = 8.4 Hz), 4.62 (2H, d, J = 5.9 Hz), 4.35 (2H, q, J = 8.7 Hz), 2.27 (3H, s) (a signal due to OH is not observed), MS (ESI) m/z: positive ion of a fragment signal 203 is observed.
<Step-3>:2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione
The title compound is prepared in 80 % yield (6.68 g, white solid) from (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol (5.26 g, 23.9 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 7.85-7.83 (2H, m), 7.12-7.69 (2H, m), 7.26 (2H, m), 6.71 (1H, d, J = 8.8 Hz), 4.76 (2H, s), 4.30 (2H, q, J = 8.1 Hz), 2.22 (3H, s), MS (ESI) m/z: 350 (M+H) +.
<Step-4>:(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine
The title compound is prepared in >99 % yield (4.25 g, pale brown oil) from 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (6.68 g, 19.1 mmol, Step-3) in a similar manner to Step-4 of Amine-13.
1H-NMR (300 MHz, CDCl3) delta 7.13-7.09 (2H, m), 6.76 (1H, d, J = 8.1 Hz), 4.34 (2H, q, J = 8.1 Hz), 3.79 (2H, s), 2.26 (3H, s), MS (ESI) m/z: positive ion of a fragment signal 203 is observed.
Amine-35:1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>:2-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide
The title compound is prepared in 68 % yield (480 mg, a pale brown solid) from 2-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (600 mg, 2.4 mmol) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.32 (1H, d, J = 8.1 Hz), 7.01 (1H, d, J = 2.2 Hz), 6.89 (1H, dd, J = 8.1, 2.2 Hz), 4.37 (2H, q, J = 8.1 Hz), 3.48 (3H, br), 3.34 (3H, br), MS (ESI) m/z: 298 (M+H) +.
<Step-2>:1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone
The title compound is prepared in >99 % yield (400 mg, pale yellow oil) from 2-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide (470 mg, 1.6 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (270 MHz, CDCl3) delta 7.68 (1H, d, J = 8.6 Hz), 7.01 (1H, d, J = 2.6 Hz), 6.89 (1H, dd, J = 8.6, 2.6 Hz), 4.38 (2H, q, J = 7.9 Hz), 2.65 (3H, s).
<Step-3>:(R)-N-(1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 72 % yield (390 mg, clear colorless oil) from 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.40 (1H, d, J = 8.8 Hz), 6.97 (1H, s), 6.90-6.83 (1H, m), 5.00-4.90 (1H, m), 4.33 (2H, q, J = 8.0 Hz), 3.52 (1H, br), 1.50 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 358 (M+H) +.
<Step-4>:1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 71 % yield (220 mg, white solid) from (R)-N-(1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (380 mg, 1.0 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.57 (2H, br s), 7.69 (1H, d, J = 8.0 Hz), 7.30 (1H, d, J = 2.9 Hz), 7.20 (1H, dd, J = 8.8, 2.9 Hz), 4.83 (2H, q, J = 8.8 Hz), 4.70-4.60 (1H, m), 1.47 (3H, d, J = 6.6 Hz).
Amine-36:1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-fluoro-5-methylnicotinate
The title compound is prepared in 77 % yield (1.34 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.60 g, 10.3 mmol) in a similar manner to Step-1 of Amine-3.
MS (ESI) m/z: 170 (M+H) +.
<Step-2>:5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid
To a solution of sodium hydride (0.844 g, 21.1 mmol) in THF (10 mL), 3,3,3-trifluoropropan-1-ol (1.61 g, 14.1 mmol) in THF (10 mL) is added at 0 oC , and stirred for 5 minutes. Then methyl 6-fluoro-5-methylnicotinate (1.19 g, 7.04 mmol, Step-1) in THF (10 mL) is added dropwise to the reaction mixture and stirred at rt for 2 hours. The reaction mixture is diluted with water (30 mL) and stirred overnight. After removal of THF, the mixture is acidified with 2 M hydrochloric acid (11 mL). The resulting white precipitate is collected by filtration and dried to give 1.76 g (>99 % yield) of the title compound as white solid. This material is used for the next reaction (Step-3) without further purification.
MS (ESI) m/z: 250 (M+H) +.
<Step-3>:N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropoxy)nicotinamide
The title compound is prepared in >99 % yield (2.16 g, colorless oil) from 5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid (1.76 g, 7.06 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.44 (1H, s), 7.81 (1H, s), 4.61 (2H, t, J = 6.5 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.71-2.57 (2H, m), 2.20 (3H, s), MS (ESI) m/z: 293 (M+H) +.
<Step-4>:1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in 90 % yield (1.63 g, colorless oil) from N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropoxy)nicotinamide (2.15 g, 7.36 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 1.4 Hz), 4.64 (2H, d, J = 6.5 Hz), 2.72-2.59 (2H, m), 2.56 (3H, s), 2.22 (3H, s).
<Step-5>:(R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 65 % yield (1.50 g, colorless oil) from 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (1.63 g, 6.59 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.93 (1H, d, J = 1.8 Hz), 7.39 (1H, d, J = 1.1 Hz), 4.55 (2H, t, J = 6.2 Hz), 4.49 (1H, m), 3.30 (1H, br s), 2.69-2.54 (2H, m), 2.18 (3H, s), 1.50 (3H, d, J = 6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 353 (M+H) +.
<Step-6>:1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (1.44 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.5 g, 4.26 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.36 (2H, br s), 8.08 (1H, s), 7.73 (1H, s), 4.49 (2H, t, J = 6.2 Hz), 4.37 (1H, m), 2.83-2.72 (2H, m), 2.13 (3H, s), 1.49 (3H, d, J = 7.0 Hz), MS (ESI) m/z: positive ion of a fragment signal 232 is observed.
Amine-37:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Amine-2)
<Step-1>:(S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide
The title compound is prepared in 83 % yield (0.79 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.66 g, 2.81 mmol, Step-3 of Amine-2) and (S)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.93 (1H, d, J = 1.84 Hz), 7.44 (1H, s), 4.76 (2H, q, J = 8.4 Hz), 4.54-4.46 (1H, m), 3.32 (1H, d, J = 2.6 Hz), 2.24 (3H, s), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 339 (M+H) +.
<Step-2>:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Amine-2)
The title compound is prepared in 88 % yield (0.56 g, white solid) from (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer; antipode of Amine-2) (0.79 g, 2.33 mmol, Step-2) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.41 (2H, br s), 8.13 (1H, d, J = 2.2 Hz), 7.82 (1H, d, J = 1.8 Hz), 5.02 (2H, q, J = 9.2 Hz), 4.44-4.37 (1H, m), 2.19 (3H, s), 1.50 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 235 (M+H) +.
Amine-38: (6-(4-fluorophenoxy)pyridin-3-yl)methanamine
(6-(4-Fluorophenoxy)pyridin-3-yl)methanamine (Amine-38) is commercially available.
Amine-39: 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(4-fluorophenoxy)-5-methylnicotinate
A mixture of methyl 6-fluoro-5-methylnicotinate (2.40 g, 14.2 mmol, Step-1 of Amine-36), 4-fluorophenol (2.39 g, 21.3 mmol), and potassium carbonate (3.92 g, 28.4 mmol) in DMF (45 mL) is stirred at 90 oC for 3 hours. After cooling to rt, the mixture is filtered through a pad of Celite and rinsed with EtOAc (200 mL). The filtrate is washed with water (200 mL) and brine (200 mL), and the organic layer is dried over sodium sulfate. After filtration, and the filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1) to give 3.46 g (93 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 8.59 (1H, d, J = 2.2 Hz), 8.12 (1H, d, J = 2.2 Hz), 7.15-7.06 (4H, m), 3.90 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 262 (M+H) +.
<Step-2>:6-(4-fluorophenoxy)-5-methylnicotinic acid
The title compound is prepared in 91 % yield (2.98 g, white solid) from methyl 6-(4-fluorophenoxy)-5-methylnicotinate (3.46 g, 13.2 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 8.67 (1H, d, J = 2.2 Hz), 8.16 (1H, d, J = 2.2 Hz), 7.18-7.06 (4H, m), 2.40 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 248 (M+H) +.
<Step-3>:6-(4-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in >99 % yield (3.00 g, colorless oilcolorless oil) from 6-(4-fluorophenoxy)-5-methylnicotinic acid (2.50 g, 10.1 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.40 (1H, d, J = 1.4 Hz), 7.94 (1H, s), 7.12 (2H, s), 7.10 (2H, s), 3.57 (3H, s), 3.36 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 291 (M+H) +.
<Step-4>:1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in 97 % yield (2.47 g, white solid) from 6-(4-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (3.00 g, 10.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.54 (1H, d, J = 2.2 Hz), 8.11 (1H, s), 7.13 (2H, s), 7.10 (2H, s), 2.55 (3H, s), 2.41 (3H, s), MS (ESI) m/z: 246 (M+H) +.
<Step-5>:(R)-N-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 76 % yield (2.67 g, white solid) from 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.47 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.93 (1H, d, J = 2.2 Hz), 7.52 (1H, d, J = 2.2 Hz), 7.09 (2H, s), 7.07 (2H, s), 4.54-4.47 (1H, m), 3.33 (1H, d, J = 2.9 Hz), 2.36 (3H, s), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 351 (M+H) +.
<Step-6>:1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (2.33 g, a pale brown solid) from (R)-N-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.67 g, 7.62 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.51 (3H, br s), 8.02 (1H, s), 8.91 (1H, s), 7.28-7.21 (2H, m), 7.17-7.127 (2H, m), 4.45-4.32 (1H, m), 2.33 (3H, s), 1.52 (3H, d, J = 7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 230 is observed.
Amine-40: 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(3-fluorophenoxy)-5-methylnicotinate
The title compound is prepared in >99 % yield (1.78 g, a pale brown oil) from 3-fluorophenol (994 mg, 8.87 mmol) in a similar manner to Step-1 of Amine-39.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, d, J = 2.2 Hz), 8.15 (1H, d, J = 2.2 Hz), 7.41-7.33 (1H, m), 6.97-6.88 (3H, m), 3.91 (3H, s), 2.45 (3H, s), MS (ESI) m/z: 262 (M+H) +.
<Step-2>:6-(3-fluorophenoxy)-5-methylnicotinic acid
The title compound is prepared in 99 % yield (1.66 g, white solid) from methyl 6-(3-fluorophenoxy)-5-methylnicotinate (1.78 g, 6.81 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 8.70 (1H, d, J = 2.2 Hz), 8.18 (1H, d, J = 1.5 Hz), 7.43-7.35 (1H, m), 7.00-6.89 (3H, m), 2.42 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 248 (M+H) +.
<Step-3>:6-(3-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in 70 % yield (1.37 g, white solid) from 6-(3-fluorophenoxy)-5-methylnicotinic acid (1.66 g, 6.71 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.43 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 1.5 Hz), 7.40-7.33 (1H, m), 6.96-6.88 (3H, m), 3.58 (3H, s), 3.37 (3H, s), 2.38 (3H, s), MS (ESI) m/z: 291 (M+H) +.
<Step-4>:1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in 98 % yield (1.13 g, white solid) from 6-(3-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (1.37 g, 4.72 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, d, J = 2.9 Hz), 8.12 (1H, d, J = 1.5 Hz), 7.42-7.35 (1H, m), 6.99-6.89 (3H, m), 2.56 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 246 (M+H) +.
<Step-5>:(R)-N-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 79 % yield (1.27 g, colorless amorphous) from 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (1.13 g, 4.61 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (838 mg, 6.91 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.98 (1H, d, J = 2.2 Hz), 7.54 (1H, d, J = 2.2 Hz), 7.38-7.30 (1H, m), 6.93-6.84 (3H, m), 4.56-4.51 (1H, m), 3.35 (1H, d, J = 2.9 Hz), 2.35 (3H, s), 1.52 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 351 (M+H) +.
<Step-6>:1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (1.19 g, an off-white solid) from (R)-N-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.27 g, 3.62 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.55 (3H, br s), 8.08 (1H, s), 7.95 (1H, s), 7.49-7.41 (1H, m), 7.10-6.94 (3H, m), 4.44-4.38 (1H, m), 2.32 (3H, s), 1.53 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 230 is observed.
Amine-41: 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinate
The title compound is prepared in 96 % yield (1.78 g, white solid) from 6-(trifluoromethyl)pyridin-3-ol (1.45 g, 8.87 mmol) in a similar manner to Step-1 of Amine-39.
1H-NMR (300 MHz, CDCl3) delta 8.61 (1H, d, J = 2.2 Hz), 8.59 (1H, d, J = 2.2 Hz), 8.20 (1H, d, J = 2.2 Hz), 7.79-7.70 (2H, m), 3.93 (3H, s), 2.44 (3H, s), MS (ESI) m/z: 313 (M+H) +.
<Step-2>:5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinic acid
The title compound is prepared in 98 % yield (1.67 g, white solid) from methyl 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinate (1.78 g, 5.70 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 8.66 (1H, d, J = 2.2 Hz), 8.63 (1H, d, J = 2.2 Hz), 8.24 (1H, s), 7.80-7.72 (2H, m), 2.46 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 299 (M+H) +.
<Step-3>:N-methoxy-N,5-dimethyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinamide
The title compound is prepared in >99 % yield (2.14 g, white solid) from 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinic acid (1.67 g, 5.60 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.61 (1H, d, J = 2.2 Hz), 8.39 (1H, d, J = 2.2 Hz), 8.00 (1H, d, J = 1.5 Hz), 7.78-7.70 (2H, m), 3.58 (3H, s), 3.38 (3H, s), 2.42 (3H, s), MS (ESI) m/z: 342 (M+H) +.
<Step-4>:1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone
The title compound is prepared in 91 % yield (1.69 g, white solid) from N-methoxy-N,5-dimethyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinamide (2.14 g, 6.27 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, d, J = 2.2 Hz), 8.53 (1H, d, J = 1.5 Hz), 8.17 (1H, s), 7.79-7.70 (2H, m), 2.58 (3H, s), 2.45 (3H, s), MS (ESI) m/z: 297 (M+H) +.
<Step-5>:(R)-2-methyl-N-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 73 % yield (1.67 g, colorless amorphous) from 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone (1.69 g, 5.70 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.56 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 2.9 Hz), 7.94 (1H, d, J = 2.9 Hz), 7.75-7.65 (2H, m), 7.60 (1H, d, J = 2.2 Hz), 4.58-4.52 (1H, m), 3.36 (1H, d, J = 3.7 Hz), 2.39 (3H, s), 1.53 (3H, d, J = 7.3 Hz), 1.24 (9H, s), MS (ESI) m/z: 402 (M+H) +.
<Step-6>:1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 89 % yield (1.25 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.69 g, 4.20 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.66 (1H, d, J = 2.2 Hz), 8.46 (3H, br s), 8.08 (1H, s), 8.03-8.99 (2H, m), 7.90 (1H, dd, J = 8.8, 2.2 Hz), 4.50-4.38 (1H, m), 2.38 (3H, s), 1.53 (3H, d, J = 7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 281 is observed.
Amine-42: 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-((4-fluorophenyl)thio)-5-methylnicotinate
The title compound is prepared in 86 % yield (2.83 g, white solid) from 4-fluorobenzenethiol (1.89 g, 14.8 mmol) in a similar manner to Step-1 of Amine-39.
1H -NMR (300 MHz, CDCl3) delta 8.75 (1H, d, J = 2.2 Hz), 7.94 (1H, d, J = 1.5 Hz), 7.56-7.49 (2H, m), 7.17-7.09 (2H, m), 3.89 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 278 (M+H) +.
<Step-2>:6-((4-fluorophenyl)thio)-5-methylnicotinic acid
The title compound is prepared in >99 % yield (2.71 g, white solid) from methyl 6-((4-fluorophenyl)thio)-5-methylnicotinate (2.83 g, 10.2 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, CDCl3) delta 8.80 (1H, d, J = 1.5 Hz), 7.96 (1H, d, J = 1.5 Hz), 7.56-7.51 (2H, m), 7.17-7.10 (2H, m), 2.41 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 264 (M+H) +.
<Step-3>:6-((4-fluorophenyl)thio)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in >99 % yield (3.16 g, colorless oil) from 6-((4-fluorophenyl)thio)-5-methylnicotinic acid (2.70 g, 10.3 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 2.2 Hz), 7.74 (1H, d, J = 1.5 Hz), 7.56-7.50 (2H, m), 7.16-7.08 (2H, m), 3.55 (3H, s), 3.35 (3H, s), 2.39 (3H, s)., MS (ESI) m/z: 307 (M+H) +.
<Step-4>:1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (2.71 g, an off-white solid) from 6-((4-fluorophenyl)thio)-N-methoxy-N,5-dimethylnicotinamide (3.16 g, 10.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.70 (1H, d, J = 2.2 Hz), 7.90 (1H, d, J = 1.5 Hz), 7.57- 7.50 (2H, m), 7.18-7.10 (2H, m), 2.53 (3H, s), 2.41 (3H, s), MS (ESI) m/z: 262 (M+H) +.
<Step-5>:(R)-N-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 74 % yield (2.82 g, white solid) from 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone (2.71 g, 10.4 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.89 g, 15.6 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.18 (1H, d, J = 2.2 Hz), 7.53-7.48 (2H, m), 7.36 (1H, d, J = 2.2 Hz), 7.14-7.06 (2H, m), 4.56-4.40 (1H, m), 3.33 (1H, br s), 2.36 (3H, s), 1.49 (3H, d, J = 6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 367 (M+H) +.
<Step-6>:1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (2.81 g, an off-white solid) from (R)-N-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.82 g, 7.69 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.65 (3H, br s), 8.27 (1H, d, J = 2.2 Hz), 7.80 (1H, d, J = 1.4 Hz), 7.57-7.52 (2H, m), 7.29 (2H, t, J = 9.2 Hz), 4.39-4.31 (1H, m), 2.33 (3H, s), 1.51 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 246 is observed.
Amine-43: 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(4-chlorophenoxy)-5-methylnicotinate
The title compound is prepared in 90 % yield (2.22 g, white solid) from 4-chlorophenol (1.71 g, 13.3 mmol) in a similar manner to Step-1 of Amine-39.
1H -NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 2.2 Hz), 8.13 (1H, s), 7.38 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 3.91 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 278 (M+H) +.
<Step-2>:6-(4-chlorophenoxy)-5-methylnicotinic acid
The title compound is prepared in >99 % yield (2.11 g, white solid) from methyl 6-(4-chlorophenoxy)-5-methylnicotinate (2.22 g, 7.99 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, CDCl3) delta 8.67 (1H, d, J = 1.5 Hz), 8.16 (1H, s), 7.39 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.0 Hz), 2.41 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 264 (M+H) +.
<Step-3>:6-(4-chlorophenoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in >99 % yield (2.50 g, colorless oil) from 6-(4-chlorophenoxy)-5-methylnicotinic acid (2.11 g, 8.00 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.41 (1H, d, J = 2.2 Hz), 7.94 (1H, d, J = 1.5 Hz), 7.38 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 3.57 (3H, s), 3.37 (3H, s), 2.38 (3H, s), MS (ESI) m/z: 307 (M+H) +.
<Step-4>:1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in 95 % yield (2.02 g, white solid) from 6-(4-chlorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (2.50 g, 8.15 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 1.4 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 2.55 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 262 (M+H) +.
<Step-5>:(R)-N-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 83 % yield (2.36 g, white solid) from 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone (2.02 g, 7.72 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.95 (1H, s), 7.53 (1H, s), 7.35 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 4.55-4.47 (1H, m), 3.34 (1H, br s), 2.35 (3H, s), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 367 (M+H) +.
<Step-6>:1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (2.17 g, an off-white solid) from (R)-N-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.36 g, 6.43 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.46 (3H, br s), 8.05 (1H, s), 7.92 (1H, s), 7.47 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 4.42-4.36 (1H, m), 2.33 (3H, s), 1.52 (3H, d, J = 7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 246 is observed.
Amine-44: 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(3,4-difluorophenoxy)-5-methylnicotinate
The title compound is prepared in 91 % yield (2.26 g, white solid) from 3,4-difluorophenol (1.73 g, 13.3 mmol) in a similar manner to Step-1 of Amine-39.
1H -NMR (300 MHz, CDCl3) delta 8.60 (1H, d, J = 2.2 Hz), 8.14 (1H, d, J = 1.5 Hz), 7.20 (1H, q, J = 9.3 Hz), 7.06-6.99 (1H, m), 9.62-6.86 (1H, m), 3.91 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 280 (M+H) +.
<Step-2>:6-(3,4-difluorophenoxy)-5-methylnicotinic acid
The title compound is prepared in >99 % yield (2.21 g, white solid) from methyl 6-(3,4-difluorophenoxy)-5-methylnicotinate (2.26 g, 8.09 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, CDCl3) delta 8.68 (1H, d, J = 2.2 Hz), 8.18 (1H, d, J = 2.2 Hz), 7.26-7.17 (1H, m), 7.07-7.00 (1H, m), 6.93-6.88 (1H, m), 2.41 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 266 (M+H) +.
<Step-3>:6-(3,4-difluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in 95 % yield (2.44 g, yellows oil) from 6-(3,4-difluorophenoxy)-5-methylnicotinic acid (2.21 g, 8.33 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.41 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 1.5 Hz), 7.20 (1H, dd, J = 19.0, 8.8 Hz), 7.06-7.00 (1H, m), 6.93-6.97 (1H, m), 3.58 (3H, s), 3.37 (3H, s), 2.38 (3H, s), MS (ESI) m/z: 309 (M+H) +.
<Step-4>:1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in 96 % yield (2.00 g, white solid) from 6-(3,4-difluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (2.44 g, 7.91 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.55 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 1.5 Hz), 7.26-7.17 (1H, m), 7.07-7.7.00 (1H, m), 6.91-6.87 (1H, m), 2.56 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 264 (M+H) +.
<Step-5>:(R)-N-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 73 % yield (2.03 g, white solid) from 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.00 g, 7.60 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.38 g, 11.4 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.95 (1H, s), 7.54 (1H, s), 7.17 (1H, dd, J = 18.7, 8.8 Hz), 7.02-6.95 (1H, m), 6.88-6.83 (1H, m), 4.52-4.48 (1H, m), 3.34 (1H, br s), 2.35 (3H, s), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 369 (M+H) +.
<Step-6>:1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (1.95 g, white solid) from (R)-N-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.03 g, 5.51 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.42 (3H, br s), 8.05 (1H, s), 7.91 (1H, s), 7.49 (1H, dd, J = 19.4, 9.8 Hz), 7.37-7.30 (1H, m), 7.02-7.96 (1H, m), 4.45-4.37 (1H, m), 2.33 (3H, s), 1.51 (3H, d, J = 7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 248 is observed.
