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WO2015161016A1 - Bicyclic cgrp receptor antagonists - Google Patents

Bicyclic cgrp receptor antagonists Download PDF

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Publication number
WO2015161016A1
WO2015161016A1 PCT/US2015/026076 US2015026076W WO2015161016A1 WO 2015161016 A1 WO2015161016 A1 WO 2015161016A1 US 2015026076 W US2015026076 W US 2015026076W WO 2015161016 A1 WO2015161016 A1 WO 2015161016A1
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WO
WIPO (PCT)
Prior art keywords
methyl
phenoxy
pyridazin
halo
methylethyl
Prior art date
Application number
PCT/US2015/026076
Other languages
French (fr)
Inventor
Brendan CROWLEY
Mark Fraley
Chris BURGEY
Helen Mitchell
Tesfaye Biftu
Anilkumar NAIR
Cheng Wang
Xianhai Huang
Min K. Park
Jiaqiang Cai
Qingsheng LIU
Original Assignee
Merck Sharp & Dohme Corp.
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
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Publication of WO2015161016A1 publication Critical patent/WO2015161016A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • CGRP Calcitonin Gene-Related Peptide
  • CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively.
  • CGRP-alpha and CGRP -beta display similar biological properties.
  • CGRP receptor which is a heterodimer consisting of the G-protein coupled calcitonin-like receptor (CLR) in association with the single transmembrane protein known as receptor activity modifying protein 1 (RAMPi).
  • CLR G-protein coupled calcitonin-like receptor
  • RAMPi receptor activity modifying protein 1
  • CGRP receptors are predominantly coupled to the activation of adenylyl cyclase and have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.
  • CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache.
  • elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al. (1990) Ann. Neurol. 28, 183-187), salivary levels of CGRP are elevated in migraine subjects between (Bellamy et al. (2006) Headache 46, 24-33) and during attacks (Cady et al. (2009) Headache 49, 1258-1266), and CGRP itself has been shown to trigger migrainous headache (Lassen et al. (2002) Cephalalgia 22, 54-61).
  • CGRP receptor antagonist BIBN4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al. (2004) New Engl. J. Med. 350, 1104-1110) and was able to prevent headache induced by CGRP infusion in a control group (Petersen et al. (2005) Clin. Pharmacol. Ther. 77, 202-213).
  • the orally bioavailable CGRP receptor antagonist telcagepant has also shown antimigraine effectiveness in phase III clinical trials (Ho et al. (2008) Lancet 372, 2115-2123; Connor et al. (2009) Neurology 73, 970-977).
  • CGRP -mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis.
  • CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9).
  • the middle meningeal artery the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP.
  • Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al. (1988) Ann. N ' eurol. 23, 193-196).
  • Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP receptor antagonist (Williamson et al. (1997) Cephalalgia 17, 525-531).
  • Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al. (1995) Brain Res. 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP receptor antagonist BIBN4096BS (Doods et al. (2000) Br. J. Pharmacol. 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP receptor antagonist.
  • CGRP -mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family:
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin and Adrenomedullin
  • distention of dural blood vessels during migraine headache may sensitize trigeminal neurons.
  • Some of the associated symptoms of migraine, including extracranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et al. (2000) Ann. Neurol. 47, 614-624).
  • a CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.
  • CGRP receptor antagonists The ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • disorders include migraine and cluster headache (Doods (2001) Curr. Opin. Invest. Drugs 2, 1261-1268; Edvinsson et al. (1994) Cephalalgia 14, 320-327); chronic tension type headache (Ashina et al. (2000) Neurology 14, 1335-1340); pain (Yu et al. (1998) Eur. J. Pharmacol. 347, 275-282); chronic pain (Hulsebosch et al.
  • Urology 166, 1720-1723 allergic dermatitis (Wallengren (2000) Contact Dermatitis 43, 137-143); psoriasis; encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al. (1999) Neurobiol. Dis. 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic
  • the present invention is directed to bicyclic compounds which are potent antagonists of CGRP receptors and may be useful in the treatment or prevention of diseases in which the CGRP receptor is involved, such as migraine.
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
  • G 1 is CR 3 orN
  • G 2 is CR 1 orN
  • G 3 is CR 2 orN
  • G 4 is CR 3 orN
  • G 5 is CR 3 or N
  • E 1 is N or CH
  • a 4 is a bond, CR 6 R 7 , O, S or NR 4 ;
  • E 2 is N or C
  • a 5 is CR 6 or N
  • a 8 is a bond, CR 7 , O, N or NR 4 ;
  • Z 1 is CR a ;
  • Z 7 is CR a R e ;
  • R 1 is hydrogen, halo, Ci_ 6 alkyl, 0(Ci_ 6 alkyl) or NR b R c , wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; is
  • Ci_6 alkyl or C 3 _ 6 cycloalkyl which may be optionally substituted with one to four
  • R' and R" can be taken together with the carbon atom to which they are attached to form a C 3 _ 8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to two substituents independently selected from the group consisting of cyano, R 4 , R 8 , halo, oxo and OR 4 ; R is hydrogen, halo, cyano or Ci_ 6 alkyl;
  • R 5 is hydrogen, Ci_ 6 alkyl, heterocyclyl or C 3 _ 8 cycloalkyl, which is optionally substituted with one to three halo;
  • R 6 is hydrogen, halo, hydroxyl, cyano, Ci_ 6 alkyl or NR b R c ;
  • R 7 is hydrogen, halo, hydroxyl, cyano, Ci_ 6 alkyl, 0(Ci_ 6 alkyl), NR b R c , C 3 _ 6 cycloalkyl, heterocyclyl, heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl groups are optionally substituted with one to three substituents independently selected
  • R 6 and R 7 can be taken together with the carbon atom or atoms to which they are attached to form a C 3 _ 8 cycloalkyl, C 3 _ 8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, R 5 , OR 5 , C 3 _6 cycloalkyl and heterocyclyl;
  • R is phenyl, heteroaryl, heterocyclyl or C 3 _ 8 cycloalkyl, wherein said phenyl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, hydroxyl, cyano, R 5 , NR b R c , OR 5 and SO m R 9 ;
  • R 9 is hydrogen, cyano, Ci_ 6 alkyl, C 3 _ 8 cycloalkyl, heterocyclyl, phenyl, heteroaryl or NR 5 R C , wherein said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and OR 5 ; or two R 4 groups, or an R 4 and R 8 group, can be taken together with the atom to which they are attached to form a C 3 _ 8 cycloalkyl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NR b R c , OR 5 , C 3 _ 6 cycloalkyl, and heterocyclyl wherein said alkyl, cycl
  • R c is hydrogen or Ci_ 6 alkyl, which is optionally substituted with one to three subsitituents independently selected from the group consisting of halo and OR 5 ; or R b and R c can be taken together with the atom to which they are attached to form a heterocyclyl ring which is optionally substituted with one to three substituents independently selected from the group consisting of R 5 , halo, oxo, OR 5 and heterocyclyl;
  • R d is Ci_6 alkyl, C 3 _ 6 cycloalkyl and NR b R c ;
  • R e is selected from the group consisting of hydrogen, Ci_ 6 alkyl, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; m is an integer from zero to two;
  • G is CR . In a subclass of the invention, G is CH. In another class of the invention, G 1 is N.
  • G is CR . In a subclass of the invention, G is CH. In
  • G is N.
  • G is CR . In another class of the invention, G is N. In a class of the invention, G 4 is CR 3 . In a subclass of the invention, G 4 is CH. In another class of the invention, G 4 is N.
  • G is CR . In a subclass of the invention, G is CH. In another class of the invention, G 5 is N.
  • Y is O. In another class of the invention, Y is CR 5 R 6 .
  • Y is NR b . In another class of the invention, Y is SO m .
  • E 1 is CH. In another class of the invention, E 1 is N.
  • a 2 is CR 6 R 7 . In another class of the invention, A 2 is
  • A is NR .
  • a 3 is CR 6 R 7 . In a subclass of the invention, A 3 is CH 2 .
  • a 4 is CR 6 R 7 . In another class of the invention, A 4 is S. In another class of the invention, A 4 is NR 4 . In another class of the invention, A 4 is O. In another class of the invention, A 4 is a bond.
  • a 5 is CR 6 . In a subclass of the invention, A 5 is CH. In another class of the invention, A 5 is N.
  • a 8 is CR 7. In a subclass of the invention, A 8 is CH. In another class of the invention, A 8 is NR 4. In another class of the invention, A 8 is N. In another class of the invention, A 8 is O. In another class of the invention, A 8 is a bond.
  • Z 1 is CH.
  • Z 7 is CH.
  • W is:
  • Ci_6 alkyl which is optionally substituted with one to four substituents
  • W is:
  • W is heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, R 4 , OR 4 and R 8 .
  • R 1 is hydrogen
  • R is heteroaryl, which is optionally substituted with one substituent selected from the group consisting of Ci_ 6 alkyl, heterocyclyl and C 3 _6 cycloalkyl.
  • R is hydrogen
  • R a is hydrogen or halo.
  • R b is hydrogen or Ci_ 6 alkyl.
  • R c is hydrogen or Ci_ 6 alkyl.
  • R d is Ci_ 6 alkyl.
  • R e is Ci_ 6 alkyl.
  • Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 53, or pharmaceutically acceptable salts thereof.
  • the invention also encompasses a pharmaceutical composition which comprises an inert carrier and the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the invention also encompasses a method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the headache is migraine headache.
  • the invention also encompasses the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of headache.
  • the headache is migraine headache.
  • the invention is also directed to medicaments or pharmaceutical compositions for treating diseases or disorders in which CGRP is involved, such as migraine, which comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to the use of a compound of Formula I for treating diseases or disorders in which CGRP is involved, such as migraine.
  • the invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which CGRP is involved, such as migraine, comprising combining a compound of Formula I with one or more pharmaceutically acceptable carriers.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (IF!) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • any variable e.g. R4, etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents and variables are permissible only if such combinations result in stable compounds.
  • Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
  • one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon.
  • size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • alkyl is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds.
  • C 0 ne to fouralkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that C 0 ne to four a lkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
  • cycloalkyl means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.
  • halo or halogen as used herein is intended to include chloro (CI), fluoro (F), bromo (Br) and iodo (I).
  • cycloalkyl or “carbocycle” shall mean cyclic rings of alkanes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkenyl refers to a non- aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Preferably 1 carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • cycloalkenyl or shall mean cyclic rings of alkenes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e.,
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N, S, and Si.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyridinonyl, pyrimidinyl, pyrroly
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 4- to 10-membered nonaromatic ring, unless otherwise specified, containing from 1 to 4
  • Heterocyclyl therefore includes, but is not limited to the following:
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • the salts are citric,
  • Specific compounds within the present invention include a compound which may be selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • the subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors.
  • a variety of other mammals can be treated according to the method of the present invention.
  • Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors.
  • the present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the terms "administration of or "administering a” compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • the compounds of the present invention may have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; obesity; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors.
  • headache migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic
  • the subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the 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 Formula I 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 therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • the present compounds may be used in conjunction with an an antimigraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5 -HTi B/ I D agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HTI D agonist such as PNU-142633 and a 5-HTi F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective
  • cyclooxygenase-2 inhibitor for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone,
  • the instant compounds may be administered with an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
  • an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
  • an interleukin inhibitor such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example aprepitant; an NMD A antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5 -lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT
  • an interleukin inhibitor such as an
  • the present compounds may be used in conjunction with gap junction inhibitors; neuronal calcium channel blockers such as civamide; AMPA/KA antagonists such as LY293558; sigma receptor agonists; and vitamin B2.
  • the present compounds may be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine,
  • methylergonovine, metergoline, ergoloid mesylates dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-a-ergocryptine, dihydro-P-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, a-ergocryptine, ⁇ -ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.
  • the present compounds may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or
  • the present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non-sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine
  • the present compounds may be used in conjunction with an anti-migraine agent, such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTI B/ I D agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib.
  • an anti-migraine agent such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTI B/ I D agonist, in particular, sumatriptan, naratriptan, zolmitriptan
  • 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 preferred.
  • 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 other active ingredient(s) 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, or from 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.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration.
  • the compounds of the present invention may be administered by oral, parenteral
  • intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for use in humans.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Oral tablets may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl -pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example
  • heptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil- in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions and the like, containing the compounds of the present invention are employed.
  • transdermal patches may also be used for topical administration.
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • the compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • NATIVE RECEPTOR BINDING ASSAY The binding of 125 I-CGRP to receptors in SK-N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 ⁇ g) were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgCl 2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 125 I-CGRP and antagonist.
  • binding buffer 10 mM HEPES, pH 7.4, 5 mM MgCl 2 and 0.2% bovine serum albumin (BSA)
  • the assay was terminated by filtration through GFB glass fibre filter plates (PerkinElmer) that had been blocked with 0.5% polyethyleneimine for 3 h.
  • the filters were washed three times with ice-cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCl 2 ), then the plates were air dried. Scintillation fluid (50 ⁇ ) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the K x was determined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108).
  • RECOMBINANT RECEPTOR Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5'NheI and 3' Pmel fragment.
  • Human RAMP1 Genbank accession number AJ001014 was subcloned into the expression vector pIRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 3'NotI fragment.
  • HEK 293 cells human embryonic kidney cells; ATCC #CRL- 1573 were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ⁇ g/mL streptomycin, and maintained at 37 °C and 95%> humidity. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS. Stable cell line generation was accomplished by co-transfecting 10 ⁇ g of DNA with 30 ⁇ g Lipofectamine 2000 (Invitrogen) in 75 cm flasks. CL receptor and RAMPl expression constructs were co-transfected in equal amounts.
  • FBS fetal bovine serum
  • a clonal cell line was generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth medium was adjusted to 150 ⁇ g/mL hygromycin and 0.5 ⁇ g/mL puromycin for cell propagation.
  • ASSAY A Cells expressing recombinant human CL receptor/RAMPl were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and CompleteTM protease inhibitors (Roche). The cell suspension was disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate membranes. The pellets were resuspended in harvest buffer plus 250 mM sucrose and stored at -70°C. For binding assays, 20 ⁇ g of membranes were incubated in 1 mL binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl 2 , and 0.2% BSA) for 3 h at room
  • Y max is total bound counts
  • Ymi n is non specific bound counts
  • (Ymax - Ymin) is specific bound counts
  • % I max is the maximum percent inhibition
  • % I min is the minimum percent inhibition
  • radiolabel is the probe
  • K & is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.
  • ASSAY B RECOMBINANT RECEPTOR FUNCTIONAL ASSAY
  • cAMP dynamic 2 assay kit 62AM4PEC; Cisbio.
  • Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC50 values were determined.
  • ASSAY C RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were resuspended in DMEM/F12 (Hyclone) supplemented with 1 g/L BSA and 300 ⁇ isobutyl- methylxanthine. Cells were then plated in a 384-well plate (Proxiplate Plus 384; 509052761 ; Perkin-Elmer) at a density of 3,500 cells/well and incubated with antagonist for 30 min at 37 °C. Human a-CGRP was then added to the cells at a final concentration of 1 nM and incubated an additional 20 min at 37 °C.
  • cAMP dynamic 2 assay kit 62AM4PEC; Cisbio.
  • Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC 50 values were determined.
  • DMEM Dulbecco's Modified Eagle Medium (High Glucose)
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • Amine 1.4 can then be coupled to acid 1.5 in the presence of EDC and HO At (other coupling reagents and bases can be used for this reaction as well) and the resultant amide treated with acetic acid at elevated temperature to afford quinazoline 1.6.
  • Other acids and dehydrating reagents may be used in the this last transformation.
  • 1.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 1.4 and 1.5 may be employed as single enantiomers or diastereomers to obtain 1.6 enriched in a single enantiomer or diastereomer.
  • Additional compounds in the present invention may be prepared according to Scheme 2. This sequence starts with reaction of aniline 1.2 with acid 2.1 in the presence of EDC and HOAt (other coupling reagents and bases can be used for this reaction as well) and the resultant amide treated with sulfuric acid to afford quinolone 2.2. Other acids may be used in the this reaction. Treatment of quinolone 2.2 with phosphorous(V) oxychloride then gives chloropyridine 2.3.
  • Chloropyridine 2.3 can then be reacted with boronate (or boronic acid or other boronic acid derivative) 2.4 under palladium-catalyzed conditions to afford quinoline 2.5 (if a vinyl boronate is employed in the coupling reaction, the coupled product made be additionally reduced by treatment with palladium on carbon under an atmosphere of hydrogen).
  • boronate or boronic acid or other boronic acid derivative
  • a variety of different catalysts including other metals such as nickel
  • ligands, bases, and solvents can be employed in this coupling reaction.
  • 2.5 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 2.3 and 2.4 may be employed as single enantiomers or diastereomers to obtain 2.5 enriched in a single enantiomer or diastereomer.
  • compounds in the present invention may be prepared according to Scheme 3.
  • the sequence begins with treatment of acid 3.1 with DPPA in the presence of triethylamine to afford the corresponding aniline, which is subsequently reacted with acetyl chloride to give aryl acetamide 3.2.
  • Aryl acetamide 3.2 can then be nitrated by treatment with nitric acid in the presence of sulfuric acid followed by deacetylation of the resulant nitroaryl intermediate by treatment with sodium hydroxide to afford aniline 3.3.
  • Aniline 3.3 can then be reduced with palladium on carbon under an atmosphere of hydrogen to give dianiline 3.4.
  • Other reducing reagents can be employed in this reaction.
  • Dianiline 3.4 can then be reacted with bromoketone 3.5 in the presence of potassium carbonate to afford quinoxaline 3.6.
  • Other bases can be used in this reaction.
  • 3.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 3.4 and 3.5 may be employed as single enantiomers or diastereomers to obtain 3.6 enriched in a single enantiomer or diastereomer.
  • Heteroaryl triflate 4.4 is then coupled to boronate (or boronic acid or other boronic acid derivative) 4.5 under palladium- catalyzed conditions to afford isoquinoline 4.6 (if a vinyl boronate is employed in the coupling reaction, the coupled product made be additionally reduced by treatment with palladium on carbon under an atmosphere of hydrogen).
  • catalysts including other metals such as nickel
  • 4.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography.
  • 4.4 and 4.5 may be employed as single enantiomers or diastereomers to obtain 4.6 enriched in a single enantiomer or diastereomer.
  • Phenol 5.3 is then coupled to aryl halide 5.4 in the presence of copper(I) chloride, cesium carbonate, and a suitable ligand to afford biaryl ether 5.5.
  • Suitable ligand can be employed in this coupling reaction. Saponification of ester 5.5 by treatement with NaOH then gives acid 1.1. If 5.3 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried into the coupling with 5.4.
  • 5.5 is a mixture of enantiomers or diastereomers
  • the mixture may be separated by chiral chromatography and each isomer carried forward.
  • 5.2 may be employed as a single enantiomer or diastereomer to obtain 5.3 enriched in a single enantiomer or diastereomer.
  • 5.2 may be employed as a single enantiomer or diastereomer to obtain 6.3
  • Intermediates like 7.4 in the present invention may be prepared according to Scheme 7.
  • the sequence begins with coupling of acid 7.1 with acyl hydrazide 7.2 in the presence of EDC and HO At to give diacyl hydrazide 7.3.
  • Other coupling reagents, bases, and solvents can be employed for this step.
  • Diacyl hydrazide 7.3 is then treated with Lawesson's reagent to give thiadiazole 7.4.
  • Thiadiazole 7.4 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 7.4 (such as intermediate 5.4).
  • Scheme 8 which begins with coupling of boronate 8.1 with aryl (or heteroaryl) halide (or triflate) 8.2 under palladium-catalyzed conditions to afford intermediate 8.3.
  • aryl (or heteroaryl) halide (or triflate) 8.2 under palladium-catalyzed conditions to afford intermediate 8.3.
  • catalysts including other metals such as nickel
  • ligands, bases, and solvents can be employed in this reaction.
  • Aniline 8.3 is then treated with sodium nitrite followed by reacting the resulting diazonium species with potassium halide 8.4 to afford aryl halide 8.5.
  • Aryl halide 8.5 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 8.5 (such as intermediate 5.4).
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • various protecting group strategies may be employed to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable intermediate, followed by processing of the single isomers individually.
  • alternative methodologies may also be employed in the synthesis of these key intermediates.
  • Asymmetric methodologies e.g. chiral catalysis, auxiliaries
  • Step B 2-(4-Iodophenyl)-5-isopropyl-l,3,4-thiadiazole
  • Step A A"-Acetyl-4-iodobenzohydrazide
  • Step B 2-(4-Iodophenyl)-5-methyl-l,3,4-thiadiazole
  • Step A 3-Chloro-6-(prop-l-en-2-yl)pyridazine
  • Step C 4-(6-Isopropylpyridazin-3-yl)aniline
  • Step D 3-(4-Iodophenyl)-6-isopropylpyridazine
  • Step A ( ⁇ -Methyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
  • Step B ( ⁇ -Methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
  • Step C CSVMethyl 3-(4-(5-isopropyl-1 .4-t adiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate
  • 2-(4-bromophenyl)-5- isopropyl-l,3,4-thiadiazole 774 mg, 2.73 mmol
  • 2,2,6,6-tetramethyl-heptane-3 5-dione (231 mg, 1.25 mmol)
  • CuCl (248 mg, 2.51 mmol
  • CS 2 CO 3 2.23 g, 6.84 mmol
  • Step D CSV3-(4-(5-Isopropyl-l .4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoic acid
  • the reaction mixture was heated at 80 °C under N 2 atmosphere for 16 h.
  • the mixture was cooled to ambient temperature, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3).
  • the combined organic phase was washed with water (30 mL x 2), dried over
  • Step B (S)-3-(4-(5 -Methyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 - yPmethyDbenzoic acid
  • Step C 4-
  • Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxopyridin-l(2H)- yl)methyl)benzoate (101.3 mg, 0.222 mmol) was dissolved in MeOH (1.50 mL)/THF (3.00 mL) at 25 °C. NaOH (0.667 mL, 0.667 mmol) was added and the reaction mixture warmed to 50 °C.
