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WO2016022644A1 - Heterocyclic cgrp receptor antagonists - Google Patents

Heterocyclic cgrp receptor antagonists Download PDF

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Publication number
WO2016022644A1
WO2016022644A1 PCT/US2015/043751 US2015043751W WO2016022644A1 WO 2016022644 A1 WO2016022644 A1 WO 2016022644A1 US 2015043751 W US2015043751 W US 2015043751W WO 2016022644 A1 WO2016022644 A1 WO 2016022644A1
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WIPO (PCT)
Prior art keywords
halo
group
optionally substituted
independently selected
cyano
Prior art date
Application number
PCT/US2015/043751
Other languages
French (fr)
Inventor
Ian M. Bell
Lianyun Zhao
Mark Fraley
Cheng Zhu
Tesfaye Biftu
Edward Joseph BRNARDIC
Cheng Wang
C. Blair Zartman
Steven Gallicchio
Diem Nguyen
Brendan CROWLEY
Craig Potteiger
Original Assignee
Merck Sharp & Dohme Corp.
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Publication date
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Publication of WO2016022644A1 publication Critical patent/WO2016022644A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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).
  • 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,
  • 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. Neurol. 23, 193-196).
  • 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, Austin Bioscience, 2000, 245-247).
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin Amylin
  • Adrenomedullin CGRP-Related Peptide
  • distention of dural blood vessels during migraine headache may sensitize trigeminal neurons.
  • Some of the associated symptoms of migraine, including extra-cranial 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 sens
  • CGRP receptor antagonists may make 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.
  • the present invention is directed to heterocyclic compounds which are potent antagonists of CGRP receptors and potentially useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine.
  • the invention is also directed to
  • 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.
  • A is benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, cinnolinyl, imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrimidyl, pyrrolopyridin
  • X is NR 9 , O, S(0) m , or CR 6 R 7 ;
  • G 1 ", "G 2 ", “ G 3 " and “G 4 " are independently: CR a ; or N;
  • “1” is: hydrogen; or Ci-6 alkyl, wherein said alkyl is optionally substituted with up to three substituents which are independently for each occurrence: halo; cyano; or hydroxy; or
  • Q is -NR e -, -0-, -N(R e )CR c R d - or -CR c R d -;
  • T 1 and T 2 are independently, for each occurrence: a bond; or -CR c R d -; R 1 , R 2 , R 3 , R 4 and R 5 are independently for each occurrence:
  • QL-6 alkyl optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR 8 ; -NR 11 R 12 ; -heterocyclyl; or -OR 10 ;
  • 0-Ci_6 alkyl optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR 8 ; -NR 11 R 12 ; or -heterocyclyl;
  • C 2 -6 alkenyl optionally substituted with up to three substitutents which are independently: halogen; -OH; -CN, or -NR R 12 -;
  • R 4 and R 5 together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and wherein said ring is optionally substituted with up to three substituents which are independently: (a) halo; (b) oxo; (c) phenyl; (d) OR 8 ; or (e) R 8 ;
  • R 6 and R 7 are independently for each occurrance:
  • Ci-6 alkyl which is optionally substituted with up to three substituents which are independently: halo; hydroxy; cyano; R 10 ; or NR U R 12 ; (e) OR ;
  • R 6 and R 7 together with the carbon atom(s) to which they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring;
  • R 8 is independently for each occurrence: hydrogen; Ci-6 alkyl; or C 3 _6 cycloalkyl, and when selected to be alkyl or cycloalkyl, said moiety is optionally substituted with up to three substituents which are independently: halo; cyano; C 3 _ 6 -cycloalkyl; phenyl; or hydroxy;
  • R 9 is independently for each occurrance:
  • R 9 and R a together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR 8 ; CN; or Ci_ 6 alkyl; (c) OR 8 ; (d) oxo; or (e) Ci_ 6 alkyl, which is optionally substituted with up to three halogen atoms; or
  • R 9 and R 1 together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR 8 ; CN; or Ci -6 alkyl; (c) OR 8 ; (d) oxo; or (e) Ci_ 6 alkyl, which is optionally substituted with up to three halogen atoms;
  • R 10 is: (i) heterocyclyl; (ii) C 3 - 6 cycloalkyl; (iii) aryl; or (iv) heteroaryl, wherein said heterocylyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with up to five substituents which are independently for each occurrence: (a) halo;
  • R 11 and R 12 are independently for each occurrence:
  • heterocyclyl optionally substituted with up to three substitutents which are independently for each occurrence: halo; cyano; OR 8 ; or R S;
  • halo; cyano; OR 8 ; or R 8 independently for each occurrence: halo; cyano; OR 8 ; or R 8 ; (g) phenyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR 8 ; or R 8 ; or
  • heteroaryl optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR 8 ; or R 8 ; or
  • R 11 and R 12 together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally when present, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionallysubstituted with up to four substituents which are independently:
  • Ci-6 alkyl which is optionally substituted with one to three halo;
  • R a is independently for each occurrence:
  • R b is independently for each occurrence:
  • Ci_6 alkyl optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR 8 ; NR R 12 ; R 10 or OR 10 ;
  • R c and R d are each independently for each occurrence:
  • Ci-6 alky optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR 8 ; or NR R 12 ;
  • R c and R d together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionally substituted with up to four substituents which are independently:
  • Ci-6 alkyl optionally substituted with up to three halogen substituents
  • R e is independently for each occurrence:
  • n is independently for each occurrence an integer from 0 to 2.
  • Another class of the invention is directed to compounds of the formula:
  • Another class of the invention is directed to compounds of the formula:
  • A is cinnolinyl, imidazopyridinyl, naphthyridinyl,
  • pyrazolopyridinyl pyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, quinazolinyl or quinolinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • A is imidazopyridinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • A is pyrazolopyridinyl, which is optionally substituted with 1 , R 2 , R 3 , R 4 and R 5 .
  • A is naphthyridinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • A is pyridinyl, which is optionally substituted with R 1 , R 2 , R 4 and R 5 .
  • A is quinolinyl, which is optionally substituted with R 1 , R 2 , R 3 , R 4 and R 5 .
  • X is NR 9 . In another class of the invention, X is 0.
  • G 1 is CR a . In another class of the invention, G 1 is N.
  • G 2 is CR a . In another class of the invention, G 2 is N.
  • G 3 is CR a . In another class of the invention, G 3 is N.
  • G 4 is CR a . In another class of the invention, G 4 is N.
  • B is a bond.
  • D 1 is CR 6 R 7
  • D 1 is CH 2 .
  • D 2 is a bond. In another class of the invention, D 2 is CR 6 R 7 .
  • D 3 is a bond. In another class of the invention, D 3 is CR 6 R 7 .
  • D 4 is CR 6 R 7
  • D 1 is CH 2 .
  • D 1 is OO.
  • D 5 is a bond. In another class of the invention, D 5 is CR 6 R 7 .
  • D 6 is a bond. In another class of the invention, D 6 is CR 6 R 7 .
  • Z is hydrogen
  • W and Z can be taken together with the carbon atom to which they are attached to form:
  • W and Z can be taken together
  • each X 2 is independently CR c R d . In another class of the invention, each X 2 is independently (OO).
  • each X 3 is independently CR b . In another class of the invention, each X 3 is independently N.
  • each X 4 is independently CR b . In another class of the invention, each X 4 is independently N.
  • each Y 1 is independently CR b . In another class of the invention, each Y 1 is independently N.
  • each Y 2 is independently CR b . In another class of the invention, each Y 2 is independently N.
  • each Y 3 is independently CR b . In another class of the invention, each Y 3 is independently N.
  • each Y 4 is independently CR b . In another class of the invention, each Y 4 is independently N.
  • each V 1 is independently CR b . In another class of the invention, each V 1 is independently N. In a class of the invention, each V 2 is independently CR b . In another class of the invention, each V 2 is independently N.
  • each V 3 is independently CR b . In another class of the invention, each V 3 is independently N. In a class of the invention, each V 4 is independently CR . In another class of the invention, each V 4 is independently N.
  • each U 1 is independently CR . In another class of the invention, each U 1 is independently N.
  • each U 2 is independently CR b . In another class of the invention, each U 2 is independently N.
  • each U 3 is independently CR b . In another class of the invention, each U 3 is independently N.
  • each U 4 is independently CR b . In another class of the invention, each U 4 is independently N. In a class of the invention, Q is NR e . In another class of the invention, Q is O.
  • Q is N(R e )CR c R d .
  • Q is CR c R d .
  • T 1 is a bond. In another class of the invention, T 1 is CR c R d .
  • T 2 is a bond. In another class of the invention, T 2 is CR c R d .
  • R 1 is selected from the group consisting of: (a) hydrogen,
  • Ci-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR n R 12 , heterocyclyl and OR 10 ;
  • OCi-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , N R N R 12 and heterocyclyl;
  • Rl is hydrogen
  • R 2 is selected from the group consisting of:
  • Ci_6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR R 12 , heterocyclyl and OR 10 ;
  • R 3 is selected from the group consisting of:
  • Ci-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR n R 12 , heterocyclyl and OR 10 ;
  • R3 is hydrogen
  • R 4 is selected from the group consisting of:
  • Ci-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR n R 12 , heterocyclyl and OR 10 ;
  • OCi-6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR R 12 and heterocyclyl;
  • R4 is methyl
  • R 5 is selected from the group consisting of:
  • Qt_ 6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR R 12 , heterocyclyl and OR 10 ;
  • OCi_6 alkyl which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR 1X R 12 and heterocyclyl;
  • R5 is methyl
  • R 6 is selected from the group consisting of:
  • R 7 is hydrogen
  • R 9 is hydrogen
  • R 11 is selected from the group consisting of
  • heterocyclyl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 ,
  • heteroaryl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 .
  • R is hydrogen.
  • R 12 is selected from the group consisting of
  • Nh heterocyclyl C 3 . 6 cycloalkyl, phenyl and heteroaryl
  • heterocyclyl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 ,
  • heteroaryl which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 8 and OR 8 .