Amine-45: 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate
A mixture of methyl 6-fluoro-5-methylnicotinate (800 mg, 4.73 mmol, Step-1 of Amine-36), 4-chloro-1H-pyrazole (509 mg, 4.97 mmol), and cesium carbonate (3.08 g, 9.46 mmol) in DMF (16 mL) stirred at 60 oC for 1 hour. After cooling to rt, the mixture is diluted with EtOAc (150 mL) and washed with water (100 mLx3). The organic phase is filtered through silica gel, and the filtrate is concentrated to give 1.19 g (>99 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 8.88 (1H, d, J = 1.5 Hz), 8.43 (1H, s), 8.26 (1H, s), 7.68 (1H, s), 3.97 (3H, s), 2.68 (3H, s), MS (ESI) m/z: 252 (M+H) +.
<Step-2>:6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid
The title compound is prepared in 80 % yield (904 mg, white solid) from methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate (1.19 g, 4.7 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.81 (1H, s), 8.69 (1H, s), 8.36 (1H, s), 7.99 (1H, s), 2.56 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 236 (M-H) -.
<Step-3>:6-(4-chloro-1H-pyrazol-1-yl)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in 98 % yield (1.50 g, colorless oil) from 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid (1.30 g, 5.47 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.67 (1H, d, J = 1.5 Hz), 8.37 (1H, s), 8.04 (1H, d, J = 1.5 Hz), 7.68 (1H, s), 3.59 (3H, s), 3.41 (3H, s), 2.64 (3H, s), MS (ESI) m/z: 281 (M+H) +.
<Step-4>:1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (1.30 g, a pale yellow solid) from 6-(4-chloro-1H-pyrazol-1-yl)-N-methoxy-N,5-dimethylnicotinamide (1.50 g, 5.34 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.83 (1H, d, J = 2.2 Hz), 8.44 (1H, s), 8.20 (1H, d, J = 2.2 Hz), 7.69 (1H, s), 2.70 (3H, s), 2.65 (3H, s), MS (ESI) m/z: 236 (M+H) +.
<Step-5>:(R)-N-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 57 % yield (1.08 g, colorless amorphous) from 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone (1.30 g, 5.52 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.00 g, 8.27 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.29 (1H, s), 8.22 (1H, s), 7.65 (2H, s), 4.65-4.57 (1H, m), 3.42 (1H, d, J = 2.9 Hz)., 2.57 (3H,s), 1.58 (3H, d, J = 8.8 Hz), 1.25 (9H, s), MS (ESI) m/z: 341 (M+H) +.
<Step-6>:1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (951 mg, white solid) from (R)-N-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.08 g, 3.17 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.70 (3H, Br s), 8.60 (1H, s), 8.51 (1H, s), 8.11 (1H, s), 7.94 (1H, s), 4.58-4.50 (1H, m), 2.51 (3H, s), 1.59 (3H, d, J = 6.6), MS (ESI) m/z: positive ion of a fragment signal 220 is observed.
Amine-46: 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (single enantiomer)
<Step-1>:5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid
A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol, Step-1 of Amine-36) and 2,2,2-trifluoroethanamine (9.37 g, 95 mmol) in N-methylpyrrolidone (24 mL) is stirred at 220 oC for 2.5 hours under microwave irradiation. The mixture is diluted with MeOH (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) is added to the mixture. After stirring at 50 oC for 1 hour, the mixture is acidified by 2 M hydrochloric acid, and extracted with EtOAc/hexane (100 mLx3). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is crystallized from diisopropyl ether to give 884 mg (32 %) of the title compound as a pale pink solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.49 (1H, s), 7.78 (1H, s), 7.17 (1H, t, J = 6.6 Hz), 4.35-4.21 (2H, m), 2.14 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 233 (M-H) -.
<Step-2>:N-methoxy-N,5-dimethyl-6-((2,2,2-trifluoroethyl)amino)nicotinamide
The title compound is prepared in >99 % yield (1.65 g, colorless oil) from 5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid (1.38 g, 5.89 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.54 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 1.4 Hz), 4.63 (1H, br s), 4.38-4.27 (2H, m), 3.60 (3H, s), 3.36 (3H, s), 2.17 (3H, s), MS (ESI) m/z: 278 (M+H) +.
<Step-3>:1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone
The title compound is prepared in 92 % yield (1.27 g, a pale yellow solid) from N-methoxy-N,5-dimethyl-6-((2,2,2-trifluoroethyl)amino)nicotinamide (1.65 g, 5.95 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.65 (1H, d, J = 2.2 Hz), 7.89 (1H, d, J = 1.5 Hz), 4.81 (1H, br s), 4.42-4.31 (2H, m), 2.53 (3H, s), 2.19 (3H, s), MS (ESI) m/z: 233 (M+H) +.
<Step-4>:(R)-2-methyl-N-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 95 % yield (1.76 g, pale yellow amorphous) from 1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (1.27 g, 5.47 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.33 g, 10.9 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.00 (1H, d, J = 2.2 Hz), 7.29 (1H, d, J = 2.2 Hz), 4.52-4.21 (4H, m), 3.30 (1H, br s), 2.15 (3H, s), 1.49 (3H, d, J = 6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 338 (M+H) +.
<Step-5>:5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (1.87 g, a off-white solid) from (R)-2-methyl-N-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.76 g, 5.22 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.38 (3H, br s), 8.05 (1H, s), 7.70 (1H, br s), 4.34 (3H, br s), 2.17 (3H, s), 1.50 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 234 (M+H) +.
Amine-47: 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:methyl 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinate
The title compound is prepared in 71 % yield (2.39 g, a off-white solid) from 4-(trifluoromethyl)-1H-pyrazole (1.93 g, 14.2 mmol) in a similar manner to Step-1 of Amine-45.
1H -NMR (300 MHz, CDCl3) delta 8.91 (1H, d, J = 1.5 Hz), 8.73 (1H, s), 8.31 (1H, d, J = 1.4 Hz), 7.94 (1H, s), 3.98 (3H, s), 2.69 (3H, s), MS (ESI) m/z: 286 (M+H) +.
<Step-2>:5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinic acid
The title compound is prepared in >99 % yield (2.35 g, a pale yellow solid) from methyl 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinate (2.39 g, 8.38 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, DMSO-d6) delta 9.02 (1H, s), 8.81 (1H, s), 8.34 (1H, s), 8.28 (1H, s), 2.49 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 272 (M+H) +.
<Step-3>:N-methoxy-N,5-dimethyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide
The title compound is prepared in 91 % yield (2.47 g, white solid) from 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinic acid (2.35 g, 7.86 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.70 (1H, d, J = 1.5 Hz), 8.67 (1H, s), 8.08 (1H, d, J = 1.5 Hz), 7.93 (1H, s), 3.60 (3H, s), 3.42 (3H, s), 2.66 (3H, s), MS (ESI) m/z: 315 (M+H) +.
<Step-4>:1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanone
The title compound is prepared in 96 % yield (2.04 g, yellow solid) from N-methoxy-N,5-dimethyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide (2.47 g, 7.86 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.86 (1H, d, J = 2.2 Hz), 8.74 (1H, s), 8.24 (1H, d, J = 1.4 Hz), 7.94 (1H, s), 2.71 (3H, s), 2.67 (3H, s), MS (ESI) m/z: 270 (M+H) +.
<Step-5>:(R)-2-methyl-N-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 78 % yield (2.16 g, yellows oil) from 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (2.00 g, 7.43 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.35 g, 11.1 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.51 (1H, s), 8.32 (1H, d, J = 2.2 Hz), 7.90 (1H, s), 7.69 (1H, d, J = 1.5 Hz), 4.67-4.59 (1H, m), 3.44 (1H, d, J = 3.7 Hz), 2.58 (3H, s), 1.60-1.58 (3H, m), 1.26 (9H, s), MS (ESI) m/z: 375 (M+H) +.
<Step-6>:1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 98 % yield (1.74 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (2.16 g, 5.77 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.98 (1H, s), 8.60 (3H, br s), 8.54 (1H, s), 8.27 (1H, s), 8.13 (1H, s), 4.62-4.51 (1H, m), 2.45 (3H, s), 1.59 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 254 is observed.
Amine-48: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (2:1)
To a stirred solution of 2,2,2-trifluoroethanol (2.03 g, 20.2 mmol), DMF (20 mL) and THF (10 mL) is added 60 % sodium hydride (0.78 g, 20.2 mmol) at 0 oC carefully. After stirring at rt for 1 hour, this solution is added to a solution of 3,6-dichloro-4-methylpyridazine (3.00 g, 18.4 mmol) in DMF (20 mL) at 0 oC slowly. The resulting mixture is stirred at rt for 1 hour. The mixture is poured onto ice-water, and extracted with EtOAc (200 mL). The organic layer is washed with water (200 mLx2), and dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (9:1) to give 3.40 g of a mixture of the title compound (81 % yield) as white solid.
MS (ESI) m/z: 227 (M+H) +.
<Step-2>: ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate and ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate
A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (3.40 g, 15.0 mmol, Step-1), palladium(II) acetate (0.34 g, 1.50 mmol), 1,3-bis(diphenylphosphino)propane (1.24 g, 3.00 mmol), triethylamine (6.27 mL, 45.0 mmol), DMF (40 mL), and EtOH (20 mL) is stirred at 80 oC under carbon monoxide atmosphere (1 atm) for 20 hours. After cooling to rt, the mixture is diluted with EtOAc (200 mL). This is washed with water (200 mLx2), and the organic layer is dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (8:1-5:1) to give 2.15 g of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (54 % yield, more polar product) as an off-white solid and 0.63 g of ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (16 % yield, less polar product) as pale yellow oil.
ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (more polar)
1H-NMR (300 MHz, CDCl3) delta 7.99 (1H, d, J = 1.5 Hz), 5.02 (2H, q, J = 8.1 Hz), 4.50 (2H, q, J = 7.3 Hz), 2.36 (3H, s), 1.46 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 265 (M+H) +.
ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (less polar)
1H-NMR (300 MHz, CDCl3) delta 7.00 (1H, s), 4.99 (2H, q, J = 8.1 Hz), 4.49 (2H, q, J = 7.3 Hz), 2.58 (3H, s), 1.46 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 265 (M+H) +.
<Step-3>:5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylic acid
The title compound is prepared in >99 % yield (1.17 g, a pale brown solid) from ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (1.32 g, 5.00 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, CDCl3) delta 7.98 (1H, s), 5.19 (2H, q, J = 8.8 Hz), 2.23 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 237 (M+H) +.
<Step-4>:N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide
The title compound is prepared in 97 % yield (1.33 g, white solid) from 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylic acid (1.85 g, 4.94 mmol, Step-3) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.61 (1H, br s), 4.99 (2H, q, J = 8.3 Hz), 3.84 (3H, s), 3.44 (3H, br s), 2.33 (3H, s), MS (ESI) m/z: 280 (M+H) +.
<Step-5>:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanone
The title compound is prepared in 98 % yield (1.09 g, yellow solid) from N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide (1.33 g, 4.76 mmol, Step-4) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.97 (1H, s), 5.04 (2H, q, J = 8.1 Hz), 2.84 (3H, s), 2.35 (3H, s), MS (ESI) m/z: 235 (M+H) +.
<Step-6>:(R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 56 % yield (402 mg, brown oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanone (500 mg, 2.14 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (388 mg, 3.20 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.31 (1H, s), 4.99-4.85 (2H, m), 4.67 (1H, q, J = 8.8 Hz), 4.57 (1H, d, J = 5.9 Hz), 2.29 (3H, s), 1.57 (3H, d, J = 6.6 Hz), 1.26 (9H, s), MS (ESI) m/z: 340 (M+H) +.
<Step-7>:1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (390 mg, brown amorphous) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (402 mg, 1.19 mmol, Step-6) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.88 (3H, br s), 7.91 (1H, s), 5.27 (2H, q, J = 8.8 Hz), 4.71-4.63 (1H, m), 2.31 (3H, s), 1.62 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 236 (M+H) +, optical purity (chiral HPLC): 99 %e.e.
Amine-49: 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:2-chloro-4-methyl-5-(2,2,2-trifluoroethoxy)pyridine
To a mixture of 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and cesium carbonate (6.81 g, 20.9 mmol) in DMF (40 mL) is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.56 g, 15.3 mmol) at 0 oC. After stirring at rt for 1 hour, the mixture is poured onto water (300 mL). The aqueous layer is extracted with EtOAc (300 mL). The separated organic layer is washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (9:1) to give 3.00 g (95 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 7.90 (1H, s), 7.17 (1H, s), 4.43 (2H, q, J = 7.3 Hz), 2.28 (3H, s), MS (ESI) m/z: 226 (M+H) +.
<Step-2>:ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate
The title compound is prepared in 90 % yield (3.14 g, white solid) from 2-chloro-4-methyl-5-(2,2,2-trifluoroethoxy)pyridine (3.00 g, 13.3 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 8.24 (1H, s), 8.00 (1H, s), 4.57-4.42 (4H, m), 2.35 (3H, s), 1.44 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 264 (M+H) +.
<Step-3>: 4-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid
The title compound is prepared in 92 % yield (2.72 g, white solid) from ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate (3.30 g, 12.5 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, CDCl3) delta 8.12 (1H, s), 8.09 (1H, s), 4.55 (2H, q, J = 7.6 Hz), 2.39 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 236 (M+H) +, 234 (M-H) -.
<Step-4>:N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide
The title compound is prepared in >99 % yield (1.6 g, a off-white solid) from 4-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (1.0 g, 4.3 mmol, Step-3) in a similar manner to Step-2 of Amine-1.
1H-NMR (300 MHz, CDCl3, 1 drop of DMSO-d6 is added) delta 8.14 (1H, s), 7.58 (1H, br s), 4.51 (2H, q, J = 8.1 Hz), 3.76 (3H, s), 3.41 (3H, s), 2.32 (3H, s), MS (ESI) m/z: 279 (M+H) +.
<Step-5>:4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde
The title compound is prepared in 95 % yield (1.2 g, a pale brown solid) from N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide (1.6 g, 5.8 mmol, Step-2) and lithium aluminum hydride (80 mg, 2.9 mmol) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 9.98 (1H, s), 8.29 (1H, s), 7.85 (1H, s), 4.57 (2H, q, J = 8.1 Hz), 2.36 (3H, s), MS (ESI) m/z: 220 (M+H) +.
<Step-6>:(R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide
A mixture of 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde (1.6 g, 7.3 mmol, Step-5), (R)-2-methylpropane-2-sulfinamide (1.33 g, 11.0 mmol), and titanium tetraethoxide (2.50 g, 11.0 mmol) in THF (30 mL) is refluxed with stirring for 2 hours. After cooling to 0 oC, water (30 mL) and EtOAc (80 mL) are added to the mixture, and this is filtered through a pad of Celite. The filtrate is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.14 g (48 % yield) of the title compound as a pale yellow solid.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, s), 8.25 (1H, s), 7.88 (1H, s), 4.53 (2H, q, J = 8.0 Hz), 2.36 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 323 (M+H) +.
<Step-7>:(R)-2-methyl-N-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)
To a solution of (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.1 g, 3.4 mmol, Step-6) in DCM (50 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.97 M, 7.0 mL, 6.8 mmol) at -78 oC. After stirring at -78 oC for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer is extracted with DCM (100 mLx2). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:3) to give 1.09 g (94 % yield) of the title compound as colorless oil.
1H-NMR (300 MHz, CDCl3) delta 8.08 (1H, s), 7.12 (1H, s), 4.65 (1H, d, J = 5.4 Hz), 4.54-4.46 (1H, m), 4.42 (2H, q, J = 7.9 Hz), 2.28 (3H, s), 1.48 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 337 (M-H) -.
<Step-8>:1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (1.1 g, white solid) from (R)-2-methyl-N-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.1 g, 3.3 mmol, Step-7) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.42 (3H, br s), 8.38 (1H, s), 7.43 (1H, s), 4.95 (2H, q, J = 8.8 Hz), 4.50-4.38 (1H, m), 2.22 (3H, s), 1.45 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 235 (M+H) +.
Amine-50: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride
<Step-1>:(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanol
To a solution of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (1.70 g, 6.43 mmol, Step-2 of Amine-48) in THF (32 mL) is added a solution of lithium borohydride in THF (3 M, 3.22 mL, 9.65 mmol) at 0 oC. After stirring at 0 oC for 4 hours, the reaction is quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture is filtered through a pad of Celite, and the filtrate is extracted with EtOAc (200 mL). The separated organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:2) to give 1.22 g (85 % yield) of the title compound as white solid.
1H -NMR (300 MHz, CDCl3) delta 7.3 (1H, s), 4.93 (2H, q, J = 8.3 Hz), 4.86 (2H, d, J = 5.1 Hz), 2.31 (3H, s), 1.20 (1H, d, J = 7.3 Hz), MS (ESI) m/z: 223 (M+H) +.
<Step-2>:2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in >99 % yield (1.41 g, white solid) from (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanol (880 mg, 3.96 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 7.90-7.87 (2H, m), 7.77-7.73(2H, m), 7.30 (1H, s) 5.08 (2H, s), 4.88 (2H, q, J = 8.3 Hz), 2.27 (3H, s), MS (ESI) m/z: 352 (M+H) +.
<Step-3>:(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride
The title compound is prepared in 83 % yield (854 mg, an off-white solid) from 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)isoindoline-1,3-dione (1.41 g, 4.01 mmol, Step-1) in a similar manner to Step-5 of Amine-12.
1H -NMR (300 MHz, DMSO-d6) delta 8.59 (3H, br s), 7.72 (1H, s), 5.22 (2H, q, J = 9.0 Hz), 4.30-4.24 (2H, m), 2.25 (3H, s), MS (ESI) m/z: 222 (M+H) +.
Amine-51: (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride
<Step-1>:(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol
The title compound is prepared in 98 % yield (0.93 g, yellows oil) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (1.00 g, 3.74 mmol, Step-1 of Amine-17) in a similar manner to Step-2 of Intermediate-A1.
1H-NMR (300 MHz, DMSO-d6) delta 7.93 (1H, s), 7.57 (1H, s), 6.68 (1H, tt, J = 52.0, 5.9 Hz), 5.19 (1H, t, J = 5.9 Hz), 4.84 (2H, t, J = 13.9 Hz), 4.43 (2H, d, J = 5.9 Hz), 2.18 (3H, s), MS (ESI) m/z: 254 (M+H) +.
<Step-2>:5-(chloromethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine
The title compound is prepared in >99 % yield (1.02 g, yellows oil) from (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (930 mg, 3.67 mmol, Step-1) in a similar manner to Step-3 of Amine-3.
MS (ESI) m/z: 272 (M+H) +.
<Step-3>:5-(azidomethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine
The title compound is prepared in 74 % yield (770 mg, yellows oil) from 5-(chloromethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine (1.02 g, 3.75 mmol, Step-2) in a similar manner to Step-4 of Amine-3.
1H -NMR (300 MHz, CDCl3) delta 7.93 (1H, s), 7.44 (1H, s), 6.00 (1H, tt, J =53.5, 4.4 Hz), 4.75 (2H, dt, J = 11.0, 1.5 Hz), 4.27 (2H, s), 2.24 (3H, s), MS (ESI) m/z: 279 (M+H) +.
<Step-4>:(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride
The title compound is prepared in 62 % yield (546 mg, yellows oil) from 5-(chloromethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine (750 mg, 2.70 mmol, Step-3) in a similar manner to Step-5 of Amine-3.
1H -NMR (300 MHz, DMSO-d6) delta 8.51 (3H, br s), 8.13 (1H, s), 7.82 (1H, s), 6.70 (1H, tt, J =52.0, 5.1 Hz), 4.88 (2H, t, J =13.9 Hz), 3.97 (2H, d, J = 5.9 Hz), 2.19 (3H, s), MS (ESI) m/z: 253 (M+H) +.
Amine-52: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride
<Step-1>: 2-chloro-5-(2,2-difluoroethoxy)-4-methylpyridine
The title compound is prepared in 95 % yield (4.14 g, white solid) from 6-chloro-4-methylpyridin-3-ol (3.0 g, 20.9 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (4.92 g, 23.0 mmol) in a similar manner to Step-1 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta, 7.89 (1H, s), 7.14 (1H, s), 6.11 (1H, tt, J = 54.3, 4.4 Hz), 4.26 (2H, td, J = 13.2, 4.4 Hz), 2.26 (3H, s), MS (ESI) m/z: 208 (M+H) +.
<Step-2>: ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate
The title compound is prepared in 87 % yield (4.24 g, white solid) from 2-chloro-5-(2,2-difluoroethoxy)-4-methylpyridine (4.14 g, 19.9 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta, 8.24 (1H, s), 7.99 (1H, s), 6.14 (1H, tt, J = 55.0, 4.4 Hz), 4.49-4.32 (4H, m), 2.32 (3H, s), 1.44 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 246 (M+H) +.
<Step-3>: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol
A mixture of ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate (2.0 g, 8.2 mmol, Step-2) and calcium chloride (3.62 g, 32.6 mmol) in THF-EtOH (1:1, 60 mL) is stirred at rt for 30 minutes. Then, the mixture is cooled to 0 oC, and sodium borohydride (771 mg, 20.4 mmol) is added portionwise. After stirring 1 day, the reaction is quenched with saturated aqueous ammonium chloride solution (200 mL), and the aqueous layer is extracted with DCM (200 mLx2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 then EtOAc only) to give 1.61 g (97 % yield) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.18 (1H, s), 7.26 (1H, s), 6.41 (1H, tt, J = 54.2, 3.7 Hz), 5.31 (1H, t, J = 5.9 Hz), 4.47-4.37 (4H, m), 2.21 (3H, s), MS (ESI) m/z: 204 (M+H)+.
<Step-4>: 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 74 % yield (720 mg, white solid) from (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol (594 mg, 2.92 mmol, Step-3) and phthalimide (473 mg, 3.22 mmol) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 8.05 (1H, s), 7.91-7.86 (2H, m), 7.78-7.70 (2H, m), 7.12 (1H, s) 6.08 (1H, tt, J = 54.9, 4.5 Hz), 4.93 (2H, s), 4.27-4.17 (2H, m), 2.23 (3H, s), MS (ESI) m/z: 333 (M+H)+.
<Step-5>: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride
The title compound is prepared in 61 % yield (700 mg, brown solid) from 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione (1.61 g, 4.84 mmol, Step-4) in a similar manner to Step-5 of Amine-12.
1H-NMR (300 MHz, DMSO-d6) delta 8.64 (3H, br s), 8.44 (1H,s), 7.61 (1H, s), 6.44 (1H, tt, J = 54.2, 3.2 Hz), 4.53 (2H, td, J = 14.7, 2.9 Hz), 4.15 (2H, d, J = 5.9 Hz), 2.26 (3H, s), MS (ESI) m/z: 203 (M+H)+.
Amine-53: (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride
<Step-1>:methyl 5-methyl-6-(1H-pyrazol-1-yl)nicotinate
The title compound is prepared in 58 % yield (2.42 g, white solid) from pyrazole (2.42 g, 35.5 mmol) in a similar manner to Step-1 of Amine-45.