  • Step B 4- ⁇ [(6 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step B methyl 4-methoxy-3-[(4-methyl-2-oxopyrrolidin-l-yl)methyllbenzoate
  • Step C methyl 4-hydroxy-3-[(4-methyl-2-oxopyrrolidin-l-yl)methyllbenzoate
  • the reaction mixture was concentrated, diluted with DCM (100 mL), and washed with saturated aqueous NaHC0 3 (50 mL x 2) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over Na 2 S0 4 , and concentrated to give the racemic title compound as a brown solid.
  • Step E 3-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-4- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid
  • Step A methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate
  • Step 4 (S)-methyl 2-bromo-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate
  • Step C (4S)-l -(4-amino-5-bromo-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step D 2-amino-5-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step E (4S)-1 -[4-amino-5-(aminomethyl)-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzyl] -4-methylpyrrolidin-2-one
  • Step F (4,5 or 4i?)-l-cyclopropyl-4-(6-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step B (4S)- 1 -(4-amino-2- (4- [5 -(propan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl]phenoxy
  • Step C (4S)-l -(4-amino-5-bromo-2- ⁇ 4-[5-(propan-2-yl)-l,3,4-thiadiazol-2-yllphenoxy
  • Step D 2-amino-5-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • reaction mxitue was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over Na 2 S0 4 , concentrated, and purified by column chromatography (Si0 2 , PE:EtOAc, 1 : 1 to 1 :3) to give the title compound as a yellow solid.
  • Step E (461-1 -[4-amino-5-(aminomethyl)-2- (4-[5-(propan-2-yl)- 1, 3,4-thiadiazol-2- yllphenoxy I benzyl] -4-methylpyrrolidin-2-one
  • Step F (AS and 4i? -l-cvclopropyl-4-(6-(r(4y)-4-methyl-2-oxopyrrolidin-l-yl1methyl
  • Step A 3-ethoxy-N-(4- ⁇ [(46 -4-methyl-2-oxopyrrolidin- 1 -yl]methyl
  • Step B 6- ([(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl
  • Step D (46 -4-methyl- 1 - ⁇ (7- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step E (46 -4-methyl-l-[(7-(4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step A fert-butyl (3-[(4-methyl-2-oxopyrrolidin-l-yl) ⁇
  • Step B l-(5-amino-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step C N-(3-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-4- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I phenyDacetamide
  • Step D N-(5-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-2-nmO-4- ⁇ 4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I phenyDacetamide
  • reaction mixture was quenched with saturated aqueous NaHC0 3 (til pH ⁇ 7) and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na 2 S0 4 and concentrated to give the racemic title compound as a yellow solid.
  • Step F 1 -(4,5-diamino-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step G tert-butyl 4-(6-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-7-(4-[6-(propan-2-yl)pyridazin- 3-yllphenoxy
  • Step H (AS and 4i?)-4-methyl-l- ⁇ [2-(piperidin-4-yl)-7-(4-[6-(propan-2-yl)pyridazin-3- yllphenoxy
  • Step I (46 -4-methyl- 1 - ⁇ (7- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • reaction mixture was stirred at 60 °C for 48 h, then quenched with aqueous NaHC0 3 (10 mL), and extracted with DCM (10 mL x 2).
  • the combined organic phases were concentrated and the residue purified by preparative HPLC (C-18, 95 ⁇ 5% water/ acetonitrile with 0.1% NH 4 OH) to give the racemic title compound as colorless oil.
  • the racemate was resolved by SFC (Chiralpak AD-3, isopropanol:C0 2 (containing 0.05%> DEA), 40:60) to give the title compound as the second eluting peak and as a yellow solid.
  • Step A (4S)- 1 -(5-bromo-2- ⁇ 4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step B 3- ([(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl
  • Step D 2,2-diethoxy-N-(3 - ( [(45V4-methyl-2-oxopyrrolidin- 1 -yllmethyll -4- (4-[6-(propan-2- yl)pyridazin-3-yllphenoxy
  • Step E (46 -l-[(3-hydroxy-6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • H 2 SO 4 (1 mL) was stirred at room temperature under N 2 atmosphere for 40 h.
  • Step F 7-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl
  • Step G (46 -4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yl "
  • Step H (46 -4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy
  • Step B (S)-methyl 5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)-2-(2-oxoethyl)benzoate
  • Step C 2-(l-cyclopropyl-5-oxopyrrolidin-3-yl)-7-(4-(6-isopropylpyridazin-3-yl)phenoxy)-6- (((S)-4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-3 ,4-dihydroisoquinolin- 1 (2H)-one (isomer 1 )

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Abstract

The present invention is directed to bicyclic compounds which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

Description

TITLE OF THE INVENTION
BICYCLIC CGRP RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localized
predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively. CGRP-alpha and CGRP -beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to the CGRP receptor which is a heterodimer consisting of the G-protein coupled calcitonin-like receptor (CLR) in association with the single transmembrane protein known as receptor activity modifying protein 1 (RAMPi). CGRP receptors are predominantly coupled to the activation of adenylyl cyclase and have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.
CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al. (1990) Ann. Neurol. 28, 183-187), salivary levels of CGRP are elevated in migraine subjects between (Bellamy et al. (2006) Headache 46, 24-33) and during attacks (Cady et al. (2009) Headache 49, 1258-1266), and CGRP itself has been shown to trigger migrainous headache (Lassen et al. (2002) Cephalalgia 22, 54-61). In clinical trials, the CGRP receptor antagonist BIBN4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al. (2004) New Engl. J. Med. 350, 1104-1110) and was able to prevent headache induced by CGRP infusion in a control group (Petersen et al. (2005) Clin. Pharmacol. Ther. 77, 202-213). The orally bioavailable CGRP receptor antagonist telcagepant has also shown antimigraine effectiveness in phase III clinical trials (Ho et al. (2008) Lancet 372, 2115-2123; Connor et al. (2009) Neurology 73, 970-977). CGRP -mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal artery, the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP. Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al. (1988) Ann. N ' eurol. 23, 193-196). Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP receptor antagonist (Williamson et al. (1997) Cephalalgia 17, 525-531). Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al. (1995) Brain Res. 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP receptor antagonist BIBN4096BS (Doods et al. (2000) Br. J. Pharmacol. 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP receptor antagonist.
CGRP -mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family:
Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extracranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et al. (2000) Ann. Neurol. 47, 614-624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.
The ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. Such disorders include migraine and cluster headache (Doods (2001) Curr. Opin. Invest. Drugs 2, 1261-1268; Edvinsson et al. (1994) Cephalalgia 14, 320-327); chronic tension type headache (Ashina et al. (2000) Neurology 14, 1335-1340); pain (Yu et al. (1998) Eur. J. Pharmacol. 347, 275-282); chronic pain (Hulsebosch et al. (2000) Pain 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer (1988) Neuroscience 24, 739-768; Delay-Goyet et al. (1992) Acta Physiol. Scanda. 146, 537-538;
Salmon et al. (2001) Nature Neurosci. 4, 357-358); eye pain (May et al. (2002) Cephalalgia 22, 195-196), tooth pain (Awawdeh et al. (2002) Int. Endocrin. J. 35, 30-36), non-insulin dependent diabetes mellitus (Molina et al. (1990) Diabetes 39, 260-265); vascular disorders; inflammation (Zhang et al. (2001) Pain 89, 265); arthritis, bronchial hyperreactivity, asthma, (Foster et al. (1992) Ann. NY Acad. Sci. 657, 397-404; Schini et al. (1994) Am. J. Physiol. 267, H2483-H2490; Zheng et al. (1993) J. Virol. 67, 5786-5791); shock, sepsis (Beer et al. (2002) Crit. Care Med. 30, 1794-1798); opiate withdrawal syndrome (Salmon et al. (2001) Nature Neurosci. 4, 357- 358); morphine tolerance (Menard et al. (1996) J. Neurosci. 16, 2342-2351); hot flashes in men and women (Chen et al. (1993) Lancet 342, 49; Spetz et al. (2001) J. Urology 166, 1720-1723); allergic dermatitis (Wallengren (2000) Contact Dermatitis 43, 137-143); psoriasis; encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al. (1999) Neurobiol. Dis. 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic
Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al. (2002) J. Membr. Biol. 189, 225); obesity (Walker et al. (2010) Endocrinology 151, 4257-4269); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. (2002) Scand. J. Gastroenterol. 37, 414-422) and cystitis. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.
SUMMARY OF THE INVENTION
The present invention is directed to bicyclic compounds which are potent antagonists of CGRP receptors and may be useful in the treatment or prevention of diseases in which the CGRP receptor is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved. DETAILED DESCRIPTION OF THE INVENTION
The inv ormula I:
Figure imgf000005_0001
Figure imgf000005_0002
G1 is CR3orN;
G2 is CR1 orN;
G3 is CR2orN;
G4 is CR3orN;
G5 is CR3 or N;
Yis O, CR5R6, NRDor SO
Vis CR5R6, C=0, 0,NRbor
E1 is N or CH;
CHR6, C=0; A2 is CR6R7, C=0 or NR4;
A3 is CR6R7, C=0, NR4, O or S;
A4 is a bond, CR6R7, O, S or NR4;
E2 is N or C;
A5 is CR6 or N;
A6 is CR7, C=0, N or NR4;
A7 is CR6, CR7, N, NR4 or C=0;
A8 is a bond, CR7, O, N or NR4;
Z1 is CRa;
Z2 is -N=, C=0, -CRa =, or C=NR4;
Z3 is -C= or N;
Z4 is -CRa=, -N=, or a bond;
Z5 is CRaRe, -CRa =, or a bond;
Z6 is CRaRe, -CRa =, or -N=;
Z7 is CRaRe;
a) hydrogen,
b) Ci_6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo, R8, (C=0)OR5, OR4, (C=0)NRbRc, SOmRd and NRbRc,
c) OR4,
d) heterocyclyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo, R 4 , R 8°, (Ci_6 alkyl)R 8°, OR 4", (C=0)OR 5J, (C=0)R8, (C=0)NRbRc and SOmRd,
e) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R 4 , R 8 , (Ci_6 alkyl)R 8 , OR 4 , (C=0)OR5, (C=0)NRbRc and SOmRd, f) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R4, OR4, (Ci_6 alkyl)R8,
(C=0)OR5, (C=0)NRbRc and SOmRd, (C=0)R8,
g) C3_8 cycloalkyl, which is optionally substituted with one to three substituents
independently selected from the group consisting of halo, oxo, R 4 , R 8 , (Ci_6 alkyl)R 8°,
(C=0)OR5, OR4, (C=0)NRbRc and SOmRd;
h) (C=0)OR5,
i) (C=0)NRbRc,
j) NRbRc;
R1 is hydrogen, halo, Ci_6 alkyl, 0(Ci_6 alkyl) or NRbRc, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; is
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci_6 alkyl or C3_6 cycloalkyl, which may be optionally substituted with one to four
substituents independently selected from the group consisting of halo, hydroxyl, NRbRc and (C=0)NRbRc;
(e) 0(Ci_6 alkyl), which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;
(f) (C=0)NRbRc,
(g) (C=0)OR4,
GO (C=0)OR8,
(i) (C=0)R8,
0) NRbRc,
(k) SOmRd, (1) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R4, R8, OR4, NRbRc, (C=0)NRbRc and SOmRd,
(m)heterocyclyl, which optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, R4, R8, OR4, NRbRc, (C=0)NRbRc and SOmRd, or
(n) heteroaryl, which optionally substituted with one to three substituents independently
selected from the group consisting of halo, hydroxyl, cyano, R4, R8, OR4, NRbRc, (C=0)NRbRc and SOmRd;
1 2
or R' and R" can be taken together with the carbon atom to which they are attached to form a C3_8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to two substituents independently selected from the group consisting of cyano, R4, R8, halo, oxo and OR4; R is hydrogen, halo, cyano or Ci_6 alkyl;
R4 is hydrogen or Ci_6 alkyl, wherein said alkyl group is optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, cyano, SOmRd, OR5, NRbRc, (C=0)NRbRc and R8;
R5 is hydrogen, Ci_6 alkyl, heterocyclyl or C3_8 cycloalkyl, which is optionally substituted with one to three halo;
R6 is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl or NRbRc; R7 is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl, 0(Ci_6 alkyl), NRbRc, C3_6 cycloalkyl, heterocyclyl, heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl groups are optionally substituted with one to three substituents independently selected
8 5 5
form the group consisting of halo, R , R and OR ; or R6 and R7 can be taken together with the carbon atom or atoms to which they are attached to form a C3_8 cycloalkyl, C3_8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, R5, OR5, C3_6 cycloalkyl and heterocyclyl;
Q
R is phenyl, heteroaryl, heterocyclyl or C3_8 cycloalkyl, wherein said phenyl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, hydroxyl, cyano, R5, NRbRc, OR5 and SOmR9;
R9 is hydrogen, cyano, Ci_6 alkyl, C3_8 cycloalkyl, heterocyclyl, phenyl, heteroaryl or NR5RC, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and OR5; or two R4 groups, or an R4 and R8 group, can be taken together with the atom to which they are attached to form a C3_8 cycloalkyl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NRbRc, OR5, C3_6 cycloalkyl, and heterocyclyl wherein said alkyl, cycloalkyl and heterocyclyl rings are optionally substituted with one to four substituents independently selected from the group consisting of oxo, Ci_6 alkyl, halo and hydroxyl; Ra is selected from the group consisting of hydrogen, halo, cyano, Ci_6 alkyl and OR5, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; Rb is hydrogen, Ci_6 alkyl, (C=0)R9, SOmR9, C3-6 cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said alkyl, phenyl, heteroaryl, and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of R9, halo, hydroxyl, OR5 and SOmR9;
Rc is hydrogen or Ci_6 alkyl, which is optionally substituted with one to three subsitituents independently selected from the group consisting of halo and OR5; or Rb and Rc can be taken together with the atom to which they are attached to form a heterocyclyl ring which is optionally substituted with one to three substituents independently selected from the group consisting of R5, halo, oxo, OR5 and heterocyclyl;
Rd is Ci_6 alkyl, C3_6 cycloalkyl and NRbRc;
Re is selected from the group consisting of hydrogen, Ci_6 alkyl, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; m is an integer from zero to two;
. In another class of
Figure imgf000010_0001
1 3 1
In a class of the invention, G is CR . In a subclass of the invention, G is CH. In another class of the invention, G1 is N.
2 1 2
In a class of the invention, G is CR . In a subclass of the invention, G is CH. In
2
another class of the invention, G is N.
In a class of the invention, G is CR . In another class of the invention, G is N. In a class of the invention, G4 is CR3. In a subclass of the invention, G4 is CH. In another class of the invention, G4 is N.
5 3 5
In a class of the invention, G is CR . In a subclass of the invention, G is CH. In another class of the invention, G5 is N.
In a class of the invention, Y is O. In another class of the invention, Y is CR5R6.
In another class of the invention, Y is NRb. In another class of the invention, Y is SOm.
In a class of the invention, V is CR5R6. In a subclass of the invention, V is CH2. In a class of the invention, V is C=0. In a class of the invention, V is O. In a class of the invention, V is NRb. In another class of the invention, V is SOm.
In a class of the invention, E1 is CH. In another class of the invention, E1 is N.
In a class of the invention, E 2 is C. In another class of the invention, E 2 is N. In a class of the invention, A1 is CHR6. In a subclass of the invention, A1 is CH2. In another class of the invention, A1 is C=0.
In a class of the invention, A2 is CR6R7. In another class of the invention, A2 is
2 4
C=0. In another class of the invention, A is NR .
In a class of the invention, A3 is CR6R7. In a subclass of the invention, A3 is CH2.
In another class of the invention, A 3 is C=0. In another class of the invention, A 3 is NR 4. In another class of the invention, A 3 is O. In another class of the invention, A 3 is S.
In a class of the invention, A4 is CR6R7. In another class of the invention, A4 is S. In another class of the invention, A4 is NR4. In another class of the invention, A4 is O. In another class of the invention, A4 is a bond.
In a class of the invention, A5 is CR6. In a subclass of the invention, A5 is CH. In another class of the invention, A5 is N.
In a class of the invention, A6 is CR7. In another class of the invention, A6 is C=0. In another class of the invention, A6 is N. In another class of the invention, A6 is NR4. In a class of the invention, A7 is CR6. In another class of the invention, A7 is CR7. In a subclass of the invention, A7 is CH. In another class of the invention, A7 is C=0. In another class of the invention, A7 is N. In another class of the invention, A7 is NR4.
In a class of the invention, A 8 is CR 7. In a subclass of the invention, A 8 is CH. In another class of the invention, A 8 is NR 4. In another class of the invention, A 8 is N. In another class of the invention, A 8 is O. In another class of the invention, A 8 is a bond.
In a class of the invention, Z1 is CH.
In a class of the invention, Z2 is -CRa=. In a subclass of the invention, Z2 is -
CH=. In another class of the invention, Z 2 is -N=. In another class of the invention, Z 2 is C=0.
In a class of the invention, Z 3 is -C=. In another class of the invention, Z 3 is N.
In a class of the invention, Z4 is -CRa=. In a subclass of the invention, Z4 is - CH=. In another class of the invention, Z4 is -N=.
In a class of the invention, Z5 is -CRa=. In a subclass of the invention, Z5 is - CH=. In another class of the invention, Z5 is a bond. In another class of the invention, Z5 is CRaRe. In a subclass of the invention, Z5 is CH2.
In a class of the invention, Z6 is -CRa=. In a subclass of the invention, Z6 is - CH=. In another class of the invention, Z6 is CRaRe. In a subclass of the invention, Z6 is CH2. In a subclass of the invention, Z6 is CHC¾
In a class of the invention, Z7 is CH.
In a class of the invention, W is:
a) Ci_6 alkyl, which is optionally substituted with one to four substituents
8 5 independently selected from the group consisting of halo, oxo, R , (C=0)OR , OR4, (C=0)NRbRc, SOmRd and NRbRc,
b) heterocyclyl, which is optionally substituted with one to three substituents
4 8 independently selected from the group consisting of halo, oxo, R , R°, (Ci_6 alkyl)R8, OR4, (C=0)OR5, (C=0)R8, (C=0)NRbRc and SOmRd, c) heteroaryl, which is optionally substituted with one to three substituents
independently selected from the group consisting of halo, oxo, Ci_6 alkyl, OR4, (Ci_6 alkyl)R8, (C=0)OR5, (C=0)NRbRc and SOmRd; or d) C3-8 cycloalkyl, which is optionally substituted with one to three substituents
4 8 independently selected from the group consisting of halo, oxo, R , R°, (Ci_6 alkyl)R8, (C=0)OR5, OR4, (C=0)NRbRc and SOmRd.
In a subclass of the invention, W is:
a) heterocyclyl, which is optionally substituted with one to three substituents
4 8
independently selected from the group consisting of halo, oxo, R , R°, (Ci_6 alkyl)R8, OR4, (C=0)OR5, (C=0)R8, (C=0)NRbRc and SOmRd, or b) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, Ci_6 alkyl, OR4, (Ci_6 alkyl)R8, (C=0)OR5, (C=0)NRbRc and SOmRd.
In a further subclass of the invention, W is heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, R4, OR4 and R8.
In a class of the invention, R1 is hydrogen.
In a class of the invention, R is heteroaryl, which is optionally substituted with one substituent selected from the group consisting of Ci_6 alkyl, heterocyclyl and C3_6 cycloalkyl.
In a class of the invention, R is hydrogen.
In a class of the invention, Ra is hydrogen or halo.
In a class of the invention, Rb is hydrogen or Ci_6 alkyl.
In a class of the invention, Rc is hydrogen or Ci_6 alkyl.
In a class of the invention, Rd is Ci_6 alkyl.
In a class of the invention, Re is Ci_6 alkyl.
Reference to the preferred classes and subclasses set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise.
Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 53, or pharmaceutically acceptable salts thereof.
The invention also encompasses a pharmaceutical composition which comprises an inert carrier and the compound of Formula I, or a pharmaceutically acceptable salt thereof. The invention also encompasses a method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In a specific embodiment of the invention, the headache is migraine headache.
The invention also encompasses the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of headache. In a specific embodiment of the invention, the headache is migraine headache.
The invention is also directed to medicaments or pharmaceutical compositions for treating diseases or disorders in which CGRP is involved, such as migraine, which comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention is also directed to the use of a compound of Formula I for treating diseases or disorders in which CGRP is involved, such as migraine.
The invention is further directed to a method for the manufacture of a medicament or a composition for treating diseases or disorders in which CGRP is involved, such as migraine, comprising combining a compound of Formula I with one or more pharmaceutically acceptable carriers.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,
diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds.
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. In addition, the absolute configuration may be determined by use of vibrational circular dichroism (VCD) spectoscopy in conjuction with computational chemistry.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
In the compounds of Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (IF!) and deuterium (¾). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. Tautomers of compounds defined in Formula I are also included within the scope of the present invention. For example, compounds including carbonyl -CH2C(0)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms are included within the scope of the present invention.
When any variable (e.g. R4, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5: 1188-1198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase
"optionally substituted with one or more substituents" should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents. As used herein, "alkyl" is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds. Thus, C0ne to fouralkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that C0ne to fouralkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
The term "cycloalkyl" means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.
As appreciated by those of skill in the art, "halo" or "halogen" as used herein is intended to include chloro (CI), fluoro (F), bromo (Br) and iodo (I).
The term "cycloalkyl" or "carbocycle" shall mean cyclic rings of alkanes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
If no number of carbon atoms is specified, the term "alkenyl" refers to a non- aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Preferably 1 carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
The term "cycloalkenyl" or shall mean cyclic rings of alkenes of three to eight total carbon atoms, unless otherwise indicated, or any number within this range (i.e.,
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl).
As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring. The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N, S, and Si. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyridinonyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl,
tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
The term "heterocycle" or "heterocyclyl" as used herein is intended to mean a 4- to 10-membered nonaromatic ring, unless otherwise specified, containing from 1 to 4
heteroatoms selected from the group consisting of O, N, S, SO, or S02 and includes bicyclic or spirocyclic groups. "Heterocyclyl" therefore includes, but is not limited to the following:
piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, oxetanyl, azetidinyl, pyrrolidonyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also emcompassed by this definition.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. In one aspect of the invention the salts are citric,
hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Exemplifying the invention is the use of the compounds disclosed in the
Examples and herein. Specific compounds within the present invention include a compound which may be selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
The subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.
Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors.