  • each R a is independently selected from the group consisting of hydrogen, halo, cyano, Ci -6 alkyl, R 10 , OR 10 and OCi- 6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR 8 , NR u R 12 and R 10 .
  • R c is selected from the group consisting of
  • Ci-6 alkyl which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR 8 and NR R 12 ;
  • C 3- 6 cycloalkyl which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR 8 ,
  • R c is hydrogen
  • R d is selected from the group consisting of
  • Ci-6 alkyl which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR 8 and NR U R 12 ;
  • OCi_6 alkyl which is optionally substituted with one to five substitutents independently sseelleecctteedd ffrrom the group consisting of halo, cyano, OR and NR R , and
  • R d is hydrogen
  • R e is hydrogen
  • Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 407, 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
  • 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, 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.
  • 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
  • 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 (1H) and deuterium (2H).
  • 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.
  • variable e.g. b, etc.
  • 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
  • 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.
  • 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.
  • alkyl is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds.
  • Cone to fouralkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that Cl-4alkyl 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 aikyl, 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.
  • 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 0, N and S.
  • 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, pyrimidinyl, pyrrolyl, quinazoliny
  • benzothiazolyl benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.
  • 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.
  • the heteroaryl contains nitrogen atoms, it is understood that the corresponding l ⁇ l-oxides thereof are also encompassed by this definition.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10- membered nonaromatic ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of 0, N, S, SO, or S0 2 and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetra hydro pyranyl, dihydropiperidinyl,
  • heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also emcompassed by this definition.
  • 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
  • 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
  • salts derived from inorganic acids include 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, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base. 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.
  • 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 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.
  • 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 anti- migraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HTI B /ID 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 antiinflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenopro
  • 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 NMDA 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 2 receptor
  • an interleukin inhibitor such as an
  • 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.
  • a GABA A receptor modulator for example acamprosate calcium
  • 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- -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,
  • 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
  • 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
  • botulinum toxin type A or B an anticonvulsant such as topiramate, zonisamide, ton
  • 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 nonsedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine,
  • a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propy
  • 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.
  • 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, zolmitrip
  • 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 (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.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, buccal or topical routes of administration
  • nasal, vaginal, rectal, sublingual, buccal or topical routes of administration 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.
  • 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 monoo
  • 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.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • 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.
  • 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.
  • 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.
  • membranes 25 pg were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgCI 2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 12S 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% polyethyieneimine for 3 h. The filters were washed three times with ice-cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCI 2 ), then the plates were air dried.
  • binding buffer 10 mM HEPES, pH 7.4, 5 mM MgCI 2 and 0.2% bovine serum albumin (BSA)
  • BSA bovine serum albumin
  • RECOMBINANT RECEPTOR Human CL receptor (Genbank accession number L76380) was subcloned into the expression vector plREShyg2 (BD Biosciences Clontech) as a 5'Nhel and 3' Pmel fragment. Human RAMP1 (Genbank accession number AJ001014) was subcloned into the expression vector plRESpuro2 (BD Biosciences Clontech) as a 5'Nhel and 3'Notl fragment.
  • HEK 293 cells human embryonic kidney cells; ATCC #CRL-1573
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • penicillin 100 ⁇ g/mL streptomycin
  • Stable cell line generation was accomplished by co-transfecting 10 g of DNA with 30 ⁇ g Lipofectamine 2000 (Invitrogen) in 75 cm 2 flasks.
  • CL receptor and RAMP1 expression constructs were co-transfected in equal amounts.
  • 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.
  • RECOMBINANT RECEPTOR BINDING ASSAY 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.
  • binding assays 20 ⁇ g of membranes were incubated in 1 mL binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCI 2 , and 0.2% BSA) for 3 h at room temperature containing 10 pM 125 l-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 MgCI 2 ). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Nonspecific binding was determined and the data analysis was carried out with the apparent dissociation constant (/ ⁇ " ,) determined by using a non-linear least squares fitting the bound CPM data to the equation below:
  • Y is observed CPM bound
  • Y max is total bound counts
  • Y min is non specific bound counts
  • (Ymax - min) is specific bound counts
  • % l ma x is the maximum percent inhibition
  • % I min is the minimum percent inhibition
  • radiolabel is the probe
  • 3 ⁇ 4 is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.
  • RECOMBI NANT 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 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.
  • cAMP dynamic 2 assay kit 62AM4PEC; Cisbio.
  • Raw data were transformed into concentration of cAMP using 33 a standard curve then dose response curves were plotted and inflection point (I P) values were determined.
  • IC 50 values in the recombinant receptor functional assay for exemplary compounds of the invention are provided in the table below:
  • 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.
  • Scheme 2 Another general approach for the preparation of compounds of the present invention is illustrated in Scheme 2.
  • This methodology typically relies on a palladium-catalyzed amination of intermediate 2.2 with the amine of interest (2.1).
  • intermediate 2.2 may be prepared using well-precedented methodology and several such intermediates are described herein ⁇ vide infra).
  • aryl bromide 2.2 may be replaced by a similar reactant, such as the corresponding aryl chloride or iodide.
  • Scheme 3 illustrates general methodology for the synthesis of key intermediate 1.1.
  • the amine of interest (2.1) can be reacted with 4-fluoronitrobenzene (3.1) under basic conditions to afford the nitrobenzene 3.2, which may be reduced to provide the desired arylamine intermediate 1.1.
  • Variations of this approach familiar to one skilled in the art of organic synthesis, may be employed to produce a variety of related intermediates. For example, the use of heteroaryl alternatives to 3.1 may lead to the corresponding
  • heteroarylamine analogues of 1.1 heteroarylamine analogues of 1.1.
  • the synthesis of the novel spirocyclic intermediate 6.10 is shown in Scheme 6.
  • the chloropyrimidine derivative 6.4 is synthesized from diethyl succinate (6.1) in three steps using known conditions (WO 2009/152027).
  • Treatment of 6.4 with a large excess of ieri-butylamine in a sealed vessel at elevated temperature provides ester 6.5, which may be subjected to standard saponification to the acid followed by cyclization of the corresponding HOBT ester to afford 6.6.
  • the key step is dialkylation of 6.6 with the dichloride 6.7, using cesium carbonate as base, to yield the spirocyclic compound 6.8, which may be converted to 6.10 as shown.
  • a number of known benzodiazepinone analogues may be used as amine 2.1 to provide compounds of the present invention.
  • Related analogues may be synthesized using
  • the synthesis of the ether derivative 9.4 is shown in Scheme 9.
  • the fluoronitrobenzene 9.1 may be reacted with a variety of alcohols (such as R 10 OH) under basic conditions to provide the ether derivative 9.2.
  • reduction of the nitro group provides the desired arylamine intermediate 9.4.
  • Scheme 11 illustrates an alternative strategy for the synthesis of spirocyclic
  • the indole derivative 11.1 may be protected, for example with a SEM group to give 11.2.
  • Treatment of 11.2 with pyridinium tribromide in dioxane, followed by zinc- mediated reductive debromination provides oxindole derivative 11.3.
  • This oxindole 11.3 is dialkylated with the b/s(2-iodoethyl)aniline 11.5, which is prepared in two steps from the corresponding diol 11.4 as shown, to afford the key spirocyclic intermediate 11.6.
  • catalytic hydrogenation provides the desired arylamine 11.7.
  • Scheme 13 details a similar sequence that may be used to provide 4- chloronaphthyridine intermediates such as 13.4.
  • Reaction of aminopyridine 13.1 with Meldrum's acid and triethyl orthoacetate at elevated temperature leads to the condensation product 13.2, and this may be converted to the chloronaphthyridine 13.4 using analogous chemistry to Scheme 12.
  • Similar procedures applied to other aminopyridine isomers may be used to provide alternative naphthyridine isomers.
  • Scheme 15 illustrates methodology for the synthesis of key intermediate 15.4, in which there is a substituent (R 10 ) on the aromatic ring ortho to the amino group.
  • This approach begins with the dihalonitroaromatic starting material 15.1, which contains fluoro and bromo substituents.
  • alternative halogens may be employed.
  • R 10 is introduced using standard Suzuki coupling conditions and the corresponding boronic acid R 10 B(OH) 2 to afford the nitro compound 15.2.
  • a variety of alternative conditions may be employed, as will be appreciated by one skilled in the art.
  • the amine of interest (2.1) can be reacted with 15.2 under basic conditions to afford the nitroaromatic 15.3, which may be reduced to provide the desired arylamine intermediate 15.4.
  • Alternative conditions may be employed throughout the illustrated route.
  • the nitro group in 15.3 may be hydrogenated using a number of alternative catalysts, or simply reduced using non-hydrogenation conditions, including the use of a metal such as iron, tin, or zinc under acidic conditions.
  • 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
  • Step A Ethyl (3Z)-3-f(5-methoxv-2-methylphenvl)iminolbutanoate
  • Step B fe/t-Butyl ⁇ 2-f(4-chloro-2.8-dimethvlquinolin-5-vl)oxvlethyl)carbamate
  • Step A Ethyl 3-[(2-methvlphenyl)aminolbut-2-enoate
  • 2,8-Dimethylquinolin-4-ol (0.70 g, 4.0 mmol) was suspended in POCI 3 (7 mL) and the stirred reaction mixture was heated at 110 °C for 6 h, then cooled to ambient temperature. The reaction mixture was concentrated to remove most of the POCI 3 and the residue was poured onto ice with stirring. The resulting mixture was adjusted to pH 7 - 8 by addition of saturated aqueous sodium bicarbonate, and the precipitate was isolated by filtration and dried to give the title compound.
  • Step A 2,2-Dimethvl-5- ⁇ l (4-methvlpvridin-3-vl)aminolethylidene ⁇ -l,3-dioxane-4,6-dione
  • 3-amino-4-met ylpyridine (2.00 g, 18.5 mmol)
  • Meldrum's acid (3.20 g, 22.2 mmoi)
  • triethyl orthoacetate (18.0 g, 111 mmol) dropwise.