1H-NMR (300 MHz, CDCl3) delta 8.91 (1H, s), 8.42 (1H, d, J = 2.9 Hz), 8.27 (1H, s), 7.78 (1H, s), 6.48 (1H, t, J = 2.2 Hz), 3.97 (3H, s), 2.70 (3H, s), MS (ESI) m/z: 218 (M+H) +.
<Step-2>:5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid
The title compound is prepared in 98 % yield (1.39 g, white solid) from methyl 5-methyl-6-(1H-pyrazol-1-yl)nicotinate (1.51 g, 6.95 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 13.5 (1H, br s), 8.82 (1H, d, J = 2.2 Hz), 8.51 (1H, d, J = 2.2 Hz), 8.33 (1H, d, J = 1.5 Hz), 7.87 (1H, d, J = 1.5 Hz), 6.58 (1H, s), 2.60 (3H, s), MS (ESI) m/z: 204 (M+H) +.
<Step-3>:(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanol
To a solution of 5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid (2.20 g, 10.8 mmol, Step-2) in THF (50 mL) is added 1,1'-carbonyldiimidazole (2.63 g, 16.2 mmol). After stirring at rt for 14 hours, the mixture is cooled to 0 oC, and a solution of sodium borohydride (2.05 g, 54.1 mmol) in cold water (15 mL) is slowly added. After stirring at 0 oC for 15 min, 2 M hydrochloric acid (25 mL) is added carefully. The resulting mixture is poured onto saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer is extracted with EtOAc (200 mL). The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.18 g (58 % yield) of the title compound as a pale yellow oil.
1H -NMR (300 MHz, CDCl3) delta 8.23 (1H, s), 8.14 (1H, t, J = 2.2 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.66 (1H, s), 6.46 (1H, t, J = 2.2 Hz), 4.70 (2H, s), 2.51 (4H, m), MS (ESI) m/z: 190 (M+H) +.
<Step-4>:2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in >99 % yield (1.65 g, white solid) from (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanol (800 mg, 3.96 mmol, Step-3) in a similar manner to Step-4 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 8.42 (1H, d, J = 1.5 Hz), 8.19 (1H, d, J = 2.2 Hz), 4.79-4.78 (2H, m), 7.77-7.72 (4H, m), 6.43 (1H, t, J = 1.8 Hz), 4.87 (2H, s), 2.54 (3H, s), MS (ESI) m/z: 319 (M+H) +.
<Step-5>:(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride
The title compound is prepared in 67 % yield (764 mg, white solid) from 2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.61 g, 5.06 mmol, Step-4) in a similar manner to Step-5 of Amine-12.
1H -NMR (300 MHz, DMSO-d6) delta 8.63 (3H, br s), 7.48 (1H, d, J = 1.5 Hz), 8.39 (1H, d, J = 2.2 Hz), 8.05 (1H, d, J = 2.2 Hz), 7.81 (1H, s), 6.55 (1H, t, J = 1.8 Hz), 4.10 (2H, q, J = 5.9 Hz), 2.49 (3H, s), MS (ESI) m/z: 189 (M+H) +.
Amine-54: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride
<Step-1>: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanol
The title compound is prepared in 69 % yield (767 mg, colorless oil) from 3-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (1.18 g, 4.63 mmol) in a similar manner to Step-3 of Amine-53.
1H-NMR (300 MHz, CDCl3) delta 7.43 (1H, d, J = 2.2 Hz), 7.26-7.22 (1H, m), 6.97 (1H, d, J = 8.1 Hz), 4.65 (2H, d, J = 5.9 Hz), 4.41 (2H, q, J = 8.1 Hz), 1.71 (1H, t, J = 5.5 Hz).
<Step-2>:2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione
The title compound is prepared in 77 % yield (894 mg, white solid) from (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanol (760 mg, 3.16 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 7.89-4.73 (2H, m), 7.74-7.71(2H, m), 7.50 (1H, d, J = 2.2 Hz) 7.33 (1H, dd, J = 8.1, 2.2 Hz), 6.91 (1H, d, J = 8.1 Hz), 4.78 (2H, s), 4.36 (2H, q, J = 8.1 Hz).
<Step-3>:(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride
The title compound is prepared in 89 % yield (593 mg, an off-white solid) from 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (890 mg, 2.41 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
1H -NMR (300 MHz, DMSO-d6) delta 8.47 (3H, br s), 7.68 (1H, s), 7.48 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.8 Hz), 4.91 (2H, q, J = 8.8 Hz), 3.98 (2H, d, J = 5.1 Hz), MS (ESI) m/z: positive ion of a fragment signal 223 is observed.
Amine-55: 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: methyl 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate
A mixture of methyl 5-chloro-6-methylpyrazine-2-carboxylate (3.00 g, 16.1 mmol), 2,2,2-trifluoroethanol (32.2 g, 322 mmol), and potassium carbonate (3.33 g, 24.1 mmol) in DMF (30 mL) is stirred at 60 oC for 2 hours. After cooling to rt, the mixture is filtered off, and the filtrate is diluted with EtOAc (300 mL). The organic layer is washed with water (100 mLx3) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting EtOAc to give 3.91 g (97 % yield) of the title compound as white solid.
MS (ESI) m/z: 251 (M+H) +.
<Step-2>: 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid
The title compound is prepared in 66 % yield (2.44 g, white solid) from methyl 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (3.91 g, 15.6 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 13.36 (1H, br s), 8.67 (1H, s), 5.11 (2H, q, J = 8.8 Hz), 2.48 (3H, s), MS (ESI) m/z: 235 (M-H) -.
<Step-3>:N-methoxy-N,6-dimethyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide
The title compound is prepared in 97 % yield (437 mg, white solid) from 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (380 mg, 1.61 mmol, Step-2) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.36 (1H, s), 4.81 (2H, q, J = 8.3 Hz), 3.78 (3H, s), 3.40 (3H, s), 2.56 (3H, s), MS (ESI) m/z: 280 (M+H) +.
<Step-4>:1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanone
The title compound is prepared in 98 % yield (355 mg, yellow solid) from N-methoxy-N,6-dimethyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide (430 mg, 1.54 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.64 (1H, s), 4.84 (2H, q, J = 8.3 Hz), 2.67 (3H, s), 2.58 (3H, s), MS (ESI) m/z: 235 (M+H) +.
<Step-5>:(R)-2-methyl-N-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 68 % yield (347 mg, a pale brown oil) from 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanone (350 mg, 1.50 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (217 mg, 1.79 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.91 (1H, s), 4.85-4.63 (2H, m), 4.56 (1H, quintet, J = 6.6 Hz), 4.37-4.34 (1H, m), 2.51 (3H, s), 1.52 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 340 (M+H) +.
<Step-6>:1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 97 % yield (264 mg, white solid) from (R)-2-methyl-N-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer) (340 mg, 1.00 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.41 (3H, br s), 8.24 (1H, s), 5.15-5.03 (2H, m), 4.59-4.51 (1H, m), 2.50 (3H, s), 1.51 (3H, d, J = 7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 219 is observed.
Amine-56: 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 6-(2,2-difluoropropoxy)-5-methylnicotinic acid
To a stirred solution of 2,2-difluoropropan-1-ol (1.13 g, 11.7 mmol) and potassium tert-butoxide (1.43 g, 12.8 mmol) in DMF (36 mL) is added methyl 6-fluoro-5-methylnicotinate (1.80 g, 10.6 mmol, Step-1 of Amine-36). After stirring at rt for 2 hours, MeOH (30 mL), water (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) are added to the mixture, and the mixture is stirred at rt for 2 hours. After evaporation of MeOH, the mixture is acidified by 2 M hydrochloric acid, and the precipitate is collected by filtration to give 2.14 g (87 %) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.56 (1H, d, J = 1.5 Hz), 8.07 (1H, d, J = 1.5 Hz), 4.64 (2H, t, J = 13.2 Hz), 2.22 (3H, s), 1.75 (3H, t, J = 19.1 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 230 (M-H) -.
<Step-2>:6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in >99 % yield (650 mg, white solid) from 6-(2,2-difluoropropoxy)-5-methylnicotinic acid (550 mg, 2.38 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.44 (1H, d, J = 2.2 Hz), 7.84 (1H, d, J = 1.5 Hz), 4.55 (2H, t, J = 12.1 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.26 (3H, s) 1.76 (3H, t, J = 18.7 Hz), MS (ESI) m/z: 275 (M+H) +.
<Step-3>:1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (545 mg, white solid) from 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylnicotinamide (640 mg, 2.33 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.59 (1H, s), 8.01 (1H, s), 4.58 (2H, t, J = 11.7 Hz), 2.57 (3H, s), 2.27 (3H, s), 1.76 (3H, t, J = 18.3 Hz), MS (ESI) m/z: 230 (M+H) +.
<Step-4>:(R)-N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 61 % yield (481 mg, colorless oil) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanone (545 mg, 2.38 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (346 mg, 2.85 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.94 (1H, d, J = 2.2 Hz), 7.42 (1H, d, J = 1.5 Hz), 4.53-4.45 (3H, m), 3.32 (1H, d, J = 2.2 Hz), 2.23 (3H, s), 1.74 (3H, t, J = 18.7 Hz), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 335 (M+H) +.
<Step-5>:1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 99 % yield (374 mg, white solid) from (R)-N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (474 mg, 1.42 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.61 (3H, br s), 8.13 (1H, s), 7.84 (1H, s), 4.58 (2H, t, J = 12.8 Hz), 4.40-4.35 (1H, m), 2.20 (3H, s), 1.74 (3H, t, J = 19.0 Hz), 1.52 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 214 is observed.
Amine-57: (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride
<Step-1>:(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
The title compound is prepared in 99 % yield (1.65 g, a pale yellow solid) from ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate (3.43 g, 13.0 mmol, Step-2 of Amine-49) in a similar manner to Step-2 of Amine-3.
1H -NMR (300 MHz, CDCl3) delta 8.09 (1H, s), 7.10 (1H, s), 4.68 (2H, s), 4.44 (2H, q, J = 8.1 Hz), 3.45 (1H, br s), 2.30 (3H, s), MS (ESI) m/z: 222 (M+H)+.
<Step-2>:2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 68 % yield (3.10 g, white solid) from (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (1.33 g, 6.01 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 8.05 (1H, s), 7.90-7.87 (2H, m), 7.75-7.72 (2H, m), 7.15 (1H, s), 4.93 (2H, s), 4.42-4.29 (2H, m), 2.25 (3H, s), MS (ESI) m/z: 351 (M+H) +.
<Step-3>:(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride
The title compound is prepared in 79 % yield (1.39 g, white solid) from 2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (3.10 g, 6.01 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
1H -NMR (300 MHz, DMSO-d6) delta 8.44 (3H, br s), 8.41 (1H, s), 7.44 (1H, s), 4.97 (2H, q, J = 8.8 Hz), 4.10 (2H, q, J = 5.9 Hz), 2.24 (3H, s), MS (ESI) m/z: 221 (M+H) +.
Amine-58: (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine
<Step-1>: 2-chloro-4-methyl-5-(3,3,3-trifluoropropoxy)pyridine
The title compound is prepared in >99 % yield (3.64 g, a pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 3,3,3-trifluoropropan-1-ol (5.72 g, 50.1 mmol) in a similar manner to Step-1 of Intermediate-A17.
1H-NMR (300 MHz, CDCl3) delta, 7.87 (1H, s), 7.12 (1H, s), 4.27 (2H, t, J = 6.6 Hz), 2.78-2.59 (2H, m), 2.22 (3H, s), MS (ESI) m/z: 240 (M+H) +.
<Step-2>: ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate
The title compound is prepared in 93 % yield (3.92 g, a pale yellow solid) from 2-chloro-4-methyl-5-(3,3,3-trifluoropropoxy)pyridine (3.64 g, 15.2 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.
1H-NMR (300 MHz, CDCl3) delta, 8.24 (1H, s), 7.97 (1H, s), 4.49-4.36 (4H, m), 2.78-2.62 (2H, m), 2.29 (3H, s), 1.44 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 278 (M+H)+.
<Step-3>: (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanol
The title compound is prepared in 93 % yield (807 mg, white solid) from ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate (1.0 g, 3.6 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.
1H-NMR (300 MHz, DMSO-d6) delta 8.16 (1H, s), 7.26 (1H, s), 5.28 (1H, t, J = 5.8 Hz), 4.45 (2H, d, J = 5.8 Hz), 4.30 (2H, t, J = 5.8 Hz), 2.89-2.74 (2H, m), 2.17 (3H, s), MS (ESI) m/z: 236 (M+H)+.
<Step-4>:2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in >99 % yield (800 mg, white solid, including byproducts) from (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanol (270 mg, 1.15 mmol, Step-3) in a similar manner to Step-4 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 8.05 (1H, s), 7.90-7.83 (2H, m), 7.8-7.7 (2H, m), 7.13 (1H, s), 4.95 (2H, s), 4.25 (2H, t, J = 6.2 Hz), 2.7-2.55 (2H, m), 2.21 (3H, s), MS (ESI) m/z: 365 (M+H) +.
<Step-5>:(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine
The title compound is prepared in 69 % yield (133 mg, a pale brown oil) from 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (300 mg, 0.82 mmol, Step-4) in a similar manner to Step-5 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 8.08 (1H, s), 7.09 (1H, s), 4.29 (2H, t, J = 6.2 Hz), 3.89 (2H, s), 2.74-2.59 (2H, m), 2.23 (3H, s), MS (ESI) m/z: 235 (M+H) +.
Amine-59: 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-(2,2-difluoroethoxy)-4-methylpicolinic acid
The title compound is prepared in 96 % yield (1.70 g, white solid) from ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate (2.00 g, 8.16 mmol, Step-2 of Amine-52) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, DMSO-d6) delta 8.41 (1H, s), 7.93 (1H, s), 6.45 (1H, tt, J = 54.2, 3.3 Hz), 4.58 (2H, td, J = 14.7, 2.9 Hz), 2.25 (3H, s), MS (ESI) m/z: 218 (M+H) +.
<Step-2>:5-(2,2-difluoroethoxy)-N-methoxy-N,4-dimethylpicolinamide
The title compound is prepared in 92 % yield (1.87 g, yellows oil) from 5-(2,2-difluoroethoxy)-4-methylpicolinic acid (1.70 g, 7.83 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.12 (1H, s), 7.57 (1H, s), 6.14 (1H, tt, J = 54.6, 3.9 Hz), 4.33 (2H, td, J = 12.8, 3.7 Hz), 3.75 (3H, s), 3.41 (3H, s), 2.30 (3H, s), MS (ESI) m/z: 261 (M+H) +.
<Step-3>:5-(2,2-difluoroethoxy)-4-methylpicolinaldehyde
The title compound is prepared in 60 % yield (872 mg, a pale brown solid) from 5-(2,2-difluoroethoxy)-N-methoxy-N,4-dimethylpicolinamide (1.87 g, 7.19 mmol, Step-2) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 9.97 (1H, s), 8.29 (1H, s), 7.84 (1H, s), 6.17 (1H, tt, J = 54.6, 4.1 Hz), 4.41 (2H, td, J = 12.9, 3.8 Hz), 2.34 (3H, s), MS (ESI) m/z: 202 (M+H) +.
<Step-4>:(R,E)-N-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
The title compound is prepared in 11 % yield (147 mg, colorless oil) from 5-(2,2-difluoroethoxy)-4-methylpicolinaldehyde (860 mg, 4.27 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (777 mg, 6.41 mmol) in a similar manner to Step-6 of Amine-49.
1H -NMR (300 MHz, CDCl3) delta 8.62 (1H, s), 8.26 (1H, s), 7.87 (1H, s), 6.15 (1H, tt., J = 54.9, 3.1 Hz), 4.37 (1H, td., J = 12.8, 4.1 Hz), 2.33 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 305 (M+H)+.
<Step-5>:(R)-N-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 68 % yield (100 mg, colorless oil) from (R,E)-N-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (140 mg, 0.46 mmol, Step-4) in a similar manner to Step-7 of Amine-49.
1H -NMR (300 MHz, CDCl3) delta 8.07 (1H, s),7.10 (1H, s), 6.11 (1H, tt, J = 54.9, 4.0 Hz), 4.64 (1H, d, J = 5.1 Hz), 4.51 (1H, quintet, J = 6.4 Hz), 4.26 (2H, td, J = 13.0, 3.9 Hz), 2.26 (3H, s), 1.48 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 321 (M+H)+.
<Step-6>:1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 92 % yield (94 mg, white solid) from (R)-N-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (130mg, 0.41 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR of free salt (300 MHz, CDCl3) delta 8.07 (1H, s), 7.13 (1H, s), 6.11 (1H, tt, J = 54.9, 4.0 Hz), 4.26 (2H, td, J = 13.0, 3.9 Hz), 4.11 (1H, q, J = 6.6 Hz), 2.26 (3H, s), 1.40 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 217 (M+H)+.
Amine-60: 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid
The title compound is prepared in 97 % yield (7.29 g, a pale brown solid) from 5,6-dichloronicotinic acid (5.00 g, 26.0 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (5.16 g, 39.1 mmol) in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.77 (1H, d, J = 1.5 Hz), 8.34 (1H, d, J = 2.2 Hz), 6.08 (1H, tt, J = 52.8, 4.5 Hz), 4.88 (2H, t, J = 12.5 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 286 (M-H) -.
<Step-2>:5-chloro-N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide
The title compound is prepared in 99 % yield (5.46 g, white solid) from 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (4.80 g, 16.7 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.14 (1H, d, J = 2.2 Hz), 8.12 (1H, d, J = 1.5 Hz), 6.09 (1H, tt, J = 53.1, 4.8 Hz), 4.83 (2H, t, J = 12.1 Hz), 3.59 (3H, s), 3.39 (3H, s), MS (ESI) m/z: 331 (M+H) +.
<Step-3>:1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in 98 % yield (4.62 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (5.46 g, 16.5 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.64 (1H, d, J = 2.2 Hz), 8.26 (1H, d, J = 1.5 Hz), 6.07 (1H, tt, J = 52.7, 4.5 Hz), 4.87 (2H, t, J = 12.1 Hz), 2.60 (3H, s).
<Step-4>:(R)-N-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 81 % yield (5.11 g, white solid) from 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (4.62 g, 16.2 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.94 g, 24.3 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.03 (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 2.2 Hz), 6.08 (1H, tt, J = 53.5, 4.9 Hz), 4.77 (2H, t, J = 12.1 Hz), 4.58-4.50 (1H, m), 3.35 (1H, br s), 1.54 (3H, d, J = 6.6 Hz), 1.24 (9H, s).
<Step-5>:1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 93 % yield (3.95 g, white solid) from (R)-N-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (5.11 g, 13.1 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.63 (3H, br s), 8.31 (1H, d, J = 2.2 Hz), 8.26 (1H, d, J = 2.2 Hz), 6.66 (1H, tt, J = 51.6, 5.1 Hz), 4.99 (2H, t, J = 14.3 Hz), 4.48 (1H, q, J = 6.8 Hz), 1.54 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 270 is observed.
Amine-61: 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:5-chloro-6-(3,3,3-trifluoropropoxy)nicotinic acid
The title compound is prepared in 66 % yield (6.48 g, white solid) from 5,6-dichloronicotinic acid (7.00 g, 36.5 mmol) and 3,3,3-trifluoropropan-1-ol (8.32 g, 72.9 mmol) in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.77 (1H, d, J = 2.2 Hz), 8.29 (1H, d, J = 1.5 Hz), 4.72 (2H, t, J = 6.6 Hz), 2.78-2.63 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 270 (M+H) +.
<Step-2>:5-chloro-N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide
The title compound is prepared in >99 % yield (3.30 g, colorless oil) from 5-chloro-6-(3,3,3-trifluoropropoxy)nicotinic acid (2.70 g, 10.0 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.52 (1H, d, J = 2.2 Hz), 8.10 (1H, d, J = 1.5 Hz), 4.67 (2H, t, J = 6.6 Hz), 3.59 (3H, s), 3.38 (3H, s), 2.77-2.62 (2H, m), MS (ESI) m/z: 313 (M+H) +.
<Step-3>:1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (2.82 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide (3.30 g, 10.6 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.63 (1H, d, J = 1.4 Hz), 8.22 (1H, d, J = 2.2 Hz), 4.70 (2H, t, J = 6.6 Hz), 2.77-2.58 (5H, m), MS (ESI) m/z: 268 (M+H) +.
<Step-4>:(R)-N-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 76 % yield (2.96 g, white solid) from 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (2.80 g, 10.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.90 g, 15.7 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.01 (1H, d, J = 1.4 Hz), 7.66 (1H, d, J = 2.2 Hz), 4.61 (2H, t, J = 6.6 Hz), 4.56-4.48 (1H, m), 3.34 (1H, d, J = 2.9 Hz), 2.74-2.60 (2H, m), 1.52 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 373 (M+H) +.
<Step-5>:1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 95 % yield (2.30 g, white solid) from (R)-N-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.96 g, 7.94 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.46 (3H, br s), 8.26 (1H, d, J = 2.2 Hz), 8.16-8.14 (1H, m), 4.59 (2H, t, J = 5.9 Hz), 4.60 (1H, quintet, J = 6.2 Hz), 2.91-2.76 (2H, m), 1.52 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 252 is observed.
Amine-62: 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:4-methyl-5-(3,3,3-trifluoropropoxy)picolinic acid
The title compound is prepared in >99 % yield (2.20 g, white solid) from ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate (3.46 g, 13.2 mmol, Step-2 of Amine-58) in a similar manner to Step-2 of Amine-15.
1H -NMR (300 MHz, DMSO-d6) delta 8.43 (1H, s), 8.04 (1H, s), 4.50 (2H, t, J = 5.1 Hz), 3.0-2.8 (2H, m), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 250 (M+H) +.
<Step-2>:N-methoxy-N,4-dimethyl-5-(3,3,3-trifluoropropoxy)picolinamide
The title compound is prepared in 98 % yield (2.54 g, white solid) from 4-methyl-5-(3,3,3-trifluoropropoxy)picolinic acid (2.20 g, 8.83 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.30 (1H, s), 7.49 (1H, s), 4.42 (2H, t, J = 5.9 Hz), 3.68 (3H, s), 3.28 (3H, s), 2.95-2.75 (2H, m), 2.20 (3H, s), MS (ESI) m/z: 293 (M+H) +.
<Step-3>:4-methyl-5-(3,3,3-trifluoropropoxy)picolinaldehyde
The title compound is prepared in 87 % yield (1.79 g, an orange solid) from N-methoxy-N,4-dimethyl-5-(3,3,3-trifluoropropoxy)picolinamide (2.58 g, 8.83 mmol, Step-2) in a similar manner to Step-2 of Amine-3.
1H -NMR (300 MHz, DMSO-d6) delta 9.87 (1H, s), 8.54 (1H, s), 7.82 (1H, s), 4.51 (2H, t, J = 5.9 Hz), 2.95-2.75 (2H, m), 2.25 (3H, s).