The present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the terms "administration of or "administering a" compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
The ability of the compounds of the present invention to act as CGRP receptor antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
The compounds of the present invention may have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; obesity; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache. The subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
The subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
The 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 Formula I 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 therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of Formula I 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 Formula I.
For example, the present compounds may be used in conjunction with an an antimigraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5 -HTiB/ ID agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HTID agonist such as PNU-142633 and a 5-HTiF agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective
cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone,
oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or
glucocorticoids. Similarly, the instant compounds may be administered with an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.
Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example aprepitant; an NMD A antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5 -lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT2 receptor antagonists; opiod agonists such as codeine, hydrocodone, tramadol, dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; an antidepressant, for example amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafirlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.
Also, the present compounds may be used in conjunction with gap junction inhibitors; neuronal calcium channel blockers such as civamide; AMPA/KA antagonists such as LY293558; sigma receptor agonists; and vitamin B2.
Also, the present compounds may be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine,
methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-a-ergocryptine, dihydro-P-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, a-ergocryptine, β-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.
Additionally, the present compounds may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or divalproex sodium; an anti-hypertensive such as an angiotensin II antagonist, for example losartan, irbesartin, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartan and candesartan cilexetil, an angiotensin I antagonist, an angiotensin converting enzyme inhibitor such as lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, ramipril and trandolapril; or botulinum toxin type A or B.
The present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non-sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine, phenylpropanolamine, or pseudoephedrine. The present compounds also may be used in conjunction with anti-emetics.
In an embodiment of the invention the present compounds may be used in conjunction with an anti-migraine agent, such as: ergotamine or dihydroergotamine; a 5-HTi agonist, especially a 5-HTIB/ID agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib. 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 preferred. 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 other active ingredient(s) 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, or from 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), and via the same or different routes of administration.
The compounds of the present invention may be administered by oral, parenteral
(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl -pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil- in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions and the like, containing the compounds of the present invention are employed. Similarly, transdermal patches may also be used for topical administration.
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require antagonism of CGRP receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 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, or may be administered once or twice per day.
When treating, preventing, controlling, ameliorating, or reducing the risk of headache, migraine, cluster headache, or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The utility of the compounds in accordance with the present invention as antagonists of CGRP receptor activity may be demonstrated by methodology known in the art.
Inhibition of the binding of 125 I-CGRP to receptors and functional antagonism of CGRP receptors were determined as follows:
NATIVE RECEPTOR BINDING ASSAY: The binding of 125I-CGRP to receptors in SK-N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 μg) were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgCl2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 125 I-CGRP and antagonist. After incubation at room temperature for 3 h, the assay was terminated by filtration through GFB glass fibre filter plates (PerkinElmer) that had been blocked with 0.5% polyethyleneimine for 3 h. The filters were washed three times with ice-cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCl2), then the plates were air dried. Scintillation fluid (50 μί) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the Kx was determined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108).
RECOMBINANT RECEPTOR: Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5'NheI and 3' Pmel fragment. Human RAMP1 (Genbank accession number AJ001014) was subcloned into the expression vector pIRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 3'NotI fragment. HEK 293 cells (human embryonic kidney cells; ATCC #CRL- 1573) were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 μg/mL streptomycin, and maintained at 37 °C and 95%> humidity. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS. Stable cell line generation was accomplished by co-transfecting 10 μg of DNA with 30 μg Lipofectamine 2000 (Invitrogen) in 75 cm flasks. CL receptor and RAMPl expression constructs were co-transfected in equal amounts. Twenty-four hours after transfection the cells were diluted and selective medium (growth medium + 300 μg/mL hygromycin and 1 μg/mL puromycin) was added the following day. A clonal cell line was generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth medium was adjusted to 150 μg/mL hygromycin and 0.5 μg/mL puromycin for cell propagation.
RECOMBINANT RECEPTOR BINDING ASSAY (ASSAY A): Cells expressing recombinant human CL receptor/RAMPl were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and Complete™ protease inhibitors (Roche). The cell suspension was disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate membranes. The pellets were resuspended in harvest buffer plus 250 mM sucrose and stored at -70°C. For binding assays, 20 μg of membranes were incubated in 1 mL binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl2, and 0.2% BSA) for 3 h at room
125
temperature containing 10 pM I-hCGRP (GE Healthcare) and antagonist. The assay was terminated by filtration through 96-well GFB glass fiber filter plates (PerkinElmer) that had been blocked with 0.05% polyethyleneimine. The filters were washed 3 times with ice-cold assay buffer (10 mM HEPES, pH 7.4, and 5 mM MgCl2). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Non-specific binding was determined and the data analysis was carried out with the apparent dissociation constant (K{) determined by using a nonlinear least squares fitting the bound CPM data to the equation below:
Yobsd =
Figure imgf000031_0001
1 + ([Drug] / Ki (l + [Radiolabel] / Kd) ^
Where Y is observed CPM bound, Ymax is total bound counts, Ymin is non specific bound counts, (Ymax - Ymin) is specific bound counts, % Imax is the maximum percent inhibition, % I min is the minimum percent inhibition, radiolabel is the probe, and the K& is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.
RECOMBINANT RECEPTOR FUNCTIONAL ASSAY (ASSAY B): Cells were resuspended in DMEM/F12 (Hyclone) supplemented with 1 g/L BSA and 300 μΜ isobutyl- methylxanthine. Cells were then plated in a 384-well plate (Proxiplate Plus 384; 509052761 ; Perkin-Elmer) at a density of 2,000 cells/well and incubated with antagonist for 30 min at 37 °C. Human a-CGRP was then added to the cells at a final concentration of 1.2 nM and incubated an additional 20 min at 37 °C. Following agonist stimulation, the cells were processed for cAMP determination using the two-step procedure according to the manufacturer's recommended protocol (HTRF cAMP dynamic 2 assay kit; 62AM4PEC; Cisbio). Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC50 values were determined.
RECOMBINANT RECEPTOR FUNCTIONAL ASSAY (ASSAY C): Cells were resuspended in DMEM/F12 (Hyclone) supplemented with 1 g/L BSA and 300 μΜ isobutyl- methylxanthine. Cells were then plated in a 384-well plate (Proxiplate Plus 384; 509052761 ; Perkin-Elmer) at a density of 3,500 cells/well and incubated with antagonist for 30 min at 37 °C. Human a-CGRP was then added to the cells at a final concentration of 1 nM and incubated an additional 20 min at 37 °C. Following agonist stimulation, the cells were processed for cAMP determination using the two-step procedure according to the manufacturer's recommended protocol (HTRF cAMP dynamic 2 assay kit; 62AM4PEC; Cisbio). Raw data were transformed into concentration of cAMP using a standard curve then dose response curves were plotted and IC50 values were determined.
Representative K{ or IC50 values in the recombinant receptor binding assay or recombinant receptor functional assay, respectively, for exemplary compounds of the invention are provided in the table below:
Figure imgf000032_0001
11 0.46 B
12 0.40 B
13 1.8 B
14 1.5 B
15 2.4 C
16 7.5 B
17 3.0 B
18 4.9 B
19 9.0 C
20 12 C
21 15 C
22 18 C
23 19 C
24 24 C
25 91 C
26 130 C
27 62 C
28 440 C
29 22 B
30 11 C
31 88 C
32 55 C
33 130 C
34 250 C
35 2200 C
36 240 C
37 470 C
38 90 C
39 140 C
40 260 C
41 1200 C
42 590 C
43 140 C 44 700 C
45 260 C
46 1400 C
47 180 C
48 2300 C
49 16 C
50 1.6 B
51 0.27 B
52 0.39 B
53 1.2 B
The following abbreviations are used throughout the text:
Ac acetyl
AIBN 2,2'-azobisisobutyronitrile
aq aqueous
Ar aryl
B2(Pin)2 bis(pinacolato)diboron
BINAP 2,2'-&w(diphenylphosphino)- 1 , 1 '-binaphthalene
Bn benzyl
Boc tert-butoxycarbonyl
(benzotriazol- 1 -yloxy)tr5(dimethylamino)phosphonium
BOP
hexafluorophosphate
br broad
BSA bovine serum albumin
Bu butyl
ca circa (approximately)
CAN ammonium cerium(IV) nitrate
Cbz carboxybenzyl
CD! 1 , 1 '-carbonyldiimidazole
d doublet
DABCO diazabicyclo[2.2.2]octane
DAST (diethylamino)sulfur trifluoride
dba dibenzylideneacetone
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCE 1 ,2-dichloroethane
DCM dichloromethane dd doublet of doublets
DEA diethylamine
DIBAL diisobutylaluminum hydride
DIEA N,N-diisopropylethylamine
DMA N,N-dimethylacetamide
DMAP 4-(dimethylamino)pyridine
DMEM: Dulbecco's Modified Eagle Medium (High Glucose)
DMF N,N-dimethylformamide
DMPU N,N'-dimethylpropyleneurea
DMSO dimethylsulfoxide
DPBF 1 ,3-diphenylisobenzofuran
DPPA Diphenylphosphoryl azide
dppf 1 , 1 '-/3z's(diphenylphosphino)ferrocene
EDC N-(3 -dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
EDTA ethylenediaminetetraacetic acid
eq equivalents
ESI electrospray ionization
Et ethyl
FBS fetal bovine serum
h hours
0-(7-azabenzotriazol- 1 -yl)-N,N,N W -tetramethyluronium
HATU
hexafluorophosphate
HEPES N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)
HMDS hexamethyldisilazane
HMTA hexamethylenetetramine
HOAt l-hydroxy-7-azabenzotriazole
HOBt 1 -hydroxybenzotriazole
HPLC high performance liquid chromatography
Hz hertz
imid imidazole
z'-Pr isopropyl
J coupling constant
LCMS liquid chromatography-mass spectrometry
LDA lithium diisopropylamide
m/z mass to charge ratio
m multiplet
mCPBA 3-chloroperbenzoic acid
Me methyl min minutes
MP macroporous polystyrene
Ms methanesulfonyl
MTBE methyl tert-butyl ether
MW molecular weight
NBS N-bromosuccinimide
NHS N-hydroxysuccinimide
ft-BuLi n-butyllithium
n-HexLi n-hexyllithium
NMM N-methyl morpholine
NMP 1 -methyl -2 -pyrrolidinone
NMR nuclear magnetic resonance
OAc acetate
P pentet
PBPB pyridinium bromide perbromide
PBS phosphate-buffered saline
Pd/C palladium on carbon
PE petroleum ether
Ph phenyl
PMBC1 4-methoxybenzyl chloride
psi pounds per square inch
p-Ts 4-toluenesulfonyl
Py pyridyl
PYBOP benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate
PyCIU chlorodipyrrolidinocarbenium
q quartet
rt room temperature
s singlet
SEM 2-trimethylsilylethoxymethyl
SEMC1 2-trimethylsilylethoxymethyl chloride
SFC supercritical fluid chromatography
SM starting material
t triplet
T3P 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
TBAB n-tetrabutylammonium bromide
TBAF R-tetrabutyiammoiiium fluoride
TBDPS tert-butyldiphenylsilyl
TBDPSC1 tert-butyldiphenylsilyl chloride t-Bu tert-butyl
TCCA trichloroisocyanuric acid
TCF tetramethylchloroformamidinium hexafluorophosphate
TEA triethylamine
Tf triflyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMG tetramethylguanidine
trisyl 2 ,4 , 6-triisopropylbenzenesulfonyl
V/V volume to volume
X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
Methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein.
The compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
REACTION SCHEMES
The compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
Many compounds of the present invention may be prepared according to Scheme
1, which begins with treatment of acid 1.1 with DPPA in the presence of triethylamine to afford the corresponding carbamate, which subsequently can be treated with HCl in methanol to give aniline 1.2. Aniline 1.2 can then be brominated by treatment with NBS to give aryl bromide 1.3. Aryl bromide 1.3 can then be reacted with zinc(II) cyanide to afford the corresponding nitrile, which is then reduced in the presence of Raney nickel under an atmosphere of hydrogen to afford amine 1.4. Amine 1.4 can then be coupled to acid 1.5 in the presence of EDC and HO At (other coupling reagents and bases can be used for this reaction as well) and the resultant amide treated with acetic acid at elevated temperature to afford quinazoline 1.6. Other acids and dehydrating reagents may be used in the this last transformation. If 1.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography. Alternatively, 1.4 and 1.5 may be employed as single enantiomers or diastereomers to obtain 1.6 enriched in a single enantiomer or diastereomer.
SCHEME 1
Figure imgf000039_0001
1.1 1.3
1. Zn(CN)2, heat
2. Raney Ni, H2
Figure imgf000039_0002
1.6 1.4
If a mixture of enantiomers or
diastereomers, then:
Chiral resolution I mixture
'—► single isomer
Additional compounds in the present invention may be prepared according to Scheme 2. This sequence starts with reaction of aniline 1.2 with acid 2.1 in the presence of EDC and HOAt (other coupling reagents and bases can be used for this reaction as well) and the resultant amide treated with sulfuric acid to afford quinolone 2.2. Other acids may be used in the this reaction. Treatment of quinolone 2.2 with phosphorous(V) oxychloride then gives chloropyridine 2.3. Chloropyridine 2.3 can then be reacted with boronate (or boronic acid or other boronic acid derivative) 2.4 under palladium-catalyzed conditions to afford quinoline 2.5 (if a vinyl boronate is employed in the coupling reaction, the coupled product made be additionally reduced by treatment with palladium on carbon under an atmosphere of hydrogen). A variety of different catalysts (including other metals such as nickel), ligands, bases, and solvents can be employed in this coupling reaction. If 2.5 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography. Alternatively, 2.3 and 2.4 may be employed as single enantiomers or diastereomers to obtain 2.5 enriched in a single enantiomer or diastereomer.
SCHEME 2
Figure imgf000040_0001
2.5
If a mixture of enantiomers or
diastereomers, then:
Chiral resolution mixture
single isomer
In addition, compounds in the present invention may be prepared according to Scheme 3. The sequence begins with treatment of acid 3.1 with DPPA in the presence of triethylamine to afford the corresponding aniline, which is subsequently reacted with acetyl chloride to give aryl acetamide 3.2. Aryl acetamide 3.2 can then be nitrated by treatment with nitric acid in the presence of sulfuric acid followed by deacetylation of the resulant nitroaryl intermediate by treatment with sodium hydroxide to afford aniline 3.3. Aniline 3.3 can then be reduced with palladium on carbon under an atmosphere of hydrogen to give dianiline 3.4. Other reducing reagents can be employed in this reaction. Dianiline 3.4 can then be reacted with bromoketone 3.5 in the presence of potassium carbonate to afford quinoxaline 3.6. Other bases can be used in this reaction. If 3.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography. Alternatively, 3.4 and 3.5 may be employed as single enantiomers or diastereomers to obtain 3.6 enriched in a single enantiomer or diastereomer.
SCHEME 3
Figure imgf000041_0001
3.2 3.3
Pd/C, H2
Figure imgf000041_0002
3.6 3-4
If a mixture of enantiomers or
diastereomers, then:
Chiral resolution mixture
single isomer
Further compounds in the present invention may be prepared according to Scheme 4. The sequence begins with reaction of acid 3.1 with ammonium chloride in the presence of EDC and HO At followed by dehydration of the resultant amide in the presence of phosphorous(V) oxychloride to afford nitrile 4.1. Nitrile 4.1 is then reduced by treatment with Raney nickel in the presence of ammonium hydroxide to give amine 4.2. Amine 4.2 is then coupled to acid 4.3 in the presence of HATU and triethylamine followed by cyclodehydration of the resultant amide to afford a hydroxyisoquinoline intermediate that is then treated with triflic anhydride in the presence of pyridine to give heteroaryl triflate 4.4. Heteroaryl triflate 4.4 is then coupled to boronate (or boronic acid or other boronic acid derivative) 4.5 under palladium- catalyzed conditions to afford isoquinoline 4.6 (if a vinyl boronate is employed in the coupling reaction, the coupled product made be additionally reduced by treatment with palladium on carbon under an atmosphere of hydrogen). A variety of different catalysts (including other metals such as nickel), ligands, bases, and solvents can be employed in this coupling reaction. If 4.6 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography. Alternatively, 4.4 and 4.5 may be employed as single enantiomers or diastereomers to obtain 4.6 enriched in a single enantiomer or diastereomer.
Figure imgf000042_0001
Figure imgf000042_0002
If a mixture of enantiomers or
diastereomers, then:
Chiral resolution I mixture
»■ single isomer
Intermediates like 1.1 in the present invention may be prepared according to Scheme 5. The sequence begins with coupling of benzyl bromide 5.1 with intermediate 5.2 in the presence of sodium hydride followed by demethylation of the resulting alkylated
intermediate by treatment with boron tribromide or HBr in acetic acid to afford intermediate phenol 5.3. Phenol 5.3 is then coupled to aryl halide 5.4 in the presence of copper(I) chloride, cesium carbonate, and a suitable ligand to afford biaryl ether 5.5. A variety of different catalysts (including other metals such as palladium), ligands, bases, and solvents can be employed in this coupling reaction. Saponification of ester 5.5 by treatement with NaOH then gives acid 1.1. If 5.3 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried into the coupling with 5.4. Similarly, if 5.5 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried forward. Alternatively, 5.2 may be employed as a single enantiomer or diastereomer to obtain 5.3 enriched in a single enantiomer or diastereomer.
SCHEME 5 H TH R = Me 5.5
Figure imgf000043_0001
K H, i-i diastereomers, then:
„, . , , ,. . mixture
Chiral resolution f— " . , .
»■ single isomer
and carry one or both forward individually
Intermediates like 3.1 in the present invention may be prepared according to Scheme 6. The sequence begins with bromination of tolyl starting material 6.1 by treatment with NBS, affording benzyl bromide 6.2. Coupling of benzyl bromide 6.2 with intermediate 5.2 in the presence of sodium hydride followed by demethylation of the resulting alkylated intermediate by treatment with boron tribromide can then give phenol 6.3. Phenol 6.3 is then coupled to aryl halide 5.4 in the presence of copper(I) chloride, cesium carbonate, and a suitable ligand to afford biaryl ether 6.4. A variety of different catalysts (including other metals such as palladium), ligands, bases, and solvents can be employed in this coupling reaction. Saponification of ester 6.4 by treatement with LiOH then gives acid 3.1. If 6.3 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried into the coupling with 5.4. Similarly, if 6.4 is a mixture of enantiomers or diastereomers, the mixture may be separated by chiral chromatography and each isomer carried forward.
Alternatively, 5.2 may be employed as a single enantiomer or diastereomer to obtain 6.3
enriched in a single enantiomer or diastereomer.
Figure imgf000043_0002
and carry one or both forward individually Intermediates like 7.4 in the present invention may be prepared according to Scheme 7. The sequence begins with coupling of acid 7.1 with acyl hydrazide 7.2 in the presence of EDC and HO At to give diacyl hydrazide 7.3. Other coupling reagents, bases, and solvents can be employed for this step. Diacyl hydrazide 7.3 is then treated with Lawesson's reagent to give thiadiazole 7.4. Thiadiazole 7.4 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 7.4 (such as intermediate 5.4).
Figure imgf000044_0001
Intermediates like 8.5 in the present invention may be prepared according to
Scheme 8, which begins with coupling of boronate 8.1 with aryl (or heteroaryl) halide (or triflate) 8.2 under palladium-catalyzed conditions to afford intermediate 8.3. A variety of different catalysts (including other metals such as nickel), ligands, bases, and solvents can be employed in this reaction. Aniline 8.3 is then treated with sodium nitrite followed by reacting the resulting diazonium species with potassium halide 8.4 to afford aryl halide 8.5. Aryl halide 8.5 can be employed as an intermediate in schemes in the present invention that involve compounds similar to 8.5 (such as intermediate 5.4).
Figure imgf000044_0002
In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies may be employed to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates. Asymmetric methodologies (e.g. chiral catalysis, auxiliaries) may be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions, depends upon the nature of the intended product.
INTERMEDIATE Al
Figure imgf000045_0001
2-(4-Iodophenyl)-5-isopropyl-l,3,4-thiadiazole
Step A: 4-Iodo-N-isobutyrylbenzohydrazide
N-Methylmorpholine (1.77 mL, 16.1 mmol) was added to a stirring solution of 4- iodobenzoic acid (1.00 g, 4.03 mmol), isobutyric acid hydrazide (495 mg, 4.84 mmol), EDC (1.35 g, 7.06 mmol), and HO At (0.274 g, 2.02 mmol) in DMF (8.1 mL) and the resulting mixture allowed to stir at 50 °C for 30 min. The reaction mixture was cooled to ambient temperature and excess water added. The resulting solids were filtered and washed with water. The substrate was dried under high vacuum with heat to give the title compound. LC-MS m/z found = 333.3 [M+l]+.
Step B: 2-(4-Iodophenyl)-5-isopropyl-l,3,4-thiadiazole
Lawesson's Reagent (1.96 g, 4.85 mmol) was added to a stirring solution of 4- iodo-N'-isobutyrylbenzohydrazide (1.29 g, 3.88 mmol) in THF (39 mL). The resulting mixture was stirred at 50 °C for 1 h. The mixture was cooled to room temperature and concentrated in vacuo. Purification of the crude mixture by silica gel chromatography (100→ 75% DCM/ EtOAc) gave the title compound. LC-MS m/z found = 331.2 [M+l]+; 1H NMR (400 MHz, DMSO): δ 7.93-7.92 (m, 2 H); 7.73-7.72 (m, 2 H); 3.48-3.47 (m, 1 H); 1.40 (d, J= 6.9 Hz, 6 H).
I 2
Figure imgf000046_0001
2-(4-Iodophenyl)-5 -methyl- 1, 3, 4-thiadiazole
Step A: A"-Acetyl-4-iodobenzohydrazide
To a solution of 4-iodobenzoic acid (10.0 g, 40.3 mmol), acetylhydrazide (3.00 g, 40.3 mmol), EDC (13.5 g, 70.6 mmol), and HO At (2.70 g, 20.2 mmol) in DMF (81 mL) was added N-methylmorpholine (17.7 mL, 161 mmol). The resulting mixture was heated at 50 °C for 30 min. The mixture was cooled to ambient temperature and excess water was added. The resulting solids were filtered, washed with water, and dried under high vacuum to give the title compound. LC-MS m/z found = 305.1 [M+l]+.