  • the resulting mixture was stirred at 100 °C for 4 h then cooled to ambient temperature and concentrated under reduced pressure.
  • Step C 4-Chloro-2,8-dimethyl-l,5-naphthvridine
  • 2,8-Dimethyl-l,5-naphthyridin-4-ol (765 mg, 4.39 mmol) was suspended in POCI 3 (20 mL) and the stirred reaction mixture was heated at 110 °C for 3 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the POCI 3 and the residue was poured onto ice with stirring, then extracted with CH 2 CI 2 (3 ⁇ 150 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH 2 CI 2 :EtOAc - 100:0 to 50:50, to give the title compound.
  • Step A 3-fl-(4-Nitrophenvl)piperidin-4-vl]-l,3,4.5-tetrahydro-2H-l,3-benzodiazepin-2-one
  • Step B 3-[l-(4-Aminophenvl)piperidin-4-vll-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
  • Step A l',4'-Dihydro-3'H-spirofpiperidine-4,2'-quinoxalin1-3'-one
  • Step B l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiroipiperidine-4,2'-quinoxalinl-3'-one
  • Step A 1-terf-Butvl 4-methyl 4-f(2-nitropvridin-3-vl)oxvlpiperidine-l,4-dicarboxylate
  • Step B ferf-Butyl 3'-oxo-3',4'-dihvdro-lH-spirorpiperidine-4,2'-pyridof3,2-b1fl,4loxazinel-l- carboxvlate
  • Step C Spirofpiperidine-4,2'-pyridoi3.2-foiri.41oxazin1-3'(4'H)-one
  • Step D l-(4-Aminophenvl)spirofpiperidine-4,2'-pyrido[3,2-falfl,41oxazin1-3'(4'H)-one 58 Essentially following the procedures described in Intermediate 5, but using
  • Step A 1-tert-Butyl 4-methyl 4-f(2-nitropvridin-3-vl)aminolpiperidine-l,4-dicarboxylate
  • Step B ferf-Butyl 3'-oxo-3',4'-dihvdro-lH,l'H-spiro[piperidine-4,2'-pyrido[2,3-fc1pvrazine]-l- carboxylate
  • Step C l',4'-Dihvdro-3'H-spirofpiperidine-4,2'-pvridoi2,3-fe1pyrazin1-3'-one
  • Step D l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiro[piperidine-4,2'-pyridof2,3-ib1Pvrazin1-3'-one
  • Step A 5-Methoxv-l-f[2-(trimethvlsilvl)ethoxvlmethvl)-lH-pyrrolo[2,3-blPvridine
  • Step B 3,3-Dibromo-5-methoxv-l- ⁇ [2-(trimethvlsilvl)ethoxy]methvl ⁇ -l,3-dihvdro-2H-
  • Step C 5-Methoxv-l- ⁇ [2-(trimethvlsilvl)ethoxv1methvl ⁇ -l,3-dihvdro-2H-pyrrolor2,3-blPVridin-2- one
  • 3 -dibromo-5-methoxy-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -l,3- dihydro-2H-pyrrolo[2,3-jb]pyridin-2-one 3.00 g, 6.75 mmol
  • THF 44 mL
  • saturated aqueous NH 4 CI 11 mL
  • zinc 4.4 g, 67 mmol
  • reaction mixture was filtered through Celite ® , washing with EtOAc.
  • organic layer of the filtrate was separated and the aqueous phase was extracted further with EtOAc.
  • the combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
  • the residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 60:40, to give the title compound.
  • Step D f(4-Nitrophenyl)imino1diethane-2,l-diyl dimethanesulfonate
  • Step E /V,A/-5/s(2-iodoethvl)-4-nitroaniline
  • Step F 5'-Methoxv-l-(4-nitrophenvl)-l'- ⁇ f2-(trimethvlsilvl)ethoxv1methvl ⁇ spiroipiperidine-4,3'- pyrrolor2,3-b1pvridinl-2'(l'H)-one
  • Step G l-(4-Aminophenvl)-5'-methoxv-l'- ⁇ [2-(trimethvlsilvl)ethoxvlmethvl)spirofpiperidine-
  • Step A l-(4-nitrophenvl)-l'- ⁇ f2-(trimethvlsilvl)ethoxv1methvl)spirofpiperidine-4.3'-pyrrolo[2,3- b1pvridinl-2'(l'H)-one
  • Step B l-(4-Aminophenvl)-5'-methoxv-l'- ⁇ f2-(trimethvlsilvl)ethoxvlmethyl ⁇ spiro[piperidine-
  • Step B l-(4-Amino-2-bromophenvl)-l'- ⁇ [2-(trimethvlsilvnethoxvlmethyl ⁇ spirofpiperidine-4,3'-
  • Step B 5'-Bromo-l-(4-nitrophenvl)-l'- ⁇ f2-(trimethylsilvl)ethoxv1methvl ⁇ spiro[piperidine-4,3'- pyrrolof2,3-i 1pvridin1-2'(l'H)-one
  • Step C l-(4-Aminophenvl)-5'-bromo-l'- ⁇ f2-(trimethvlsilvl3 ⁇ 4ethoxvlmethvl ⁇ spiro[piperidine-4,3'- pyrrolo[2,3-i 1pvridinl-2'(l' V)-one
  • Step B M-(4-Hvdroxv-2.6,8-trimethvlquinolin-7-vl)acetamide
  • Step C A/-(4-Chloro-2,6.8-trimethylquinolin-7-vl)acetamide
  • Step A 2,2,2-Trifluoro-/ ⁇ /-(2-met vl-4-nitrophenvnacetamicle
  • Step B A/-(4-Amino-2-methvlphenyl)-2,2.2-trifluoroacetamide
  • Step C A/-f4-(Acetvlamino)-2-methylphenvn-2,2,2-trifluoroacetamide To a stirred mixture of /V-(4-amino-2-methylphenyl)-2,2,2-trifluoroacetamide (7.12 g,
  • Step B 4-[(2,6,8-Trimethvlquinolin-4-yl)amino1benzoic acid 71
  • methyl 4-[(2,6,8-trimethylquinolin-4-yl)amino]benzoate (1.30 g, 4.06 mmol) in THF (60 mL) and MeOH (20 mL) was added a solution of lithium hydroxide (389 mg ; 16.2 mmol) in water (20 mL).
  • the resulting precipitate was collected by filtration and dried to afford the title compound.
  • Step B Ethyl f4-hvdroxv-2-(methylsulfanvl)pvrimidin-5-vllacetate 72
  • diethyl 2-formy!butanedioate 50.0 g, 0.247 moi
  • S- methylthiourea semisulfate (34.4 g, 0.247 mol) in water (220 mL)
  • a solution of sodium hydroxide (14.8 g, 0.37 mol) in water (55 mL).
  • the resulting mixture was stirred at 100 °C for 90 min, cooled to ambient temperature, and acetic acid (21.2 mL, 0.37 mol) was added slowly.
  • the resulting mixture was stirred at ambient temperature for 18 h and the solid was isolated by filtration, washing with water, and drying under reduced pressure to provide the title compound.
  • MS: m/z 229.1 (M + 1).
  • Step C Ethyl [4-chloro-2-(methylsulfanvl)pvrimidin-5-vnacetate
  • Step D Ethyl [4-(ferf-butvlamino)-2-(methvlsulfanyl)pvrimidin-5-vl1acetate
  • Step E 7-tert-Butvl-2-(methvlsulfanvl)-5,7-dihvdro-6H-pvrrolof2,3-cflpyrimidin-6-one
  • Step G 7'-tert-Butvlspiro[piperidine-4,5'-pvrrolo[2,3-d1pvrimidin1-6'(7'/- )-one
  • benzyl 7'-iert-butyl-2'-(methylsulfanyl)-6'-oxo-6',7 , -dihydro-lH- spiro[piperidine-4,5'-pyrrolo[2,3--/]pyrimidine]-l-carboxylate (1.10 g, 2.50 mmol) in EtOH (20 mL) was added aney 3 ⁇ 4 Nickel (slurry in water, ca.
  • Step H 7'-ferf-Butvl-l-(4-nitrophenyl)spiroipiperidine-4,5'-pvrrolo[2,3-c/lpvrimidin1-6'(7'H)-one
  • Step I l-(4-Aminophenvl)-7'-fert-butvlspirofpiperidine-4,5'-pvrrolo[2,3-- lPvrimidinl-6'(7'H)- one
  • Step B 2-(2-Bromo-6-nitrophenvl)ethyl methanesulfonate
  • Step D ferf-Butyl 4- ⁇ r2-(2-bromo-6-nitrophenyl)ethvllamino ⁇ piperidine-l-carboxvlate
  • Step E ferf-Butyl 4-(r2-(2-amino-6-bromophenvl)ethyllamino ⁇ piperidine-l-carboxvlate
  • Step F ferf-Butyl 4-(6-bromo-2-oxo-1.2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl)piperidine-l- carboxvlate
  • Step G tert-Butyl 4-(6-cvano-2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidine-l- carboxylate
  • Step H 2-Oxo-3-(piperidin-4-yl)-2,3,4,5-tetrahvdro-lH-l,3-benzodiazepine-6-carbonitrile
  • Step I 3-[l-(4-Nitrophenvl)piperidin-4-vll-2-oxo-2,3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
  • Step J 3-[l-(4-Aminophenvl)piperidin-4-vll-2-oxo-2 J 3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
  • Step A A/-(4-Bromophenvl)-2,6-dimethvlpyridin-4-amine
  • Step B A/-(4-Bromophenvl)-A/,2,6-trimethvlpyridin-4-amine
  • Step B l-(4-Nitro-3-phenoxvphenvl)spirofpiperidine-4,3'-Pvrrolo[2,3-felPvridin1-2'(l'H)-one
  • Step C l-(4-Amino-3-phenoxvphenvl)spirofpiperidine-4,3'-pyrrolo[2,3--?lpvridinl-2'(l'H)-one A mixture of l-(4-nitro-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-Jb]pyridin]-
  • Step A tert-Butyl 5-bromo-2,3-dihvdro-lH-indole-l-carboxylate
  • Step B fe/t-Butyl 5-i4-(2-oxo-l,2,4,5-tetrahvdro-3W-l,3-benzodiazepin-3-yl)piperidin-l-vn-2,3- dihvdro-lH-indole-l-carboxylate
  • Step C 3-fl-(2,3-Dihvdro-lH-indol-5-vl)piperidin-4-vn-l,3,4,5-tetrahydro-2 -/-l,3- benzodiazepin-2-one
  • Step A Benzyl 2'-oxo-l'- ⁇ r2-(trimethvlsilvl)ethoxv1methvl)-l',2'-dihvdro-lH-spirorpiperidine-
  • Step B l'- ⁇ [2-(Trimethvlsilvl)ethoxv1methvl)spirofpiperidine-4,3'-Pvrrolor2,3-fe1pyridin1-2'(l'H)- one
  • a mixture of benzyl Z'-oxo-l'-iia-itrimethylsilylJethoxyJmethylJ-l' ⁇ '-dihydro-lH- spiro[piperidine-4,3'-pyrrolo[2,3-ib]pyridine]-l-carboxylate (5.50 g, 11.8 mmol) and 10% Pd/C (1.00 g, 0.94 mmol) in EtOAc (30 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The resulting mixture was filtered through Celite ® , washing with MeOH, and concentrated in vacuo to give the title compound, which was used without further purification.