<Step-4>:(S,E)-2-methyl-N-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide
The title compound is prepared in 65 % yield (1.67 g, white solid) from 4-methyl-5-(3,3,3-trifluoropropoxy)picolinaldehyde (1.79 g, 7.68 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.5 mmol) in a similar manner to Step-6 of Amine-49.
1H -NMR (300 MHz, CDCl3) delta 8.61 (1H, s), 8.26 (1H, s), 7.85 (1H, s), 4.40 (2H, t, J = 6.6 Hz), 2.81-2.62 (2H, m), 2.29 (3H, s), 1.28 (9H, s).
<Step-5>:(S)-2-methyl-N-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 29 % yield (500 mg, colorless oil) from (S,E)-2-methyl-N-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.67 g, 4.96 mmol, Step-4) in a similar manner to Step-7 of Amine-49.
1H -NMR (300 MHz, CDCl3) delta 8.06 (1H, s), 7.08 (1H, s), 4.64 (1H, d, J = 5.1 Hz), 4.55-4.45 (1H, m), 4.28 (2H, t, J = 6.6 Hz), 2.75-2.58 (2H, m), 2.22 (3H, s), 1.47 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 353 (M+H) +.
<Step-6>:1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (456 mg, amorphous solid) from (S)-2-methyl-N-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer) (500 mg, 1.42 mmol, Step-5) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.55 (3H, br s), 8.35 (1H, s), 7.52 (1H, s), 4.55-4.35 (3H, m), 2.95-2.78 (2H, m), 2.22 (3H, s), 1.49 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 249 (M+H) +.
Amine-63: 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid
The title compound is prepared in 85 % yield (1.12 g, colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.
1H-NMR (300 MHz, CDCl3) delta 8.77 (1H, d, J = 2.2 Hz), 8.31 (1H, d, J = 2.2 Hz), 4.64 (2H, t, J = 11.7 Hz), 1.80 (3H, t, J = 18.3 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 252 (M+H) +.
<Step-2>:5-chloro-6-(2,2-difluoropropoxy)-N-methoxy-N-methylnicotinamide
The title compound is prepared in >99 % yield (5.39 g, yellows oil) from 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid (3.90 g, 15.5 mmol, Step-1) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.51 (1H, d, J = 2.2 Hz), 8.12 (1H, d, J = 2.2 Hz), 4.60 (2H, t, J = 11.7 Hz), 3.59 (3H, s), 3.38 (3H, s), 1.79 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 295 (M+H) +.
<Step-3>:1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone
The title compound is prepared in 88 % yield (4.0 g, a pale yellow oil) from 5-chloro-6-(2,2-difluoropropoxy)-N-methoxy-N-methylnicotinamide (5.39 g, 18.3 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.63 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 2.2 Hz), 4.63 (2H, t, J = 11.7 Hz), 2.59 (3H, s), 1.79 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 250 (M+H) +.
<Step-4>:(R)-N-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 62 % yield (3.5 g, yellows oil) from 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone (4.0 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (2.91 g, 24.0 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.01 (1H, d, J = 2.2 Hz), 7.68 (1H, d, J = 2.2 Hz), 4.58-4.50 (3H, m), 3.35 (1H, d, J = 2.9 Hz), 1.78 (3H, t, J = 18.7 Hz), 1.52 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 355 (M+H) +.
<Step-5>:1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 99 % yield (2.45 g, white solid) from (R)-N-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (3.52 g, 9.92 mmol, Step-4) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.53 (3H, br s), 8.27 (1H, d, J = 2.2 Hz), 8.20 (1H, d, J = 2.2 Hz), 4.68 (2H, t, J = 12.8 Hz), 4.47 (1H, q, J = 6.6 Hz), 1.75 (3H, t, J = 19.4 Hz), 1.53 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 251 (M+H) +.
Amine-64: 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: methyl 6-chloro-5-methylnicotinate
The title compound is prepared in 93 % yield (2.02 g, white solid) from 6-chloro-5-methylnicotinic acid (2.00 g, 11.7 mmol) in a similar manner to Step-1 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 8.83 (1H, d, J = 2.2 Hz), 8.16 (1H, d, J = 2.2 Hz), 3.95 (3H, s), 2.44 (3H, s), MS (ESI) m/z: 186 (M+H) +.
<Step-2>: methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate
To a suspension of zinc powder (2.49 g, 38.1 mmol) in THF (15 mL), 1,2-dibromoethane (0.21 g, 1.1 mmol) and trimethylsilyl chloride (0.12 g, 1.1 mmol) are added. After stirring at rt for 20 minutes, 1,1,1-trifluoro-3-iodopropane (6.10 g, 27.2 mmol) is added, and the mixture is stirred at 55 oC for 1 hour to give a solution of (3,3,3-trifluoropropyl)zinc iodide in THF. To a mixture of methyl 6-chloro-5-methylnicotinate (2.02 g, 10.9 mmol, Step-1) and tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.87 mmol) in DMF (15 mL) is added the zinc reagent, and the mixture is stirred at 55 oC for 12 hours. After cooling to rt, the mixture is poured onto water (100 mL), and the aqueous layer is extracted with EtOAc (30 mLx2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (5:1 to EtOAc only) to give 2.32 g (86 % yield) of the title compound as an orange solid.
1H-NMR (300 MHz, CDCl3) delta 8.97 (1H, d, J = 1.5 Hz), 8.05 (1H, d, J = 1.5 Hz), 3.94 (3H, s), 3.10-3.04 (2H, m), 2.76-2.62 (2H, m), 2.38 (3H, s) MS (ESI) m/z: 248 (M+H) +.
<Step-3>:5-methyl-6-(3,3,3-trifluoropropyl)nicotinic acid
The title compound is prepared in 99 % yield (935 mg, a pale brown solid) from methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate (1.00 g, 4.05 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.82 (1H, s), 8.04 (1H, s), 3.05-3.00 (2H, m), 2.83-2.70 (2H, m), 2.34 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 232 (M-H)-.
<Step-4>:N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropyl)nicotinamide
The title compound is prepared in 95 % yield (1.04 g, colorless oil) from 5-methyl-6-(3,3,3-trifluoropropyl)nicotinic acid (920 mg, 3.95 mmol, Step-3) in a similar manner to Step-2 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.73 (1H, s), 7.80 (1H, s), 3.57 (3H, s), 3.38 (3H, s), 3.08-3.02 (2H, m), 2.71-2.62 (2H, m), 2.36 (3H, s), MS (ESI) m/z: 277 (M+H) +.
<Step-5>:1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (866 mg, a pale yellow solid) from N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropyl)nicotinamide (1.00 g, 3.62 mmol, Step-4) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.91 (1H, s), 7.99 (1H, s), 3.10-3.04 (2H, m), 2.73-2.64 (2H, m), 2.62 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 232 (M+H) +.
<Step-6>:(R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 57 % yield (700 mg, white solid) from 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanone (850 mg, 3.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (668 mg, 5.51 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.35 (1H, s), 7.42 (1H, s), 4.56-4.52 (1H, m), 3.03-3.46 (3H, m), 2.67-2.55 (2H, m), 2.33 (3H, s), 1.54 (3H, t, J = 8.0 Hz), 1.24 (9H, s), MS (ESI) m/z: 337 (M+H) +.
<Step-7>:1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99 % yield (643 mg, a pale brown solid) from (R)-2-methyl-N-((R)-1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)propane-2-sulfinamide (700 mg, 2.08 mmol, Step-6) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.96 (3H, br s), 8.85 (1H, s), 8.55 (1H, s), 4.64 (1H, q, J = 5.9 Hz), 3.31-3.25 (2H, m), 3.18 (3H, s), 2.89-2.83 (2H, m), 1.60, (3H, d, J = 6.6 Hz), MS (ESI) m/z: 233 (M+H) +.
Amine-65: 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: diethyl 3-chloropyridine-2,5-dicarboxylate
The title compound is prepared in 34 % yield (486 mg, brown solid) from ethyl 5,6-dichloronicotinate (2.44 g, 5.54 mmol) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 9.11 (1H, d, J = 1.5 Hz), 8.29 (1H, d, J = 1.4 Hz), 4.54-4.42 (4H, m), 1.57-1.41 (6H, m), MS (ESI) m/z: 258 (M+H) +.
<Step-2>: ethyl 5-chloro-6-(hydroxymethyl)nicotinate
The title compound is prepared in 96 % yield (1.25 g, brown solid) from diethyl 3-chloropyridine-2,5-dicarboxylate (1.23 g, 4.77 mmol, Step-1) in a similar manner to Step-3 of Amine-52.
MS (ESI) m/z: 216 (M+H) +.
<Step-3>: ethyl 5-chloro-6-(chloromethyl)nicotinate hydrochloride
To a solution of ethyl 5-chloro-6-(hydroxymethyl)nicotinate (990 mg, 4.59 mmol, Step-2) in DCM (20 mL) is added thionyl chloride (0.80 mL, 9.2 mmol) at 0 oC. After stirring at rt for 2 hours, the solvent is removed in vacuo to give 1.20 g (97 % yield) of the title compound as brown oil.
MS (ESI) m/z: 234 (M+H) +.
<Step-4>: 5-chloro-6-((2,2,2-trifluoroethoxy)methyl)nicotinic acid
To a mixture of 2,2,2-trifluoroethanol (2.66 g, 26.6 mmol) and cesium carbonate (5.78 g, 17.7 mmol) in DMF (22 mL) is added ethyl 5-chloro-6-(chloromethyl)nicotinate hydrochloride (1.20 g, 4.44 mmol). After stirring at rt for 1 hour, 2 M aqueous sodium hydroxide solution (10 mL), water (20 mL), and THF (20 mL) are added to the mixture. After stirring at 60 oC for 2 hours, the mixture is acidified by 2 M hydrochloric acid (pH 4). The organic solvent is removed by evaporation, and the residual aqueous layer is extracted with EtOAc/hexane. The separated organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo to give 1.19 g (>99 %) of the title compound as brown solid.
MS (ESI) m/z: 268 (M-H) -.
<Step-5>:5-chloro-N-methoxy-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)nicotinamide
The title compound is prepared in 65 % yield (894 mg, brown oil) from 5-chloro-6-((2,2,2-trifluoroethoxy)methyl)nicotinic acid (1.19 g, 4.41 mmol, Step-4) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.87 (1H, d, J = 1.5 Hz), 8.08 (1H, d, J = 1.5 Hz), 4.96 (2H, s), 4.50 (2H, q, J = 8.8 Hz), 3.58 (3H, s), 3.40 (3H, s), MS (ESI) m/z: 313 (M+H) +.
<Step-6>:1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanone
The title compound is prepared in 96 % yield (728 mg, brown oil) from 5-chloro-N-methoxy-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)nicotinamide (890 mg, 2.85 mmol, Step-5) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 9.03 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 2.2 Hz), 4.98 (2H, s), 4.05 (2H, q, J = 8.5 Hz), 2.65 (3H, s), MS (ESI) m/z: 268 (M+H) +.
<Step-7>:(R)-N-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 82 % yield (827 mg, yellows oil) from 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanone (720 mg, 2.69 mmol, Step-6) and (R)-2-methylpropane-2-sulfinamide (489 mg, 4.04 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.51 (1H, d, J = 1.5 Hz), 7.73 (1H, d, J = 1.5 Hz), 4.91 (2H, s), 4.64-4.56 (1H, m), 4.01 (2H, q, J = 8.8 Hz), 3.45 (1H, d, J = 2.9 Hz), 1.56 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 373 (M+H)+.
<Step-8>:1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 82 % yield (614 mg, a pale brown solid) from (R)-N-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (820 mg, 2.20 mmol, Step-7) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.67 (4H, m), 8.20 (1H, t, J = 2.2 Hz), 4.85 (2H, s), 4.58-4.50 (1H, m), 4.21 (2H, q, J = 9.3 Hz), 1.56 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 269 (M+H)+.
Amine-66: (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride
<Step-1>:methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate
To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40 % solution in toluene) at 0 oC. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60 oC for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (18:1) to give 1.9 g (90 % yield) of the title compound as white solid.
1H-NMR (300 MHz, CDCl3) delta 7.90-7.85 (2H, m), 6.79 (1H, d, J = 8.8 Hz), 6.13 (1H, tt, J = 54.9, 4.4 Hz), 4.24 (2H, td, J = 12.5, 3.7 Hz), 3.89 (3H, s), 2.27 (3H, s).
<Step-2>: (4-(2,2-difluoroethoxy)-3-methylphenyl)methanol
The title compound is prepared in >99 % yield (712 mg, colorless oil) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (750 mg, 3.3 mmol, Step-1) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.18-7.15 (2H, m), 6.78 (1H, d, J = 8.1 Hz), 6.11 (1H, tt, J = 54.9, 4.2 Hz), 4.61 (2H, d, J = 5.9 Hz), 4.19 (2H, td, J = 13.0, 4.2 Hz), 2.25 (3H, s) (a signal due to OH is not observed).
<Step-3>:4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene
The title compound is prepared in >99 % yield (1.75 g, colorless oil) from (4-(2,2-difluoroethoxy)-3-methylphenyl)methanol (1.60 g, 7.91 mmol, Step-2) in a similar manner to Step-3 of Amine-3.
<Step-4>:4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene
The title compound is prepared in 39 % yield (700 mg, colorless oil) from 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene (1.75 g, 7.93 mmol, Step-3) in a similar manner to Step-4 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 7.13-7.11 (2H, m), 6.78 (1H, d, J = 8.8 Hz), 6.11 (1H, tt, J = 55.3, 4.0 Hz), 4.25 (2H, s), 4.19 (2H, td, J = 13.2, 4.4 Hz), 2.25 (3H, s).
<Step-5>:(4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride
The title compound is prepared in 95 % yield (688 mg, white solid) from 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene (695 mg, 3.06 mmol, Step-4) in a similar manner to Step-5 of Amine-3.
1H-NMR (300 MHz, DMSO-d6) delta 8.30 (2H, br s), 7.30-7.28 (2H, m), 7.05 (1H, d, J = 8.8 Hz), 6.40 (1H, tt, J = 54.2, 3.4 Hz), 4.33 (2H, td, J = 14.7, 3.7 Hz), 3.91 (2H, d, J = 5.1 Hz), 2.18 (3H, s), MS (ESI) m/z: positive ion of a fragment signal 185 is observed.
Amine-67: (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride
<Step-1>:(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanol
The title compound is prepared in >99 % yield (1.90 g, white solid) from 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (2.00 g, 8.47 mmol, Step-2 of Amine-55) in a similar manner to Step-3 of Amine-53.
1H -NMR (300 MHz, DMSO-d6) delta 8.07 (1H, s), 5.50-5.42 (1H, m), 5.02 (2H, q, J = 8.0 Hz), 4.54 (2H, d, J = 5.9 Hz), 2.42 (3H, s), MS (ESI) m/z: 223 (M+H) +.
<Step-2>:2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 97 % yield (1.54 g, white solid) from (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanol (1.00 g, 4.50 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H -NMR (300 MHz, CDCl3) delta 7.95 (1H, s), 7.90-7.84 (2H, m), 7.80-7.65 (2H, m), 4.95 (2H, s), 4.73 (2H, q, J = 8.8 Hz), 2.45 (3H, s), MS (ESI) m/z: 352 (M+H) +.
<Step-3>:(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride
The title compound is prepared in 87 % yield (979 mg, white solid) from 2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)isoindoline-1,3-dione (1.54 g, 4.38 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
1H -NMR (300 MHz, DMSO-d6) delta 8.59 (3H, br s), 8.26 (1H, s), 5.09 (2H, q, J = 8.8 Hz), 4.12 (2H, d, J = 5.1 Hz ), 2.50 (3H, s), MS (ESI) m/z: 222 (M+H) +.
Amine-68: 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>:N-methoxy-N,5-dimethyl-6-(1H-pyrazol-1-yl)nicotinamide
The title compound is prepared in >99 % yield (1.14 g, colorless oil) from 5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid (930 mg, 4.58 mmol, Step-2 of Amine-53) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.70 (1H, d, J = 2.2 Hz), 8.35 (1H, d, J = 2.9 Hz), 8.05 (1H, d, J = 1.4 Hz), 7.78 (1H, d, J = 1.5 Hz), 6.48 (1H, t, J = 1.8 Hz), 3.59 (3H, s), 3.41 (3H, s), 2.66 (3H, s), MS (ESI) m/z: 247 (M+H) +.
<Step-2>:1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone
The title compound is prepared in >99 % yield (928 mg, a colorless) from N-methoxy-N,5-dimethyl-6-(1H-pyrazol-1-yl)nicotinamide (1.14 g, 4.63 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.85 (1H, d, J = 2.2 Hz), 8.44 (1H, d, J = 2.9 Hz), 8.02 (1H, d, J = 1.5 Hz), 7.79 (1H, d, J = 1.5 Hz), 6.49 (1H, t, J = 2.2 Hz), 2.71 (3H, s), 2.65 (3H, s), MS (ESI) m/z: 202 (M+H) +.
<Step-3>:(R)-2-methyl-N-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 79 % yield (1.11 g, colorless oil) from 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone (920 mg, 4.57 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (665 mg, 5.49 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 8.31 (1H, d, J = 2.2 Hz), 8.21 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.65 (1H, d, J = 2.2 Hz), 6.45 (1H, t, J = 2.2 Hz), 4.65-4.57 (1H, m), 3.44 (1H, d, J = 2.9 Hz), 2.57 (3H, s), 1.58 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 307 (M+H) +.
<Step-4>:1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 93 % yield (805 mg, an off-white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.11 g, 3.62 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.93 (3H, br s), 8.55 (1H, s), 8.38 (1H, d, J = 2.2 Hz), 8.16 (1H, s), 7.81 (1H, s), 6.55 (1H, s), 4.52 (1H, t, J = 5.9 Hz), 2.49 (3H, s), 1.61 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 203 (M+H) +.
Amine-69: 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>: N-methoxy-N,3-dimethyl-4-(2,2,2-trifluoroethoxy)benzamide
The title compound is prepared in 98 % yield (8.16 g, colorless oil) from 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (7.00 g, 29.9 mmol, Step-1 of Amine-34) in a similar manner to Step-2 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.65-7.55 (2H, m), 6.78 (1H, d, J = 9.5 Hz), 4.39 (2H, q, J = 8.1 Hz), 3.56 (3H, s), 3.39 (3H, s), 2.28 (3H, s), MS (ESI) m/z: 278 (M+H) +.
<Step-2>: 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanone
The title compound is prepared in 96 % yield (6.55 g, white solid) from N-methoxy-N,3-dimethyl-4-(2,2,2-trifluoroethoxy)benzamide (8.16 g, 29.4 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.82 (1H, d, J = 6.6 Hz), 7.81 (1H, s), 6.81 (1H, d, J = 8.8 Hz), 4.43 (2H, q, J = 8.1 Hz), 2.57 (3H, s), 2.31 (3H, s), MS (ESI) m/z: 233 (M+H) +.
<Step-3>: (R)-2-methyl-N-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 64 % yield (6.05 g, colorless oil) from 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (6.55 g, 28.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (5.13 g, 42.3 mmol) in a similar manner to Step-4 of Amine-1.
1H -NMR (300 MHz, CDCl3) delta 7.16 (1H, s), 7.13 (1H, d, J = 8.8 Hz), 6.75 (1H, d, J = 9.5 Hz), 4.52-4.45 (1H, m), 4.33 (2H, q, J = 8.1 Hz), 3.32 (1H, d, J = 2.2 Hz), 2.26 (3H, s), 1.47 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 338 (M+H) +.
<Step-4>: 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 95 % yield (4.58 g, white solid) from (R)-2-methyl-N-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer) (6.05 g, 17.9 mmol, Step-3) in a similar manner to Step-5 of Amine-1.
1H -NMR (300 MHz, DMSO-d6) delta 8.40 (3H, br s), 7.33 (1H, s), 7.32 (1H, d, J =6.6 Hz), 7.09 (1H, d, J =8.8 Hz), 4.75 (2H, q, J =8.8 Hz), 4.35-4.25 (1H, m), 2.17 (3H, s), 1.46 (3H, d, J = 6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 217 is observed.
Amine-70: 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 6-(cyclopropylmethoxy)-5-methylnicotinic acid
The title compound is prepared in 78% yield (3.8 g, white solid) from methyl 6-fluoro-5-methylnicotinate (4.00 g, 23.7 mmol, Step-1 of Amine-36) in a similar manner to Step-2 of Amine-36.
1H-NMR (300 MHz, DMSO-d6) delta 8.50 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 1.4 Hz), 4.18 (2H, d, J = 7.0 Hz), 2.17 (3H, s), 1.35-1.20 (1H, m), 0.60-0.46 (2H, m), 0.45-0.28 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 206 (M-H)-.
<Step-2>: 6-(cyclopropylmethoxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in 98% yield (4.52 g, colorless oil) from 6-(cyclopropylmethoxy)-5-methylnicotinic acid (3.82 g, 18.4 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.84 (1H, s), 7.79 (1H, s), 4.20 (2H, d, J = 7.0 Hz), 3.57 (3H, s), 3.35 (3H, s), 2.23 (3H, s), 1.38-1.22 (1H, m), 0.62-0.56 (2H, m), 0.38-0.33 (2H, m), MS (ESI) m/z: 251 (M+H) +.
<Step-3>: 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in 86% yield (3.18 g, white solid) from 6-(cyclopropylmethoxy)-N-methoxy-N,5-dimethylnicotinamide (4.52 g, 18.1 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.57 (1H, s), 7.94 (1H, s), 4.23 (2H, d, J = 7.0 Hz), 2.54 (3H, s), 2.23 (3H, s), 1.34-1.25 (1H, m), 0.63-0.57 (2H, m), 0.39-0.34 (2H, m), MS (ESI) m/z: 206 (M+H) +.
<Step-4>: (R)-N-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 85% yield (4.10 g, colorless oil) from 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanone (3.18 g, 15.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.82 g, 23.3 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.91 (1H, s), 7.36 (1H, s), 4.50-4.44 (1H, m), 4.13 (2H, d, J = 6.6 Hz), 3.30 (1H, br s), 2.21 (3H, s), 1.48 (3H, d, J = 6.2 Hz), 1.28-1.20 (1H, m), 1.22 (9H, s), 0.61-0.54 (2H, m), 0.36-0.31 (2H, m), MS (ESI) m/z: 311 (M+H) +.
<Step-5>: 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 79% yield (2.52 g, white solid) from (R)-N-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (4.10 g, 13.2 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.42 (3H, br s), 8.05 (1H, s), 7.71 (1H, s), 4.38-4.29 (1H, m), 4.11 (2H, d, J = 7.0 Hz), 2.15 (3H, s), 1.49 (3H, d, J = 7.0 Hz), 1.29-1.16 (1H, m), 0.57-0.48 (2H, m), 0.33-0.27 (2H, m), MS (ESI) m/z: 207 (M+H) +.