Step B: 2-(4-Iodophenyl)-5-methyl-l,3,4-thiadiazole
To a solution of N"-acetyl-4-iodobenzohydrazide (12.0 g, 39.5 mmol) in THF (395 mL) was added Lawesson's reagent (21.2 g, 52.5 mmol) and the resulting mixture heated at 50 °C for 2 h. The mixture was concentrated. Purification of the crude mixture by silica gel chromatography (100→ 50% hexanes/EtOAc) and recrystallization from EtOAc gave the title compound. LC-MS m/z found = 303.1 [M+l]+; 1H NMR (400 MHz, DMSO): δ 7.72-7.71 (m, 2 H); 7.92-7.91 (m, 2 H); 2.78 (s, 3 H).
INTERMEDIATE A3
Figure imgf000047_0001
3-(4-Iodophenyl)-6-isopropylpyridazine
Step A: 3-Chloro-6-(prop-l-en-2-yl)pyridazine
A mixture of 3,6-dichloropyridazine (35 g, 0.24 mol), 4,4,5,5-tetramethyl-2-
(prop-l-en-2-yl)-l,3,2-dioxaborolane (40 g, 0.24 mol), Pd(dppf)Cl2.CH2Cl2 (19.6 g, 0.0240 mol), Κ3Ρ04·3Η20 (127 g, 0.480 mol) in toluene (350 mL) and H20 (75 mL) was heated at reflux under N2 atmosphere for 16 h. After cooling to 23 °C, the reaction mixture was filtered. The filtrate was washed with water (100 mL x 2), dried over Na2S04, and concentrated. The residue was purified by column chromatography (Si02, petroleum ether to petroleum ether: EtOAc, 20: 1) to afford 3-chloro-6-(prop-l-en-2-yl)pyridazine. MS: m/z = 154.9 [M+l]+. 1H NMR (300 MHz, CDC13): δ 7.67 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 5.86 (d, J = 0.6 Hz, 1H), 5.53 (d, J = 0.6 Hz, 1H), 2.33 (s, 3H). Step B: 3-Chloro-6-isopropylpyridazine
A mixture of 3-chloro-6-(prop-l-en-2-yl)pyridazine (6.0 g, 39 mmol),
Pvh(PPh3)3Cl (2.5 g, 2.7 mmol) in MeOH (250 mL) was shaken under H2 atmosphere (15 psi) at ambient temperature overnight. The reaction mixture was filtered and the filtrate concentrated to afford 3-chloro-6-isopropylpyridazine. 1H NMR (300 MHz, CDC13): δ 7.43 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 3.38-3.25 (m, 1H), 1.35 (d, J = 6.9 Hz, 6H).
Step C: 4-(6-Isopropylpyridazin-3-yl)aniline
To a solution of 3-chloro-6-isopropylpyridazine (10.0 g, 63.9 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (16.8 g, 76.7 mmol), and Pd(dppf)Cl2 (9.30 g,12.8 mmol) in toluene (100 mL) was added K3P04 (27.1 g, 0.130 mol) and water (20 mL). The reaction mixture was stirred at 90 °C for 18 h and then concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over Na2S04 and concentrated. The residue was purified by column chromatography (Si02, petroleum ether: EtOAc, 5: 1 to 1 : 1) to give the title compound. MS: m/z = 213.9 [M+l]+. 1H NMR (400 MHz, CDC13): δ 7.92 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 3.91 (br, 2H), 3.47-3.15 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H).
Step D: 3-(4-Iodophenyl)-6-isopropylpyridazine
To a suspension of 4-(6-isopropylpyridazin-3-yl)aniline (11.6 g, 54.5 mmol) in aq. HC1 (IN, 150 mL) at 0 °C was added dropwise aq. NaN02 (4.50 g in 15 mL of H20, 65.9 mmol). After the addition, the reaction mixture was stirred at 0 °C for 1 h, and then a solution of KI (18.1 g, 0.110 mol) in H20 (18 mL) was added dropwise. The resulting mixture was stirred at 0 °C for another 5 h and then extracted with EtOAc (120 mL x 6). The combined organic phase was washed with aqueous Na2S03 (200 mL x 2) and saturated aqueous sodium chloride (200 mL), dried over Na2S04, and concentrated to give the title compound as a yellow solid. MS: m/z
324.9 [M+1]+.1H NMR (400 MHz, CDC13): δ 7.84 (m, 4H), 7.66 (d, J
8.8 Hz, 1H), 3.38-3.31 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H).
Figure imgf000048_0001
(6 -3-(4-(5-Isopropyl-l ,3,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yPmethyDbenzoic acid
Step A: (^-Methyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
To a solution of 4-methylpyrrolidin-2-one (574 mg, 5.79 mmol) in anhydrous DMF (15 mL) was added NaH (255 mg, 6.37 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.50 g, 5.79 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 14 h and then quenched with saturated aqueous NH4CI (10 mL). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H20 (30 mL x 3) and saturated aqueous sodium chloride (30 mL), dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (petroleum ether :EtO Ac, 20: 1 to 3: 1) to give the racemic title compound. The racemic title compound was resolved by SFC (Chiralpak AD column, eluting with C02:MeOH ((0.2% NH4OH), 75:25) to give the title compound as the first eluting isomer. MS (ESI) m/z: 278.1 [M+l]+. 1H NMR (400 MHz, CDCI3): δ 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.42- 3.38 (m, 1H), 2.86-2.84 (m, 1H), 2.63-2.57 (m, 1H), 2.47-2.38 (m, 1H), 2.10-2.04 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H).
Step B: (^-Methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
A solution of BBr3 (0.65 mL, 6.9 mmol) in CH2C12 (5 mL) was added dropwise to a solution of (5)-methyl 3-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (637 mg, 2.30 mmol) in CH2C12 (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 4 h, warmed to ambient temperature, and allowed to stir for 18 h. The reaction mixture was quenched by very slow addition of MeOH (5 mL) and concentrated. The residue was dissolved in MeOH (20 mL) and heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and then concentrated. The residue was dissolved in CH2C12 (25 mL) and washed with saturated aqueous NaHC03 (15 mL) and water (15 mL). The organic phase was dried over Na2S04 and concentrated to give the title compound as a yellow oil. MS (ESI) m/z = 263.9 [M+l]+. 1H NMR (400 MHz, CDC13): δ 9.35 (br s, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 1.6, 8.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 4.35 (s, 2H), 3.88 (s, 3H), 3.60 (dd, J = 8.0, 9.6 Hz, 1H), 3.05 (dd, J = 6.0, 9.6 Hz, 1H), 2.61 (dd, J = 8.8, 16.8 Hz, 1H), 2.53-2.44 (m, 1H), 2.05 (dd, J = 6.8, 17.2 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H).
Step C: CSVMethyl 3-(4-(5-isopropyl-1 .4-t adiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate To a solution of (5)-methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (600 mg, 2.28 mmol) in NMP (20 mL) was added 2-(4-bromophenyl)-5- isopropyl-l,3,4-thiadiazole (774 mg, 2.73 mmol), 2,2,6,6-tetramethyl-heptane-3, 5-dione (231 mg, 1.25 mmol), CuCl (248 mg, 2.51 mmol) and CS2CO3 (2.23 g, 6.84 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 16 h. The mixture was cooled, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:EtOAc, 50: 1 to 10:1) to give the title compound as a yellow solid. MS (ESI) m/z: 466.1 [M+l]+. 1H NMR (400 MHz, CD3OD): δ 8.00 (d, J = 6.8 Hz, 2H), 7.90 (dd, J = 1.6, 8.0Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 6.8 Hz, 2H), 4.61 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 3.89 (s, 3H), 3.56-3.49 (m, 2H), 2.97 (m, 1H), 2.52-2.40 (m, 2H), 1.98 (dd, J = 6.4, 16.0Hz, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H). Step D: CSV3-(4-(5-Isopropyl-l .4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoic acid
A solution of (5)-methyl 3-(4-(5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)- 4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (700. mg, 1.50 mmol) and LiOH (110 mg, in 15 mL of water, 4.5 mmol) in MeOH (45 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and the pH was then adjusted to 4 with aqueous HCl
(IN). The mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over Na2S04 and concentrated to give the title compound as a yellow solid. MS (ESI) m/z: 452.0 [M + 1]. 1H NMR (400 MHz,
CD3OD): δ 8.00 (d, J = 6.8 Hz, 2H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 6.8 Hz, 2H), 4.61 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 3.58-3.48 (m, 2H), 2.97 (m, 1H), 2.52-2.39 (m, 2H), 2.00 (dd, J = 7.2, 17.2Hz, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H).
INTERMEDIATE B2
Figure imgf000051_0001
(S)-3-(4-(5-Methyl-l J^-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoic acid Step A: (S)-Methyl 3-(4-(5-methyl-13^-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolid 1 -yl)methyl)benzoate
To a solution of (5)-methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (600 mg, 2.28 mmol) in NMP (20 mL) was added 2-(4-bromophenyl)- 5-methyl-l,3,4-thiadiazole (868 mg, 3.42 mmol), 2,2,6, 6-tetramethyl-heptane-3,5-dione (0.260 mL, 1.25 mmol), CuCl (248 mg, 2.51 mmol), and Cs2C03 (2.23 g, 6.84 mmol).
The reaction mixture was heated at 80 °C under N2 atmosphere for 16 h. The mixture was cooled to ambient temperature, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over
Na2S04, and concentrated. The residue was purified by silica gel chromatography
(petroleum ether:EtOAc, 50: 1 to 10:1) to give the title compound as a yellow oil. MS: mlz = 438.0 [M+l]+. 1H NMR (400 MHz, CD3OD): δ 7.95 (d, J = 7.2 Hz, 2H), 7.87 (dd, J = 1.6, 8.0 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 6.8 Hz, 2H), 4.57 (d, J = 15.2 Hz, 1H), 4.52 (d, J = 15.2 Hz, 1H), 3.86 (s, 3H), 3.48 (dd, J = 7.6, 9.6 Hz, 1H), 2.94 (m, 1H), 2.80 (s, 3H), 2.50-2.36 (m, 2H), 1.95 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H).
Step B : (S)-3-(4-(5 -Methyl- 1 ,3 ,4-thiadiazol-2-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 - yPmethyDbenzoic acid
A solution of (S)-methyl 3-(4-(5-methyl-l,3,4-thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (770. mg, 1.76 mmol) and LiOH (127 mg, in 15 mL of water, 5.28 mmol) in MeOH (30 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated, and the pH was then adjusted to 4 with aqueous HC1 (IN). The resulting mixture was concentrated to dryness to give the title compound as a yellow solid. MS: mlz 424.0 (M + 1).
Figure imgf000052_0001
4-|Y2-oxopyridin- 1 (2H)-yl)methyl]-3- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzoic acid
Step A: Methyl 3-methoxy-4-((2-oxopyridin-l(2H)-yl)methyl)benzoate
A solution of pyridin-2(lH)-one (8.81 g, 93 mmol) in DMF (100 mL) was added to a stirring 0 °C slurry of NaH (3.86 g, 60% dispersion in mineral oil, 23.2 mmol) in DMF (100 mL). The mixture was stirred for 15 min at 0 °C and a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (20.0 g, 77.2 mmol) in DMF (100 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The organics were extracted using EtOAc (3x). The combined organics were washed with saturated aqueous sodium chloride (3x), dried over MgS04, filtered, and concentrated in vacuo. The concentrate was taken up in DCM (260 mL) and cooled to 0 °C. Boron tribromide (232 mL, 1 M in DCM, 232 mmol) was added very slowly to the stirring 0 °C solution. The mixture was stirred at 0 °C for 1 h and then warmed to ambient temperature over 1 h. The mixture was cooled back to 0 °C and carefully quenched with excess MeOH (until the solution stopped bubbling). The mixture was concentrated in vacuo. The concentrate was taken up in MeOH and concentrated (2x). The concentrate was taken up in DCM and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with DCM. The combined organics were washed with saturated aqueous sodium chloride, dried over MgS04, filtered, and concentrated in vacuo to give the title compound. LC-MS m/z = 260.2 [M+l]+. Step B: Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxopyridin-l(2H)- yDmethyObenzoate
2,2,6, 6-Tetramethylheptane-3,5-dione (0.664 mL, 3.18 mmol) was added to a solution of methyl 3-hydroxy-4-((2-oxopyridin-l(2H)-yl)methyl)benzoate (1.50 g, 5.79 mmol), 3-(4-iodophenyl)-6-isopropylpyridazine (2.81 g, 8.68 mmol), copper(I) chloride (0.630 g, 6.36 mmol), and cesium carbonate (5.66 g, 17.4 mmol) in NMP (20 mL). The resulting solution was degassed with Ar and heated at 80 °C for 18 h. The reaction mixture was cooled to ambient temperature. Saturated aqueous ammonium chloride was added and the aqueous phase was extracted using EtOAc (3x). The combined organics were washed with saturated aqueous sodium chloride, dried over MgS04, filtered, and concentrated in vacuo. Purification by silica gel chromatography (100→ 90% DCM/MeOH) followed by a second purification by reverse phase HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) followed by conversion to the free base gave the title compound. LC -MS m/z = 456.1 [M+l]+. 1H NMR (400 MHz, DMSO): δ 8.20-8.19 (m, 3 H); 7.76-7.75 (m, 3 H); 7.45-7.44 (m, 2 H); 7.22-7.21 (m, 3 H); 6.42 (dd, J= 9.2, 1.2 Hz, 1 H); 6.26 (td, J= 6.7, 1.4 Hz, 1 H); 5.24 (s, 2 H); 3.79 (s, 3 H); 3.30-3.29 (m, 1 H); 1.35 (d, J= 6.9 Hz, 6 H).
Step C : 4-|Y2-oxopyridin- 1 (2H)-yl)methyl"|-3- (4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid
Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((2-oxopyridin-l(2H)- yl)methyl)benzoate (101.3 mg, 0.222 mmol) was dissolved in MeOH (1.50 mL)/THF (3.00 mL) at 25 °C. NaOH (0.667 mL, 0.667 mmol) was added and the reaction mixture warmed to 50 °C.
The reaction mixture was allowed to stir for 15 min. The reaction was stopped, cooled to room temperature, quenched by addition of HCl (cone, aq., 0.055 mL, 0.667 mmol), and concentrated in vacuo. The residue was azeotroped with MeOH (2 x 20 mL). The title compound, along with three equivalents of sodium chloride, was recovered as a light yellow/white solid. MS (ESI) m/z
= 442.2 [M+l]+.
INTERMEDIATE B4
Figure imgf000054_0001
4- {[(5V4-methyl-2-oxopyrrolidin- 1 -yl]methyl| -3- (4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid Step A: (^-Methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate
To a solution of (5)-methyl 3-hydroxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (3.50 g, 13.3 mmol) in NMP (70 mL) was added 3-(4-iodophenyl)- 6-isopropylpyridazine (4.74 g, 14.6 mmol), 2,2,6, 6-tetramethyl-heptane-3,5-dione (1.50 mL, 7.30 mmol), copper(I) chloride (1.44 g, 14.6 mmol), and CS2CO3 (8.67 g, 26.6 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 16 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (3x). The combined organics were washed with water (2x), dried over Na2S04, and
concentrated in vacuo. Purification by silica gel chromatography (98%→ 90% petroleum ether / EtOAc) gave the title compound. LC-MS m/z: 459.9 [M+l]+; 1H NMR (CDCI3,
400 MHz): δ 8.08 (d, J= 8.8Hz, 2H), 7.83 (dd, J= 1.6 Hz, 8.0 Hz, 1H), 7.76 (d, J= 8.8
Hz, 1H), 7.64 (d, J= 1.6 Hz, 1H), 7.42 (d, J= 8.0 Hz, 2H), 7.07 (d, J= 8.8 Hz, 2H), 4.60 (d, J= 15.6 Hz, 1H), 4.54 (d, J= 15.6 Hz, 1H), 3.87 (s, 3H), 3.46-3.32 (m, 2H), 2.92 (dd, J = 6.0 Hz, 9.60 Hz, 1H), 2.54 (dd, J= 8.4 Hz, 16.4 Hz, 1H), 2.45-2.36 (m, 1H), 2.05-2.00 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.08 (d, J= 6.8 Hz, 3H).
Step B: 4-{[(6 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-3-(4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid
To a solution of (5)-methyl 3-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (4.4 g, 9.57 mmol) in THF (100 mL) and MeOH (20 mL) was added aqueous LiOH (458 mg in 8 mL of water, 19.2 mmol). The reaction mixture was stirred at 20 C for 16 h and the pH was then adjusted to ~4 with aqueous HCl (IN). The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with water (100 mL), dried over Na2S04, and
concentrated to give the title compound as white solid. 1H NMR (CDC13, 400 MHz): δ 8.05 (d, J = 8.8Hz, 2H), 7.86 (dd, J = 1.6Hz, 8.0Hz, 1H), 7.77 (d, J= 8.8Hz, 1H), 7.68 (d, J= 1.6Hz, 1H), 7.45-7.41(m, 3H), 7.06 (d, J= 8.4Hz, 2H), 4.61 (d, J= 15.2Hz, 1H), 4.55 (d, J= 15.6Hz, 1H), 3.47-3.36 (m, 2H), 2.91 (dd, J= 6.4Hz, 10.0Hz, 1H), 2.60-2.54 (m, 1H), 2.43-2.38 (m, 1H), 2.08-2.02 (m, 1H), 1.41 (d, J= 6.8Hz, 6H), 1.07 (d, J= 6.8Hz, 3H).
Figure imgf000055_0001
3-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-4- {4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid Step A: methyl 3-(bromomethyl)-4-methoxybenzoate
To a solution of methyl 4-methoxy-3-methylbenzoate (25 g, 139 mmol) in PhCl (180 mL) was added NBS (27.2 g, 153 mmol) and benzoyl peroxide (672 mg, 2.8 mmol). The mixture was heated at 130 °C for 3 h and then concentrated. The residue was purified by column chromatography (PE:EtOAc, 100: 1 to 20: 1) to give the title compound as a white solid. 1H NMR (CDC13, 400 MHz): δ 7.62 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J= 7.6 Hz, 1H), 4.55 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H).
Step B: methyl 4-methoxy-3-[(4-methyl-2-oxopyrrolidin-l-yl)methyllbenzoate
To a solution of 4-methylpyrrolidin-2-one (3.8 g, 38.4 mmol) in DMF (50 mL) at 0 °C was added NaH (1.7 g, 60%, 42.5 mmol). The suspension was stirred at 0 °C for 40 min, and then methyl 3-(bromomethyl)-4-methoxybenzoate (10 g, 38.8 mmol) in DMF (50 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight and then quenched with saturated aqueous NH4C1 (30 mL). The resulting mixture was diluted with water (120 mL) and extracted EtOAc (150 mL x 3). The combined organic phases were washed with H20 (150 mL x 3) and saturated aqueous sodium chloride (150 mL), dried over Na2S04, and concentrated. The residue was purified by column chromatography (PE:EtOAc, 10: 1 to 1 : 1) to give the racemic title compound as yellow oil. 1H NMR (CDCI3, 400 MHz): δ 8.02-7.97 (dd, J= 2.4 Hz, 8.4 Hz, 1H), 7.83 (d, J= 2.0Hz, 1H), 6.90 (d, J= 8.4Hz„ 1H), 5.30 (s, 2H), 3.88 (s, 6H), 3.42-3.37 (m, 1H), 2.96-2.83 (m, 1H), 2.62-2.56 (m, 1H), 2.46-2.37 (m, 1H), 2.11-2.05 (m, 1H), 1.09 (d, J= 6.8Hz, 1H).
Step C: methyl 4-hydroxy-3-[(4-methyl-2-oxopyrrolidin-l-yl)methyllbenzoate
To a solution of methyl 4-methoxy-3-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]benzoate (7.8 g, 28.16mmol) in DCM (80 mL) at 0 °C under N2 atmosphere was added BBr3 (21.4 g, 84.4 mmol) in DCM (50 mL) dropwise. The resulting mixture was stirred at 0 °C for 4 h, then warmed to room temperature, and stirred overnight. The reaction mixture was carefully quenched at 0 °C with MeOH (40 mL) and then concentrated to dryness. The residue was dissolved in MeOH (80 mL) and heated at reflux for 4 h. The reaction mixture was concentrated, diluted with DCM (100 mL), and washed with saturated aqueous NaHC03 (50 mL x 2) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over Na2S04, and concentrated to give the racemic title compound as a brown solid. 1H NMR (CDC13, 400 MHz): δ 9.90 (s, 1H), 7.92 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.81 (d, J= 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 3.89 (s, 3H), 3.66-3.62 (m, 1H), 3.11-3.07 (m, 1H), 2.68-2.64 (m, 1H), 2.52 (br s, 1H), 2.18-2.12 (m, 1H), 1.09 (d, J = 6.8Hz, 3H). Step D: methyl 3-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-4-{4-[6-(propan-2-yl)pyridazin-3- yllphenoxylbenzoate
To a solution of methyl 4-hydroxy-3-[(4-methyl-2-oxopyrrolidin-l- yl)methyl]benzoate (2 g, 7.6 mmol) in NMP (30 mL) under N2 atmosphere was added 3-(4- iodophenyl)-6-isopropylpyridazine (2.95 g, 9.12 mmol), 2,2,6,6-tetramethyl-heptane-3,5-dione (770 mg, 4.2 mmol), CuCl (827 mg, 8.36 mmol), and Cs2C03 (4.95 g, 15.2 mmol). The reaction mixture was stirred at 80 C for 16 h. The reaction mixture was then quenched with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water (50 mL x 2), dried over Na2S04, and concentrated. The residue was purified by column chromatography (PE:EtOAc, 10: 1 to 1 : 1) to give the racemic title compound as a brown solid. MS (ESI) m/z: 460.1 [M+l]+; 1H NMR (CDCI3, 400 MHz): δ 8.16 - 8.08 (m, 2H), 8.04 - 7.99 (m, 1H), 7.96 - 7.93 (m, 1H), 7.85 - 7.73 (m, 1H), 7.54 - 7.37 (m, 1H), 7.13 (d, J= 8.0Hz, 2H), 6.95 (d, J= 8.4Hz, 1H), 4.63 (d, J= 15.2 Hz, 1H), 4.57 (d, J= 15.2Hz, 1H), 3.91 (s, 3H), 3.36-3.31 (m, 1H), 2.97-2.89 (m, 1H), 2.62-2.52 (m, 1H), 2.46-2.39 (m, 1H), 2.09-2.04 (m, 2H), 1.43 (s, 6H), 1.10 (d, J= 6.8Hz, 3H).