  • Step C l-(6-Chloropvridazin-3-vl)-l'-(f2-(trimethvlsilvl)ethoxvlmethyl)spirofpiperidine-4,3'- pvrrolo[2,3-blpvridin]-2'(l'H)-one
  • DIEA 3,5,5-dichloropyridazine
  • Step A /V-(3-Formvlpyridin-2-vl)pivalamide
  • Step B 3-(Piperidin-4-vl)-l,8-naphthyridin-2(lH)-one hydrochloride
  • Step D 3-[l-(5-Aminopvridin-2-vl)piperidin-4-vll-l,8-naphthyridin-2(lti)-one
  • Step B fe/t-Butyl 4-f5-oxo-lH-l,2,4-triazol-4(5H)-vnpiperidine-l-carboxylate
  • EtOH 2-(ethoxymethylene)hydrazinecarboxylate
  • ieri-butyl 4-aminopiperidine-l-carboxylate (0.12 g, 0.60 mmol) and the reaction mixture was heated at 50 °C for 64 h.
  • MeOH MeOH (2 mL)
  • sodium methoxide 0.324 g, 6.00 mmol
  • Step C 4-(Piperidin-4-yl)-l /-1.2,4-triazol-5(4H)-one trifluoracetate
  • Step D 4-ri-(5-Nitropyridin-2-vl)piperidin-4-vll-lH-l,2,4-triazol-5(4fV)-one
  • Step A fe/t-Buty) 3-[(2-aminopvridin-3-yl)aminolazetidine-l-carboxvlate
  • Step B fert-Butyl 3-(2-oxo-2,3-dihvdro-lH-imidazof4,5-b1pyridin-l-vl)azetidine-l-carboxvlate To a stirred solution of te/t-butyl 3-[(2-aminopyridin-3-yl)amino]azetidine-l-carboxylate
  • Step C l-(Azetidin-3-yl)-lW-imidazof4,5-blpvridin-2(3H)-one hydrochloride
  • Step D l-fl-(5-Aminopvridin-2-vl)azetidin-3-vn-lH-imidazor4,5-b1pyridin-2(3H)-one
  • Step A 2'-Chloro-l-methvl-5'-nitro-3,4'-bipyridin-6(lH)-one
  • Step B l-Methvl-5'-nitro-2'-r4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl3 ⁇ 4piperidin- l-vll-3.4'-bipyridin-6(l/V)-one
  • Step C 5'-Amino-l-methvl-2'-f4-(2-oxo-l,2,4.5-tetrahydro-3H-l,3-benzodiazepin-3- vl)piperidin-l-vn-3,4'-bipyridin-6(lH)-one
  • Step B Methyl /V-(ferf-butoxvcarbonvl)-A/-(2-nitrobenzyl)glvcinate
  • Step C Methyl N-(2-aminobenzyl)-/V-(1 ⁇ 2rr-butoxvcarbonvl)glvcinate
  • Step D ferr-Butyl 2-oxo-l,2.3.5-tetrahydro-4H-l,4-benzodiazepine-4-carboxvlate
  • Step E l,3,4,5-Tetrahydro-2H-l,4-benzodiazepin-2-one
  • a stirred mixture of ie/t-butyl 2-oxo-l,2,3,5-tetrahydro-4H-l,4-benzodiazepine-4- carboxylate (3.1 g, 12 mmol), and trifluoroacetic acid (7.0 mL, 91 mmol) in CH 2 CI 2 (100 mL) was stirred at ambient temperature for 2 h.
  • the reaction mixture was concentrated in vacuo, the residue was triturated with ether and the resulting solid was isolated by filtration and dried in vacuo to give the title compound in sufficient purity for use in the next step.
  • MS: m/z 163.1 (M + l).
  • Step F te/t-Butvl 4-(2-oxo-1.2,3,5-tetrahvdro-4H-l,4-benzodiazepin-4-yl)piperidine-l- carboxylate
  • Step G 4-(Piperidin-4-yl)-l,3,4,5-tetrahvdro-2H-l,4-benzodiazepin-2-one
  • tert-butyl 4-(2-oxo-l,2,3,5-tetrahydro-4W-l,4-benzodiazepin-4- yl)piperidine-l-carboxylate (1.8 g, 5.2 mmol) in CH 2 CI 2 (50 mL)
  • TFA 10 mL, 25 mmol
  • Step A 5-(5-Fluoro-2-nitrophenvl)-2-(trifluoromethyl)pvridine
  • Step B 3-(l- ⁇ 4-Nitro-3-i6-(trifluoromethvl)pvridin-3-vllphenvl ⁇ piperidin-4-vl)-l,3,4,5- tetrahydro-2H-l,3-benzodiazepin-2-one
  • Step C 3-(l- ⁇ 4-Amino-3-r6-(trifluoromethvl)pvridin-3-vnphenyl)piperidin-4-vl)-l.3.4,5- tetrahydro-2tf-l,3-benzodiazepin-2-one
  • Step A 5-Bromo-2-chloro-4-f4-(methvlsulfonyl)phenvnpvridine
  • Step B 6-Chloro-A/-(2,6-dimethvlpvridin-4-vl)-4-[4-(methylsulfonvl)phenvllpvridin-3-amine
  • a deoxygenated mixture of 5-bromo-2-chloro-4-[4-(methylsulfonyl)phenyl]pyridine (500 mg, 1.4 mmol), 4-amino-2,6-dimethylpyridine (260 mg, 2.1 mmol) and chloro(2- dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2-aminoethylphenyl)]palladium(ll)- methyl-ferr-butyl ether adduct ( uPhos precatalyst) (120 mg, 0.14 mmol) in 1,4-dioxane (15 mL) was treated with sodium iert-butoxide (2.0 M in THF, 1.4 mL, 2.9 mmol) and the resulting mixture was heated at 40 °C for 18 h.
  • Step A 5-Bromo-2-chloro-4-(4-fluorophenvl)pyridine
  • 4-fluorophenyl)boronic acid (0.92 g, 6.9 mmoi)
  • tris-(3-suifonatophenyl)phosphine-hydrate sodium salt (0.30 g, 0.47 mmol)
  • pailadium(ll) acetate 35 mg, 0.16 mmol
  • DMF 24 mL
  • water (7.9 mL) was added diisopropylamine (2.7 mL, 19 mmol).
  • Step B 4- ⁇ l-f5-Bromo-4-(4-fluorophenvl)pvridin-2-yllpiperidin-4-vl)-l,3,4,5-tetrahvdro-2H-l,4- benzodiazepin-2-one
  • Step A A/-(2,6-Dimethylpvridin-4-vl)-2,2-dimethvlpropanamide
  • Step B A/-(3-Bromo-2,6-dimethvlpvridin-4-vl)-2,2-dimethylpropanamide
  • Step C / ⁇ /- ⁇ 3-[(£)-2-Ethoxvethenvn-2,6-dimethvlpvridin-4-vl ⁇ -2,2-dimethylpropanamide
  • Step D 4,6-Dimethvl-l/-7-pvrrolo[3,2-c1pyridine
  • Step A 4-(2-Chloro-5-nitropyridin-4-vl)thiomorpholine 1,1-dioxide
  • Step B 3- ⁇ l-r4-(l,l-Dioxidothiomorpholin-4-vl)-5-nitropyridin-2-vnpiperidin-4-vl ⁇ -l,3,4.5- tetrahydro-2H-l,3-benzodiazepin-2-one
  • a mixture of 4-(2-chloro-5-nitropyridin-4-yl)thiomorpholine 1,1-dioxide 450 mg, 1.54 mmol
  • 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (435 mg, 1.54 mmol)
  • DIEA (0.81 mL, 4.63 mmol
  • Step C 3- ⁇ l-f5-Amino-4-(l,l-dioxidothiomorpholin-4-vl)pyridin-2-vnpiperidin-4-vl)-l, 3.4.5- tetrahydro-2H-1.3-benzodiazepin-2-one
  • Step A 5-Nitro-2-f4-(2-oxo-l,2,4,5-tetrahvdro-3H-1.3-benzodiazepin-3-yl)piperidin-l-
  • Step B 5-Amino-2-f4-(2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidin-l- vnpyridine-4-carbonitrile
  • Step A 4-(4,4,5,5-Tetramethvl-l,3,2-dioxaborolan-2-vl)-2-(trifluoromethvl)pyridine
  • Step C 2-(l,4-Dioxa-8-azaspirof4.51dec-8-vl)-5-nitro-2'-(trifluoromethyl)-4,4'-bipvridine
  • Step D 6-(l,4-Dioxa-8-azaspiroi4.5ldec-8-vl)-2'-(trifluoromethvl)-4,4'-bipvridin-3-amine
  • Step E / ⁇ /-(2,6-Dimethvlpvridin-4-vl)-6-(l,4-dioxa-8-azaspiro[4.51dec-8-vl)-2'-(trifluoromethyl)-
  • Step F l- ⁇ 5-f(2,6-Dimethvlpvridin-4-vl)amino)-2'-(trifluoromethvl)-4,4'-bipvridin-2-yl ⁇ piperidin- 4-one
  • ⁇ /-(2,6- ⁇ -4- ⁇ )-6-(1,4- ⁇ 3-8-3 ⁇ 35 ⁇ [4.5] ⁇ €-8- yi)-2'-(trifluoromethyl)-4,4'-bipyridin-3-amine 260 mg, 0.536 mmol
  • H 2 0 (1 mL) was added cone.