Amine-71: 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (single enantiomer)
<Step-1>: 6-((4-fluorobenzyl)oxy)-5-methylnicotinic acid
The title compound is prepared in 69% yield (4.26 g, white solid) from methyl 6-fluoro-5-methylnicotinate (4.00 g, 23.7 mmol, Step-1 of Amine-36) in a similar manner to Step-2 of Amine-36.
1H-NMR (300 MHz, CDCl3/DMSO-d6) delta 8.69 (1H, d, J = 2.2 Hz), 8.01 (1H, d, J = 2.2 Hz), 7.45 (2H, dd, J = 8.0, 5.1 Hz), 7.06 (2H, t, J = 8.8 Hz), 5.43 (2H, s), 2.24 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 260 (M-H)-.
<Step-2>: 6-((4-fluorobenzyl)oxy)-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in >99% yield (2.80 g, colorless oil) from 6-((4-fluorobenzyl)oxy)-5-methylnicotinic acid (2.00 g, 7.66 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.48 (1H, s), 7.83 (1H, s), 7.47-7.42 (2H, m), 7.10-7.04 (2H, m), 5.42 (2H, s), 3.59 (3H, s), 3.38 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 305 (M+H) +.
<Step-3>: 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanone
The title compound is prepared in 81% yield (1.94 g, white solid) from 6-((4-fluorobenzyl)oxy)-N-methoxy-N,5-dimethylnicotinamide (2.80 g, 9.2 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, d, J = 1.5 Hz), 7.99 (1H, d, J = 1.5 Hz), 7.47-4.42 (2H, m), 7.10-7.04 (2H, m), 5.45 (2H, s), 2.57 (3H, s), 2.26 (3H, s).
<Step-4>: (R)-N-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 79% yield (2.15 g, white solid) from 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanone (1.94 g, 7.48 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.96 (1H, d, J = 2.2 Hz), 7.46-7.41 (3H, m), 7.06 (2H, t, J = 8.8 Hz), 5.36 (2H, s), 4.54-4.46 (1H, m), 3.33 (1H, d, J = 2.2 Hz), 2.23 (3H, s), 1.51 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 365 (M+H) +.
<Step-5>: 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (single enantiomer)
The title compound is prepared in 76% yield (1.16 g, colorless oil) from (R)-N-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (2.14 g, 5.87 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.92 (1H, d, J = 2.2 Hz), 7.46-7.41 (3H, m), 7.09-7.01 (2H, m), 5.35 (2H, s), 4.10 (1H, d, J = 6.6 Hz), 2.23 (3H, s), 1.38 (3H, d, J = 6.6 Hz).
Amine-72: 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 2-chloro-4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridine
The title compound is prepared in 89% yield (7.97 g, pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (5.00 g, 34.8 mmol) and 1,1,2,2-tetrafluoro-3-iodopropane (16.9 g, 69.7 mmol) in a similar manner to Step-1 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 7.91 (1H, s), 7.16 (1H, s), 6.02 (1H, tt, J = 53.1, 4.0 Hz), 4.43 (2H, t, J = 11.7 Hz), 2.26 (3H, s), MS (ESI) m/z: 258 (M+H) +.
<Step-2>: ethyl 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinate
The title compound is prepared in 90% yield (5.55 g, white solid) from 2-chloro-4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridine (5.39 g, 20.9 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 8.26 (1H, s), 8.00 (1H, s), 6.04 (1H, tt, J = 53.1, 4.0 Hz), 4.60-4.35 (4H, m), 2.32 (3H, s), 1.44 (3H, t, J = 7.1 Hz), MS (ESI) m/z: 296 (M+H) +.
<Step-3>: 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinic acid
The title compound is prepared in 94% yield (1.27 g, white solid) from ethyl 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinate (1.50 g, 5.08 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.43 (1H, s), 7.92 (1H, s), 6.71 (1H, tt, J = 51.6, 5.5 Hz), 4.86 (2H, t, J = 13.0 Hz), 2.24 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 268 (M+H) +.
<Step-4>: N-methoxy-N,4-dimethyl-5-(2,2,3,3-tetrafluoropropoxy)picolinamide
The title compound is prepared in 92% yield (1.36 g, white solid) from 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinic acid (1.27 g, 4.75 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.14 (1H, s), 7.58 (1H, s), 6.05 (1H, tt, J = 52.9, 4.2 Hz), 4.51 (2H, t, J = 11.7 Hz), 3.77 (3H, s), 3.41 (3H, s), 2.30 (3H, s), MS (ESI) m/z: 311 (M+H) +.
<Step-5>: 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinaldehyde
The title compound is prepared in >99% yield (1.20 g, yellow solid) from N-methoxy-N,4-dimethyl-5-(2,2,3,3-tetrafluoropropoxy)picolinamide (1.36 g, 4.38 mmol, Step-4) and lithium aluminum hydride (83 mg, 2.2 mmol) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 10.0 (1H, s), 8.30 (1H, s), 7.85 (1H, s), 6.05 (1H, tt, J = 52.9, 4.0 Hz), 4.58 (2H, t, J = 11.7 Hz), 2.34 (3H, s), MS (ESI) m/z: 252 (M+H) +.
<Step-6>: (R,E)-2-methyl-N-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide
The title compound is prepared in 81% yield (1.38 g, pale yellow solid) from 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinaldehyde (1.20 g, 4.79 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (872 mg, 7.19 mmol) in a similar manner to Step-6 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, s), 8.27 (1H, s), 7.88 (1H, s), 6.05 (1H, tt, J = 53.1, 3.9 Hz), 4.55 (2H, t, J = 11.7 Hz), 2.33 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 355 (M+H) +.
<Step-7>: (R)-2-methyl-N-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 80% yield (1.16 g, colorless oil) from (R,E)-2-methyl-N-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.16 g, 3.13 mmol, Step-6) in a similar manner to Step-7 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.09 (1H, s), 7.11 (1H, s), 6.04 (1H, tt, J = 53.1, 4.4 Hz), 4.62 (1H, d, J = 5.5 Hz), 4.52 (1H, quintet, J = 6.6 Hz), 4.43 (2H, t, J = 11.7 Hz), 2.25 (3H, s), 1.48 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 371 (M+H) +.
<Step-8>: 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (976 mg, white solid) from (R)-2-methyl-N-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (1.16 g, 3.13 mmol, Step-7, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.36 (3H, br s), 8.38 (1H, s), 7.41 (1H, s), 6.72 (1H, tt, J = 51.9, 5.5 Hz), 4.79 (2H, t, J = 13.0 Hz), 4.50-4.36 (1H, m), 2.24 (3H, s), 1.47 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 267 (M+H) +.
Amine-73: 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 2-chloro-5-(cyclopropylmethoxy)-4-methylpyridine
The title compound is prepared in 86% yield (3.57 g, colorless oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and (bromomethyl)cyclopropane (3.39 g, 25.1 mmol) in a similar manner to Step-1 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 7.84 (1H, s), 7.10 (1H, s), 3.88 (2H, d, J = 6.6 Hz), 2.25 (3H, s), 1.37-1.22 (1H, m), 0.72-0.62 (2H, m), 0.43-0.33 (2H, m), MS (ESI) m/z: 198 (M+H) +.
<Step-2>: ethyl 5-(cyclopropylmethoxy)-4-methylpicolinate
The title compound is prepared in 52% yield (2.21 g, white solid) from 2-chloro-5-(cyclopropylmethoxy)-4-methylpyridine (3.57 g, 18.1 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 8.21 (1H, s), 7.95 (1H, s), 4.44 (2H, q, J = 6.6 Hz), 3.99 (2H, d, J = 6.6 Hz), 2.31 (3H, s), 1.43 (3H, t, J = 6.6 Hz), 1.39-1.23 (1H, m), 0.72-0.63 (2H, m), 0.45-0.36 (2H, m), MS (ESI) m/z: 236 (M+H) +.
<Step-3>: 5-(cyclopropylmethoxy)-4-methylpicolinic acid
The title compound is prepared in >99% yield (1.04 g, white solid) from ethyl 5-(cyclopropylmethoxy)-4-methylpicolinate (1.08 g, 4.59 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.31 (1H, s), 8.05 (1H, s), 4.10 (2H, d, J = 7.0 Hz), 2.30 (3H, s), 1.35-1.20 (1H, m), 0.65-0.56 (2H, m), 0.42-0.31 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 208 (M+H) +.
<Step-4>: 5-(cyclopropylmethoxy)-N-methoxy-N,4-dimethylpicolinamide
The title compound is prepared in 50% yield (622 mg, colorless oil) from 5-(cyclopropylmethoxy)-4-methylpicolinic acid (1.04 g, 5.01 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.10 (1H, s), 7.56 (1H, s), 3.96 (2H, d, J = 7.0 Hz), 3.77 (3H, s), 3.42 (3H, s), 2.29 (3H, s), 1.41-1.24 (1H, m), 0.73-0.62 (2H, m), 0.50-0.31 (2H, m), MS (ESI) m/z: 251 (M+H) +.
<Step-5>: 5-(cyclopropylmethoxy)-4-methylpicolinaldehyde
The title compound is prepared in >99% yield (495 mg, pale orange solid) from 5-(cyclopropylmethoxy)-N-methoxy-N,4-dimethylpicolinamide (622 mg, 2.49 mmol, Step-4) and lithium aluminum hydride (47 mg, 1.2 mmol) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 9.95 (1H, s), 8.25 (1H, s), 7.81 (1H, s), 4.04 (2H, d, J = 6.6 Hz), 2.34 (3H, s), 1.44-1.21 (1H, m), 0.75-0.60 (2H, m), 0.51-0.36 (2H, m), MS (ESI) m/z: 192 (M+H) +.
<Step-6>: (R,E)-N-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
The title compound is prepared in 90% yield (688 mg, yellow oil) from 5-(cyclopropylmethoxy)-4-methylpicolinaldehyde (495 mg, 2.59 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (471 mg, 3.88 mmol) in a similar manner to Step-6 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.60 (1H, s), 8.23 (1H, s), 7.83 (1H, s), 4.00 (2H, d, J = 6.9 Hz), 2.32 (3H, s), 1.41-1.22 (1H, m), 1.28 (9H, s), 0.75-0.61 (2H, m), 0.47-0.35 (2H, m), MS (ESI) m/z: 295 (M+H) +.
<Step-7>: (R)-N-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 67% yield (485 mg, colorless oil) from (R,E)-N-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (688 mg, 2.34 mmol, Step-6) in a similar manner to Step-7 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.04 (1H, s), 7.06 (1H, s), 4.65 (1H, d, J = 5.5 Hz), 4.51 (1H, quintet, J = 6.2 Hz), 3.88 (2H, d, J = 6.6 Hz), 2.25 (3H, s), 1.47 (3H, d, J = 6.6 Hz), 1.40-1.23 (1H, m), 1.25 (9H, s), 0.71-0.58 (2H, m), 0.42-0.30 (2H, m), MS (ESI) m/z: 311 (M+H) +.
<Step-8>: 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (384 mg, white solid) from (R)-N-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (485 mg, 1.56 mmol, Step-7) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.32 (3H, br s), 8.23 (1H, s), 7.37 (1H, s), 4.52-4.38 (1H, m), 3.99 (2H, d, J = 7.0 Hz), 2.23 (3H, s), 1.46 (3H, d, J = 6.6 Hz), 1.32-1.20 (1H, m), 0.65-0.51 (2H, m), 0.41-0.29 (2H, m), MS (ESI) m/z: 207 (M+H) +.
Amine-74: 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (single enantiomer)
<Step-1>: 5-chloro-6-(cyclopropylmethoxy)nicotinic acid
The title compound is prepared in 98% yield (4.65 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and cyclopropylmethanol (2.25 g, 31.3 mmol) in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.63 (1H, d, J = 2.2 Hz), 8.22 (1H, d, J = 2.2 Hz), 4.28 (2H, d, J = 7.3 Hz), 1.38-1.20 (1H, m), 0.63-0.54 (2H, m), 0.42-0.34 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 226 (M-H) -.
<Step-2>: 5-chloro-6-(cyclopropylmethoxy)-N-methoxy-N-methylnicotinamide
The title compound is prepared in 85% yield (1.21 g, colorless oil) from 5-chloro-6-(cyclopropylmethoxy)nicotinic acid (1.20 g, 5.27 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.51 (1H, d, J = 2.2 Hz), 8.08 (1H, d, J = 2.2 Hz), 4.28 (2H, d, J = 7.0 Hz), 3.59 (3H, s), 3.38 (3H, s), 1.43-1.29 (1H, m), 0.72-0.57 (2H, m), 0.48-0.35 (2H, m), MS (ESI) m/z: 271 (M+H) +.
<Step-3>: 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanone
The title compound is prepared in 92% yield (923 mg, white solid) from 5-chloro-6-(cyclopropylmethoxy)-N-methoxy-N-methylnicotinamide (1.21 g, 4.46 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.61 (1H, d, J = 2.2 Hz), 8.20 (1H, d, J = 2.2 Hz), 4.32 (2H, d, J = 7.3 Hz), 2.57 (3H, s), 1.44-1.23 (1H, m), 0.71-0.54 (2H, m), 0.50-0.35 (2H, m), MS (ESI) m/z: 226 (M+H) +.
<Step-4>: (R)-N-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 90% yield (1.22 g, colorless oil) from 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanone (923 mg, 4.09 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (744 mg, 6.14 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.98 (1H, d, J = 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 4.58-4.43 (1H, m), 4.21 (2H, d, J = 7.0 Hz), 3.33 (1H, d, J = 2.9 Hz), 1.51 (3H, d, J = 6.6 Hz), 1.40-1.25 (1H, m), 1.23 (9H, s), 0.68-0.57 (2H, m), 0.43-0.33 (2H, m), MS (ESI) m/z: 331 (M+H) +.
<Step-5>: 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (single enantiomer)
The title compound is prepared in 62% yield (517 mg, yellow oil) from (R)-N-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.22 g, 3.70 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.19 (1H, d, J = 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz), 4.45 (1H, q, J = 6.6 Hz), 4.21 (2H, d, J = 7.0 Hz), 1.49 (3H, d, J = 7.0 Hz), 1.42-1.19 (1H, m), 0.64-0.51 (2H, m), 0.45-0.28 (2H, m) (a signal due to NH 2 is not observed), MS (ESI) m/z: 227 (M+H) +.
Amine-75: 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 6-cyclobutoxy-5-methylnicotinic acid
The title compound is prepared in 88% yield (1.18 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and cyclobutanol (837 mg, 11.6 mmol) in a similar manner to Step-1 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.50 (1H, s), 7.97 (1H, s), 5.21 (1H, quintet, J = 7.3 Hz), 2.48-2.35 (2H, m), 2.16 (3H, s), 2.15-1.99 (2H, m), 1.84-1.57 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 208 (M+H) +.
<Step-2>: 6-cyclobutoxy-N-methoxy-N,5-dimethylnicotinamide
The title compound is prepared in 93% yield (1.24 g, colorless oil) from 6-cyclobutoxy-5-methylnicotinic acid (1.10 g, 5.31 mmol, Step-1) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.43 (1H, d, J = 1.6 Hz), 7.78 (1H, d, J = 1.6 Hz), 5.26 (1H, quintet, J = 7.3 Hz), 3.59 (3H, s), 3.36 (3H, s), 2.55-2.40 (2H, m), 2.21 (3H, s), 2.22-2.05 (2H, m), 1.90-1.55 (2H, m), MS (ESI) m/z: 251 (M+H) +.
<Step-3>: 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanone
The title compound is prepared in >99% yield (1.03 g, yellow oil) from 6-cyclobutoxy-N-methoxy-N,5-dimethylnicotinamide (1.24 g, 4.94 mmol, Step-2) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.58 (1H, d, J = 2.0 Hz), 7.94 (1H, d, J = 2.0 Hz), 5.29 (1H, quintet, J = 7.7 Hz), 2.58-2.43 (2H, m), 2.54 (3H, s), 2.27-2.09 (2H, m), 2.22 (3H, s), 1.93-1.62 (2H, m), MS (ESI) m/z: 206 (M+H) +.
<Step-4>: (R)-N-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 76% yield (1.17 g, colorless oil) from 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanone (1.03 g, 5.00 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (909 mg, 7.50 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.92 (1H, d, J = 1.8 Hz), 7.35 (1H, d, J = 1.8 Hz), 5.19 (1H, quintet, J = 7.5 Hz), 4.52-4.40 (1H, m), 3.31 (1H, br s), 2.53-2.38 (2H, m), 2.21-2.05 (2H, m), 2.19 (3H, s), 1.89-1.55 (2H, m), 1.48 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 311 (M+H) +.
<Step-5>: 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (939 mg, white solid) from (R)-N-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.17 g, 3.78 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.59 (3H, br s), 8.07 (1H, s), 7.76 (1H, s), 5.15 (1H, quintet, J = 7.3 Hz), 4.38-4.24 (1H, m), 2.50-2.23 (2H, m), 2.18-1.94 (2H, m), 2.15 (3H, s), 1.85-1.60 (2H, m), 1.59 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 207 (M+H) +.
Amine-76: 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 2-chloro-5-(2,2-difluoropropoxy)-4-methylpyridine
The title compound is prepared in 98% yield (4.52 g, pale yellow oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (11.9 g, 52.2 mmol) in a similar manner to Step-1 of Amine-49.
1H-NMR (270 MHz, CDCl3) delta 7.88 (1H, s), 7.14 (1H, s), 4.18 (2H, t, J = 11.2 Hz), 2.27 (3H, s), 1.80 (3H, t, J = 18.5 Hz), MS (ESI) m/z: 222 (M+H) +.
<Step-2>: ethyl 5-(2,2-difluoropropoxy)-4-methylpicolinate
The title compound is prepared in 92% yield (5.35 g, pale yellow solid) from 2-chloro-5-(2,2-difluoropropoxy)-4-methylpyridine (4.99 g, 22.5 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 8.23 (1H, s), 7.99 (1H, s), 4.46 (2H, q, J = 7.3 Hz), 4.28 (2H, t, J = 11.0 Hz), 2.33 (3H, s), 1.81 (3H, t, J = 19.1 Hz), 1.44 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 260 (M+H) +.
<Step-3>: 5-(2,2-difluoropropoxy)-4-methylpicolinic acid
The title compound is prepared in 96% yield (1.72 g, white solid) from ethyl 5-(2,2-difluoropropoxy)-4-methylpicolinate (2.00 g, 7.71 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (270 MHz, DMSO-d6) delta 8.40 (1H, s), 7.93 (1H, s), 4.56 (2H, t, J = 12.5 Hz), 2.26 (3H, s), 1.78 (3H, t, J = 19.1 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 232 (M+H) +.
<Step-4>: 5-(2,2-difluoropropoxy)-N-methoxy-N,4-dimethylpicolinamide
The title compound is prepared in 81% yield (1.25 g, white solid) from 5-(2,2-difluoropropoxy)-4-methylpicolinic acid (1.30 g, 5.62 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.12 (1H, s), 7.58 (1H, s), 4.25 (2H, t, J = 11.0 Hz), 3.77 (3H, s), 3.42 (3H, s), 2.31 (3H, s), 1.81 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 275 (M+H) +.
<Step-5>: 5-(2,2-difluoropropoxy)-4-methylpicolinaldehyde
The title compound is prepared in >99% yield (1.01 g, pale orange solid) from 5-(2,2-difluoropropoxy)-N-methoxy-N,4-dimethylpicolinamide (1.25 g, 4.57 mmol, Step-4) and lithium aluminum hydride (87 mg, 2.3 mmol) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 9.97 (1H, s), 8.28 (1H, s), 7.84 (1H, s), 4.32 (2H, t, J = 11.0 Hz), 2.35 (3H, s), 1.83 (3H, t, J = 18.7 Hz), MS (ESI) m/z: 216 (M+H) +.
<Step-6>: (R,E)-N-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
The title compound is prepared in 74% yield (1.10 g, pale yellow solid) from 5-(2,2-difluoropropoxy)-4-methylpicolinaldehyde (1.01 g, 4.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (851 mg, 7.02 mmol) in a similar manner to Step-6 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.62 (1H, s), 8.25 (1H, s), 7.87 (1H, s), 4.29 (2H, t, J = 11.0 Hz), 2.34 (3H, s), 1.82 (3H, t, J = 18.7 Hz), 1.28 (9H, s), MS (ESI) m/z: 319 (M+H) +.
<Step-7>: (R)-N-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 93% yield (1.07 g, colorless oil) from (R,E)-N-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.10 g, 3.45 mmol, Step-6) in a similar manner to Step-7 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.06 (1H, s), 7.10 (1H, s), 4.64 (1H, d, J = 6.2 Hz), 4.51 (1H, quintet, J = 6.2 Hz), 4.18 (2H, t, J = 11.0 Hz), 2.26 (3H, s), 1.79 (3H, t, J = 18.7 Hz), 1.47 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 335 (M+H) +.
<Step-8>: 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 99% yield (841 mg, white solid) from (R)-N-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.07 g, 3.19 mmol, Step-7) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.47 (3H, br s), 8.35 (1H, s), 7.46 (1H, s), 4.58-4.35 (1H, m), 4.48 (2H, t, J = 12.5 Hz), 2.25 (3H, s), 1.77 (3H, t, J = 19.4 Hz), 1.47 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 231 (M+H) +.
Amine-77: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: A mixture of 6-chloro-4-methyl-3-(2,2,3,3-tetrafluoropropoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine (ca 1.5:1)
The title compound is prepared in 85% yield (5.42 g, colorless oil) from 3,6-dichloro-4-methylpyridazine (4.00 g, 24.5 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.56 g, 27.0 mmol) in a similar manner to Step-1 of Amine-48.
MS (ESI) m/z: 259 (M+H) +.
<Step-2>: ethyl 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylate
The title compound is prepared in 27% yield (1.66 g, yellow solid) from a mixture of 6-chloro-4-methyl-3-(2,2,3,3-tetrafluoropropoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine (ca 1.5:1) (5.40 g, 20.9 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 7.99 (1H, s), 6.02 (1H, tt, J = 53.1, 3.7 Hz), 5.04 (2H, t, J = 12.5 Hz), 4.50 (2H, q, J = 7.3 Hz), 2.34 (1H, s), 1.46 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 297 (M+H)+.
<Step-3>: 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylic acid
The title compound is prepared in >99% yield (1.70 g, pale orange solid) from ethyl 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylate (1.60 g, 5.40 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.09 (1H, s), 6.76 (1H, tt, J = 51.9, 5.1 Hz), 5.14 (2H, t, 13.2 Hz), 2.29 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 267 (M-H) -.
<Step-4>: N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxamide
The title compound is prepared in >99% yield (1.80 g, white solid) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylic acid (1.40 g, 5.22 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.27 (1H, s), 6.01 (1H, tt, J = 52.7, 3.7 Hz), 5.00 (2H, t, J = 12.5 Hz), 3.85 (3H, s), 3.42(1H, br s), 2.31(1H, s), MS (ESI) m/z: 312 (M+H) +.