Step E: 3-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-4-{4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzoic acid
To a solution of methyl 3-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-4-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}benzoate (1.7 g, 3.7 mmol) in MeOH (20 mL) and water (5 mL) was added LiOH (177 mg, 7.4 mmol) and the resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to remove most of the MeOH. The residue was diluted with H20 (20 mL), and the pH value was adjusted to ca 4 with aq. HC1 (IN). The resulting mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2S04, and concentrated to give the racemic title compound as a brown solid. MS (ESI) m/z: 446.3 [M+l]+; 1H NMR (CD3OD, 400 MHz): δ 8.15-8.10 (m, 3H), 8.03-7.98 (m, 2H), 7.73 (d, J= 8.8Hz„ 1H), 7.18 (d, J= 8.8Hz, 2H), 7.04 (d, J= 8.8Hz, 1H), 4.63 (d, J= 15.2Hz, lH), 4.57 (d, J= 15.2Hz, 1H), 3.58-3.51 (m, 1H), 3.34-3.31 (m, 1H), 3.31-2.85 (m, 1H), 2.53- 2.48 (m, 2H), 2.03-2.01 (m, 1H), 1.43 (d, J= 7.0Hz, 6H), 1.09 (d, J= 6.5Hz, 3H).
Figure imgf000057_0001
(S)-methyl 2-bromo-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin- 1 - yDmethyObenzoate
Step A: methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate
To a solution of methyl 2-bromo-5-methoxy-4-methylbenzoate (2.0 g) in carbon tetrachloride was added NBS (0.44 g) and then benzoyl peroxide (0.056 g). The mixture was vacuum/nitrogen exchanged (3x) and then sealed before it was heated at 70 °C for 14 h. The mixture was cooled to room temperature and directly loaded to ISCO (80g, gold) column and eluted with EtOAc/hexane gradient (0-50%) to give the title compound.
Step 2: (S)-methyl 2-bromo-5-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
(S)-4-methylpyrrolidin-2-one (634 mg, 6.39 mmol) was dissolved in DMF (35 mL) at 25 °C under Ar. The reaction mixture was cooled to 0 °C. NaH (256 mg, 6.39 mmol) was added and the reaction mixture was allowed to stir for 5 min. Methyl 2-bromo-4- (bromomethyl)-5-methoxybenzoate (1800 mg, 5.33 mmol) in DMF (1.0 mL) was added. The reaction mixture was allowed to stir for 45 min. The reaction was stopped, quenched by addition of aqueous HC1 (1 M, ~20 mL) and the mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with water (3x) and saturated aqueous sodium chloride (1 x 10 mL), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure. The residue was taken up in toluene (12 mL) and MeOH (3 mL) and treated with TMS-diazomethane (2 mL, 2.0 M in diethyl ether). The reaction mixture was stirred for 20 minutes. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexanes (0-55%), to give the title compound. MS m/z: 358.0 [M+l]+.
Step 3: (S)-methyl 2-bromo-5-hydroxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate
BBr3 (1.0 M in DCM) (8.34 ml, 8.34 mmol) was carefully added to a stirring 0 °C solution of (S)-methyl 2-bromo-5-methoxy-4-((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (990 mg, 2.78 mmol) in DCM (15 ml). The reaction mixture was allowed to warm to room temperature over the course of 1 h and was stirred for 18 h. The reaction mixture was carefully quenched with MeOH at room temperature. The reaction mixture was then concentrated under reduced pressure. The crude mixture was taken back up in MeOH and concentrated under reduced pressure twice. The mixture was purified by silica gel column chromatography, eluting with EtOAc/hexane (0-100%) then EtOAc-NH3 (l%)-EtOH/hexane (0-100%). The desired fractions were concentrated under reduced pressure. The residue was taken up in MeOH/toluene (3 mL/9 mL) and treated with TMS-diazomethane (2.0 M in diethyl ether, 1.5 mL). The mixture was stirred for 30 minutes. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexane gradient 0-100%) to give the title compound. MS m/z: 344.0 [M+l]+.
Step 4: (S)-methyl 2-bromo-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate
A mixture of (S)-methyl 2-bromo-5-hydroxy-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)benzoate (2000 mg, 5.84 mmol), 3-(4-iodophenyl)-6-isopropylpyridazine (3.79 g, 11.69 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (592 mg, 3.21 mmol), copper(I) chloride (579 mg, 5.84 mmol), and cesium carbonate (5.71 g, 17.53 mmol) in NMP (40 ml) were degassed with nitrogen/vacuum exchange (3x) before it was heated to 75 °C for 14 h. EtOAc and HC1 (IN, 8 mL) were added (aqueous pH~6) and the aqueous phase was extracted using EtOAc (3x). Combined organics were washed with water (3x) and saturated aqueous sodium chloride, dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc/hexane 0-100%>, then 0-10% MeOH/DCM) gave the title compound. MS m/z: 539.9 [M+l]+.
EXAMPLE 1
Figure imgf000060_0001
(4S or 4R)- 1 -cyclopropyl-4-(6- ( [(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl| -7- (4-[6-(propan-2- yl)pyridazin-3-yllphenoxy|quinazolin-2-yl)pyrrolidin-2-one Step A: fert-butyl (4-{[(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-3-(4-[6-(propan-2- yl)pyridazin-3 -yllphenoxy I phenyDcarbamate
To a solution of 4-{[(5)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-3-{4-[6-(propan- 2-yl)pyridazin-3-yl]phenoxy} benzoic acid (2.30 g, 5.16 mmol) in tert- uOH (40 mL) was added DPPA (2.13 g, 7.74 mmol) and Et3N (1.57 g, 15.5 mmol). The mixture was stirred at room temperature for 2 h, then heated at 60 °C for 1 h, and then at 90 °C for 15 h. The reaction mixture was concentrated and the residue diluted with EtOAc (40 mL). The organic phase was washed with saturated aqueous NaHC03 (20 mL) and saturated aqueous sodium chloride (20 mL), dried over Na2S04, and concentrated. The residue was purified by column chromatography (Si02, PE:EtOAc, 5: 1 to 1 :2) to give the title compound as brown oil. MS (ESI) m/z: 517.23 [M+l]+; 1H NMR (CDC13, 400 MHz): δ 8.05 (d, J= 8.8Hz, 2H), 7.76-7.66 (m, 2H), 7.46-7.39 (m, 3H), 7.14 (s, 1H), 7.04 (d, J= 8.8Hz, 2H), 4.45-4.44 (m, 2H), 3.41-3.33 (m, 2H), 2.85 (dd, J = 6.0Hz, 9.6Hz, 1H), 2.52-2.46 (m, 1H), 2.40-2.28 (m, 1H), 2.00-1.94 (m, 1H), 1.48 (s, 9H), 1.42 (d, J= 6.8Hz, 6H), 1.04 (d, J= 6.8Hz, 3H). Step B: (46 -l-(4-amino-2-{4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyl)-4- methylpyrrolidin-2-one
A mixture of tert-butyl (4-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-3-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}phenyl)carbamate (800 mg, 1.55 mmol) and HCl/MeOH (8 mL, 4N) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the title compound as brown oil. MS (ESI) m/z: 417.2 [M+l]+; 1H NMR (CDC13,
400MHz): δ 8.04 (d, J= 8.8Hz, 2H), 7.80-7.70 (m, 1H), 7.50-7.41 (m, 1H), 7.14 (d, J= 8.4Hz, 1H), 7.05 (d, J= 8.4Hz, 2H), 6.48 (d, J = 6.0Hz, 1H), 6.30 (d, J= 1.6Hz, 1H), 4.40 (d, J = 14.8Hz, 1H), 4.35 (d, J= 14.8Hz, 1H), 3.73 (br, 1H), 3.41-3.36 (m, 1H), 2.86-2.82 (m, 1H), 2.46 (dd, J= 8.4Hz, 16.4Hz, 1H), 2.33-2.20 (m, 1H), 1.94 (dd, J= 7.2Hz, 16.4Hz, 1H), 1.42 (d, J = 6.8Hz, 6H), 1.04 (d, J= 6.8Hz, 3H).
Step C: (4S)-l -(4-amino-5-bromo-2-{4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyl)-4- methylpyrrolidin-2-one
To a solution of (45)-l-(4-amino-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (300 mg, 0.72 mmol) and NH4OAc (6 mg, 0.06 mmol) in CH3CN (6 mL) was added NBS (120 mg, 0.78 mmol). The reaction mixture was stirred at room temperature under N2 atmosphere for 10 min, concentrated, and then purified by column chromatography (Si02, PE:EtOAc, 2: 1 to 1 : 1 to 1 :2) to give the title compound as a yellow solid. MS (ESI) m/z: 517.1 [M+23]+; 1H NMR (CDCI3, 400 MHz): δ 8.05 (d, J= 8.8 Hz, 2H), 7.75 (d, J= 8.8 Hz, 1H), 7.47-7.38 (m, 2H), 7.06 (d, J= 8.8 Hz, 2H), 6.39 (s, 1H), 4.40 (d, J = 14.8 Hz, 1H), 4.33 (d, J= 14.4 Hz, 1H), 4.13 (br s, 2H), 3.42 - 3.31 (m, 2H), 2.86 (dd, J= 6.4Hz, 9.2 Hz, 1H), 2.49-2.45 (m, 1H), 2.36-2.32 (m, 1H), 1.96 (dd, J= 7.2Hz, 16.4 Hz, 1H), 1.42 (d, J= 6.8 Hz, 6H), 1.06 (d, J= 6.8 Hz, 3H).
Step D: 2-amino-5-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-4-{4-[6-(propan-2- yl)pyridazin-3 -yllphenoxy I benzonitrile
A mixture of (45)-l-(4-amino-5-bromo-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (300 mg, 0.6 mmol), Zn (80 mg, 1.2 mmol), Zn(CN)2 (138 mg, 1.2 mmol), Pd2(dba)3 (60 mg, 0.06 mmol) and DPPF (36 mg, 0.06 mmol) in
DMA (6 mL) was stirred at 180 °C in a microwave reactor for 30 min. The reaction mxitue was then diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over Na2S04, concentrated, and purified by preparative TLC (Si02, EtOAc) to give the title compound as a yellow solid. MS (ESI) m/z: 464.0 [M+23]+; 1H NMR (CDC13, 400 MHz): δ 8.13-8.03 (m, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.13- 7.07 (m, 2H), 6.18 (s, 1H), 4.57 (br s, 2H), 4.40 (d, J= 15.6 Hz, 1H), 4.33 (d, J= 15.6 Hz, 1H), 3.45-3.43 (m, 1H), 3.38-3.26 (m, 1H), 2.89 (dd, J= 6.0 Hz, 9.6 Hz, 1H), 2.56-2.47 (m, 1H), 2.45- 2.33 (m, 1H), 2.01-1.94 (m, 1H), 1.40 (d, J= 6.8 Hz, 6H), 1.07 (d, J= 6.4 Hz, 3H). Step E: (4S)-1 -[4-amino-5-(aminomethyl)-2- {4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I benzyl] -4-methylpyrrolidin-2-one
A mixture of 2-amino-5-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-4-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}benzonitrile (240 mg, 0.55 mmol) and Raney Ni (50 mg) in MeOH (15 mL, containing 0.1 mL of NH4OH) was stirred at room temperature under H2 atmosphere (15 psi) for 6 h. The reaction mixture was filtered and the filtrate concentrated to give the title compound as a brown solid. MS (ESI) m/z: 468.3 [M+23]+; 1H NMR (CD3OD, 400 MHz): δ 8.11-8.02 (m, 3H), 7.76-7.68 (m, 1H), 7.22-7.03 (m, 3H), 6.51-6.41 (m, 1H), 4.43-4.29 (m, 2H), 4.00-3.90 (m, 2H), 3.51-3.37 (m, 2H), 2.95-2.84 (m, 1H), 2.45-2.26 (m, 2H), 1.94-1.82 (m, 1H), 1.41 (d, J = 6.8Hz, 6H), 1.07 (d, J= 6.8Hz, 3H).
Step F: (4,5 or 4i?)-l-cyclopropyl-4-(6-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-7-(4-[6- (propan-2-yl)pyridazin-3-yllphenoxy|quinazolin-2-yl)pyrrolidin-2-one
To a solution of l-cyclopropyl-5-oxopyrrolidine-3-carboxylic acid (76 mg, 450 umol) in DMF (4 mL) was added HATU (170 mg, 450 umol) and Et3N (312 uL, 2.2 mmol). The mixture was stirred at room temperature for 30 min and (45)-l-[4-amino-5-(aminomethyl)-2-{4- [6-(propan-2-yl)pyridazin-3-yl]phenoxy} benzyl] -4-methylpyrrolidin-2-one (200 mg, 450 umol) was added. The reaction mixture was stirred at room temperature for 16 h and then HO Ac (0.8 mL) was added. The resulting mixture was stirred at 90 °C for another 6 h, then concentrated, and purified by preparative HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% NH4OH) to give the racemic title compound as a yellow solid. The racemate was further separated by SFC
(Chiralcel OD, 250x30 mm, supercritical C02:MeOH containing 0.1% NH4OH (60:40)) to give the enantiomer of the title compound (first eluting peak) and the title compound (second eluting peak). Second peak (title compound): MS (ESI) m/z: 577.5 [M+l]+; 1H NMR (CD3OD, 400
MHz): δ 9.39 (s, 1H), 8.23 (d, J= 8.8 Hz, 2H), 8.15 (d, J= 8.8 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.38 (d, J= 8.8 Hz, 2H), 7.16 (s, 1H), 4.80 (d, J= 16 Hz, 1H), 4.74 (d, J= 16 Hz, 1H), 3.97-3.83 (m, 2H), 3.77-3.66 (m, 2H), 3.42-3.34 (m, 1H), 3.15-3.13 (m, 1H), 2.97-2.82 (m 2H), 2.67-2.54 (m, 3H), 2.14-2.12 (m, 1H), 1.43 (d, J= 6.8 Hz, 6H), 1.15 (d, J= 6.8 Hz, 3H), 0.74-0.70 (m, 4H).
Figure imgf000063_0001
(4S and 4i -l-cyclopropyl-4-(6-([(45V4-methyl-2-oxopw
2-yD- 1 ,3 ,4-thiadiazol-2-yl]phenoxy | quinazolin-2-yl)pyrrolidin-2-one Step A: tert-butyl (4-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-3-(4-[5-(propan-2-yl)-l ,3,4- thiadiazol-2-yl]phenoxy|phenyl)carbamate
To a solution of (5)-3-(4-(5-isopropyl-l,3,4-thiadiazol-2-yl)phenoxy)-4-((4- methyl-2-oxopyrrolidin-l-yl)methyl)benzoic acid (5 g, 11.1 mmol) in tert- uOH (100 mL) was added DPP A (3.6 mL, 16.6 mmol) and Et3N (4.6 mL, 33.3 mmol). The reaction mixture was stirred at room temperature for 2 h under N2 atmosphere and then heated at 90 °C overnight. The reaction mixture was concentrated, the residue diluted with aq. Na2C03 (2 M, 80 mL), and extracted with EtOAc (100 mL x 2). The combined organic phases were dried over Na2S04 and concentrated. The residue was purified by column chromatography (Si02, PE:EtOAc, 1 : 1 , to EtOAc) to give the title compound as an oil. MS (ESI) m/z: 523.0 [M+l]+. 1H NMR (CDC13, 300 MHz): δ 7.81 (d, J= 8.7Hz, 2H), 7.20 (d, J= 8.1Hz, 1H), 7.11 (s, 1H), 7.03 (d, J= 8.1Hz, 1H), 6.91 (d, J= 8.7Hz, 2H), 6.54 (s, 1H), 4.34-4.33 (m, 2H), 3.46-3.37 (m, 1H), 3.31-3.25 (m, 1H), 2.77-2.72 (m, 1H), 2.44-2.36 (m, 1H), 2.33-2.19 (m, 1H), 1.88 (dd, J= 6.9Hz, 16.2Hz, 1H), 1.41 (d, J = 6.9Hz, 6H), 1.40 (s, 9H), 0.96 (d, J = 6.9Hz, 3H). Step B : (4S)- 1 -(4-amino-2- (4- [5 -(propan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl]phenoxy| benzyl)-4- methylpyrrolidin-2-one
A mixture of tert-butyl (4-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-3-{4-[5- (propan-2-yl)-l,3,4-thiadiazol-2-yl]phenoxy}phenyl)carbamate (3.5 g, 6.7 mmol) in HCl-MeOH (4 M, 30 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was basified with aqueous Na2C03 (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic phases were dried over Na2S04 and concentrated to give the title compound as an off-white solid. MS (ESI) m/z: 423.0 [M+l]+; 1H NMR (CDC13, 400 MHz): δ 7.89-7.85 (m, 2H), 7.13 (d, J= 8.0Hz, 1H), 7.00-6.97 (m, 2H), 6.50 (dd, J= 2.4Hz, 8.4Hz, 1H), 6.29 (d, J= 2.0Hz, 1H), 4.38-4.33 (m, 2H), 3.52-3.45 (m, 1H), 3.37-3.33 (m, 1H), 2.81 (dd, J = 6.0Hz, 9.6Hz, 1H), 2.48-2.41 (m, 1H), 2.31-2.29 (m, 1H), 1.93 (dd, J= 6.8Hz, 16.4Hz, 1H), 1.47 (d, J= 6.8Hz, 6H), 1.01 (d, J= 6.8Hz, 3H).
Step C: (4S)-l -(4-amino-5-bromo-2-{4-[5-(propan-2-yl)-l,3,4-thiadiazol-2-yllphenoxy|benzyl)- 4-methylpyrrolidin-2-one
To a solution of (45)-l-(4-amino-2-{4-[5-(propan-2-yl)-l,3,4-thiadiazol-2- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (1.1 g, 2.6 mmol) in CH3CN (12 mL) containing NH4OAc (20 mg, 0.26 mmol) was added NBS (487.7 mg, 2.74 mmol). The reaction mixture was stirred under N2 atmosphere at room temperature for 10 min. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, PE:EtOAc, 2: 1 to 1 :2) to give the title compound as a yellow solid. MS (ESI) m/z: 501.3 [M+l]+; 1H NMR (CDC13, 400 MHz): δ 7.87 (d, J= 8.8 Hz, 2H), 7.37 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 4.40 (d, J= 15.6 Hz, 1H), 4.35 (d, J= 15.6 Hz, 1H), 4.21 (br s, 2H), 3.50-3.47 (m, 1H), 2.86 (dd, J= 7.6Hz, 9.6 Hz, 1H), 2.83 (dd, J= 6.0Hz, 9.6Hz, 1H), 2.46-2.42 (m, 1H), 2.36-2.32 (m, 1H), 1.95 (dd, J= 7.2Hz, 16.4Hz, 1H), 1.46 (d, J= 7.2Hz, 6H), 1.04 (d, J= 6.8Hz, 3H).
Step D: 2-amino-5-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-4-{4-[5-(propan-2-yl)-l,3,4- thiadiazol-2-yl]phenoxy|benzonitrile
A mixture of (45)-l-(4-amino-5-bromo-2-{4-[5-(propan-2-yl)-l,3,4-thiadiazol-2- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (1.0 g, 2 mmol), Zn (260 mg, 4 mmol), Zn(CN)2 (468 mg, 4 mmol) Pd2(dba)3 (183 mg, 0.2 mmol) and DPPF (110.8 mg, 0.2 mmol) in DMA (15 mL) was stirred at 180 °C in a microwave reactor for 30 min. The reaction mxitue was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over Na2S04, concentrated, and purified by column chromatography (Si02, PE:EtOAc, 1 : 1 to 1 :3) to give the title compound as a yellow solid. MS (ESI) m/z: 447.9 [M+l]+; 1H NMR (CDC13, 400 MHz): δ 7.90 (d, J= 8.8 Hz, 2H), 7.37 (s, 1H), 7.08 (d, J = 8.8Hz, 2H), 6.19 (s, 1H), 4.49 (m, 2H), 4.40 (d, J= 14.8 Hz, 1H), 4.35 (d, J= 14.8 Hz, 1H), 3.63-3.58 (m, 1H), 3.46 (dd, J= 8.0Hz, 9.6Hz, 1H), 2.94-2.90 (m, 1H), 2.67-2.64 (m, 1H), 2.44-2.41 (m, 1H), 2.14 (dd, J = 7.2Hz, 16.8Hz, 1H), 1.47 (d, J= 6.8Hz, 6H), 1.09 (d, J= 6.8Hz, 3H).
Step E: (461-1 -[4-amino-5-(aminomethyl)-2- (4-[5-(propan-2-yl)- 1, 3,4-thiadiazol-2- yllphenoxy I benzyl] -4-methylpyrrolidin-2-one
A mixture of 2-amino-5-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-4-{4-[5- (propan-2-yl)-l,3,4-thiadiazol-2-yl]phenoxy}benzonitrile (650 mg, 1.45 mmol) and Raney Ni (120 mg) in MeOH (10 mL) and aqueous NH3 (28% w/w, 0.1 mL) was stirred under H2 atmosphere (15 psi) at room temperature for 6 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a brown solid. MS (ESI) m/z: 473.3 [M+23]+; 1H NMR (CD3OD, 400 MHz): δ 8.06-7.94 (m, 2H), 7.37-7.09 (m, 3H), 6.60-6.42 (m, 1H), 4.40-4.33 (m, 2H), 3.54-3.50 (m, 4H), 2.92-2.87 (m, 1H), 2.45-2.38 (m, 2H), 1.93-1.87 (m, 1H), 1.49 (d, J= 6.8 Hz, 6H), 1.03 (d, J= 6.8 Hz, 3H).