  • HCI (0.44 mL, 5.36 mmol).
  • Step B 4-Chloro-2-(fluoromethvl)-6-methylpvridine hydrochloride
  • Step A (lZ,4g)-l-Hvdroxv-5-methoxv-l-fl-(trifluoromethvl)cvclopropvnpenta-l,4-dien-3-one
  • reaction mixture was quenched with saturated NH 4 CI (20 mL), concentrated under reduced pressure to remove THF and the residue was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na 2 S0 , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of PE:EtOAc - 100:0 to 50:1, to give the title compound.
  • Step B 2-fl-(Trifluoromethyl)cvclopropvll-4H-pvran-4-one
  • Step C 2-ri-(Trifluoromethvl)cvclopropyl]pvridin-4(l/Tf)-one
  • Step D 4-Bromo-2-Fl-(trifluoromethyl)cvclopropvnpvridine
  • Step E A/-(2,6-Dimethvlpyridin-4-vl)-6-(l,4-dioxa-8-azaspirof4.51dec-8-vl)-2'-fl- (trifluoromethvl)cyclopropvll-4,4'-bipvridin-3-amine
  • Step F A/-(2,6-Dimethylpvridin-4-vl)-6-(l,4-dioxa-8-azaspiror4.5ldec-8-yl)-/ ⁇ /-methvl-2'-fl- (trifluoromethyl)cvclopropvll-4,4'-bipvridin-3-amine
  • Step G l- ⁇ 5-i(2,6-Dimethvlpvridin-4-vl)(methvl)aminol-2'-il-(trifluoromethvl)cyclopropvn-4,4'- bipyridin-2-vl ⁇ piperidin-4-one

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Abstract

The present invention is directed to heterocyclic compounds which are antagonists of CGRP receptors and may be 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
HETEROCYCLIC 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. Neurol. 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 extra-cranial 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 may make 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) 4cia 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 ei 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 ei 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 heterocyclic compounds which are potent antagonists of CGRP receptors and potentially useful in the treatment or prevention of diseases in which the 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.
DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of Formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: "A" is benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, cinnolinyl, imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrimidyl, pyrrolopyridinyl, pyrrolopyrimidinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, or triazolyl, wherein A is optionally substituted with one or more of R1, R2, R3, R4 and R5;
"X" is NR9, O, S(0)m, or CR6R7;
"G1", "G2", " G3" and "G4" are independently: CRa; or N;
"B" is: a bond; (C=0); or CR6R7; and "D4" are independently CRD 6Rr>7' or (C=0);
"D2", "D3", "D5" and "D6" are independently: a bond; or CR6R7;
"W" is:
Figure imgf000005_0001
"1" is: hydrogen; or Ci-6 alkyl, wherein said alkyl is optionally substituted with up to three substituents which are independently for each occurrence: halo; cyano; or hydroxy; or
"W" and "Z" together with the carbon atom to which they are attached form a moiety of the formula:
Figure imgf000005_0002
wherein:
"X1" is independently for each occurrence: -CRC CRr,°d-, -NRe-, -(C=0)- and -0-,
"X2" is independently for each occurrence: -CRcRd-, -NRe-, -(C=0)-,
"X3", "X4", "Y1", "Y2". "Y3", "Y4", ", "V1", "V2". "V3", "V4", "U1", "U2". "U3" and "U4" are independently sfor each occurrence: -CRb- and -N-;
"Q" is -NRe-, -0-, -N(Re)CRcRd- or -CRcRd-;
"T1" and "T2" are independently, for each occurrence: a bond; or -CRcRd-; R1, R2, R3 , R4 and R5 are independently for each occurrence:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) hydroxy;
(e) QL-6 alkyl, optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR8; -NR11R12; -heterocyclyl; or -OR10;
(f) 0-Ci_6 alkyl, optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR8; -NR11R12; or -heterocyclyl; (g) C2-6 alkenyl, optionally substituted with up to three substitutents which are independently: halogen; -OH; -CN, or -NR R12-;
(j) (C=0)RB;
(k) (C=0)OR8;
(I) (C=0)NRuR12;
(m) (C=0)R10;
(n) NRnR12; or
(o) S(0)mR9; or
R4and R5 together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and wherein said ring is optionally substituted with up to three substituents which are independently: (a) halo; (b) oxo; (c) phenyl; (d) OR8; or (e) R8;
R6 and R7 are independently for each occurrance:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) Ci-6 alkyl, which is optionally substituted with up to three substituents which are independently: halo; hydroxy; cyano; R10; or NRUR12; (e) OR ;
(f) (C=0)OR8; or
(g) (C=0)NRu 12; or
R6 and R7, together with the carbon atom(s) to which they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring;
R8 is independently for each occurrence: hydrogen; Ci-6 alkyl; or C3_6 cycloalkyl, and when selected to be alkyl or cycloalkyl, said moiety is optionally substituted with up to three substituents which are independently: halo; cyano; C3_6-cycloalkyl; phenyl; or hydroxy;
R9 is independently for each occurrance:
(a) hydrogen,
(b) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; C3.5 cycloalkyl; cyano; OR8; NRUR12; (C=0)OR8; R10; or OR10,
(c) C3-6 cycloalkyl, optionally substituted with up to three substituents which are
independently: halo; cyano; OR8; or R8;
(d) R10;
(e) (OO)R8;
(f) (C=0)OR8; or
(g) (C=0)NR R12; or
R9 and Ra together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR8; CN; or Ci_6 alkyl; (c) OR8; (d) oxo; or (e) Ci_6 alkyl, which is optionally substituted with up to three halogen atoms; or
R9 and R1 together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR8; CN; or Ci-6 alkyl; (c) OR8; (d) oxo; or (e) Ci_6 alkyl, which is optionally substituted with up to three halogen atoms;
R10 is: (i) heterocyclyl; (ii) C3-6 cycloalkyl; (iii) aryl; or (iv) heteroaryl, wherein said heterocylyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with up to five substituents which are independently for each occurrence: (a) halo;
(b) cyano;
(c) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently: halo; C3.6 cycloalkyl; cyano; OR8; (C=0)OR8; N H(C=0)OR8; NH2; or aryl;
(d) C3-6 cycloalkyl, optionally substituted with up to three substitutents which are
independently: halo; cyano; -OR8; or R8;
(e) OR8;
(f) oxo;
(g) C2-6 alkynyl, which is optionally substituted with up to three substitutents which are independently: halo; hydroxy; cyano; or NRUR12;
(h) C2-6 alkenyl, which is optionally substituted with up to three substitutents which are independently: halo; hydroxy; cyano; or NRUR12;
(i) (C=0)R8;
(j) (OO)OR8;
(k) (C=0)NR"R12;
(l) N RNR12; or
(m) S(0)MR8;
R11 and R12 are independently for each occurrence:
(a) hydrogen;
(b) Ci-6 alkyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; (C=0)OR8; NH(C=0)OR8; NH2; heterocyclyl; C3.6-cycloalkyl; phenyl; or heteroaryl;
(c) (OO)R8;
(d) (C=0)OR8;
(e) heterocyclyl, optionally substituted with up to three substitutents which are independently for each occurrence: halo; cyano; OR8; or RS;
(f) C3-6 cycloalkyl, optionally substituted with up to three substitutentswhich are
independently for each occurrence: halo; cyano; OR8; or R8; (g) phenyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; or R8; or
(h) heteroaryl, , optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; or R8; or
R11 and R12 together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally when present, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionallysubstituted with up to four substituents which are independently:
(a) halo,
(b) phenyl, optionally substituted with up to three substituents which are independently halo; OR8; CN; or C« alkyl;
(c) OR8; or
(d) Ci-6 alkyl, which is optionally substituted with one to three halo;
Ra is independently for each occurrence:
(a) hydrogen; (b) halo; (c) cyano; (d) hydroxy; (e) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; S(0)mR9;
(OO)OR8; (C=0)NR R12; NRnR12; R10; or OR10; (f) OC1-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; S(0)mR9; NRnR12; or R10; (g) S(0)mR9; (h) (C=0)OR8; (i) (O0)NRnR12; (j) R10;(k) OR10; (I) (C=0)R8; (m) (C=0)R10; or (n) NRnR12;
Rb is independently for each occurrence:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) hydroxy;
(e) Ci_6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; NR R12; R10 or OR10;
(f) OCi_6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; NR11R12 or heterocyclyl; (h) (C=0)RB;
(i) (C=0)OR8;
(j) (O0)NR R12; or
(k) NRnR12;
Rc and Rd are each independently for each occurrence:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) Ci-6 alky), optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; or NR R12;
(e) C3-6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8,
(f) OCi-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; or NRnR12; or
(g) phenyl; or
Rc and Rd together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionally substituted with up to four substituents which are independently:
(a) halo;
(b) phenyl, optionally substituted with up to three substituents which are independently: halo, OR8; CN; or C1.6 alkyl;
(c) OR8; or
(d) Ci-6 alkyl, optionally substituted with up to three halogen substituents;
Re is independently for each occurrence:
(a) hydrogen; (b) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; or NRUR12; C3.6 cycloalkyl; or phenyl; or
(c) R10; and
m is independently for each occurrence an integer from 0 to 2.