<Step-5>: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanone
The title compound is prepared in 90% yield (1.23 g, white solid) from N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxamide (1.60 g, 5.14 mmol, Step-4) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.96 (1H, s), 6.01(1H, tt, J =52.7, 4.4 Hz), 5.05 (2H, t, J = 12.5 Hz), 2.81 (3H, s), 2.34 (3H, s), MS (ESI) m/z: 267 (M+H) +.
<Step-6>: (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 66% yield (1.14 g, yellow oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanone (1.22 g, 4.61 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (839 mg, 6.92 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.31 (1H, s), 6.00 (1H, tt, J = 52.7, 4.4 Hz), 2.05 (2H, t, J = 12.5 Hz), 4.67(1H, quintet, J = 5.9 Hz), 4.60 (1H, br s), 2.28 (3H, s), 1.57 (3H, d, J = 6.6 Hz), 1.26 (9H, s), MS (ESI) m/z: 372 (M+H) +.
<Step-7>: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (967 mg, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (1.10 g, 2.96 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.83 (3H, br s), 7.84 (1H, s), 6.78 (1H, tt, J =51.2, 5.9 Hz), 5.07 (2H, t, J = 13.2 Hz), 4.61 (1H, quintet, J = 5.9 Hz), 2.26 (3H, s), 1.55 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 268 (M+H) +.
Amine-78: 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: A mixture of 6-chloro-3-(2,2-difluoropropoxy)-4-methylpyridazine and 3-chloro-6-(2,2-difluoropropoxy)-4-methylpyridazine (ca 2:1 w/w)
The title compound is prepared in 76% yield (5.19 g, colorless oil) from 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol) and 2,2-difluoropropan-1-ol (3.54 g, 36.8 mmol) in a similar manner to Step-1 of Amine-48.
MS (ESI) m/z: 223 (M+H) +.
<Step-2>: ethyl 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylate
The title compound is prepared in 27% yield (1.60 g, yellow solid) from a mixture of 6-chloro-3-(2,2-difluoropropoxy)-4-methylpyridazine and 3-chloro-6-(2,2-difluoropropoxy)-4-methylpyridazine (ca 2:1 w/w) (5.0 g, 22.5 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 7.97 (1H, s), 4.78 (2H, t, J = 11.7 Hz), 4.49 (2H, q, J = 7.3 Hz), 2.34 (3H, s), 1.78 (3H, t, J = 19.0 Hz), 1.46 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 261 (M+H) +.
<Step-3>: 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylic acid
The title compound is prepared in >99% yield (1.55 g, pale orange solid) from ethyl 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylate (1.62 g, 6.19 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.01 (1H, s), 4.84 (2H, t, J = 13.2 Hz), 3.17 (3H, s), 1.80 (3H, t, J = 19.8 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 231 (M-H) -.
<Step-4>: 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylpyridazine-3-carboxamide
The title compound is prepared in 73% yield (1.30 g, white solid) from 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylic acid (1.50 g, 6.46 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.57 (1H, br s), 4.75 (2H, t, J = 12.5 Hz), 3.85 (3H, s), 3.43 (3H, br s), 2.32 (3H, s), 1.79 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 276 (M+H) +.
<Step-5>: 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanone
The title compound is prepared in 82% yield (862 mg, white solid) from 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylpyridazine-3-carboxamide (1.25 g, 4.54 mmol, Step-4) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.94 (1H, s), 4.80 (2H, t, J = 11.7 Hz), 2.81 (3H, s), 2.34(3H, s), 1.80 (3H, t, J = 19.0 Hz), MS (ESI) m/z: 231 (M+H) +.
<Step-6>: (R)-N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 74% yield (928 mg, yellow solid) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanone (860 mg, 3.74 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (679 mg, 5.60 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.28 (1H, s), 4.72-4.63 (4H, m), 2.28 (3H, s), 1.77 (3H, t, J = 19.1 Hz), 1.56 (3H, d, J = 6.6 Hz) 1.26 (9H, s), MS (ESI) m/z: 336 (M+H) +.
<Step-7>: 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (750 mg, white solid) from (R)-N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (920 mg, 2.74 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.79 (3H, br s), 7.80 (1H, s), 4.76 (2H, t, J = 12.5 Hz), 4.61 (1H, m), 2.25 (3H, s), 1.79 (3H, t, J = 19.8 Hz), 1.55 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 232 (M+H)+.
Amine-79: 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
<Step-1>: 2-chloro-5-((4-fluorobenzyl)oxy)-4-methylpyridine
The title compound is prepared in 96% yield (3.38 g, white solid) from 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and 1-(chloromethyl)-4-fluorobenzene (3.22 g, 22.3 mmol) in a similar manner to Step-1 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 7.94 (1H, s), 7.44-7.35 (2H, m), 7.18-7.05 (3H, m), 5.09 (2H, s), 2.25 (3H, s), MS (ESI) m/z: 252 (M+H) +.
<Step-2>: ethyl 5-((4-fluorobenzyl)oxy)-4-methylpicolinate
The title compound is prepared in 59% yield (2.31 g, white solid) from 2-chloro-5-((4-fluorobenzyl)oxy)-4-methylpyridine (3.38 g, 13.4 mmol, Step-1) in a similar manner to Step-2 of Amine-48.
1H-NMR (300 MHz, CDCl3) delta 8.31 (1H, s), 7.98 (1H, s), 7.49-7.38 (2H, m), 7.17-7.04 (2H, m), 5.21 (2H, s), 4.45 (2H, q, J = 7.3 Hz), 2.32 (3H, s), 1.43 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 290 (M+H) +.
<Step-3>: 5-((4-fluorobenzyl)oxy)-4-methylpicolinic acid
The title compound is prepared in 93% yield (934 mg, white solid) from ethyl 5-((4-fluorobenzyl)oxy)-4-methylpicolinate (1.11 g, 3.83 mmol, Step-2) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 8.42 (1H, s), 7.92 (1H, s), 7.59-7.51 (2H, m), 7.28-7.21 (2H, m), 5.35 (2H, s), 2.26 (3H, s), MS (ESI) m/z: 262 (M+H) +.
<Step-4>: 5-((4-fluorobenzyl)oxy)-N-methoxy-N,4-dimethylpicolinamide
The title compound is prepared in >99% yield (1.32 g, colorless oil) from 5-((4-fluorobenzyl)oxy)-4-methylpicolinic acid (897 mg, 3.43 mmol, Step-3) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 8.19 (1H, s), 7.59 (1H, s), 7.49-7.38 (2H, m), 7.15-7.05 (2H, m), 5.18 (2H, s), 3.77 (3H, s), 3.42 (3H, s), 2.30 (3H, s), MS (ESI) m/z: 305 (M+H) +.
<Step-5>: 5-((4-fluorobenzyl)oxy)-4-methylpicolinaldehyde
The title compound is prepared in 97% yield (1.03 g, pale red solid) from 5-((4-fluorobenzyl)oxy)-N-methoxy-N,4-dimethylpicolinamide (1.32 g, 4.33 mmol, Step-4) and lithium aluminum hydride (82 mg, 2.2 mmol) in a similar manner to Step-2 of Amine-3.
1H-NMR (300 MHz, CDCl3) delta 9.95 (1H, s), 8.36 (1H, s), 7.83 (1H, s), 7.51-7.35 (2H, m), 7.19-7.05 (2H, m), 5.25 (2H, s), 2.33 (3H, s), MS (ESI) m/z: 246 (M+H) +.
<Step-6>: (R,E)-N-((5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
The title compound is prepared in 67% yield (972 mg, pale yellow solid) from 5-((4-fluorobenzyl)oxy)-4-methylpicolinaldehyde (1.03 g, 4.19 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (762 mg, 6.29 mmol) in a similar manner to Step-6 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.60 (1H, s), 8.33 (1H, s), 7.86 (1H, s), 7.46-7.38 (2H, m), 7.15-7.03 (2H, m), 5.22 (2H, s), 2.33 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 349 (M+H) +.
<Step-7>: (R)-N-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 92% yield (934 mg, colorless oil) from (R,E)-N-((5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (972 mg, 2.79 mmol, Step-6) in a similar manner to Step-7 of Amine-49.
1H-NMR (300 MHz, CDCl3) delta 8.12 (1H, s), 7.45-7.34 (2H, m), 7.18-7.02 (3H, m), 5.10 (2H, s), 4.65 (1H, d, J = 5.5 Hz), 4.51 (1H, quintet, J = 6.2 Hz), 2.26 (3H, s), 1.47 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 365 (M+H) +.
<Step-8>: 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (788 mg, white solid) from (R)-N-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (934 mg, 2.56 mmol, Step-7) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.52 (3H, br s), 8.37 (1H, s), 7.61-7.44 (3H, m), 7.32-7.18 (2H, m), 5.29 (2H, s), 2.27 (3H, s), 1.49 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 261 (M+H) +.
Amine-80: 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>: N-methoxy-N,3-dimethyl-4-(trifluoromethoxy)benzamide
The title compound is prepared in 86% yield (1.23 g, colorless oil) from 3-methyl-4-(trifluoromethoxy)benzoic acid (1.20 g, 5.45 mmol) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.61 (1H, s), 7.57 (1H, d, J = 8.1 Hz), 7.23 (1H, d, J = 7.3 Hz), 3.57 (3H, s), 3.38 (3H, s), 2.36 (3H, s), MS (ESI) m/z: 264(M+H) +.
<Step-2>: 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanone
The title compound is prepared in >99% yield (1.13 g, colorless oil) from N-methoxy-N,3-dimethyl-4-(trifluoromethoxy)benzamide (1.20 g, 4.56 mmol, Step-1) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.87 (1H, s), 7.82 (1H, d, J = 8.0 Hz), 7.28 (1H, d, J = 9.5 Hz), 2.60 (3H, s), 2.37 (3H, s).
<Step-3>: (R)-2-methyl-N-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)
The title compound is prepared in 66% yield (971 mg, colorless oil) from 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanone (1.00 g, 4.58 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (833 mg, 6.88 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.21-7.18 (3H, m), 4.55-4.47 (1H, m), 3.37 (1H, br s), 2.31 (3H, s), 1.49 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 324 (M+H) +.
<Step-4>: 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 91% yield (700 mg, white solid) from (R)-2-methyl-N-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (970 mg, 3.00 mmol, Step-3, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.52 (3H, br s), 7.56-7.39 (3H, m), 4.42-4.40 (1H, m), 2.30 (3H, s), 1.50 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 220 (M+H) +.
Amine-81: 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>: methyl 4-(2,2-difluoropropoxy)-3-methylbenzoate
The title compound is prepared in 76% yield (2.09 g, white solid) from methyl 4-hydroxy-3-methylbenzoate (1.86 g, 11.2 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.37 g, 27.9 mmol) in a similar manner to Step-1 of Amine-10.
1H-NMR (300 MHz, CDCl3) delta 7.92-7.85 (2H, m), 6.79 (1H, d, J = 8.1 Hz), 4.16 (2H, t, J = 11.0 Hz), 3.89 (3H, s), 2.28 (3H, s), 1.81 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 245 (M+H) +.
<Step-2>: 4-(2,2-difluoropropoxy)-3-methylbenzoic acid
The title compound is prepared in 95% yield (967 mg, white solid) from methyl 4-(2,2-difluoropropoxy)-3-methylbenzoate (1.08 g, 4.42 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 12.67 (1H, br s), 7.80-7.76 (2H, m), 7.08 (1H, d, J = 8.1 Hz), 4.37 (2H, t, J = 12.5 Hz), 2.21 (3H, s), 1.77 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 231 (M+H) +.
<Step-3>: 4-(2,2-difluoropropoxy)-N-methoxy-N,3-dimethylbenzamide
The title compound is prepared in 66% yield (669 mg, colorless oil) from 4-(2,2-difluoropropoxy)-3-methylbenzoic acid (850 mg, 3.69 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.60-7.57 (2H, m), 6.77 (1H, d, J = 8.4 Hz), 4.14 (2H, t, J = 11.4 Hz), 3.56 (3H, s), 3.35 (3H, s), 2.27 (3H, s), 1.81 (3H, t, J = 18.7 Hz), MS (ESI) m/z: 274 (M+H) +.
<Step-4>: 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanone
The title compound is prepared in 96% yield (539 mg, yellow oil) from 4-(2,2-difluoropropoxy)-N-methoxy-N,3-dimethylbenzamide (669 mg, 2.45 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.86-7.80 (2H, m), 6.81 (1H, d, J = 9.2 Hz), 4.18 (2H, t, J = 11.0 Hz), 2.56 (3H, s), 2.29 (3H, s), 1.81 (3H, t, J = 18.7 Hz), MS (ESI) m/z: 229 (M+H) +.
<Step-5>: (R)-N-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 88% yield (693 mg, pale yellow oil) from 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanone (539 mg, 2.36 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (716 mg, 5.90 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.18-7.12 (2H, m), 6.74 (1H, d, J = 8.6 Hz), 4.50-4.40 (1H, m), 4.09 (2H, t, J = 11.2 Hz), 3.32 (1H, br s), 2.25 (3H, s), 1.79 (3H, t, J = 18.8 Hz), 1.47 (3H, d, J = 6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 334 (M+H) +.
<Step-6>: 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 97% yield (535 mg, white solid) from (R)-N-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (693 mg, 2.08 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.24 (3H, br s), 7.32-7.26 (2H, m), 7.03 (1H, d, J = 8.4 Hz), 4.35-4.20 (3H, m), 2.18 (3H, s), 1.74 (3H, t, J = 19.1 Hz), 1.45 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 230 (M+H) +.
Amine-82: (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride
<Step-1>: 6-(4,4-difluoropiperidin-1-yl)-5-methylnicotinic acid
A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol), 4,4-difluoropiperidine hydrochloride (4.66 g, 29.6 mmol), and cesium carbonate (13.5 g, 41.4 mmol) in DMF is stirred at 120 oC for 16 hours. After cooling to rt, 1 M aqueous sodium hydroxide solution (50 mL) and MeOH (50 mL) are added to the resulting mixture. After stirring at 60 oC for 3 hours, the mixture is acidified by 2 M hydrochloric acid (pH is around 4), and MeOH is removed in vacuo. The formed white precipitate is collected by filtration to give 1.17 g (39%) of the title compound as white solid.
1H-NMR (300 MHz, DMSO-d6) delta 8.60 (1H, s), 7.95 (1H, s), 3.60-3.20 (4H, m), 2.30 (3H, s), 2.19-2.02 (4H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 257 (M+H) +.
<Step-2>: (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanol
The title compound is prepared in 91% yield (1.00 g, white solid) from 6-(4,4-difluoropiperidin-1-yl)-5-methylnicotinic acid (1.17 g, 4.55 mmol, Step-1) in a similar manner to Step-3 of Amine-53.
1H-NMR (300 MHz, CDCl3) delta 8.10 (1H, d, J = 2.2 Hz), 7.48 (1H, d, J = 2.2 Hz), 4.62 (2H, s), 3.31-3.22 (4H, m), 2.29 (3H, s), 2.20-2.05 (4H, m), 1.66 (1H, br s), MS (ESI) m/z: 243 (M+H)+.
<Step-3>: 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 32% yield (497 mg, white solid) from (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanol (1.00 g, 4.14 mmol, Step-2) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 8.23 (1H, d, J = 2.2 Hz), 7.90-7.80 (2H, m), 7.76-7.68 (2H, m), 7.50 (1H, d, J = 2.2 Hz), 4.76 (2H, s), 3.26-3.22 (4H, m), 2.24 (3H, s), 2.18-2.02 (4H, m), MS (ESI) m/z: 372 (M+H)
<Step-4>: (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride
The title compound is prepared in >99% yield (292 mg, white solid) from 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (326 mg, 0.88 mmol, Step-3) in a similar manner to Step-5 of Amine-12.
1H-NMR (300 MHz, DMSO-d6) delta 8.46 (3H, br s), 8.24 (1H, s), 7.87 (1H, s), 4.02-3.95 (2H, m), 3.36-3.29 (4H, m), 2.31 (3H, s), 2.21-2.07 (4H, m), MS (ESI) m/z: 242 (M+H) +.
Amine-83: 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>: (R)-N-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 81% yield (1.41 g, colorless oil) from 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanone (1.20 g, 5.03 mmol) and (R)-2-methylpropane-2-sulfinamide (914 mg, 7.54 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.46 (1H, s), 7.30 (2H, s), 4.56-4.51 (1H, m), 3.41 (1H, s), 1.53 (3H, d, J = 6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 344 (M+H) +.
<Step-2>: 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in >99% yield (1.20 g, white solid) from (R)-N-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 4.07 mmol, Step-1, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.75 (3H, br s), 7.96 (1H, s), 7.68 (2H, s), 4.49 (1H, q, J = 7.3 Hz), 1.53 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 240 (M+H) +.
Amine-84: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine
<Step-1>: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanol
The title compound is prepared in 58% yield (1.15 g, colorless oil) from 6-(2,2-difluoropropoxy)-5-methylnicotinic acid (2.11 g, 9.12 mmol, Step-1 of Amine-56) in a similar manner to Step-3 of Amine-53.
1H-NMR (300 MHz, CDCl3) delta 7.92 (1H, s), 7.49 (1H, s), 4.61 (2H, d, J = 5.1 Hz), 4.50 (2H, t, J = 12.5 Hz), 2.24 (3H, s), 1.75 (3H, t, J = 18.3 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 218 (M+H) +.
<Step-2>: 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 93% yield (1.18 g, white solid) from (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanol (800 mg, 3.68 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 8.08 (1H, s), 7.88-7.80 (2H, m), 7.75-7.70 (2H, m), 7.52 (1H, s), 4.76 (2H, s), 4.47 (2H, t, J = 12.5 Hz), 2.18 (3H, s), 1.71 (3H, t, J = 18.3 Hz), MS (ESI) m/z: 347 (M+H) +.
<Step-3>: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine
The title compound is prepared in 95% yield (699 mg, colorless oil) from 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (1.18 g, 3.41 mmol) in a similar manner to Step-5 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 7.87 (1H, s), 7.44 (1H, s), 4.49 (2H, t, J = 11.7 Hz), 3.79 (2H, s), 2.23 (3H, s), 1.75 (3H, t, J = 18.3 Hz) (a signal due to NH 2 is not observed), MS (ESI) m/z: 217 (M+H) +.
Amine-85: 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (single enantiomer)
<Step-1>: methyl 3-chloro-4-(2,2-difluoropropoxy)benzoate
The title compound is prepared in 54% yield (1.54 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.7 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.11 g, 26.8 mmol) in a similar manner to Step-1 of Amine-10.
1H-NMR (300 MHz, CDCl3) delta 8.09 (1H, d, J = 2.2 Hz), 7.94 (1H, dd, J = 8.8, 2.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 4.22 (2H, t, J = 11.0 Hz), 3.91 (3H, s), 1.85 (3H, t, J = 18.8 Hz), MS (ESI) m/z: 265 (M+H) +.
<Step-2>: 3-chloro-4-(2,2-difluoropropoxy)benzoic acid
The title compound is prepared in 92% yield (1.34 g, white solid) from methyl 3-chloro-4-(2,2-difluoropropoxy)benzoate (1.54 g, 4.82 mmol, Step-1) in a similar manner to Step-2 of Amine-15.
1H-NMR (300 MHz, DMSO-d6) delta 7.92 (1H, d, J = 1.8 Hz), 7.88 (1H, dd, J = 8.4, 1.8 Hz), 7.32 (1H, d, J = 8.4 Hz), 4.48 (2H, t, J = 12.4 Hz), 1.76 (3H, t, J = 19.4 Hz), MS (ESI) m/z: 249 (M-H) -.
<Step-3>: 3-chloro-4-(2,2-difluoropropoxy)-N-methoxy-N-methylbenzamide
The title compound is prepared in >99% yield (719 mg, yellow oil) from 3-chloro-4-(2,2-difluoropropoxy)benzoic acid (600 mg, 2.39 mmol, Step-2) in a similar manner to Step-2 of Amine-2.
1H-NMR (300 MHz, CDCl3) delta 7.84 (1H, d, J = 2.2 Hz), 7.68 (1H, dd, J = 8.6, 2.2 Hz), 6.92 (1H, d, J = 8.6 Hz), 4.21 (2H, t, J = 11.0 Hz), 3.56 (3H, s), 3.36 (3H, s), 1.85 (3H, t, J = 18.8 Hz), MS (ESI) m/z: 294 (M+H) +.
<Step-4>: 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanone
The title compound is prepared in quantitative yield (610 mg, yellow oil) from 3-chloro-4-(2,2-difluoropropoxy)-N-methoxy-N-methylbenzamide (719 mg, 2.45 mmol, Step-3) in a similar manner to Step-3 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 8.02 (1H, d, J = 2.2 Hz), 7.87 (1H, dd, J = 8.8, 2.2 Hz), 6.96 (1H, d, J = 8.8 Hz), 4.23 (2H, t, J = 11.0 Hz), 2.57 (3H, s), 1.85 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 249 (M+H) +.
<Step-5>: (R)-N-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)
The title compound is prepared in 80% yield (696 mg, colorless oil) from 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanone (610 mg, 2.45 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (446 mg, 3.68 mmol) in a similar manner to Step-4 of Amine-1.
1H-NMR (300 MHz, CDCl3) delta 7.38 (1H, d, J = 1.8 Hz), 7.21 (1H, dd, J = 8.4, 1.8 Hz), 6.89 (1H, d, J = 8.4 Hz), 4.53-4.40 (1H, m), 4.15 (2H, t, J = 11.3 Hz), 3.35 (1H, br s), 1.83 (3H, t, J = 18.9 Hz), 1.49 (3H, d, J = 6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 354 (M+H) +.
<Step-6>: 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (single enantiomer)
The title compound is prepared in 94% yield (528 mg, white solid) from (R)-N-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (696 mg, 1.97 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.
1H-NMR (300 MHz, DMSO-d6) delta 8.33 (3H, br s), 7.63 (1H, d, J = 2.2 Hz), 7.43 (1H, dd, J = 8.6, 2.2 Hz), 7.28 (1H, d, J = 8.6 Hz), 4.48-4.34 (1H, m), 4.40 (2H, t, J = 12.5 Hz), 1.75 (3H, t, J = 19.4 Hz), 1.46 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 250 (M+H) +.
Amine-86: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine
<Step-1>: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanol
The title compound is prepared in 49% yield (1.15 g, white solid) from 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid (2.50 g, 9.94 mmol, Step-1 of Amine-63) in a similar manner to Step-3 of Amine-53.
1H-NMR (300 MHz, CDCl3) delta 8.00 (1H, d, J = 2.2 Hz), 7.74 (1H, d, J = 2.2 Hz), 4.65 (2H, d, J = 5.1 Hz), 4.55 (2H, t, J = 11.7 Hz), 1.78 (3H, t, J = 19.1 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 238 (M+H)+.