Step F: (AS and 4i? -l-cvclopropyl-4-(6-(r(4y)-4-methyl-2-oxopyrrolidin-l-yl1methyl|-7-(4-r5-
(propan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl]phenoxy | quinazolin-2-yl)pyrrolidin-2-one
To a solution of l-cyclopropyl-5-oxopyrrolidine-3-carboxylic acid (12.4 mg, 0.0732 mmol) in DMF (2 mL) was added HATU (27.8 mg, 0.0732 mmol) and Et3N (33 mg,
0.333 mmol). The mixture was stirred at room temperature for 30 min and (45)-l-[4-amino-5-
(aminomethyl)-2- {4- [5 -(propan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl]phenoxy } benzyl] -4- methylpyrrolidin-2-one (30 mg, 0.067 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then HO Ac (0.8 mL) was added. The resulting mixture was stirred at 90 °C for another 6 h, then concentrated, and purified by prep-HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% NH4OH) to give the title compound as a yellow solid and a mixture of two diastereomers. MS (ESI) m/z: 583.4 [M+l]+; 1H NMR (CD3OD, 400 MHz): δ 9.44 (s, 1H), 8.11 (d, J= 8.8 Hz, 2H), 8.07 (s, 1H), 7.37 (d, J= 8.8 Hz, 2H), 7.21 (s, 1H), 4.84 (d, J =16.0 Hz, 1H), 4.79 (d, J =16.0 Hz, 1H), 3.99 - 3.85 (m, 2H), 3.76-3.74 (m, 1H), 3.70 - 3.64 (m, 1H), 3.59 - 3.51 (m, 1H), 3.16 - 3.10 (m, 1H), 2.98 - 2.83 (m, 2H), 2.70 - 2.52 (m, 3H), 2.16 - 2.08 (m, 1H), 1.52 (d, J = 6.8 Hz, 6H), 1.15 (d, J = 6.8 Hz, 3H), 0.83 - 0.68 (m, 4H).
Figure imgf000066_0001
(46 -4-methyl- 1 -\(7- {4-[6-(propan-2-yl)pyridazin-3-yllphenoxy| -2-\ 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-yllquinolin-6-yl)methyllpyrrolidin-2-one
Step A: 3-ethoxy-N-(4- {[(46 -4-methyl-2-oxopyrrolidin- 1 -yl]methyl| -3- (4-[6-(propan-2- yl)pyridazin-3-yllphenoxy|phenyl)prop-2-enamide
To a solution of (45)-l-(4-amino-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (1.5 g, 3.60 mmol) in DMF (20 mL) at room temperature was added 3-ethoxyprop-2-enoic acid (627 mg, 5.40 mmol), EDC (1.06 g, 5.40 mmol), HOBt (734 mg, 5.40 mmol), and Et3N (2.5 mL, 18.0 mmol). The reaction mixture was stirred at 40 °C for 24 h, then quenched with H20 (40 mL), and extracted with EtOAc (40 mL x 2). The combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL), dried over Na2S04, and concentrated. The residue was purified by column chromatography (Si02, PE:EtOAc, 1 : 1 then 0: 1) to give the title compound as a brown solid. MS (ESI) m/z: 515.1 [M+l]+. 1H NMR (CDC13, 400MHz): δ 8.06 (s, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.73 (d, J= 9.2Hz, 1H), 7.55 (d, J= 12.0Hz, 1H), 7.40 (d, J= 8.8Hz, 1H), 7.32-7.27 (m, 2H), 7.23-7.19 (m, 1H), 7.01 (d, J= 8.8Hz, 2H), 5.37 (d, J = 12.0Hz, 1H), 4.48-4.37 (m, 2H), 3.86 (q, J= 7.2Hz, 2H), 3.42-3.29 (m, 2H), 2.85 (dd, J= 6.0Hz, 10.0Hz, 1H), 2.51-2.43 (m, 1H), 2.33-2.30 (m, 1H), 1.95 (dd, J= 7.2Hz, 16.6Hz, 1H), 1.40 (d, J= 6.8Hz, 6H), 1.29 (t, J = 7.2Hz, 3H), 1.03 (d, J= 6.8Hz, 3H).
Step B : 6- ([(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl| -7- (4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I quinolin-2( 1 H)-one
A solution of 3-ethoxy-N-(4-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-3-{4- [6-(propan-2-yl)pyridazin-3-yl]phenoxy}phenyl)prop-2-enamide (800 mg, 1.55 mmol) in cone. H2SO4 (5 mL) was stirred at room temperature for 1 h and then poured onto ice (30 g). The resulting mixture was neutralized with aq. NaOH (4N) to ca pH 8 and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with water (40 mL), dried over Na2S04, and concentrated to give the title compound as a brown solid. MS (ESI) m/z: 469.4 [M+l]+; 1H NMR (CDCI3, 400MHz): δ 11.60 (s, 1H), 8.09 (d, J= 8.8Hz, 2H), 7.77 (d, J= 8.8Hz, 1H), 7.72 (d, J= 9.2Hz, 1H), 7.56 (s, 1H), 7.42 (d, J= 8.8Hz, 1H), 7.11 (d, J = 8.8Hz, 2H), 6.94 (s, 1H), 6.54 (d, J= 9.6Hz, 1H), 4.58 (d, J= 15.2Hz, 1H), 4.52 (d, J= 14.8Hz, 1H), 3.50-3.43 (m, 1H), 3.36 (t, J= 6.8Hz, 1H), 2.94-2.91 (m, 1H), 2.57-2.48 (m, 1H), 2.40-2.36 (m, 1H), 2.03-1.96 (m, 1H), 1.42 (d, J= 7.2 Hz, 6H), 1.06 (d, J= 6.8 Hz, 3H). Step C: (46 -l-[(2-chloro-7-(4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|quinolin-6-yl)methyll- 4-methylpyrrolidin-2-one
A solution of 6-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-7-{4-[6-(propan-2- yl)pyridazin-3-yl]phenoxy}quinolin-2(lH)-one (800 mg, 1.71 mmol) in POCI3 (10 mL) was stirred at 40 °C for 2 h. The reaction mixture was concentrated. The residue was diluted with saturated aq. NaHC03 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water (40 mL), dried over Na2S04, and concentrated to give the title compound as a brown solid. MS (ESI) m/z: 487.3 [M+l]+; 1H NMR (CD3OD, 400MHz): δ 8.30 (d, J= 8.8Hz, 1H), 8.17 (d, J= 8.4Hz, 2H), 8.10 (d, J= 8.8Hz, 1H), 7.92 (s, 1H), 7.72 (d, J = 8.8Hz, 1H), 7.41 (d, J= 8.8Hz, 1H), 7.31-7.26 (m, 3H), 4.77 (d, J= 15.6Hz, 1H), 4.70 (d, J = 16.8Hz, 1H), 3.62-3.58 (m, 1H), 3.35-3.31 (m, 1H), 3.08-3.04 (m, 1H), 2.57-2.49 (m, 2H), 2.05 (dd, J= 6.4Hz, 16.0Hz, 1H), 1.41 (d, J = 7.2 Hz, 6H), 1.09 (d, J = 6.8 Hz, 3H).
Step D : (46 -4-methyl- 1 -\(7- {4-[6-(propan-2-yl)pyridazin-3-yllphenoxy| -2-[ 1 -(tetrahydro-2H- pyran-4-yD- 1 ,2,3 ,6-tetrahydropyridin-4-yllquinolin-6-yl)methyllpyrrolidin-2-one
A mixture of (4S)-l-[(2-chloro-7-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}quinolin-6-yl)methyl]-4-methylpyrrolidin-2-one (200 mg, 0.41 1 mmol), 1- (tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l, 2,3,6- tetrahydropyridine (181 mg, 0.616 mmol), Pd(dppf)Cl2 (34 mg, 0.041 mmol), and K2C03 (113 mg, 0.820 mmol) in (methoxymethoxy)methanol/H20 (4 mL/1 mL) was stirred at 100 °C under N2 atmosphere for 3 h. The reaction mixture was cooled to room temperature, diluted with H20 (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with H20 (20 mL) and saturated aqueous sodium chloride (20 mL), dried over Na2S04, and concentrated. The residue was purified by preparative TLC (DCM:MeOH, 10: 1) to give the title compound as colorless oil. MS (ESI) m/z: 618.6 [M+l]+; 1H NMR (CDC13, 400 MHz): δ 8.12 (d, J= 8.0Hz, 2H), 8.03 (d, J= 8.8Hz, 1H), 7.79 (d, J= 8.8Hz, 1H), 7.73 (s, 1H), 7.50 (d, J= 8.8Hz, 1H), 7.47-7.38 (m, 2H), 7.22 (d, J= 8.0Hz, 2H), 6.69 (s, 1H), 4.75 (d, J = 15.2Hz, 1H), 4.69 (d, J = 15.2Hz, 1H), 4.05 (d, J = 8.0Hz, 2H), 3.58-3.33 (m, 6H), 3.05-3.00 (m, 1H), 2.82 (s, 4H), 2.58 (dd, J= 8.4Hz, 16.4Hz, 2H), 2.49-2.37 (m, 1H), 2.11-2.04 (m, 1H), 1.85 (d, J= 11.2Hz, 2H), 1.67 (d, J= 8.0Hz, 2H), 1.42 (d, J= 6.8Hz, 6H), 1.10 (d, J= 6.4Hz, 3H).
Step E: (46 -4-methyl-l-[(7-(4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|-2-[l-(tetrahydro-2H- pyran-4-yl)piperidin-4-yllquinolin-6-yl)methyllpyrrolidin-2-one
A mixture of (45)-4-methyl-l-[(7-{4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy}-2- [l-(tetrahydro-2H-pyran-4-yl)-l,2,3,6-tetrahydropyridin-4-yl]quinolin-6-yl)methyl]pyrrolidin-2- one (100 mg, 0.162 mmol) and Pd/C (30 mg, 10%) in MeOH (15 mL) was stirred under H2 atmosphere (15 psi) at 30 °C for 16 h. The reaction mixture was filtered. The filtrate was concentrated and the residue purified by preparative HPLC (C-18, 95→ 5%> water/ acetonitrile with 0.1% NH4OH) to give the title compound as colorless oil. MS (ESI) m/z: 620.5 [M+l]+; 1H NMR (CDC13, 400MHz): δ 8.12 (d, J= 8.8Hz, 2H), 8.06 (d, J= 8.8Hz, 1H), 7.80-7.73 (m, 2H), 7.45-7.38 (m, 2H), 7.30 (d, J= 8.4Hz, 1H), 7.22 (d, J= 8.4Hz, 2H), 4.76 (d, J= 15.2Hz, 1H), 4.70 (d, J= 15.2Hz, 1H), 4.03 (dd, J= 3.2Hz, 10.8Hz, 2H), 3.54 (dd, J= 8.0Hz, 9.2Hz, 1H), 3.43-3.33 (m, 3H), 3.14 (d, J= 9.6Hz, 2H), 3.05-3.00 (m, 1H), 2.89-2.80 (m, 1H), 2.63-2.54 (m, 2H), 2.49-2.28 (m, 3H), 2.10-1.91 (m, 5H), 1.82 (d, J= 12.0Hz, 2H), 1.72-1.59 (m, 2H), 1.43 (d, J= 6.8Hz, 6H), 1.10 (d, J= 6.8Hz, 3H).
Figure imgf000069_0001
(46 -4-methyl- 1 -\(7- {4-[6-(propan-2-yl)pyridazin-3-yllphenoxy| -2-[ 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-yllquinoxalin-6-yl)methyllpyrrolidin-2-one
Step A: fert-butyl (3-[(4-methyl-2-oxopyrrolidin-l-yl)^
yllphenoxy I phenyDcarbamate
To a solution of 3-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-4-{4-[6-(propan-2- yl)pyridazin-3-yl]phenoxy} benzoic acid (1.3 g, 2.92 mmol) in tert- uOH (26 mL) under N2 atmosphere was added DPPA (0.95 mL, 4.38 mmol) and Et3N (1.2 mL, 8.76 mmol). The mixture was stirred at 30 °C for 4 h, then stirred at 60 °C for 1 h, and at 90 °C overnight. The reaction mixture was concentrated, the residue diluted with EtOAc (50 mL), washed with aqueous NaHC03 (40 mL) and saturated aqueous sodium chloride (40 mL), dried over Na2S04, and concentrated. The residue was purified by column chromatography (Si02, PE:EtOAc, 1 : 1 to EtOAc) to give the racemic title compound as a brown oil. 1H NMR (CD3OD, 400MHz): δ 8.03 (d, J= 8.8Hz, 2H), 7.74 (d, J= 8.8Hz, 1H), 7.51-7.47 (m, 1H), 7.39 (d, J= 8.8Hz, 1H), 7.23 (s, 1H), 7.01-6.98 (m, 3H), 6.59 (s, 1H), 4.48 (d, J= 14.8Hz, 1H), 4.40 (d, J= 14.8Hz, 1H), 3.42- 3.34 (m, 2H), 2.86 (dd, J= 6.0Hz, 9.6Hz, 1H), 2.48-2.44 (m, 1H), 2.41-2.28 (m, 1H), 1.98-1.90 (m, 1H), 1.52 (s, 9H), 1.41 (d, J= 7.2Hz, 6H), 1.05 (d, J= 6.8Hz, 3H).
Step B: l-(5-amino-2-{4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyl)-4-methylpyrroli one
A solution of tert-butyl (3-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-4-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}phenyl)carbamate (900 mg, 1.74 mmol) in HCl/MeOH (15 mL, 4N) was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was diluted with H20 (30 mL), basified with aqueous NaHC03 (10 mL), and extracted with DCM (30 mL x 3). The combined organic phase was dried over Na2S04 and concentrated to give the racemic title compound as a brown oil. 1H NMR (CD3OD, 400MHz): δ 8.01 (d, J = 8.8Hz, 2H), 7.72 (d, J= 8.8Hz, 1H), 7.37 (d, J= 8.8Hz, 1H), 6.96 (d, J= 8.8Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.67-6.64 (m, 2H), 4.39 (d, J= 14.8Hz, 1H), 4.30 (d, J= 14.4Hz, 1H), 3.39-3.30 (m, 2H), 2.83 (dd, J= 6.4Hz, 9.6Hz, 1H), 2.47-2.43 (m, 1H), 2.35-2.27 (m, 1H), 1.94 (dd, J= 7.2Hz, 9.2Hz, 1H), 1.40 (d, J= 13.2Hz, 6H), 1.03 (d, J= 10.8Hz, 3H).
Step C : N-(3-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-4- {4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I phenyDacetamide
To a solution of l-(5-amino-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (450 mg, 1.08 mmol) and Et3N (450 mL, 3.24 mmol) in DCM (20 mL) at 0 °C was added AcCl (127 mg, 1.62 mmol). The reaction mixture was stirred at 10 °C for 2 h. The reaction mixture was diluted with H20 (30 mL) and extracted with DCM (30 mL x 2). The combined organic phases were dried over Na2S04 and
concentrated. The residue was purified by column chromatography (Si02, PE:EtOAc, 20: 1 to 1 : 1) to give the racemic title compound as a brown solid. MS (ESI) m/z: 459.0 [M+l]+; 1H NMR (400 MHz, CDC13): δ 8.04 (d, J= 8.8Hz, 2H), 7.75 (d, J= 8.8Hz, 1H), 7.67-7.64 (m, 1H), 7.54 (s, 1H), 7.40 (d, J= 8.8Hz, 1H), 7.33 (d, J= 2.8Hz, 1H), 7.05-6.96 (m, 3H), 4.53-4.37 (m, 2H), 3.47-3.43 (m, 1H), 3.40-3.28 (m, 1H), 2.97-2.85 (m, 1H), 2.52-2.49 (m, 1H), 2.45-2.32 (m, 1H), 2.16 (s, 3H), 2.03-1.98 (m, 1H), 1.41 (d, J= 7.2Hz, 6H), 1.07 (d, J= 7.2Hz, 3H). Step D : N-(5-[(4-methyl-2-oxopyrrolidin- 1 -yl)methyl]-2-nmO-4- {4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I phenyDacetamide
To a solution of N-(3-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-4-{4-[6-(propan- 2-yl)pyridazin-3-yl]phenoxy}phenyl)acetamide (350 mg, 0.76 mmol) in AcOH (5 mL) at 0 °C was added fuming HNO3 (96 mg, 1.53 mmol). The reaction mixture was stirred 0 °C for 10 mm and then cone. H2SO4 (149 mg, 1.53 mmol) was added. The reaction mixture was stirred at 10 °C for 4 h. The reaction mixture was quenched with saturated aqueous NaHC03 (til pH ~7) and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2S04 and concentrated to give the racemic title compound as a yellow solid. MS (ESI) m/z: 503.9 [M+l]+; 1H NMR (400 MHz, CD3OD): δ 8.14 (d, J= 9.2Hz, 2H), 8.10 (d, J= 8.8Hz, 1H), 8.05 (s, 1H), 7.72 (d, J= 8.8 Hz, 1H), 7.67 (s, 1H), 7.22 (d, J= 8.8Hz, 2H), 4.65-4.53 (m, 2H), 3.57-3.55 (m, 1H), 3.38-3.33 (m, 1H), 3.05-3.02 (m, 1H), 2.59-2.44 (m, 2H), 2.21 (s, 3H), 2.04-2.00 (m, 1H), 1.41 (d, J= 6.8Hz, 6H), 1.12 (d, J= 6.4 Hz, 3H). Step E: l-(5-amino-4-nitro-2-{4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyl)-4- methylpyrrolidin-2-one
To a solution of N-(5-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-2-nitro-4-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}phenyl)acetamide (320 mg, 0.635 mmol) in MeOH (10 mL) was added NaOH (500 mg, 12.50 mmol, in 5 mL of water). The reaction mixture was stirred at room temperature for 2 h, then diluted with water (20 mL), and extracted with DCM
(20 mL x 2). The combined organic phases were dried over Na2S04 and concentrated to give the racemic title compound as a yellow solid. MS (ESI) m/z: 462.0 [M+l]+; 1H NMR (400 MHz, CD3OD): δ 8.15-8.07 (m, 3H), 7.74 (s, 1H), 7.72 (d, J= 9.2Hz, 1H), 7.15-7.10 (m, 2H), 6.98 (s, 1H), 4.52-4.34 (m, 2H), 3.53-3.48 (m, 1H), 3.38-3.33 (m, 1H), 3.02-2.98 (m, 1H), 2.53-2.41 (m, 2H), 2.03-1.95 (m, 1H), 1.42 (d, J= 6.8Hz, 6H), 1.10 (d, J= 6.4 Hz, 3H).
Step F: 1 -(4,5-diamino-2- {4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyl)-4- methylpyrrolidin-2-one
A mixture of l-(5-amino-4-nitro-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (240 mg, 0.520 mmol) and Pd/C (10%, 90 MeOH (10 mL) was stirred at 10 C under H2 atmosphere (15 psi) for 10 h. The reaction mixture was filtered and the filtrate concentrated to give the racemic title compound as a yellow solid. MS (ESI) m/z: 431.9 [M+l]+; 1H NMR (400 MHz, CDC13): δ 8.03-7.99 (m, 2H), 7.75-7.71 (m, 1H), 7.40-7.36 (m, 1H), 7.02-6.97 (m, 2H), 6.76 (s, 1H), 6.45 (s, 1H), 4.36-4.23 (m, 2H), 3.38- 3.30 (m, 2H), 2.84-2.80 (m, 1H), 2.48-2.44 (m, 1H), 2.37-2.23 (m, 1H), 1.94-1.90 (m, 1H), 1.41 (d, J= 7.2 Hz, 6H), 1.10 (d, J = 6.8 Hz, 3H).
Step G: tert-butyl 4-(6-[(4-methyl-2-oxopyrrolidin-l-yl)methyll-7-(4-[6-(propan-2-yl)pyridazin- 3-yllphenoxy|quinoxalin-2-yl)piperidine-l-carboxylate
To a suspension of tert-bvXy\ 4-(bromoacetyl)piperidine-l-carboxylate (125 mg,
0.408 mmol), TBAB (0.05 mmol), and K2C03 (2.0 mmol) in water (10 mL) and MeOH (5 mL) was added 1 -(4,5-diamino-2- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy}benzyl)-4- methylpyrrolidin-2-one (160 mg, 0.371 mmol) at room temperature. The reaction mixture was heated at 70 °C for 8 h. The reaction mixture was then diluted with water (10 mL) and extracted with CH2C12 (20 mL x 3). The combined organic phases were washed with water (20 mL x 2), dried over Na2S04, and concentrated. The residue was purified by preparative TLC (DCM: MeOH, 20: 1) to give the racemic title compound as a yellow solid. MS (ESI) m/z: 637.5 [M+l]+; 1H NMR (400 MHz, CDC13): δ 8.66 (s, 1H), 8.16 (d, J= 8.8 Hz, 2H), 7.92 (s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.43 (d, J= 8.8Hz, 1H), 7.34 (s, 1H), 7.24 (d, J= 8.8 Hz, 2H), 4.87-4.73 (m, 2H), 4.32-4.25 (m, 2H), 3.60-3.57 (m, 1H), 3.37-3.34 (m, 1H), 3.13-3.01 (m, 2H), 2.90-2.85 (m, 2H), 2.68-2.60 (m, 1H), 2.58-2.47 (m, 1H), 2.14-2.11 (m, 1H), 2.95-1.82 (m, 4H), 1.45 (s, 9H), 1.43 (d, J= 6.4Hz, 6H), 1.15 (d, J= 6.8 Hz, 3H).