Another class of the invention is directed to compounds of the formula:
Figure imgf000011_0001
Another class of the invention is directed to compounds of the formula:
Figure imgf000011_0002
In a class of the invention, A is cinnolinyl, imidazopyridinyl, naphthyridinyl,
pyrazolopyridinyl, pyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, quinazolinyl or quinolinyl, which is optionally substituted with R1, R2, R3, R4 and R5. In a subclass of the invention, A is imidazopyridinyl, which is optionally substituted with R1, R2, R3, R4 and R5. In a subclass of the invention, A is pyrazolopyridinyl, which is optionally substituted with 1, R2, R3, R4 and R5. In a subclass of the invention, A is naphthyridinyl, which is optionally substituted with R1, R2, R3, R4 and R5. In a subclass of the invention, A is pyridinyl, which is optionally substituted with R1, R2, R4 and R5. In a subclass of the invention, A is quinolinyl, which is optionally substituted with R1, R2, R3, R4 and R5.
In a class of the invention, X is NR9. In another class of the invention, X is 0.
In a class of the invention, G1 is CRa. In another class of the invention, G1 is N.
In a class of the invention, G2 is CRa. In another class of the invention, G2 is N.
In a class of the invention, G3 is CRa. In another class of the invention, G3 is N.
In a class of the invention, G4 is CRa. In another class of the invention, G4 is N.
In a class of the invention, B is a bond. In a class of the invention, D1 is CR6R7 In a subclass of the invention, D1 is CH2. In another class of the invention, D1 is C=0.
In a class of the invention, D2 is a bond. In another class of the invention, D2 is CR6R7.
In a class of the invention, D3 is a bond. In another class of the invention, D3 is CR6R7.
In a class of the invention, D4 is CR6R7 In a subclass of the invention, D1 is CH2. In another class of the invention, D1 is OO.
In a class of the invention, D5 is a bond. In another class of the invention, D5 is CR6R7.
In a class of the invention, D6 is a bond. In another class of the invention, D6 is CR6R7.
Figure imgf000012_0001
In a class of the invention, Z is hydrogen.
In a class of the invention, W and Z can be taken together with the carbon atom to which they are attached to form:
Figure imgf000013_0001
In a subclass of the invention, W and Z can be taken together
Figure imgf000013_0002
In a class of the invention, each X1 is independently C cRd. In another class of the invention, each X1 is independently NRe. In another class of the invention, each X1 is independently (C=0). In another class of the invention, each X1 is independently O.
In a class of the invention, each X2 is independently CRcRd. In another class of the invention, each X2 is independently (OO).
In a class of the invention, each X3 is independently CRb. In another class of the invention, each X3 is independently N.
In a class of the invention, each X4 is independently CRb. In another class of the invention, each X4 is independently N.
In a class of the invention, each Y1 is independently CRb. In another class of the invention, each Y1 is independently N.
In a class of the invention, each Y2 is independently CRb. In another class of the invention, each Y2 is independently N.
In a class of the invention, each Y3 is independently CRb. In another class of the invention, each Y3 is independently N.
In a class of the invention, each Y4 is independently CRb. In another class of the invention, each Y4 is independently N.
In a class of the invention, each V1 is independently CRb. In another class of the invention, each V1 is independently N. In a class of the invention, each V2 is independently CRb. In another class of the invention, each V2 is independently N.
In a class of the invention, each V3 is independently CRb. In another class of the invention, each V3 is independently N. In a class of the invention, each V4 is independently CR . In another class of the invention, each V4 is independently N.
In a class of the invention, each U1 is independently CR . In another class of the invention, each U1 is independently N.
In a class of the invention, each U2 is independently CRb. In another class of the invention, each U2 is independently N.
In a class of the invention, each U3 is independently CRb. In another class of the invention, each U3 is independently N.
In a class of the invention, each U4 is independently CRb. In another class of the invention, each U4 is independently N. In a class of the invention, Q is NRe. In another class of the invention, Q is O.
Q is N(Re)CRcRd. In another class of the invention, Q is CRcRd.
In a class of the invention, T1 is a bond. In another class of the invention, T1 is CRcRd.
In a class of the invention, T2 is a bond. In another class of the invention, T2 is CRcRd.
In a class of the invention, R1 is selected from the group consisting of: (a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12, heterocyclyl and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, N RNR12 and heterocyclyl;
(g) 2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NR"R12, (h) R1U, (j) (C=0)R8,
(k) (C=0)OR8,
(I) (C=0)NR11R12,
(m) (C=0)R10, (n) NRuR12, and
(0) S(0)mR9
In a subclass of the invention, Rl is hydrogen.
In a class of the invention, R2 is selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci_6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12, heterocyclyl and OR10;
(f) OCi.6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NRUR12 and heterocyclyl;
(g) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NRUR12,
(h) R10,
(1) OR10,
(j) (C=0)R8,
(k) (C=0)OR8,
(I) (O0)NR R12,
(m) (C=0)R10,
(n) NRnR12, and
(o) S(0)mR9. In a subclass of the invention, R2 is methyl.
In a class of the invention, R3 is selected from the group consisting of:
(a) hydrogen,
(b) halo, (c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12, heterocyclyl and OR10;
(f) OCi„6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12 and heterocyclyl;
(g) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NRnR12,
(h) R10,
(i) OR10,
(j) (C=0)R8,
(k) (OO)OR8,
(I) (C=0)NRnR12,
(m) (C=0)R10,
(n) NRnR12, and
(o) S(0)mR9.
In a subclass of the invention, R3 is hydrogen.
In a class of the invention, R4 is selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy, (e) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12, heterocyclyl and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12 and heterocyclyl;
(g) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NRUR12,
(h) R10,
(i) OR10,
(j) (C=0)R8,
(k) (OO)OR8,
(I) (C=0)NRuR12,
(m) (OO)R10,
(n) NR R12, and
(0) S(0)mR9.
In a subclass of the invention, R4 is methyl.
In a class of the invention, R5 is selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Qt_6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12, heterocyclyl and OR10;
(f) OCi_6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR1XR12 and heterocyclyl;
(g) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NR R12,
(h) R10,
(1) OR10, (j) (C=0)RB,
(k) (C=0)OR8,
(I) (C=0)NR R12,
(m) (OO)R10,
(n) NRUR12, and
(o) S(0)mR9.
In a subclass of the invention, R5 is methyl.
In a class of the invention, R6 is selected from the group consisting of:
hydrogen, (C=0)OR8 and Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NRUR12.
In a class of the invention, R7 is hydrogen.
In a class of the invention, R9 is hydrogen.
In a class of the invention, R11 is selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (OO)OR8, NH(C=0)OR8,
NH2 heterocyclyl, C3-6 cycloalkyl, phenyl and heteroaryl,
(c) (C=0)R8,
(d) (C=0)OR8,
(e) heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(f) C3-6 cycloalkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(g) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8, and
(h) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8. In a subclass of the invention, R is hydrogen. In another subclass of the invention, R is Ci_6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8 and (C=0)OR8.
In a class of the invention, R12 is selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (C=0)OR8, NH(C=0)OR8,
Nh heterocyclyl, C3.6 cycloalkyl, phenyl and heteroaryl,
(c) (C=0)R8,
(d) (OO)OR8,
(e) heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(f) C3_6 cycloalkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(g) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8, and
(h) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8..
In a subclass of the invention, R12 is hydrogen. In another subclass of the invention, R12 is Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8 and (C=0)OR8.
In a class of the invention, each Ra is independently selected from the group consisting of hydrogen, halo, cyano, Ci-6 alkyl, R10, OR10 and OCi-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NRuR12 and R10.
In a class of the invention, Rc is selected from the group consisting of
(a) hydrogen,
(b) haio,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NR R12; (e) C3-6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8,
(f) OC1-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NR R12, and
(g) phenyl.
In a subclass of the invention, Rc is hydrogen.
In a class of the invention, Rd is selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NRUR12;
(e) C3.6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8,
(f) OCi_6 alkyl, which is optionally substituted with one to five substitutents independently sseelleecctteedd ffrrom the group consisting of halo, cyano, OR and NR R , and
(g) phenyl
In a subclass of the invention, Rd is hydrogen.
In a class of the invention, Re is hydrogen.
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 407, 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.
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 (1H) and deuterium (2H). 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 hydroxy -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. b, 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. 0. et al. Organometallics (2006) 5:1188-1198; Showed, 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, Cone to fouralkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that Cl-4alkyl 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 aikyl, 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 "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 0, N and S. 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, 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 l\l-oxides thereof are also encompassed by this definition.
The term "heterocycle" or "heterocyclyl" as used herein is intended to mean a 5- to 10- membered nonaromatic ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of 0, N, S, SO, or S02 and includes bicyclic groups.
"Heterocyclyl" therefore includes, but is not limited to the following: piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetra hydro pyranyl, dihydropiperidinyl,
tetrahydrothiophenyl 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 non-toxic 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. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base. 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 anti- migraine 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 antiinflammatory 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 NMDA 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- -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 nonsedating 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 125I-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 pg) were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgCI2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 12SI-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% polyethyieneimine for 3 h. The filters were washed three times with ice-cold assay buffer (10 mM HEPES, pH 7.4 and 5 mM MgCI2), then the plates were air dried.