<Step-2>: 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in 90% yield (1.18 g, white solid) from (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanol (850 mg, 3.58 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 8.15 (1H, d, J = 2.2 Hz), 7.90-7.72 (5H, m), 4.78 (2H, s), 4.52 (2H, t, J = 11.7 Hz), 1.75 (3H, t, J = 18.3 Hz), MS (ESI) m/z: 367 (M+H)+.
<Step-3>: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine
The title compound is prepared in 96% yield (734 mg, colorless oil) from 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.18 g, 3.22 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 7.95 (1H, d, J = 1.5 Hz), 7.71 (1H, d, J = 1.5 Hz), 4.54 (2H, t, J = 11.7 Hz), 3.38 (2H, s), 1.78 (3H, t, J = 18.3 Hz), (a signal due to NH 2 is not observed), MS (ESI) m/z: 237 (M+H)+.
Amine-87: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine
<Step-1>: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol
The title compound is prepared in 96% yield (2.29 g, white solid) from 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (2.49 g, 8.66 mmol, Step-1 of Amine-63) in a similar manner to Step-3 of Amine-53.
1H-NMR (300 MHz, CDCl3) delta 8.02 (1H, d, J = 1.8 Hz), 7.76 (1H, d, J = 1.8 Hz), 6.09 (1H, tt, J = 53.1, 5.1 Hz), 4.78 (2H, t, J = 12.5 Hz), 4.67 (2H, d, J = 5.1 Hz), 1.80 (1H, t, J = 5.1 Hz), MS (ESI) m/z: 274 (M+H)+.
<Step-2>: 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione
The title compound is prepared in >99% yield (1.62 g, white solid) from (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (1.00 g, 3.65 mmol, Step-1) in a similar manner to Step-4 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 8.16 (1H, d, J = 1.5 Hz), 7.90-7.84 (2H, m), 7.82 (1H, d, J = 1.5 Hz), 7.77-7.71 (2H, m), 6.05 (1H, tt, J = 53.5, 5.1 Hz), 4.78 (2H, s), 4.74 (2H, t, J = 11.7 Hz), MS (ESI) m/z: 403 (M+H)+.
<Step-3>: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine
The title compound is prepared in 87% yield (947 mg, colorless oil) from 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.61 g, 4.00 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
1H-NMR (300 MHz, CDCl3) delta 7.97 (1H, d, J = 1.5 Hz), 7.73 (1H, d, J = 1.5 Hz), 6.09 (1H, tt, J = 53.5, 5.1 Hz), 4.76 (2H, t, J = 12.5 Hz), 3.85 (2H, s) (a signal due to NH 2 is not observed), MS (ESI) m/z: 273 (M+H)+.
Example synthesis part
Example-compounds (1 to 686) are prepared as follows.
Representative procedure for Method-A
The following preparation of Example-1 represents the Method-A.
Example-1: N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide (single enantiomer)
A mixture of 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 0.054 mmol, Intermediate 1, single enantiomer), isobutyramide (9.0 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.2 micro mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.0 mg, 0.016 mmol) and tripotassium phosphate (16 mg, 0.075 mmol) in dioxane (2 mL) is heated at 170 oC for 40 min by microwave irradiation. The reaction mixture is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated. The residue is purified by a strong cation exchange cartridge (BondEluteTM SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 7.3 mg (32 % yield) of the title compound.
Representative procedure for Method-B
The following preparation of Example-16 represents the Method-B.
Example-16: 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide (single enantiomer)
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 0.052 mmol, Intermediate-2, single enantiomer), 1-amino-2-methyl-1-oxopropan-2-yl acetate (15 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.2 micro mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.0 mg, 0.016 mmol) and tripotassium phosphate (16 mg, 0.075 mmol) in dioxane (2 mL) is heated at 170 oC for 40 min by microwave irradiation. The reaction mixture is filtered through a short column of NH-gel eluting with EtOAc and volatiles are removed. The residue is dissolved in THF (1.0 mL) and 2 M aqueous sodium hydroxide solution (0.50 mL) is added, and the mixture is stirred overnight at rt. The mixture is neutralized by the addition of 2 M hydrochloric acid (0.50 mL), diluted with THF (4.0 mL) and extracted with EtOAc. The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The mixture is purified by a strong cation exchange cartridge (BondEluteTM SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 7.2 mg (31 % yield) of the title compound.
Representative procedure for Method-C
The following preparation of Example-17 represents the Method-C.
Example-17: 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)
To a solution of N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (159 mg, 0.39 mmol, Example-2, single enantiomer) in THF (3.0 mL) is added 2 M aqueous hydrochloric acid (3.0 mL) at rt. The mixture is stirred at 80 oC for 6 hours. The reaction mixture is concentrated to give 187 mg (>99 % yield) of the title compound as orange solid. A part of the sample is purified by preparative LC-MS to give the title compound.
1H -NMR (300 MHz, DMSO-d6) delta 8.61 (2H, br s), 8.07 (1H, d, J = 6.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 7.66 (1H, d, J = 2.2 Hz), 7.09 (1H, J = 6.2 Hz), 5.46 (1H, q, J = 7.0 Hz), 5.00 (2H, q, J = 9.2 Hz), 4.53 (1H, d, J = 19.8 Hz), 4.20 (1H, J = 19.8 Hz), 2.18 (3H, s), 1.63 (3H, d, J = 6.9 Hz), MS (ESI) m/z: 367 (M+H) +, 365 (M-H) -.
Representative procedure for Method-D
The following preparation of Example-18 represents the Method-D.
Example-18: 2-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (single enantiomer)
To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (20 mg, 0.050 mmol, Example-17, single enantiomer) and triethylamine (0.069 mL, 0.50 mmol) in THF (1 .0 mL) is added 2-methoxyacetyl chloride (27 mg, 0.25 mmol) at rt. The reaction mixture is stirred for 21 hours at rt and diluted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated in vacuo. The residue is purified by preparative LC-MS to give 8.5 mg (39 % yield) of the title compound.
Representative procedure for Method-E
The following preparation of Example-186 represents the Method-E.
Example-186: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)
To a mixture of 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (20 mg, 0.051 mmol, Intermediate-47, single enantiomer), ammonium chloride (8.1 mg, 0.15 mmol), and N,N-diisopropylethylamine in MeCN (2.0 mL) is added HBTU (23 mg, 0.061 mmol) at rt. The reaction mixture is stirred at rt for 1 hour. After removal of the solvent, the residue is filtered through a short column of NH-gel eluting with EtOAc and volatiles are removed. The residue is purified by preparative LC-MS to give 10.2 mg (50 % yield) of the title compound.
Representative procedure for Method-F
The following preparation of Example-266 represents the Method-F.
Example-266: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)
<Step-1>: 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (single enantiomer)
The title compound is prepared in 96 % yield (270 mg, pale brown solid) from 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and 2-chloroacetyl chloride (90 mg, 0.79 mmol) in a similar manner to Example-18 (Method-D).
1H -NMR (300 MHz, CDCl3) delta 8.79 (1H, br s), 8.50 (1H, d, J = 5.1 Hz), 8.00 (1H, s), 7.68 (1H, d, J = 5.1 Hz), 7.44 (1H, s), 5.74 (1H, q, J = 6.8 Hz), 4.78-4.68 (3H, m), 4.28-4.21 (3H, m), 3.61 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 443 (M+H) +.
<Step-2>: N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-morpholinoacetamide (single enantiomer)
A mixture of 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (25 mg, 0.056 mmol, Step-1, single enantiomer), and morpholine (15 mg, 0.17 mmol) in DMF (1.0 mL) is heated at 60 oC for 3 hours . The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 10.6 mg (38 % yield) of the title compound.
Representative procedure for Method-G
The following preparation of Example-435 represents the Method-G.
Example-435: N-((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)
A mixture of phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (20 mg, 0.042 mmol, Intermediate-91, single enantiomer) and (S)-2-aminopropan-1-ol in THF (1.0 mL) is heated at 90 oC overnight. The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 9.9 mg (52 % yield) of the title compound.
Representative procedure for Method-H
The following preparation of Example-259 represents the Method-H.
Example-259: N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide (single enantiomer)
The reaction is carried out in a similar manner to Example-1 (Method-A) using 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (63 mg, 0.26 mmol). The obtained crude is diluted with DCM / TFA (1:1, 2 mL), and the mixture is stirred at rt for 1 h. Then, the solvent is removed in vacuo, and the residue is purified by preparative LC-MS to give 6.3 mg (11 % yield) of the title compound.
The following examples are prepared using one of the methods described above from intermediates and reagents shown in Table 1 and Table 2. The retention time and observed MS (positive or negative mode) by LC-MS are described in Table 3. 1H-NMR and MS data of Example 2, 3, 23, 36, 222, 231, 235, 236, 293, 307, 308, 407, 414, 418, 420, 421, 430, 438, 446, 462, 473, 476, 496, 505, and 520 are described in Table 4.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048


Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070

Pharmacological assays
In vitro human voltage gated sodium channels activity
The inhibitory activities of compounds against voltage gated sodium channels are determined by methodology well known in the art.
The ability of the pyrrolopyridinone derivatives of the formula (I) to inhibit the NaV1.3, Nav1.7 and Nav1.5 channels is measured by Fluorescence Resonance Energy Transfer (FRET) assay and electrophysiology assay described below.
FRET Assay
This screen is used to determine the effects of compounds on human NaV1.3, human Nav1.7, and human Nav1.5 channels, utilising electrical field stimulation (EFS) system in 96-well plate format on FDSS (Hamamatsu Photonics) platform. The change of membrane potential is monitored with FRET dye pair, oxonol (DiSBAC2(3)) and coumarin (CC2-DMPE).
Cell Maintenance:
Each HEK293 cells expressing human NaV1.3 channels and HEK293 cells expressing human NaV1.5 channels are grown in T225 flasks, in a 5 % CO2 humidified incubator to about 80 % confluence. Media composition consists of Dulbecco's Modified Eagle Medium (high glucose), 10 % FCS, 100 units/mL penicillin, 100 microgram/mL streptomycin and 500 microgram/mL GeneticinTM.
CHO cells expressing human NaV1.7 channels are grown in T225 flasks, in a 5 % CO2 humidified incubator to about 80 % confluence. Media composition consists of HAM/F12 with GlutaMAXTM I, 10 % FCS, 100 units/mL penicillin and 100 microgram/mL hygromycin.
Protocol:
- Seed each cell lines (1 x 105 cells/well) into poly-D-lysine coated 96-well plates prior to experimentation.
- Incubate at 37oC in 5 % CO2 for 24 hours.
- Wash each well with assay buffer (140 mM NaCl, 4.5 mM KCl, 10 mM D-Glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4 adjusted with NaOH) twice.
- Add 1st loading solution containing 10 microM CC2-DMPE and 0.06 % PluronicTM F-127 in assay buffer.
- Incubate the plate at rt in dark for 1 hour.
- Remove 1st loading solution and added 2nd loading solution containing 15 microM DiSBAC2(3), 0.555 mM VABSC-1 and 0.004 % PluronicTM F-127 in assay buffer.
- Place the plate under the dark at rt for 25 minutes.
- Add compound solutions into the assay plate.
- Set the assay plate in FDSS and placed an EFS device on the plate.
- Measure EFS-induced fluorescent response by FDSS.
The data are analyzed and reported as normalized ratios of intensities measured at 440 nm. The process of calculating these ratios is performed as follows:
Figure JPOXMLDOC01-appb-M000001
 This analysis is performed using a computerized specific program designed for FDSS generated data. Fluorescence ratio values are plotted using XLfitTM to determine an IC50 value for each compound.
All tested compounds show less than about 3 microM of IC50 against Nav1.3 and/or Nav1.7 in the above assays. Preferable compounds show less than about 1 microM of IC50 against Nav1.7 and/or Nav1.3 in the above assays.
Compounds with IC50 against Nav1.7 <1 microM and/or Nav1.3<1 microM are:
Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 36, 37, 38, 39, 40, 42, 45, 46, 50, 51, 52, 53, 54, 55, 58, 62, 63, 64, 66, 72, 73, 79, 84, 86, 87, 89, 91, 92, 95, 96, 97, 98, 99, 111, 112, 113, 114, 115, 116, 122, 123, 124, 125, 128, 130, 132, 133, 134, 135, 136, 141, 149, 150, 153, 154, 155, 157, 158, 159, 160, 161, 163, 164, 165, 166, 168, 169, 172, 178, 179, 180, 181, 184, 186, 187, 188, 189, 190, 191, 193, 195, 203, 210, 211, 214, 215, 220, 221, 222, 224, 226, 228, 230, 231, 233, 235, 236, 237, 242, 243, 246, 249, 250, 252, 253, 256, 257, 259, 261, 262, 265, 266, 267, 269, 275, 281, 284, 285, 288, 289, 291, 292, 293, 295, 296, 297, 300, 301, 302, 303, 304, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 322, 324, 325, 326, 328, 329, 330, 331, 332, 333, 336, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 350, 351, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 381, 382, 383, 384, 385, 386, 387, 388, 390, 391, 392, 393, 398, 399, 400, 401, 403, 405, 407, 408, 409, 410, 411, 414, 415, 418, 419, 420, 421, 422, 423, 426, 428, 429, 430, 433, 435, 438, 439, 440, 441, 442, 443, 444, 445, 446, 448, 449, 450, 451, 452, 453, 454, 456, 459, 460, 462, 463, 465, 470, 471, 472, 473, 474, 476, 477, 478, 479, 480, 481, 482, 483, 484, 486, 488, 490, 492, 496, 497, 498, 502, 503, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 537, 538, 539, 540, 541, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 583, 584, 585, 586, 587, 588, 594, 595, 599, 600, 602, 603, 604, 605, 606, 607, 608, 610, 611, 612, 613, 615, 616, 617, 618, 620, 621, 622, 623, 624, 626, 627, 628, 629, 630, 632, 633, 634, 635, 636, 638, 639, 641, 642, 643, 646, 648, 656, 658, 659, 660, 662, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 676, 678, 679, 680, 682, 683, 684, 685, and 686.
Regarding all tested compounds, the ratio of activities against Nav1.5 vs. Nav1.3 or Nav1.7 is more than three times. For example, the activities of Example 2 against Nav1.5, Nav1.7 and Nav1.3 are more than 30 microM, 1.1 microM, and 0.44 microM, respectively.
Electrophysiology assay for Navs
Whole cell patch clamp recording is used to assess the efficacy or selectivity of Na channel blocker on human Nav1.3 (hSCN3A) expressing HEK293 cells or human Nav1.7 (hSCN9A) expressing CHO cells. Human Nav1.3 expressing HEK293 cells are grown in growth media which contain: Dulbecco's Phosphate-Buffered Saline (DMEM), 10 % heat-inactivated fetal bovine serum (FBS) (Hyclone Laboratories Inc), 100 microgram/mL penicillin/100U/mL streptomycin, 150 microgram/mL ZeocinTM, and 3 microgram/mL Geneticin. Human Nav1.7 expressing CHO cells are grown in growth media which contain: HAM/F-12, 9 % heat-inactivated FBS (Hyclone Laboratories Inc), and 100 microgram/mL penicillin/100U/mL streptomycin, and 100 microgram/mL hygromycin.
Na channel expressing cells are dissociated by 0.05 % trypsin-EDTA, and then seeded on cover glass for 24 to 48hr.
Glass pipettes are pulled to a tip diameter of 1 to 2 micrometer on a pipette puller. The pipettes are filled with the intracellular solution and a chloridized silver wire is inserted along its length, which is then connected to the headstage of the voltage-clamp amplifier (Axon Instruments or HEKA elektronik). The extracellular recording solution consists of (mM): 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, and 10 Glucose, pH 7.4 adjusted with NaOH. The internal solution consists of (mM): 120 CsF, 15 NaCl, 10 EGTA, and 10 HEPES, pH 7.2 adjusted with CsOH. Upon insertion of the pipette tip into the bath, the pipette resistance is noted (acceptable range is between 1 to 3 megaohm). The junction potential between the pipette and bath solutions is zeroed on the amplifier. After establishing the whole-cell configuration, approximately 10 minutes are allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents are lowpass filtered between 2 to 5 kHz and digitally sampled at 10 kHz.
The normalized steady-state inactivation curve is constructed using 2 sec (for vehicle) or 60 sec (for drugs) conditioning pulse to different potentials followed immediately by the test pulse to -10 mV. Peak currents are plotted as fraction of the maximum current at the conditioning potentials ranging from -120 mV to -40 mV for Nav1.3 and from -130 mV to -60 mV for Nav1.7. V1/2 or k values are estimated from Boltzmann fits. The affinity of drugs to resting state of Na channels (Kresting or Kr) is assessed by 30 msec test pulse from a negative holding potential of -120 or -130 mV, where virtually all channels are in the resting state. Kr value is calculated by a conventional 1:1 binding model:
Figure JPOXMLDOC01-appb-M000002
 where Kresting (=Kr) is a dissociation constant for the resting state and [drug] is compound concentration. Imax,control and Imax,drug are peak currents in the absence and presence of compound, respectively.
The affinity of drug to inactivated state of Na channels (Kinact or Ki) is estimated from the shift of the availability curve by compound. Interaction of the compound with the channel on inactivated state is evaluated by the following equation:
Figure JPOXMLDOC01-appb-M000003
All tested compounds of the invention show potent activities in this model. For example, the activities (Ki) of Example 3 against NaV1.7 and NaV1.3 are 0.091 microM and 0.14 microM, respectively.
In vivo assay
Chronic constriction injury (CCI)-induced static allodynia in rats
Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CCI-induced static allodynia is assessed by von Frey hair (VFH) test. Surgery is performed according to the method of Bennett GJ and Xie YK (Pain 1988, 33: 87-107). The animals are anesthetized with intraperitoneal injection of pentobarbital sodium. The left common sciatic nerve is exposed at the level of the middle of the thigh, freed of adhering tissue, and four ligatures are loosely tided around it by using 4-0 silk thread. The incision is sutured, and the rats are allowed to recover in their cages with soft bedding. Sham operation is performed in the same manner except of sciatic nerve ligation. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate before the day of testing. On postoperative day (POD) 14-28, evaluation is performed using a series of calibrated VFH (Semmes-Winstein monofilaments) with 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g force. VFH starting with the 2 g force is applied in an ascending or descending fashion according to a modified Dixon up-down method described by Chaplan SR et al. (J Neurosci Methods 1994, 53: 55-63). Each VFH is presented to the plantar surface of the operated hind paw with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal, a stronger stimulus is presented. In the event of a paw withdrawal, the next weaker stimulus is chosen. After the initial change from positive to negative or vice versa, 4 more stimulations are applied. The 6-score pattern of positive and negative responses is converted into a 50 % paw withdrawal threshold (PWT) using the following formula:
Figure JPOXMLDOC01-appb-M000004
In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.25 and 15 g are assigned, respectively. The animals showing static allodynia (<4 g of 50 % PWT) by CCI surgery are selected for evaluation and randomized to be nearly equal mean 50 % PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The 50 % PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or one-way analysis of variance (ANOVA) with Dunnett's post-hoc test compared to the vehicle group.
All tested compounds of the invention show potent activities in this model.
Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia in rats
Male Sprague-Dawley rats at 6 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced thermal hyperalgesia is assessed using the plantar test apparatus (Ugo Basile) as described by Hargreaves K et al. (Pain 1988, 32: 77-88). The animals are placed in an apparatus consisting of individual testing box on an elevated glass table and allowed to acclimate for at least 10 minutes. Following the habituation, a mobile radiant heat source is located under the table and heat stimulation is applied to the plantar surface of the right hind paw. The latency to remove its hind paw is defined as paw withdrawal latency (PWL) in sec. The cut-off point is set at 30 seconds to prevent tissue damage. CFA is prepared at a concentration of 2 to 3 mg/mL of Mycobacterium tuberculosis H37 RA in liquid paraffin. After disinfections with 70 % ethanol, the rats are injected intraplantarly with 100 microL of CFA (200-300 microgram) into the right hind paw. Two days after CFA injection, PWL is measured in the same manner as mentioned above. The animals showing decrease of the PWL (hyperalgesia) by CFA injection are selected for evaluation and randomized to be nearly equal mean PWL across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the apparatus for at least 10 minutes before each measurement. The PWL is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.
All tested compounds of the invention show potent activities in this model.
CFA-induced weight bearing deficit in rats
Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced weight bearing (WB) deficit is assessed using Incapacitance tester (Linton Instrumentation). The animals are habituated to a plastic case that comes with Incapacitance tester before the day of CFA injection. On the day of CFA injection, the weight distribution of each hind paw is measured 3 times per rat using the tester, and the difference of weight distribution, weight on the right (injected) paw minus weight on left (non-injected) paw, is defined as WB deficit value in g. The duration of the each measurement is adjusted to 3 seconds. CFA is prepared at a concentration of 2 to 3 mg/mL of Mycobacterium tuberculosis H37 RA in liquid paraffin. After disinfections with 70 % ethanol, the rats are injected intraplantarly with 100 microL of CFA (200-300 microgram) into the right hind paw. Two days after CFA injection, the weight distribution of each hind paw is measured and the WB deficit value is calculated in the same manner as mentioned above. The animals showing decrease of the WB deficit (>30 %) by CFA injection are selected for evaluation and randomized to be nearly equal across all groups. The compounds of the invention or their vehicles are administered systemically. The weight distribution of each hind paw is measured at the appropriated time after compound administration, and the WB deficit value is calculated as previously explained. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.
All tested compounds of the invention show potent activities in this model.
Paw incision-induced static allodynia in rats
Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Paw incision-induced static allodynia is assessed by VFH test. Surgery is performed according to the procedure described by Brennan et al. (Pain 1996, 64: 493-501). The animals are initially anesthetized with 3 to 4 % isoflurane/O2 mixture in an anesthetic chamber and maintained with 2 to 3 % delivered through a nose cone. The plantar surface of the right hind paw is sterilized with 7.5 % povidone-iodine solution. A 1-cm longitudinal incision is made with a number 11 blade, through skin and fascia of the plantar aspect of the paw, starting 0.5 cm from the proximal edge of the heel and extending toward the toes. The plantaris muscle is elevated using forceps and retracted. The muscle origin and insertion remain intact. After hemostasis with gentle pressure, the skin is apposed with 2 sutures of 5-0 nylon. The wound site is covered with TerramycinTM ointment, and the rats are allowed to recover in their cages with soft bedding. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate for 1 hour before the day of surgery. On POD1, evaluation is performed using a series of calibrated VFH (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 g). Starting with the 0.16 g force in an ascending or descending fashion, each VFH is presented to the proximal end of the wound near the lateral heel with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal (negative response), a stronger stimulus is presented. In the event of a paw withdrawal (positive response), the next weaker stimulus is chosen. The lowest amount of force required to elicit two positive responses is defined as PWT in g. In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.008 and 26 g are assigned, respectively. The animals showing <1.4 g of PWT by incisional surgery are selected for evaluation and randomized to be nearly equal median PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by Mann-Whitney U-test or Kruskcal-Wallis with Dunn's post-hoc test compared to the vehicle group.