Step H: (AS and 4i?)-4-methyl-l-{[2-(piperidin-4-yl)-7-(4-[6-(propan-2-yl)pyridazin-3- yllphenoxy|quinoxalin-6-yllmethyl|pyrrolidin-2-one
A solution of tert-butyl 4-(6-[(4-methyl-2-oxopyrrolidin-l-yl)methyl]-7-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}quinoxalin-2-yl)piperidine-l-carboxylate (110 mg, 0.173 mmol) in HCl-EtOAc (4N, 5 mL) was stirred at room temperature for 1 h and then concentrated to give the title compound as a white solid. MS (ESI) m/z: 537.4 [M+l]+; 1H NMR (400 MHz, CD3OD): δ 9.01 (d, J= 9.2 Hz, 1H), 8.88 (s, 1H), 8.63 (d, J= 9.6 Hz, 1H), 8.32 (d, J= 8.8 Hz, 2H), 8.08 (s, 1H), 7.50 (s, 1H), 7.43 (d, J= 8.8 Hz, 2H), 4.86-4.73 (m, 2H), 3.68-3.61 (m, 2H), 3.58-3.54 (m, 2H), 3.49-3.38 (m, 1H), 3.29-3.19 (m, 2H), 3.11-3.09 (m, 1H), 2.63-2.47 (m, 2H), 2.32-2.04 (m, 5H), 1.55 (d, J= 6.8 Hz, 6H), 1.14 (d, J= 6.4 Hz, 3H). Step I: (46 -4-methyl- 1 -\(7- {4-[6-(propan-2-yl)pyridazin-3-yllphenoxy| -2-[l -(tetrahydro-2H- pyran-4-yl)piperidin-4-yllquinoxalin-6-yl)methyllpyrrolidin-2-one
A mixture of (4S and 4i?)-4-methyl-l-{[2-(piperidin-4-yl)-7-{4-[6-(propan-2- yl)pyridazin-3-yl]phenoxy}quinoxalin-6-yl]methyl}pyrrolidin-2-one (110 mg, 0.192 mmol), Et3N (58.3 mg, 0.576 mmol), tetrahydro-4H-pyran-4-one (38.4 mg, 0.384 mmol), and AcOH (0.016 ml, 0.288 mmol) in THF (10 mL) was stirred at 20 °C for 2 h and then NaBH(OAc)3 (122 mg, 0.576 mmol) was added. The reaction mixture was stirred at 60 °C for 48 h, then quenched with aqueous NaHC03 (10 mL), and extracted with DCM (10 mL x 2). The combined organic phases were concentrated and the residue purified by preparative HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% NH4OH) to give the racemic title compound as colorless oil. The racemate was resolved by SFC (Chiralpak AD-3, isopropanol:C02 (containing 0.05%> DEA), 40:60) to give the title compound as the second eluting peak and as a yellow solid. MS (ESI) m/z: 621.3 [M+l]+; 1H NMR (400 MHz, CD3OD): δ 8.77 (d, J= 12.4Hz 1H), 8.20 (d, J= 8.8Hz, 2H), 8.13 (d, J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.38-7.35 (m, 3H), 4.84- 4.75 (m, 2H), 4.03-3.93 (m, 2H), 3.65-3.62 (m, 1H), 3.48-3.36 (m, 3H), 3.28-3.08 (m, 3H), 3.00- 2.94 (m, 1H), 2.66-2.48 (m, 3H), 2.39-2.34 (m, 1H), 2.13-1.91 (m, 6H), 1.86-1.82 (m, 2H), 1.67- 1.47 (m, 2H), 1.42 (d, J = 7.2 Hz, 6H), 1.14 (d, J = 6.4 Hz, 3H).
Figure imgf000073_0001
(4S)-4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy| -3-[ 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-yllisoquinolin-7-yl)methyllpyrrolidin-2-one
Step A: (4S)- 1 -(5-bromo-2- {4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyl)-4- methylpyrrolidin-2-one
To a solution of (45)-l-(4-amino-5-bromo-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (280 mg, 0.57 mmol) in DMF (3 mL) was added tert-butyl nitrite (87.4 mg, 0.85 mmol). The reaction was stirred at 75 °C overnight, then diluted with water (5 mL), and extracted with EtOAc (3 mL x 3). The combined organic phases were dried over Na2S04 and concentrated to give the title compound as a yellow solid. MS (ESI) m/z 480.0 [M+l]+; 1H NMR (CDC13, 400 MHz): δ 8.07 (d, J= 8.8 Hz, 2H), 7.75 (d, J= 8.4 Hz, 1H), 7.47-7.39 (m, 3H), 7.04 (d, J= 8.8 Hz, 2H), 6.97 (d, J= 8.8 Hz, 1H), 4.53 (d, J= 14.8 Hz, 1H), 4.43 (d, J= 15.2 Hz, 1H), 3.36-3.31 (m, 2H), 2.91-2.89 (m, 1H), 2.54-2.50 (m, 1H), 2.49-2.47 (m, 1H), 2.00 (dd, J= 7.2, 16.4 Hz, 1H), 1.41 (d, J= 6.8 Hz, 6H), 1.08 (d, J= 6.8 Hz, 3H).
Step B : 3- ([(45V4-methyl-2-oxopyrrolidin- 1 -yl]methyl| -4- {4-[6-(propan-2-yl)pyridazin-3- yllphenoxylbenzonitrile
To a solution of (45)-l-(5-bromo-2-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}benzyl)-4-methylpyrrolidin-2-one (220 mg, 0.46 mmol), Zn (59.6 mg, 0.91 mmol), and Zn(CN)2 (107 mg, 0.91 mmol) in DMA (3 mL) was added Pd2(dba)3 (42 mg, 0.046 mmol) and dppf (25.3 mg, 0.046 mmol). The reaction mxiture was heated at 180 °C in a microwave reactor for 30 min. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over Na2S04, concentrated, and purified by preparative TLC (EtOAc) to give the title compound as a yellow solid. MS (ESI) m/z: 449.0 [M+23]+; 1H NMR (CDCI3, 400 MHz): δ 8.13 (d, J= 8.8 Hz, 2H), 7.78 (d, J= 8.8 Hz, 1H), 7.60 (d, J= 1.6Hz, 1H), 7.51 (d, J= 8.4Hz, 1H), 7.43 (d, J = 8.8Hz, 1H), 7.14 (d, J= 8.8Hz, 2H), 6.93 (d, J= 8.8Hz, 1H), 4.63 (d, J= 15.6Hz, 1H), 4.54 (d, J = 15.6Hz, 1H), 3.51-3.35 (m, 2H), 3.01-2.98 (m, 1H), 2.62-2.57 (m, 2H), 2.11-2.08 (m, 1H), 1.42 (d, J= 6.8Hz, 6H), 1.13(d, J= 6.8Hz, 3H). Step C: (4S)-l -[5-(aminomethyl)-2-{4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|benzyll-4- methylpyrrolidin-2-one
To a solution of 3- {[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl} -4-{4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}benzonitrile (0.15 g, 0.352 mmol) in MeOH (15 mL) was added NH3-H2O (0.1 mL) and Raney Ni (0.1 g). The reaction mixture was stirred under H2 atmosphere (15 psi) at room temperature for 5 h. The reaction mixture was then filtered and concentrated to give the title compound as a yellow oil. MS (ESI) m/z: 431.0 [M+l]+; 1H NMR (CD3OD, 400 MHz): δ 8.10-8.08 (m, 3H), 7.73-7.70 (m, 1H), 7.49-7.45 (m, 2H), 7.12-7.07 (m, 3H), 4.60 (d, J = 14.4Hz, 1H), 4.50 (d, J = 14.4Hz, 1H), 4.14 (s, 1H), 3.55-3.50 (m, 2H), 3.05- 2.99 (m, 2H), 2.48-2.44 (m, 2H), 1.99-1.95 (m, 1H), 1.40 (d, J = 7.2Hz, 6H), 1.05 (d, J = 6.0Hz, 3H).
Step D : 2,2-diethoxy-N-(3 - ( [(45V4-methyl-2-oxopyrrolidin- 1 -yllmethyll -4- (4-[6-(propan-2- yl)pyridazin-3-yllphenoxy|benzyl)acetamide
To the solution of diethoxyacetic acid (96 mg, 0.65 mmol) in DMF (7 mL) was added TEA (0.18 mL, 1.3 mmol), EDC (125 mg, 0.65 mmol), HOBt (88 mg, 0.65 mmol) and (4iS)- 1 -[5-(aminomethyl)-2- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy}benzyl]-4- methylpyrrolidin-2-one (0.14 g, 0.33 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (12 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water (10 mL x 2), dried over Na2S04, concentrated, and purified by preparative TLC (DCM:MeOH, 10: 1) to give the title compound as a yellow oil. MS (ESI) m/z: 561.1 [M+l]+; 1H NMR (CDCI3, 400 MHz): δ 8.05-8.03 (m, 2H), 7.74 (d, J = 8.8Hz, 1H), 7.38 (d, J= 8.8Hz, 1H), 7.25-7.21 (m, 2H), 7.03-6.94 (m, 4H), 4.84 (s, 1H), 4.50-4.44 (m, 3H), 3.71-3.61 (m, 4H), 3.39-3.37 (m, 2H), 2.80-2.84 (m, 1H), 2.52-2.50 (m, 1H), 2.49-2.45 (m, 1H), 1.98-1.94 (m, 1H), 1.40 (d, J = 6.8Hz, 6H), 1.24 (t, J = 7.2Hz, 6H), 1.05 (d, J = 6.8Hz, 3H).
Step E: (46 -l-[(3-hydroxy-6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy|isoquinolin-7- yl)methyll-4-methylpyrrolidin-2-one A solution of 2,2-diethoxy-N-(3-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-4- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy}benzyl)acetamide (70 mg, 0.125 mmol) in cone. H2SO4 (1 mL) was stirred at room temperature under N2 atmosphere for 40 h. The reaction mixture was poured into ice water (4 mL) and basified with NaOH (aq, 2N) til pH ~ 8. The resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (4 mL), dried over Na2S04, and concentrated. The residue was purified by preparative TLC (DCM:MeOH, 10: 1) to give the title compound as a yellow solid. MS (ESI) m/z: 469.4 [M+l]+; 1H NMR (CD3OD, 400 MHz): δ 8.56 (s, 1H), 8.20 (d, J= 8.8Hz, 2H), 8.13 (d, J= 9.2Hz, 1H), 7.78 - 7.71 (m, 2H), 7.32 (d, J= 8.8Hz, 2H), 6.77 (s, 1H), 6.59 (s, 1H), 4.66 (d, J= 15.2Hz, 1H), 4.62 (d, J= 15.2Hz, 1H), 3.65-3.59 (m, 1H), 3.40 - 3.32 (m, 1H), 3.09-3.05 (m, 1H), 2.61-2.44 (m, 2H), 2.06 (dd, J = 6.4Hz, 15.6Hz, 1H), 1.42 (d, J = 6.8Hz, 6H), 1.12 (d, J = 6.8Hz, 3H).
Step F: 7-([(46 -4-methyl-2-oxopyrrolidin-l-yllmethyl|-6-(4-[6-(propan-2-yl)pyridazin-3- yllphenoxy I isoquinolin-3 -yl trifluoromethanesulfonate
To a solution of (45)-l-[(3-hydroxy-6-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}isoquinolin-7-yl)methyl]-4-methylpyrrolidin-2-one (50 mg, 0.107 mmol) in pyridine (2 mL) was added trifluoromethanesulfonic anhydride (134 mg, 0.427 mmol) dropwise at 0 °C. The mixture was stirred at 30 °C for 24 h, and then concentrated. The residue was purified by preparative TLC (EtOAc) to afford the title compound as a yellow solid. MS (ESI) m/z: 600.9 [M+l]+; 1H NMR (CDCI3, 300 MHz): δ 9.00 (s, 1H), 8.23 (d, J= 8.7Hz, 2H), 8.01 (s, 1H), 7.63 (d, J= 8.7Hz, 1H), 7.48 (d, J= 8.7Hz, 1H), 7.35-7.21 (m, 3H), 7.13 (s, 1H), 4.88-4.75 (m, 2H), 3.67-3.61 (m, 1H), 3.44-3.39 (m, 1H), 3.12-3.07 (m, 1H), 2.70-2.50 (m, 2H), 2.20-2.05 (m, 1H), 1.47 (d, J= 6.9Hz, 6H), 1.24 (t, J= 7.2Hz, 6H), 1.19 (d, J = 6.6Hz, 3H).
Step G: (46 -4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yl"|phenoxy| -3-[ 1 -(tetrahydro-2H- pyran-4-yD- 1 ,2,3 ,6-tetrahydropyridin-4-yllisoquinolin-7-yl)methyllpyrrolidin-2-one
A solution of 7-{[(45)-4-methyl-2-oxopyrrolidin-l-yl]methyl}-6-{4-[6-(propan-2- yl)pyridazin-3-yl]phenoxy} isoquinolin-3 -yl trifluoromethanesulfonate (50 mg, 0.083 mmol), 1- (tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l, 2,3,6- tetrahydropyridine (29.3 mg, 0.100 mmol), Pd(dppf)Cl2 (6.09 mg, 8.32 μηιοΐ), and Na2C03 (17.7 mg, 0.166 mmol) in DMF (2 mL) and water (0.6 mL) was stirred at 100 °C in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and purified by prep- HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% NH4OH) to afford the title compound as colorless oil. MS (ESI) m/z: 618.5 [M+l]+; 1H NMR (CD3OD, 400 MHz): δ 9.14 (s, 1H), 8.18 (d, J= 8.8Hz, 2H), 8.12 (d, J=9.2Hz, 1H), 8.04 (s, 1H), 7.74 (d, J= 8.8Hz, 1H), 7.57 (s, 1H), 7.32-7.28 (m, 3H), 6.85 (s, 1H), 4.79 (d, J =15.2Hz, 1H), 4.72 (d, J= 15.2Hz, 1H), 4.03-3.99 (m, 2H), 3.65-3.56 (m, 1H), 3.43-3.30 (m, 5H), 3.07-3.02 (m, 1H), 2.87-2.85 (m, 2H), 2.70-2.62 (m, 2H), 2.60-2.49 (m, 3H), 2.07-2.02 (m, 1H), 1.92-1.89 (m, 2H), 1.65-1.55 (m, 2H), 1.42 (d, J = 7.2Hz, 6H), 1.11 (d, J= 6.4Hz, 3H).
Step H: (46 -4-methyl- 1 -[(6- (4-[6-(propan-2-yl)pyridazin-3-yllphenoxy| -3-[ 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-yllisoquinolin-7-yl)methyllpyrrolidin-2-one
A mixture of compound (45)-4-methyl-l-[(6-{4-[6-(propan-2-yl)pyridazin-3- yl]phenoxy}-3-[l-(tetrahydro-2H-pyran-4-yl)-l,2,3,6-tetrahydropyridin-4-yl]isoquinolin-7- yl)methyl]pyrrolidin-2-one (10 mg, 0.016 mmol) and Pd/C (10%, 10 mg) in MeOH (5 mL) was stirred under H2 atmosphere (15 psi) at room temperature for 16 h. The reaction mixture was then filtered. The filtrate was concentrated and the residue purified by preparative HPLC (C-18, 95→ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) to afford the title compound as a yellow oil. MS (ESI) m/z: 620.5 [M+l]+; 1H NMR (CD3OD, 400 MHz): δ 9.42 (s, 1H), 8.27-8.21 (m, 3H), 7.89-7.82 (m, 2H), 7.39 (d, J= 8.4Hz, 2H), 7.34 (s, 1H), 7.21-7.14 (m, 1H), 4.80-4.76 (m, 2H), 4.10-4.08 (m, 2H), 3.75-3.60 (m, 4H), 3.50-3.45 (m, 4H), 3.30-3.13 (m, 3H), 2.65-2.50 (m, 3H), 2.15-2.05 (m, 5H), 1.85-1.75 (m, 2H), 1.44 (d, J= 6.4Hz, 6H), 1.15 (d, J= 6.8Hz, 3H).
EXAMPLE 6
Figure imgf000078_0001
2-(l -cyclopropyl-5-oxopyrrolidin-3-yl)-6- {[(4S)-4-methyl-2-oxopyrroridin- 1 -yl]methyl| -7- (4- [6-(propan-2-yl)pyridazin-3 -yllphenoxy I -3 ,4-dihydroisoquinolin- 1 (2H)-one (isomer 1 ) Step A: (S)-methyl 2-allyl-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin- 1 -yl)methyl)benzoate
The mixture of (S)-methyl 2-bromo-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4- ((4-methyl-2-oxopyrrolidin-l-yl)methyl)benzoate (250 mg, 0.464 mmol),
tetrakis(triphenylphosphine)palladium(0) (53.7 mg, 0.046 mmol), lithium chloride (59.1 mg, 1.393 mmol), allyltributyltin (0.172 mL, 0.557 mmol) and 2,6-di-tert-butyl-4-methylphenol (1.023 mg, 4.64 μιηοΐ) in dioxane (3.5 mL) was degassed with vacuum/N2 exchanged 4 times. The resultant mixture was allowed to stir at 88 °C for 14 h. The reaction mixture was directly purified by silica gel column chromatography, eluting with EtOAc/isohexane (0%-60%) to give the title compound. MS m/z: 500.2 [M+l]+.