Scintillation fluid (50 pL) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the K, 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 plREShyg2 (BD Biosciences Clontech) as a 5'Nhel and 3' Pmel fragment. Human RAMP1 (Genbank accession number AJ001014) was subcloned into the expression vector plRESpuro2 (BD Biosciences Clontech) as a 5'Nhel and 3'Notl 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 H BSS. Stable cell line generation was accomplished by co-transfecting 10 g of DNA with 30 μg Lipofectamine 2000 (Invitrogen) in 75 cm2 flasks. CL receptor and RAMP1 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: 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 MgCI2, and 0.2% BSA) for 3 h at room temperature containing 10 pM 125l-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 MgCI2). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Nonspecific binding was determined and the data analysis was carried out with the apparent dissociation constant (/<",) determined by using a non-linear least squares fitting the bound CPM data to the equation below:
Figure imgf000034_0001
Where Y is observed CPM bound, Ymax is total bound counts, Ymin is non specific bound counts, (Ymax - min) is specific bound counts, % lmax is the maximum percent inhibition, % I min is the minimum percent inhibition, radiolabel is the probe, and the ¾ is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation experiments.
RECOMBI NANT RECEPTOR FUNCTIONAL ASSAY: 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 33 a standard curve then dose response curves were plotted and inflection point (I P) values were determined.
Representative IC50 values in the recombinant receptor functional assay for exemplary compounds of the invention are provided in the table below:
Figure imgf000035_0001
34
Figure imgf000036_0001
35
Figure imgf000037_0001
The following abbreviations are used throughout the text:
Me: methyl
Et: ethyl
t-Bu: ieri-buty!
Bu: butyl
/'-Pr: isopropyl
Ar: aryl
Ph: phenyl
Bn: benzyl
Figure imgf000037_0002
Py: pyridyl
36
Figure imgf000038_0001
37
Figure imgf000039_0001
Figure imgf000040_0001
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 39 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, in which arylamine 1.1 is reacted with the heterocyclyl chloride ACI in the presence of acetic acid to afford the product 1.2. This general approach may be successful for the preparation of a range of heterocyclic A moieties, and alternatives to the chloride, such as the heterocyclyl bromide ABr, may also be employed. The reaction may be conducted using other acids, such as HCI in fert-butanol, in addition to the acetic acid illustrated in Scheme 1. Additionally, various metal catalysts, such as palladium catalysts, may also be utilized to promote the transformation shown in Scheme 1.
SCHEME 1
Figure imgf000041_0001
Another general approach for the preparation of compounds of the present invention is illustrated in Scheme 2. This methodology typically relies on a palladium-catalyzed amination of intermediate 2.2 with the amine of interest (2.1). In most cases, intermediate 2.2 may be prepared using well-precedented methodology and several such intermediates are described herein {vide infra). In some cases, it may be advantageous to use an alternative to a palladium- 40 based catalyst, or to employ thermal condensation conditions. Additionally, aryl bromide 2.2 may be replaced by a similar reactant, such as the corresponding aryl chloride or iodide.
SCHEME 2
Pd catalyst
2 2.3
Figure imgf000042_0001
Scheme 3 illustrates general methodology for the synthesis of key intermediate 1.1. The amine of interest (2.1) can be reacted with 4-fluoronitrobenzene (3.1) under basic conditions to afford the nitrobenzene 3.2, which may be reduced to provide the desired arylamine intermediate 1.1. Variations of this approach, familiar to one skilled in the art of organic synthesis, may be employed to produce a variety of related intermediates. For example, the use of heteroaryl alternatives to 3.1 may lead to the corresponding
heteroarylamine analogues of 1.1.
SCHEME 3
Figure imgf000042_0002
1.1
Some specific examples of the use of the general approach outlined in Scheme 3 are described in the following schemes. In Scheme 4, arylation of alcohol 4.1 by fluoride 4.2 under basic conditions leads to the pyridyl ether 4.3. The nitro moiety in 4.3 may be reduced to the corresponding amine using iron in acetic acid to afford, after in situ cyclization, the spirocyclic
41 intermediate 4.4. Removal of the Boc protecting group provides 4.5, which may be elaborated in analogy with Scheme 3 to give amine 4.7.
SCHEME 4
Figure imgf000043_0001
The synthesis of a representative azetidine-containing compound is illustrated in Scheme 5. Reductive amination of 2,3-diaminopyridine (5.1) with the protected azetidinone 5.2 yields diamine 5.3. Treatment of 5.3 with 1,1 '-carbonyldiimidazole at elevated temperature, followed by acid-promoted deprotection, affords the key azetidine intermediate 5.4. In Scheme 5, a modification of the procedures shown in Scheme 3 is illustrated: 2-chloro- 5-nitropyridine is used in place of 4-fluoronitrobenzene to provide the 3-aminopyridine 5.6.
SCHEME 5
42
Figure imgf000044_0001
The synthesis of the novel spirocyclic intermediate 6.10 is shown in Scheme 6. The chloropyrimidine derivative 6.4 is synthesized from diethyl succinate (6.1) in three steps using known conditions (WO 2009/152027). Treatment of 6.4 with a large excess of ieri-butylamine in a sealed vessel at elevated temperature provides ester 6.5, which may be subjected to standard saponification to the acid followed by cyclization of the corresponding HOBT ester to afford 6.6. The key step is dialkylation of 6.6 with the dichloride 6.7, using cesium carbonate as base, to yield the spirocyclic compound 6.8, which may be converted to 6.10 as shown.
SCHEME 6
43
Figure imgf000045_0001
A modification of the methodology shown in Scheme 6, which provides substituted analogues of 6.10, is shown in Scheme 7. In this modified version, the thioether group in intermediate 6.8 is oxidized to the corresponding sulfone under standard conditions. The sulfone derivative 7.1 may be reacted with, for example, a Grignard reagent to introduce a substituent (Rb) as shown. A range of nucleophiles may also be reacted with 7.1, in place of the Grignard reagent shown in Scheme 7, to furnish a variety of substituted analogues of 7.2. Deprotection of 7.2 under standard conditions and subsequent elaboration leads to the useful intermediate 7.4.
SCHEME 7
44
Figure imgf000046_0001
A number of known benzodiazepinone analogues (see, for example, US 2006/0019946 and Han et al. (2009) Tetrahedron Lett. 50, 386-388) may be used as amine 2.1 to provide compounds of the present invention. Related analogues may be synthesized using
modifications of the known methodology and an example is illustrated in Scheme 8. Treatment of nitrotoluene 8.1 with potassium hydroxide and paraformaldehyde provides the arylethanol derivative 8.2, and this may be converted to the corresponding styrene 8.3 using a
straightforward two-step procedure. Addition of the 4-aminopiperidine 8.4 to styrene 8.3 leads to intermediate 8.5, which is subjected to nitro reduction, followed by carbonylation, to afford the bromobenzodiazepinone analogue 8.6. Further elaboration of bromide 8.6 may provide a number of compounds of interest. In Scheme 8, cyanation using a palladium catalyst provides the corresponding nitrile 8.7, which may be converted to key intermediate 8.9 using standard methodology as shown.
SCHEME 8
45
Figure imgf000047_0001
The synthesis of the ether derivative 9.4 is shown in Scheme 9. The fluoronitrobenzene 9.1 may be reacted with a variety of alcohols (such as R10OH) under basic conditions to provide the ether derivative 9.2. Reaction of 9.2 with amine 2.1, in the presence of X-Phos precatalyst and lithium b/s(trimethylsilyl)amide, leads to the nitro compound 9.3. Finally, reduction of the nitro group provides the desired arylamine intermediate 9.4.
SCHEME 9
Figure imgf000047_0002
The synthesis of the naphthyridinone intermediate 10.6 is outlined in Scheme 10. Following protection of the aminopyridine 10.1 with a pivaloyl group, a solution of the sodium 46 salt of 10.2 is added to a solution of the lithium enolate of ester 10.3 at -78 °C and the resulting mixture is allowed to warm to ambient temperature. Following work-up, acid-mediated deprotection yields the piperidine derivative 10.4, which may be reacted with 2-chloro-5- nitropyridine to provide 10.5. Reduction of the nitro group in 10.5 may be effected by the use of sodium hydrosulfite, providing the desired aminopyridine 10.6.
SCHEME 10
Figure imgf000048_0001
Scheme 11 illustrates an alternative strategy for the synthesis of spirocyclic
intermediate 11.7. The indole derivative 11.1 may be protected, for example with a SEM group to give 11.2. Treatment of 11.2 with pyridinium tribromide in dioxane, followed by zinc- mediated reductive debromination provides oxindole derivative 11.3. This oxindole 11.3 is dialkylated with the b/s(2-iodoethyl)aniline 11.5, which is prepared in two steps from the corresponding diol 11.4 as shown, to afford the key spirocyclic intermediate 11.6. Lastly, catalytic hydrogenation provides the desired arylamine 11.7.
SCHEME 11
47
Figure imgf000049_0001
Most of the heterocyclic A ring derivatives (such as ACI in Scheme 1) required for the synthesis of the compounds of the present invention are known in the literature or may be prepared using straightforward modifications of known methodology. By way of illustration, some specific cases are shown in the following schemes. A synthetic route to 4-chloroquinoline intermediates of general structure 12.4 is shown in Scheme 12. These compounds may be prepared from the substituted aniline 12.1 as shown. Condensation of aniline 12.1 with ethyl acetoacetate affords the unsaturated ester 12.2, which may be thermally cyclized to provide the 4-hydroxyquinoline derivative 12.3. Standard treatment of 12.3 with POCI3 may be utilized to furnish the corresponding 4-chloroquinoline 12.4.
SCHEME 12
Figure imgf000049_0002
48 Scheme 13 details a similar sequence that may be used to provide 4- chloronaphthyridine intermediates such as 13.4. Reaction of aminopyridine 13.1 with Meldrum's acid and triethyl orthoacetate at elevated temperature leads to the condensation product 13.2, and this may be converted to the chloronaphthyridine 13.4 using analogous chemistry to Scheme 12. Similar procedures applied to other aminopyridine isomers may be used to provide alternative naphthyridine isomers.