All tested compounds of the invention show potent activities in this model.
Paclitaxel-induced static allodynia in rats
Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Paclitaxel-induced static allodynia is assessed by VFH test. Treatment of paclitaxel is performed according to the method of Polomano RC et al. (Pain 2001, 94: 293-304). Paclitaxel (2 mg) is injected intraperitoneally on four alternate days (Days 1, 3, 5 and 7) in a volume of 1 mL/kg. Cumulative dose is 8 mg/kg. In sham group, the vehicle (a mixture of 16.7 % CremophorTM EL and 16.7 % ethanol in saline) is treated as the same schedule. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate before the day of testing. On Days 15-29, evaluation is performed using a series of calibrated VFH with 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g force. VFH starting with the 2 g force is applied in an ascending or descending fashion according to a modified Dixon up-down method described by Chaplan SR et al. (J Neurosci Methods 1994, 53: 55-63). Each VFH is presented to the plantar surface of the operated hind paw with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal, a stronger stimulus is presented. In the event of a paw withdrawal, the next weaker stimulus is chosen. After the initial change from positive to negative or vice versa, 4 more stimulations are applied. The 6-score pattern of positive and negative responses is converted into a 50 % PWT using the following formula:
Figure JPOXMLDOC01-appb-I000009
In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.25 and 15 g are assigned, respectively. The animals showing static allodynia (<4 g of 50 % PWT) by paclitaxel treatment are selected for evaluation and randomized to be nearly equal mean 50 % PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The 50 % PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.
All tested compounds of the invention show potent activities in this model.
Formalin-induced nociceptive behaviors in rats
Male Sprague-Dawley rats at 6 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Formalin test is performed during the light cycle. The animals are acclimated to the testing chamber for at least 30 minutes prior to formalin injection. A mirror is placed behind and/or under the chamber to aid observation. The 50 microL of 5 % formalin solution is injected subcutaneously into the plantar surface of the right hind paw. Immediately after the injection, the rats are individually placed in the chamber, and the pain-related behaviors are recorded. After the testing, the time spent licking and/or biting of the injected paw are counted in 5-minutes bins for 45 minutes following the formalin treatment. The sum of time spent licking/biting in seconds from time 0 to 5 minutes is considered as the early phase, whereas the late phase is taken as the sum of time spent licking/biting typically from 15 to 45 minutes. The compounds of the invention or their vehicles are administered systemically at the appropriated time point before the formalin injection. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.
All tested compounds of the invention show potent activities in this model.
Human dofetilide binding assay
Human HERG transfected HEK293S cells are prepared and grown in-house. The collected cells are suspended in 50 mM Tris-HCl (pH 7.4 at 4 oC) and homogenized using a hand held PolytronTM PT 1200 disruptor set at full power for 20 sec on ice. The homogenates are centrifuged at 48,000 x g at 4 oC for 20 min. The pellets are then resuspended, homogenized, and centrifuged once more in the same manner. The final pellets are resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl2 (pH 7.4 at 4 oC), homogenized, ali-quoted and stored at -80 oC until use. An aliquot of membrane fractions is used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays are conducted in a total volume of 30 microL in 384-well plates. The activity is measured by PHERAstar (BMG LABTECH) using fluorescence polarization technology. Ten microL of test compounds are incubated with 10 microL of fluorescence ligand (6 nM Cy3B tagged dofetilide derivative) and 10 microL of membrane homogenate (6 microgram protein) for 120 minutes at rt. Nonspecific binding is determined by 10 microM E4031 at the final concentration.
All tested compounds of the invention show higher IC50 values in human dofetilide binding than IC50 values in NaV1.3 or NaV1.7 FRET Assay. The high IC50 values in human dofetilide binding activities lead to reducing the risk of cardiovascular adverse events.
Metabolic stability assay
Half-life in human liver microsomes (HLM)
Test compounds (1 microM) are incubated with 3.3 mM MgCl2 and 0.78 mg/mL HLM (HL101) or 0.74 mg/mL HLM (Gentest UltraPool 150) in 100 mM potassium phosphate buffer (pH 7.4) at 37 oC on the 96-deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group. Nicotinamide adenine dinucleotide phosphate (NADPH) is only added to the reaction mixture of the P450 group. (NADPH generation system is also used instead of NADPH.) An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH is added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group is collected at -10 and 65 min time point. Collected aliquots are extracted with MeCN solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system.
The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yield the rate of metabolism (k). This is converted to a half-life value using following equations: Half-life = ln 2/k
The compounds of this invention show preferable stability, which show the above-mentioned practical use.
Drug-drug interaction assay
This method essentially involves determining the percent inhibition of metabolites formation from probes (tacrine (Sigma A3773-1G) 2 microM, dextromethorphan (Sigma D-9684) 5 microM, diclofenac (Sigma D-6899-10G) 5 microM, and midazolam(ULTRAFINE UC-429) 2 microM) at 3 microM of the each compound.
More specifically, the assay is carried out as follows. The compounds (60 microM, 10 microL) are pre-incubated in 170 microL of mixture including 0.1 mg protein/mL human liver microsomes, 100 mM potassium phosphate buffer (pH 7.4), 1 mM MgCl2 and probes as substrate for 5min. Reaction is started by adding a 20 microL of 10mM NADPH (20 microL of NADPH generating system, which consist of 10 mM NADP+, 50 mM DL-isocitric acid and 10 U/mL isocitric dehydrogenase, is also used). The assay plate is incubated at 37 oC. MeCN is added to the incubate solution at appropriate time (e.g. 8 min).
The metabolites' concentration in the supernatant is measured by LC/MS/MS system.
The degree of drug-drug interaction is interpreted based on generation % of metabolites in the presence or absence of test compound.
The compounds of this invention show preferable results, which show the above-mentioned practical use.
Plasma protein binding assay
Plasma protein binding of the test compound (1 microM) is measured by the method of equilibrium dialysis using 96-well plate type equipment. HTD96aTM, regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm x 120 mm) are soaked for over night in distilled water, then for 15 minutes in 30 % ethanol, and finally for 20 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, pH7.4). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs are used. The dialysis equipment is assembled and added 150 microL of compound-fortified plasma to one side of each well and 150 microL of dialysis buffer to the other side of each well. After 4 hours incubation at 37 oC for 150 rpm, aliquots of plasma and buffer are sampled. The compound in plasma and buffer are extracted with 300 microL of MeCN containing internal standard compounds for analysis. The concentration of the compound is determined with LC/MS/MS analysis.
The fraction of the compound unbound is calculated by the following equation (A) or (B):
Figure JPOXMLDOC01-appb-M000005
 wherein [plasma]eq and [buffer]eq are the concentrations of the compound in plasma and buffer, respectively.
Figure JPOXMLDOC01-appb-M000006
 wherein Cp is the peak area of the compound in plasma sample;
Cis,p is the peak area of the internal standard in plasma sample;
Cb is the peak area of the compound in buffer sample;
Cis,b is the peak area of the internal standard in buffer sample;
4 and 4/3 is the reciprocal of the dilution rate in plasma and buffer, respectively.
The compounds of this invention show preferable plasma protein binding, which show the above-mentioned practical use.
Equilibrium aqueous solubility study
The DMSO solution (2 microL, 30 mM) of each compound is dispensed into each well of a 96-well glass bottom plate. Potassium phosphate buffer solution (50 mM, 198 microL, pH 6.5) is added to each well, and the mixture is incubated at 37 oC with rotation shaking for 24 hours. After centrifugation at 2000 g for 5 minutes, the supernatant is filtered through the polycarbonate IsoporeTM Membrane. The concentration of samples is determined by a general gradient HPLC method (J. Pharm. Sci. 2006, 95, 2115-2122).
All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.
The pyrrolopyridinone derivatives of the present invention are useful in the treatment of a wide range of disorders, particularly pain, such as acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back pain, orofacial pain and chemo-induced pain.

Claims (17)

  1. A compound of the following formula (I):
    Figure JPOXMLDOC01-appb-C000009
     Wherein:
    A is aryl;
    B is selected from the group consisting of a chemical bond, -C1-6 alkylene-, -C1-6 alkylene-NR2-, -NR2-, and -(C=O)-;
    C is selected from the group consisting of a chemical bond, -(C=O)-, and -NR2-;
    R1 is independently selected from the group consisting of;
    (1) hydrogen, (2) -On-C1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (3) -On-C3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (4) -On-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -S-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11; (7) -NH-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (8) -NH- aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R2 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) -On-phenyl or -On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) -On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R7, (9) -(C=O)-NR8R9, (10) -NR8R9, (11) -S(O)2-NR8R9, (12) -NR8-S(O)2R9, (13) -S(O)t-R9, where t is 0, 1 or 2, (14) -NR8(C=O)R9, (15) -CN, and (16) -NO2;
    wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
    p is 1, 2, 3, or 4; when p is two or more than two, R2 may be same or different;
    R3 and R4 are independently hydrogen or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -O-C1-6 alkyl;
    or R3 forms a 3 to 7 membered ring with R4 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
    wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R5 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, and (5) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7;
    wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
    R5 may be substituted anywhere on the pyrrolopyridinone ring;
    q is 1, 2 or 3; when q is two or more than two, R5 may be same or different;
    R6 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, -NR8R9, heterocyclyl, aryl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
    where the C1-6 alkyl, the C1-6 alkoxy, the C2-6 alkenyl, the C3-7 cycloalkyl, the heterocyclyl, the aryl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, -C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyl-C1-6 alkoxy, -CN, -NR8R9, -(C=O)-R8, -(C=O)-NR8R9, -NR8-(C=O)-R9, -NR8-(C=O)-NR9R10, -NR8-(C=O)-OR9, -NR8-S(O)2-R9, -NR8-S(O)2- NR9R10, and -S(O)2-R8; when B is -NR2- and C is -(C=O)-, R6 may form a 4-7 membered ring with R2;
    R7 is selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O)m-Ol-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -Ol-(C1-3)perfluoroalkyl, (6) -(C=O)m-Ol-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (7) -(C=O)m-Ol-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R11, (8) -(C=O)m-Ol-phenyl or -(C=O)m-Ol-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R11, (9) -(C=O)m-Ol-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R11, (10) -(C=O)-NR8R9, (11) -NR8R9, (12) -S(O)2-NR8R9, (13) -S(O)t-R8, where t is 0, 1 or 2, (14) -CO2H, (15) -CN, and (16) -NO2;
    wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of -Ol- or -(C=O)m-, and when l is 0 and m is 0, a chemical bond is present in the place of -(C=O)m-Ol-;
    R8, R9, and R10 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
    where the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the aryl, the heterocyclyl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, trifluoromethyl, and trifluoromethoxy;
    or R8 form a 4 to 7 membered ring with R9 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
    wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R11 is independently selected from the group consisting of:
    (1) hydrogen, (2) hydroxyl, (3) halogen, (4) -C1-6 alkyl, which is unsubstituted or substituted with one or more halogens, (5) -C3-6 cycloalkyl, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) -O(C=O)-C1-6 alkyl, (8) -NH-C1-6 alkyl, (9) phenyl, (10) heterocyclyl, (11) -CN, and (12) -Si(C1-6 alkyl)3;
    k is 1 or 2;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  2. The compound as described in claim 1 wherein the compound is for the treatment of a condition or disorder in which TTX-S channel is involved.
  3. The compound described in claim 1 or claim 2 wherein
    k is 1;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  4. A compound of the following formula (II)
    Figure JPOXMLDOC01-appb-C000010
     wherein:
    A is aryl;
    R1 is independently selected from the group consisting of;
    (1) hydrogen, (2) -On-C1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (3) -On-C3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (4) -On-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -S-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11; (7) -NH-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (8) -NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R2 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) -On-phenyl or -On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) -On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R7, (9) -(C=O)-NR8R9, (10) -NR8R9, (11) -S(O)2-NR8R9, (12) -NR8-S(O)2R9, (13) -S(O)t-R9, where t is 0, 1 or 2, (14) -NR8(C=O)R9, (15) -CN, and (16) -NO2;
    wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
    p is 1, 2, 3, or 4; when p is two or more than two, R2 may be same or different;
    R3 and R4 are independently hydrogen or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -O-C1-6 alkyl;
    or R3 forms a 3 to 7 membered ring with R4 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
    wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R5 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, and (5) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7;
    wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
    R5 may be substituted anywhere on the pyrrolopyridinone ring;
    q is 1, 2 or 3; when q is two or more than two, R5 may be same or different;
    R6 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, -NR8R9, heterocyclyl, aryl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
    where the C1-6 alkyl, the C1-6 alkoxy, the C2-6 alkenyl, the C3-7 cycloalkyl, the heterocyclyl, the aryl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, -C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyl-C1-6 alkoxy, -CN, -NR8R9, -(C=O)-R8, -(C=O)-NR8R9, -NR8-(C=O)-R9, -NR8-(C=O)-NR9R10, -NR8-S(O)2-R9, -NR8-S(O)2- NR9R10, and -S(O)2-R8;
    R7 is selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O)m-Ol-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -Ol-(C1-3)perfluoroalkyl, (6) -(C=O)m-Ol-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (7) -(C=O)m-Ol-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R11, (8) -(C=O)m-Ol-phenyl or -(C=O)m-Ol-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R11, (9) -(C=O)m-Ol-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R11, (10) -(C=O)-NR8R9, (11) -NR8R9, (12) -S(O)2-NR8R9, (13) -S(O)t-R8, where t is 0, 1 or 2, (14) -CO2H, (15) -CN, and (16) -NO2;
    wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of -Ol- or -(C=O)m-, and when l is 0 and m is 0, a chemical bond is present in the place of -(C=O)m-Ol-;
    R8, R9, and R10 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
    where the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the aryl, the heterocyclyl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, trifluoromethyl, and trifluoromethoxy;
    or R8 form a 4 to 7 membered ring with R9 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
    wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R11 is independently selected from the group consisting of:
    (1) hydrogen, (2) hydroxyl, (3) halogen, (4) -C1-6 alkyl, which is unsubstituted or substituted with one or more halogens, (5) -C3-6 cycloalkyl, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) -O(C=O)-C1-6 alkyl, (8) -NH-C1-6 alkyl, (9) phenyl, (10) heterocyclyl, (11) -CN, and (12) -Si(C1-6 alkyl)3;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  5. The compound described in claim 4 wherein:
    R2 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;
    p is 1;
    R3 is hydrogen;
    R4 is hydrogen or methyl;
    R6 is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl, heterocyclyl, or aryl
    where the methyl, the ethyl, the isopropyl, the cyclopropyl, the heterocyclyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, and -CN;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  6. A compound of the following formula (III)
    Figure JPOXMLDOC01-appb-C000011
     wherein:
    A is aryl;
    R1 is independently selected from the group consisting of;
    (1) hydrogen, (2) -On-C1-6 alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (3) -On-C3-7 cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (4) -On-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -S-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11; (7) -NH-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (8) -NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R2 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) -On-phenyl or -On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) -On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R7, (9) -(C=O)-NR8R9, (10) -NR8R9, (11) -S(O)2-NR8R9, (12) -NR8-S(O)2R9, (13) -S(O)t-R9, where t is 0, 1 or 2, (14) -NR8(C=O)R9, (15) -CN, and (16) -NO2;
    wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
    p is 1, 2, 3, or 4; when p is two or more than two, R2 may be same or different;
    R3 and R4 are independently hydrogen or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and -O-C1-6 alkyl;
    or R3 forms a 3 to 7 membered ring with R4 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
    wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R5 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) -On-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, and (5) -On-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7;
    wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of -On-;
    R5 may be substituted anywhere on the pyrrolopyridinone ring;
    q is 1, 2 or 3; when q is two or more than two, R5 may be same or different;
    R6 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, heterocyclyl, aryl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
    where the C1-6 alkyl, the C1-6 alkoxy, the C2-6 alkenyl, the C3-7 cycloalkyl, the heterocyclyl, the aryl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, -C3-7 cycloalkyl, -O-C3-7 cycloalkyl, hydroxyl-C1-6 alkoxy, -CN, -NR8R9, -(C=O)-R8, -(C=O)-NR8R9, -NR8-(C=O)-R9, -NR8-(C=O)-NR9R10, -NR8-(C=O)-OR9, -NR8-S(O)2-R9, -NR8-S(O)2- NR9R10, and -S(O)2-R8;
    R7 is selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O)m-Ol-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (5) -Ol-(C1-3)perfluoroalkyl, (6) -(C=O)m-Ol-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11, (7) -(C=O)m-Ol-C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R11, (8) -(C=O)m-Ol-phenyl or -(C=O)m-Ol-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R11, (9) -(C=O)m-Ol-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R11, (10) -(C=O)-NR8R9, (11) -NR8R9, (12) -S(O)2-NR8R9, (13) -S(O)t-R8, where t is 0, 1 or 2, (14) -CO2H, (15) -CN, and (16) -NO2;
    wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of -Ol- or -(C=O)m-, and when l is 0 and m is 0, a chemical bond is present in the place of -(C=O)m-Ol-;
    R8, R9, and R10 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, heterocyclyl, aryl-C1-6 alkyl, or heterocyclyl-C1-6 alkyl,
    where the C1-6 alkyl, the C2-6 alkenyl, the C3-7 cycloalkyl, the aryl, the heterocyclyl, the aryl-C1-6 alkyl, or the heterocyclyl-C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C1-6 alkyl, -O-C1-6 alkyl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, trifluoromethyl, and trifluoromethoxy;
    or R8 form a 4 to 7 membered ring with R9 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,
    wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R11, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R11, and (7) -O-C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R11;
    R11 is independently selected from the group consisting of:
    (1) hydrogen, (2) hydroxyl, (3) halogen, (4) -C1-6 alkyl, which is unsubstituted or substituted with one or more halogens, (5) -C3-6 cycloalkyl, (6) -O-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) -O(C=O)-C1-6 alkyl, (8) -NH-C1-6 alkyl, (9) phenyl, (10) heterocyclyl, (11) -CN, and (12) -Si(C1-6 alkyl)3;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  7. The compound described in claim 6 wherein:
    R2 is independently selected from the group consisting of:
    (1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;
    p is 1;
    R3 is hydrogen;
    R4 is hydrogen or methyl;
    R6 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, or butyl
    where the methyl, the ethyl, the isopropyl, the propyl, or the butyl is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, -O-C1-6 alkyl, -CN, and -NR8-(C=O)-R9 in which each of R8 and R9 has the same meaning as in the claim 6;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  8. The compound as claimed in any one of claims 1 to 7 which is selected from:
    N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide;
    3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
    2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    2-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    ethyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    methyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    isopropyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
    2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
    methyl (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    isopropyl (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide;
    (5S)-3-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-isopropyloxazolidin-2-one;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide;
    methyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    ethyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    isopropyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    methyl (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    ethyl (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,3-oxazinan-2-one;
    N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    ethyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    methyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    isopropyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    3-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(3-methyl-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    3-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-isopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-isopropyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(dimethylamino)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide;
    2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide;
    5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide;
    4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-phenylacetamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)picolinamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrazine-2-carboxamide;
    3-cyano-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    N-((2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)acetamide;
    N-(2-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-cyano-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    4-(3-isopropyl-2-oxoimidazolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    N-(2-(dimethylamino)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-morpholinoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    6-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-5-carboxamide;
    N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-amino-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    2-amino-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    N-(2-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    2-amino-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    2-amino-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    2-amino-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    4-(isoxazol-3-ylamino)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(oxazol-2-ylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    2-amino-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    N-(2-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-3-carboxamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyridazine-3-carboxamide;
    (2S)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isonicotinamide;
    (2S)-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrrolidine-2-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(4-methoxypiperidin-1-yl)-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide;
    N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide;
    1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide;
    (2S)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    (2R)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    (3R)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide;
    1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-2-carboxamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide;
    (3S)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide;
    (2R)-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide;
    2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide;
    (2S)-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxyacetamide;
    2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    (S)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    4-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    2-acetamido-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    (2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    (R)-2-hydroxy-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    (2R)-N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    (2R)-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    (2R)-N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    (R)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    (R)-N-(2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    (S)-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    (2R)-N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    (R)-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    (R)-2-hydroxy-N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    (2R)-N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    (2R)-N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    (2R)-N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(cyanomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(cyanomethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxy-2-methylpropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxy-2-methylpropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-cyclopropyl-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((S)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-amino-2-oxoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-amino-2-oxoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(2-hydroxyethoxy)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((S)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (R)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (S)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-((S)-1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-amino-3-oxopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-amino-3-oxopropyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (S)-N-(1-hydroxypropan-2-yl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-methoxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(4-((cyclopropylmethyl)carbamoyl)-3-methylbenzyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(3-methyl-4-(phenylcarbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(3-methyl-4-((4-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-methyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(4-methyl-1H-imidazol-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-N-(3-(2-oxopyrrolidin-1-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((S)-1-(methylamino)-1-oxopropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((1H-imidazol-2-yl)methyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((5-methyl-6-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    and N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  9. The compound as claimed in any one of claims 1 to 8 which is selected from:
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide;
    3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one;
    ethyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    isopropyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide;
    2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide;
    2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide;
    N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
    (2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide;
    (2R)-N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    (2R)-N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    (R)-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    (2R)-N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    (2R)-N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    (2R)-N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide;
    N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide;
    N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide;
    N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide;
    2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    and N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  10. A pharmaceutical composition comprising a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 9, and a pharmaceutically acceptable carrier.
  11. The pharmaceutical composition as described in claim 10, further comprising another pharmacologically active agent.
  12. A method for the treatment of a condition or disorder in which TTX-S channel blockers are involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 9.
  13. The method as claimed in claim 12, wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain; and combinations thereof.
  14. A use of a compound described in any one of claims 1 to 9 or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which TTX-S channel blockers are involved.
  15. The use as described in claim 14, wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain;
    and combinations thereof.
  16. A compound described in any one of claims 1 to 9 or a prodrug thereof or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which TTX-S channel blockers are involved.
  17. A process for preparing a pharmaceutical composition comprising mixing a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 9, and a pharmaceutically acceptable carrier or excipient.
PCT/JP2013/002825 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as ttx-s blockers WO2013161312A1 (en)

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MX2014012915A MX360323B (en) 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as ttx-s blockers.
RU2014147243A RU2646754C2 (en) 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as ttx-s blockers
JP2014551356A JP6175672B2 (en) 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as TTX-S blockers
US14/394,532 US9187475B2 (en) 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as TTX-S blockers
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CA2871229A CA2871229C (en) 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as ttx-s blockers
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ES13782571.7T ES2645984T3 (en) 2012-04-25 2013-04-25 Pyrrolopyridinone derivatives as TTX-S blockers
HK15104385.8A HK1203940A1 (en) 2012-04-25 2015-05-08 Pyrrolopyridinone derivatives as ttx-s blockers ttx-s
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