Step B: (S)-methyl 5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2-oxopyrrolidin-l- yl)methyl)-2-(2-oxoethyl)benzoate
Sodium periodate (128 mg, 0.600 mmol) was added to a stirred, room temperature mixture of (S)-methyl 2-allyl-5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)benzoate (100 mg, 0.200 mmol) and osmium tetroxide in t-BuOH (2.5%) (0.126 mL, 10.01 μιηοΐ) in tetrahydrofuran (2.0 mL) and water (2.0 mL). The reaction mixture was allowed to stir at room temperature for 14 h. Saturated aqueous sodium thiosulfate (3.0 mL) and saturated aqueous sodium hydrogen carbonate (3.0 mL) were added and the mixture was stirred at room temperature for 10 min. The resultant mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (10 mL), dried (MgS04), filtered, and the solvent was evaporated under reduced pressure to give the title compound. MS m/z: 502.2 [M+l]+. Step C: 2-(l-cyclopropyl-5-oxopyrrolidin-3-yl)-7-(4-(6-isopropylpyridazin-3-yl)phenoxy)-6- (((S)-4-methyl-2-oxopyrrolidin- 1 -yl)methyl)-3 ,4-dihydroisoquinolin- 1 (2H)-one (isomer 1 )
4-Amino-l-cyclopropylpyrrolidin-2-one hydrochloride (0.061 g, 0.348 mmol) was added to a solution of (S)-methyl 5-(4-(6-isopropylpyridazin-3-yl)phenoxy)-4-((4-methyl-2- oxopyrrolidin-l-yl)methyl)-2-(2-oxoethyl)benzoate (0.166 g, 0.331 mmol) in dichloromethane (3.31 ml) and the mixture was allowed to stir at room temperature for 10 min. Sodium
triacetoxyborohydride (0.281 g, 1.324 mmol) was added. The mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with ethyl acacate, washed with aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride, dried (MgS04), filtered, and concentrated. Purification by column chromatography on silica gel, eluting with 0- 5% MeOH (2% NH3) in CH2C12 gave a mixture of diastereomers. LCMS m/z: 594.2 [M+l]+. The isomers were resolved by chiral SFC (OD-H column, 30% EtOH:MeCN (2: 1, containing 0.1% NH4OH)/C02 to give the title compound (first eluting peak, isomer 1). LCMS m/z: 594.2 [M+l]+ ; 1H NMR (500 MHz, CDC13) δ 8.07 (δ, J = 6.8Hz, 2H), 7.75 (d, J = 8.8Hz, 1H), 7.69 (s, 1H), 7.41 (d, J = 8.8Hz, 1H), 7.21 (s, 1H) , 7.06 (d, J = 8.7Hz, 2H), 5.45 (m, 1H), 4.53 (dd, J = 45.9, 13.2Hz, 2H), 3.68(m, 1H), 3.50 - 3.43 (m, 3H), 3.35 (m, 1H), 3.26 (dd, J = 10.7, 4.2Hz,
1H), 2.98 (m, 2H), 2.93 (m, 1H), 2.78 (dd, J = 17.7, 9.5Hz, 1H), 2.69 (m, 1H), 2.55(dd, J = 16.6, 8.6Hz, 1H), 2.48 (dd, J = 17.7, 5.1Hz, 1H), 2.41 (m, 1H), 2.02 (dd, J = 16.5, 6.9Hz, 1H), 1.42 (d, J = 6.8Hz, 6H), 1.08 (d, J = 6.8 Hz, 3H), 0.81 (m, 2H), 0.71(m, 2H). The examples appearing in the following tables were prepared by analogy to the above examples, as described or prepared as a result of similar transformations with
modifications known to those skilled in the art. The requisite starting materials were described herein, commercially available, known in the literature, or readily synthesized by one skilled in the art. Straight forward protecting group strategies were applied in some routes. TABLE E-l
Figure imgf000080_0001
Figure imgf000081_0001
2(lH)-one
Figure imgf000082_0001
2(lH)-one
Figure imgf000083_0001
Figure imgf000084_0001
2(lH)-one
Figure imgf000085_0001
2-one
Figure imgf000086_0001
methylpyrrolidin-2-one
Figure imgf000087_0001
yl)methyl]pyrrolidin-2- one
(4S)-l-[(2-{[(35,4R and
3R,4S)-3-fluoro-l- (tetrahydro-2H-pyran-4- yl)piperidin-4- yl]amino}-7-{4-[6-(l- 653.5 2 methylethyl)pyridazin-
Figure imgf000088_0001
3 -yl]phenoxy } quinolin-
6-yl)methyl]-4- methylpyrrolidin-2-one
(4S)-4-methyl-l-[(7-{4- [6-(l- methylethyl)pyridazin- O N N J 3-yl]phenoxy}-2-[4-(l- methylpiperidin-4- 634.6 1 yl)piperazin-l- yl]quinolin-6- yl)methyl]pyrrolidin-2- one
(4S)-4-methyl-l-{[7-{4- [6-(l- methylethyl)pyridazin- 3-yl]phenoxy}-2-[(3S
and 3R)-3- 552.4 2 methylmorpholin-4- yl]quinolin-6- yl]methyl}pyrrolidin-2- one
0 (4S)-4-methyl-l-[(7-{4- [6-(l- 0 N N J methylethyl)pyridazin-
3 -yl]phenoxy } -2- [4 - 615.5 1 (methylsulfonyl)piperazi
n- 1 -yl] quinolin-6- yl)methyl]pyrrolidin-2-
Figure imgf000089_0001
carboxylate (4S)-4-methyl-l-[(7-{4- [6-(l- methylethyl)pyridazin-
3 -yl]phenoxy } -2- [ 1 -
47 (tetrahydro-2H-pyran-4- 621.5 1 yl)piperidin-4- yl]quinoxalin-6- yl)methyl]pyrrolidin-2- one
(4S)-4-methyl-l-[(7-{4- [6-(l- methylethyl)pyridazin- 3-yl]phenoxy}-2-
48 piperidin-4- 537.4 1 ylquinoxalin-6- yl)methyl]pyrrolidin-2- one
(4S)-4-methyl-l-[(6-{4- [6-(l- methylethyl)pyridazin-
3 -yl]phenoxy } -3 - [ 1 - (tetrahydro-2H-pyran-4-
49 yl)-l,2,3,6- 618.5 1 tetrahydropyridin-4- yl]isoquinolin-7- yl)methyl]pyrrolidin-2- one
2-[(3S,4R)-3-fluoro-l- (tetrahydro-2H-pyran-4- yl)piperidin-4-yl]-7- {4- [6-(l- methylethyl)pyridazin-
50 656.7 1
3-yl]phenoxy}-6-{[(4S)- 4-methyl-2- oxopyrrolidin-1- yl]methyl}-3,4- dihydroisoquinolin-
Figure imgf000091_0001
Although specific enantiomers and diastereomers appear in the above Examples and Intermediates, it is well understood by those skilled in the art that modifications to reaction conditions and reagents (for example, but not limited to: using the opposite chirality for starting materials; different catalysts; using the opposite chirality for reagents; choosing to use a different enantiomer or diastereomer subsequent to a chiral resolution) will provide alternative enantiomers and diastereomers, all of which are included in the spirit and scope of the invention. It is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula
Figure imgf000093_0001
Figure imgf000093_0002
G1 is CR3 or N;
G^sCR1 orN;
G3 is CR~or ;
G4 is CR3or ;
G5 is CR3orN;
Yis O, CR5R6, NRbor SOm;
V is CR5R6, C=0, O, NRb or
E1 is N or CH; A1 is CHR6, C=0;
A2 is CR6R7, C=0 or NR4;
A3 is CR6R7, C=0, NR4, O or S;
A4 is a bond, CR6R7, O, S or NR4;
E2 is N or C;
A5 is CR6 or N;
A6 is CR7, C=0, N or NR4;
A7 is CR6, CR7, N, NR4 or C=0;
A8 is a bond, CR7, O, N or NR4;
Z1 is CRa;
Z2 is -N=, C=0, -CRa =, or C=NR4;
Z3 is -C= or N;
Z4 is -CRa=, -N=, or a bond;
Z5 is CRaRe, -CRa =, or a bond;
Z6 is CRaRe, -CRa =, or -N=;
Z7 is CRaRe;
W is
k) hydrogen,
1) Ci_6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo, R8, (C=0)OR5, OR4, (C=0)NRbRc, SOmRd and NRbRc,
m) OR4,
n) heterocyclyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, oxo, R 4 , R 8°, (Ci_6 alkyl)R 8°, OR 4", (C=0)OR 5J,
(C=0)R8, (C=0)NRbRc and SOmRd,
o) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R 4 , R 8 , (Ci_6 alkyl)R 8 , OR 4 , (C=0)OR5, (C=0)NRbRc and SOmRd, p) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R4, OR4, (Ci_6 alkyl)R8,
(C=0)OR5, (C=0)NRbRc and SOmRd, (C=0)R8,
q) C3_8 cycloalkyl, which is optionally substituted with one to three substituents
independently selected from the group consisting of halo, oxo, R 4 , R 8 , (Ci_6 alkyl)R 8°,
(C=0)OR5, OR4, (C=0)NRbRc and SOmRd;
r) (C=0)OR5,
s) (C=0)NRbRc,
t) NRbRc;
R1 is hydrogen, halo, Ci_6 alkyl, 0(Ci_6 alkyl) or NRbRc, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; R2 is
(o) hydrogen,
(p) halo,
(q) cyano,
(r) Ci_6 alkyl or C3_6 cycloalkyl, which may be optionally substituted with one to four
substituents independently selected from the group consisting of halo, hydroxyl, NRbRc and (C=0)NRbRc;
(s) 0(Ci_6 alkyl), which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;
(t) (C=0)NRbRc,
(u) (C=0)OR4,
(v) (C=0)OR8,
(w)(C=0)R8,
(x) NRbRc,
(y) SOmRd, (z) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R4, R8, OR4, NRbRc,
(C=0)NRbRc and SOmRd,
(aa) heterocyclyl, which optionally substituted with one to three substituents
independently selected from the group consisting of halo, hydroxyl, R4, R8, OR4, NRbRc,
(C=0)NRbRc and SOmRd, or
(bb) heteroaryl, which optionally substituted with one to three substituents
independently selected from the group consisting of halo, hydroxyl, cyano, R4, R8, OR4,
NRbRc, (C=0)NRbRc and SOmRd;
1 2
or R' and R" can be taken together with the carbon atom to which they are attached to form a C3_8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to two substituents independently selected from the group consisting of cyano, R4, R8, halo, oxo and OR4; R is hydrogen, halo, cyano or Ci_6 alkyl;
R4 is hydrogen or Ci_6 alkyl, wherein said alkyl group is optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, cyano, SOmRd, OR5, NRbRc, (C=0)NRbRc and R8;
R5 is hydrogen, Ci_6 alkyl, heterocyclyl or C3_8 cycloalkyl, which is optionally substituted with one to three halo;
R6 is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl or NRbRc; R7 is hydrogen, halo, hydroxyl, cyano, Ci_6 alkyl, 0(Ci_6 alkyl), NRbRc, C3_6 cycloalkyl, heterocyclyl, heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl groups are optionally substituted with one to three substituents independently selected
8 5 5
form the group consisting of halo, R , R and OR ; or R6 and R7 can be taken together with the carbon atom or atoms to which they are attached to form a C3_8 cycloalkyl, C3_8 cycloalkenyl, aryl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, R5, OR5, C3_6 cycloalkyl and heterocyclyl;
Q
R is phenyl, heteroaryl, heterocyclyl or C3_8 cycloalkyl, wherein said phenyl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, hydroxyl, cyano, R5, NRbRc, OR5 and SOmR9;
R9 is hydrogen, cyano, Ci_6 alkyl, C3_8 cycloalkyl, heterocyclyl, phenyl, heteroaryl or NR5RC, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and OR5; or two R4 groups, or an R4 and R8 group, can be taken together with the atom to which they are attached to form a C3_8 cycloalkyl, heteroaryl or heterocyclyl ring wherein said cycloalkyl, heteroaryl and heterocyclyl rings are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NRbRc, OR5, C3_6 cycloalkyl, and heterocyclyl wherein said alkyl, cycloalkyl and heterocyclyl rings are optionally substituted with one to four substituents independently selected from the group consisting of oxo, Ci_6 alkyl, halo and hydroxyl; Ra is selected from the group consisting of hydrogen, halo, cyano, Ci_6 alkyl and OR5, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; Rb is hydrogen, Ci_6 alkyl, (C=0)R9, SOmR9, C3-6 cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein said alkyl, phenyl, heteroaryl, and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of R9, halo, hydroxyl, OR5 and SOmR9;
Rc is hydrogen or Ci_6 alkyl, which is optionally substituted with one to three subsitituents independently selected from the group consisting of halo and OR5; or Rb and Rc can be taken together with the atom to which they are attached to form a heterocyclyl ring which is optionally substituted with one to three substituents independently selected from the group consisting of R5, halo, oxo, OR5 and heterocyclyl;
Rd is Ci_6 alkyl, C3_6 cycloalkyl and NRbRc;
Re is selected from the group consisting of hydrogen, Ci_6 alkyl, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl; m is an integer from zero to two;
or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 wherein G1 is CH; G4 is CH; G5 is CH; or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 2 wherein Z1 is CH; Z5 is CH; or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 3 wherein Y is O and V is CH2; or a pharmaceutically
acceptable salt thereof.
5. The compound of Claim 4 wherein Ra is selected from the group consisting of hydrogen and halo; or a pharmaceutically acceptable salt thereof.
6. The compound of Claim 5 wherein W is:
a) Ci_6 alkyl, which is optionally substituted with one to four substituents
8 5 independently selected from the group consisting of halo, oxo, R , (C=0)OR , OR4, (C=0)NRbRc, SOmRd and NRbRc,
b) heterocyclyl, which is optionally substituted with one to three substituents
4 8 independently selected from the group consisting of halo, oxo, R , R°, (Ci_6 alkyl)R8, OR4, (C=0)OR5, (C=0)R8, (C=0)NRbRc and SOmRd,
c) heteroaryl, which is optionally substituted with one to three substituents
independently selected from the group consisting of halo, oxo, Ci_6 alkyl, OR4, (Ci_6 alkyl)R8, (C=0)OR5, (C=0)NRbRc and SOmRd;
d) C3-8 cycloalkyl, which is optionally substituted with one to three substituents
4 8 independently selected from the group consisting of halo, oxo, R , R°, (Ci_6 alkyl)R8, (C=0)OR5, OR4, (C=0)NRbRc and SOmRd; or a pharmaceutically acceptable salt thereof.
7. The compound of Claim 6 wherein E 1 is N or E 2 is C or N; or a pharmaceutically
acceptable salt thereof.
8. The compound of Claim 7 wherein A1 is CH2 or A5 = CH; or a pharmaceutically
acceptable salt thereof.
9. The compound of Claim 8 wherein G is CH; or a pharmaceutically acceptable salt thereof.
10. The compound of Claim 9 wherein Z4 is CH; or a pharmaceutically acceptable salt thereof.
1 1. The compound of Claim 10 wherein W is:
a) heterocyclyl, which is optionally substituted with one to three substituents
4 8
independently selected from the group consisting of halo, oxo, R , R°, (Ci_6 alkyl)R8, OR4, (C=0)OR5, (C=0)R8, (C=0)NRbRc and SOmRd,
b) heteroaryl, which is optionally substituted with one to three substituents
independently selected from the group consisting of halo, oxo, Ci_6 alkyl, OR4, (Ci_6 alkyl)R8, (C=0)OR5, (C=0)NRbRc and SOmRd; or a pharmaceutically acceptable salt thereof.
1 2
12. The compound of Claim 1 1 wherein E is N or E is N; or a pharmaceutically acceptable salt thereof.
3 4 7 8
13. The compound of Claim 12 wherein A is CH2; A is a bond; or A is CH; A is CH; or a pharmaceutically acceptable salt thereof.
14. The compound of Claim 13 wherein R is heteroaryl, which is optionally substituted with one substituent selected from the group consisting of Ci_6 alkyl, heterocyclyl, and C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.
15. The compound of Claim 14 wherein W is heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, OR4, R4 and R8,or a pharmaceutically acceptable salt thereof.
16. The compound selected from
(4S or 4R)- 1 -cyclopropyl-4-(6- { [(45)-4-methyl-2-oxopyrrolidin- 1 -yl]methyl} -7- {4-[6- (propan-2-yl)pyridazin-3-yl]phenoxy}quinazolin-2-yl)pyrrolidin-2-one
(4S and 4R)- 1 -cyclopropyl-4-(6- { [(45)-4-methyl-2-oxopyrrolidin- 1 -yl]methyl} -7- {4-[5- (propan-2-yl)- 1 ,3 ,4-thiadiazol-2-yl]phenoxy } quinazolin-2-yl)pyrrolidin-2-one (4iS)-4-methyl- 1 -[(7- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy} -2-[ 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-yl]quinolin-6-yl)methyl]pyrrolidin-2-one
(4iS)-4-methyl- 1 -[(7- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy} -2-[ 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-yl]quinoxalin-6-yl)methyl]pyrrolidin-2-one
(45)-4-methyl- 1 -[(6- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy} -3-[ 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-yl]isoquinolin-7-yl)methyl]pyrrolidin-2-one
2-(l -cyclopropyl-5-oxopyrrolidin-3-yl)-6- {[(4S)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} -
7- {4-[6-(propan-2-yl)pyridazin-3-yl]phenoxy} -3,4-dihydroisoquinolin-l(2H)-one
(45)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[l -(tetrahydro-2H- pyran-4-yl)piperidin-4-yl]quinazolin-6-yl)methyl]pyrrolidin-2-one
(4S)- 1 - {[2-(l -cyclopentylpiperidin-4-yl)-7- {4-[5-(l -methylethyl)- 1 ,3,4-thiadiazol-2- yl]phenoxy} quinazolin-6-yl]methyl} -4-methylpyrrolidin-2-one
1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[ 1 -(tetrahydro-2H-pyran-4- yl)piperidin-4-yl]quinazolin-6-yl)methyl]pyridin-2(lH)-one
(4S and 4R)- 1 -cyclopropyl-4-(6- { [(45)-4-methyl-2-oxopyrrolidin- 1 -yl]methyl} -7-[4-(5- methyl-l ,3,4-thiadiazol-2-yl)phenoxy]quinazolin-2-yl)pyrrolidin-2-one
(3R or 3S,4R or 45)-l-cyclopropyl-3-methyl-4-(7- {4-[6-(l-methylethyl)pyridazin-3- yl]phenoxy} -6- { [(45)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} quinazolin-2-yl)pyrrolidin-
2-one
(45)-4-methyl- 1 -[(7- {4-[5-(l -methylethyl)- 1 ,3,4-thiadiazol-2-yl]phenoxy} -2-[ 1 -
(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]quinazolin-6-yl)methyl]pyrrolidin-2-one l-[(2-[l -(4,4-difluorocyclohexyl)piperidin-4-yl]-7-{4-[6-(l-methylethyl)pyridazin-3- yl]phenoxy}quinazolin-6-yl)methyl]pyridin-2(lH)-one
l- {[2-(l-cyclobutylpiperidin-4-yl)-7- {4-[6-(l -methylethyl)pyridazin-3- yl]phenoxy}quinazolin-6-yl]methyl}pyridin-2(lH)-one
1 - { [2-( 1 -cyclopentylpiperidin-4-yl)-7- {4- [6-( 1 -methylethyl)pyridazin-3 - yl]phenoxy}quinazolin-6-yl]methyl}pyridin-2(lH)-one
1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[l -(tetrahydro-2H-pyran-4- ylmethyl)piperidin-4-yl] quinazolin-6-yl)methyl]pyridin-2( 1 H)-one 1 - [(2- [ 1 -(cyclopropylmethyl)piperidin-4-yl] -7- {4- [6-( 1 -methylethyl)pyridazin-3- yl]phenoxy} quinazolin-6-yl)methyl]pyridin-2( 1 H)-one
(4R or 4S)- 1 -cyclopropyl-4-(7- {4-[6-( 1 -methylethyl)pyridazin-3-yl]phenoxy} -6- { [(4S)-4- methyl-2-oxopyrrolidin- 1 -yljmethyl} quinazolin-2-yl)pyrrolidin-2-one
1 - [(2- [ 1 -( 1 -methyl ethyl)piperidin-4-yl] -7- {4- [6-( 1 -methylethyl)pyridazin-3 - yl]phenoxy}quinazolin-6-yl)methyl]pyridin-2(lH)-one
1 - [(2- [ 1 -(2-methoxyethyl)piperidin-4-yl] -7- {4- [6-( 1 -methylethyl)pyridazin-3 - yl]phenoxy}quinazolin-6-yl)methyl]pyridin-2(lH)-one
1 - {[7- {4- [6-(l -methyl ethyl)pyridazin-3-yl]phenoxy} -2-(l -methylpiperidin-4- yl)quinazolin-6-yl]methyl}pyridin-2(lH)-one
1 -[(2-[l -(2-fluoroethyl)piperidin-4-yl]-7- {4-[6-(l -methylethyl)pyridazin-3- yl]phenoxy}quinazolin-6-yl)methyl]pyridin-2(lH)-one
1 - {[2-(l-ethylpiperidin-4-yl)-7-{4-[6-(l -methyl ethyl)pyridazin-3-yl]phenoxy}quinazolin- 6-yl]methyl}pyridin-2(l H)-one
1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[l -(2,2,2-trifluoroethyl)piperidin- 4-yl]quinazolin-6-yl)methyl]pyridin-2(lH)-one
(3R or 3S,4S or 4i?)-l-cyclopropyl-3-methyl-4-(7-{4-[6-(l -methyl ethyl)pyridazin-3- yl]phenoxy} -6- { [(45)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} quinazolin-2-yl)pyrrolidin-
2- one
1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-piperidin-4-ylquinazolin-6- yl)methyl]pyridin-2( 1 H)-one
(4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[(35 and 5R)- 1 - (tetrahydro-2H-pyran-4-yl)piperidin-3-yl]quinazolin-6-yl)methyl]pyrrolidin-2-one (4S)-4-methyl- 1 -[(7- {4-[5-(l -methylethyl)- 1 ,3,4-thiadiazol-2-yl]phenoxy} -2-[(3R and 35)-l-(2,2,2-trifluoroethyl)piperidin-3-yl]quinazolin-6-yl)methyl]pyrrolidin-2-one (4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-piperidin-4- ylquinazolin-6-yl)methyl]pyrrolidin-2-one
(45 .4.methyl-l-[(2-[(llS,45)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-{4-[6-(l- methylethyl)pyridazin-3-yl]phenoxy}quinolin-6-yl)methyl]pyrrolidin-2-one ( S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[3-
(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]quinolin-6- yl)methyl]pyrrolidin-2-one
(45)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[l -(tetrahydro-2H- pyran-4-yl)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]quinolin-6-yl)methyl]pyrrolidin-2-one (4S)-4-methyl- 1 - { [2-(4-methyl- 1 ,4-diazepan- 1 -yl)-7- {4-[6-(l -methylethyl)pyridazin-3- yl]phenoxy}quinolin-6-yl]methyl}pyrrolidin-2-one
(4S)- 1 - { [2-(3 ,5-dimethylpiperazin- 1 -yl)-7- {4-[6-(l -methylethyl)pyridazin-3- yl]phenoxy} quinolin-6-yl]methyl} -4-methylpyrrolidin-2-one
(45)-4-methyl- 1 - { [7- {4-[6-( 1 -methylethyl)pyridazin-3-yl]phenoxy} -2-[ 1 -(tetrahydro-2H- pyran-4-yl)piperidin-4-yl]-4-(trifluoromethyl)quinolin-6-yl]methyl}pyrrolidin-2-one (4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[4-(tetrahydro-2H- pyran-4-yl)piperazin- 1 -yl] quinolin-6-yl)methyl]pyrrolidin-2-one
(4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[(2R)-2-methyl-4- (tetrahydro-2H-pyran-4-yl)piperazin- 1 -yl] quinolin-6-yl)methyl]pyrrolidin-2-one
(4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[(25)-2-methyl-4- (tetrahydro-2H-pyran-4-yl)piperazin- 1 -yl] quinolin-6-yl)methyl]pyrrolidin-2-one
(4S)- 1 -[(2- { [(35,4R and 3i?,45)-3-fluoro- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4- yl]amino} -7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} quinolin-6-yl)methyl]-4- methylpyrrolidin-2-one
(4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[4-(l - methylpiperidin-4-yl)piperazin- 1 -yl] quinolin-6-yl)methyl]pyrrolidin-2-one
(4S)-4-methyl- 1 - {[7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[(35 and 3R)-3- methylmorpholin-4-yl]quinolin-6-yl]methyl}pyrrolidin-2-one
(4S)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[4- (methylsulfonyl)piperazin- 1 -yl] quinolin-6-yl)methyl]pyrrolidin-2-one
(4S)- 1 -[(2- {4-[(3R and 3S)- 1 , 1 -dioxidotetrahydrothiophen-3-yl]piperazin- 1 -yl} -7- {4-[6- ( 1 -methyl ethyl)pyridazin-3 -yl]phenoxy } quinolin-6-yl)methyl] -4-methylpyrrolidin-2-one (4S)-1 -[(2-[(3R and 35)-3-tert-butylpiperazin- 1 -yl]-7- {4-[6-(l -methylethyl)pyridazin-3- yl]phenoxy } quinolin-6-yl)methyl] -4-methylpyrrolidin-2-one (4S)- 1 -[(2- { [(35,4R and 3i?,4S)-3-fiuoro- 1 -(tetrahydro-2H-pyran-4-yl)piperidin-4- yljamino} -7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} quinolin-6-yl)methyl]-4- methylpyrrolidin-2-one
tert-butyl 4-(6- { [(45)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} -7- {4-[6-(l - methylethyl)pyridazin-3-yl]phenoxy}quinoxalin-2-yl)piperidine-l-carboxylate
(4iS)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-[l -(tetrahydro-2H pyran-4-yl)piperidin-4-yl]quinoxalin-6-yl)methyl]pyrrolidin-2-one
(4iS)-4-methyl- 1 -[(7- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -2-piperidin-4- ylquinoxalin-6-yl)methyl]pyrrolidin-2-one
(4iS)-4-methyl- 1 -[(6- {4-[6-(l -methylethyl)pyridazin-3-yl]phenoxy} -3-[l -(tetrahydro-2H pyran-4-yl)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]isoquinolin-7-yl)methyl]pyrrolidin-2-one
2-[(3S,4R)-3-fluoro-l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-7-{4-[6-(l- methylethyl)pyridazin-3-yl]phenoxy} -6- { [(4S)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} - 3 ,4-dihydroisoquinolin- 1 (2H)-one
2-(l-cyclopropyl-5-oxopyrrolidin-3-yl)-4-methyl-7-{4-[6-(l-methylethyl)pyridazin-3- yl]phenoxy} -6- { [(4S)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} -3 ,4-dihydroisoquinolin- l(2H)-one
2-(l-cyclopropyl-5-oxopyrrolidin-3-yl)-7-{4-[5-(l-methylethyl)-l,3,4-thiadiazol-2- yl]phenoxy} -6- { [(4S)-4-methyl-2-oxopyrrolidin- 1 -yljmethyl} -3 ,4-dihydroisoquinolin- l(2H)-one
2-(l-cyclopropyl-5-oxopyrrolidin-3-yl)-6-{4-[5-(l-methylethyl)-l,3,4-thiadiazol-2- yljphenoxy} -5- {[(4S)-4-methyl-2-oxopyrrolidin-l -yljmethyl} -2, 3-dihydro-lH-isoindol- 1-one
17. A pharmaceutical composition comprising a compound of any of claims 1 to 16, and a pharmaceutically acceptable carrier.
18. Use of a pharmaceutical composition of any of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a migraine.
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US11746103B2 (en) 2020-12-10 2023-09-05 Sumitomo Pharma Oncology, Inc. ALK-5 inhibitors and uses thereof
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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US11746103B2 (en) 2020-12-10 2023-09-05 Sumitomo Pharma Oncology, Inc. ALK-5 inhibitors and uses thereof
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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