SCHEME 13
Figure imgf000050_0001
The synthesis of the 1,4-benzodiazepinone derivative 14.7 is shown in Scheme 14. Alkylation of glycine methyl ester with the 2-nitrobenzyl bromide 14.1 provides amine 14.2, which is protected with a Boc group and then subjected to nitro reduction to give aniline 14.3. Treatment of 14.3 with HOBT in toluene at elevated temperature affords the 1,4- benzodiazepinone 14.4. After removal of the Boc group, 14.4 is reductively alkylated using 1- Boc-piperidin-4-one and sodium triacetoxyborohydride to provide, after deprotection, compound 14.7.
SCHEME 14
49
Figure imgf000051_0001
Scheme 15 illustrates methodology for the synthesis of key intermediate 15.4, in which there is a substituent (R10) on the aromatic ring ortho to the amino group. This approach begins with the dihalonitroaromatic starting material 15.1, which contains fluoro and bromo substituents. Depending on the precise nature of the reactants in this scheme, alternative halogens may be employed. For example, if the aromatic ring is a pyridine (G1 = N), it may be desirable to replace the fluoro substituent with a corresponding chloro moiety. In Scheme 15, R10 is introduced using standard Suzuki coupling conditions and the corresponding boronic acid R10B(OH)2 to afford the nitro compound 15.2. Depending on the nature of R10, a variety of alternative conditions may be employed, as will be appreciated by one skilled in the art.
The amine of interest (2.1) can be reacted with 15.2 under basic conditions to afford the nitroaromatic 15.3, which may be reduced to provide the desired arylamine intermediate 15.4. Alternative conditions may be employed throughout the illustrated route. For example, the nitro group in 15.3 may be hydrogenated using a number of alternative catalysts, or simply reduced using non-hydrogenation conditions, including the use of a metal such as iron, tin, or zinc under acidic conditions.
SCHEME 15
50
Figure imgf000052_0001
15.3 15.4
A variation on the route shown in Scheme 15 is outlined in Scheme 16, in which an amine substituent is added to the core aromatic ring. Treatment of 2,4-dichloro-5- nitropyridine (16.1) with the amine of interest (RR'NH) under basic conditions provides the aminopyridine 16.2. This may be elaborated in analogy with Scheme 15, reacting 16.2 with amine 2.1, and then effecting nitro reduction using zinc and ammonium chloride to afford the key intermediate 16.4. In addition to the amine RR'NH, other nucleophiles, such as cyanide, may be employed in similar methodology to provide a variety of compounds of interest.
SCHEME 16
Figure imgf000052_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
51 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.
INTERMEDIATE 1
Figure imgf000053_0001
4-Chloro-5-methoxv-2,8-dimethvlquinoline
Step A: Ethyl (3Z)-3-f(5-methoxv-2-methylphenvl)iminolbutanoate
A stirred mixture of 2-methyl-5-methoxyaniline (5.0 g, 36.4 mmol) and ethyl acetoacetate (4.74 g, 36.4 mmol) in toluene (100 mL) was heated at reflux for 3 h, using a Dean- Stark trap to remove water. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and purified through a short silica gel column to give the title compound in sufficient purity for use in the next step.
Step B: 5-Methoxv-2,8-dimethylquinolin-4-ol
A stirred solution of ethyl (3Z)-3-[(5-methoxy-2-methylphenyl)imino]butanoate (5.57 g, 23.6 mmol) in diphenyl ether (20 mL) was heated at 250 °C for 1 h, then cooled to ambient temperature. The resulting precipitate was isolated by filtration, washing with petroleum ether, and dried to give the title compound.
Step C: 4-Chloro-5-methoxv-2,8-dimethylquinoline
5-Methoxy-2,8-dimethylquinolin-4-ol (2.5 g, 12.3 mmol) was suspended in acetonitrile
(20 mL) and POCI3 (6 mL) and the stirred reaction mixture was heated at 90 °C for 3 h, then cooled to ambient temperature. The solvent was removed under reduced pressure and ice- water was added. The mixture was adjusted to pH = 9 by addition of 10 N aqueous sodium hydroxide and the resulting precipitate was collected by filtration and dried to afford the title
52 compound. MS: m/z = 222.1 (M + 1); 1H NMR (400 MHz, CDCI3) δ 7.43 (d, 1H, J = 8.0 Hz), 7.29 (s, 1 H), 6.78 (d, 1H, J = 8.0 Hz), 3.91 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H).
Figure imgf000054_0001
ferf-Butvl {2-r(4-chloro-2,8-dimethylquinolin-5-vl)oxvlethvl)carbamate
Step A: 4-Chloro-2,8-dimethylquinolin-5-o[
To a solution of 4-chloro-5-methoxy-2,8-dimethylquinoline (described in Intermediate 1) (1.00 g, 4.51 mmol) in CH2CI2 (100 mL) was added BBr3 (1 M in pentane, 13.5 mL, 13.5 mmol), dropwise. The reaction mixture was heated at 40 °C with stirring for 18 h, then it was allowed to cool and the solvent was removed under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate carefully and the resulting solid was collected by filtration, washed with water and dried to give the title compound. MS: m/z = 208.0 (M + 1).
Step B: fe/t-Butyl {2-f(4-chloro-2.8-dimethvlquinolin-5-vl)oxvlethyl)carbamate
To a solution of W-Boc-ethanolamine (272 mg, 1.69 mmol) in THF (20 mL) was added 4- chloro-2,8-dimethylquinolin-5-ol (350 mg, 1.69 mmol) and triphenylphosphine (530 mg, 2.02 mmol). The stirred mixture was cooled to 0 °C, diethyl azodicarboxylate (0.317 mL, 2.20 mmol) was added dropwise, and the mixture was allowed to warm to ambient temperature. After 18 h, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of hexanes: EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 352.1 (M + 1); 1H NMR (400 MHz, CDCI3) δ 7.42 (dd, 1H, J = 8.0, 1.1 Hz), 7.32 (s, 1H), 6.75 (d, 1H, J = 8.0 Hz), 5.17 (s, 1H), 4.11 (t, 2H, J = 5.0 Hz), 3.66 (q, 2H, J = 5.3 Hz), 2.68 (s, 3H), 2.66 (s, 3H), 1.48 (s, 9H). 53 INTERMEDIATE 3
Figure imgf000055_0001
4-Chloro-2.8-dimethylquinoline
Step A: Ethyl 3-[(2-methvlphenyl)aminolbut-2-enoate
A stirred mixture of 2-methylaniline (4.0 g, 37 mmol) and ethyl acetoacetate (5.9 g, 45 mmol) in EtOH (80 mL) was heated at reflux for 16 h. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo to give the title compound in sufficient purity for use in the next step.
Step B: 2,8-Dimethylquinolin-4-ol
A stirred solution of ethyl 3-[(2-methylphenyl)amino]but-2-enoate (2.0 g, 9.1 mmol) in diphenyl ether (20 mL) was heated at 250 °C for 1 h, then cooled to ambient temperature. The resulting precipitate was isolated by filtration, washing with petroleum ether, and dried to give the title compound.
Step C: 4-Chloro-2,8-dimethylquinoline
2,8-Dimethylquinolin-4-ol (0.70 g, 4.0 mmol) was suspended in POCI3 (7 mL) and the stirred reaction mixture was heated at 110 °C for 6 h, then cooled to ambient temperature. The reaction mixture was concentrated to remove most of the POCI3 and the residue was poured onto ice with stirring. The resulting mixture was adjusted to pH 7 - 8 by addition of saturated aqueous sodium bicarbonate, and the precipitate was isolated by filtration and dried to give the title compound. MS: m/z = 192.0 (M + 1); 1H NMR (400 MHz, CDCi3) δ 8.04 (d, 1H, J = 8.4 Hz), 7.58 (d, 1H, J = 6.8 Hz), 7.45 (m, 1H), 7.39 (s, 1H), 2.80 (s, 3H), 2.73 (s, 3H).
INTERMEDIATE 4 54
Figure imgf000056_0001
4-Chloro-2,8-dimethyl-l,5-naphthvridine
Step A: 2,2-Dimethvl-5-{l (4-methvlpvridin-3-vl)aminolethylidene}-l,3-dioxane-4,6-dione To a stirred mixture of 3-amino-4-met ylpyridine (2.00 g, 18.5 mmol) and Meldrum's acid (3.20 g, 22.2 mmoi) at 100 °C was added triethyl orthoacetate (18.0 g, 111 mmol) dropwise. The resulting mixture was stirred at 100 °C for 4 h then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 277.1 (M + 1).
Step B: 2,8-Dimethyl-1.5-naphthyridin-4-ol
A stirred solution of 2,2-dimethyl-5-{l-[(4-methylpyridin-3-yl)amino]ethylidene}-l,3- dioxane-4,6-dione (2.29 g, 8.29 mmol) in diphenyl ether (50 mL) was heated at reflux for 1 h, then cooled to ambient temperature. The resulting precipitate was isolated by filtration, washing with diphenyl ether, and dried to give the title compound. MS: m/z = 175.0 (M + 1).
Step C: 4-Chloro-2,8-dimethyl-l,5-naphthvridine
2,8-Dimethyl-l,5-naphthyridin-4-ol (765 mg, 4.39 mmol) was suspended in POCI3 (20 mL) and the stirred reaction mixture was heated at 110 °C for 3 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the POCI3 and the residue was poured onto ice with stirring, then extracted with CH2CI2 (3 χ 150 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:EtOAc - 100:0 to 50:50, to give the title compound. MS: m/z = 193.0 (M + 1); 1H NMR (500 MHz, CDCI3) δ 8.84 (d, 1H, J = 4.2 Hz), 7.63 (s, 1H), 7.50 (d, 1H, J = 4.4 Hz), 2.82 (s, 3H), 2.75 (s, 3H).
INTERMEDIATE 5 55
Figure imgf000057_0001
3-fl-(4-Aminophenvl)piperidin-4-yl1-l,3.4,5-tetrahvdro-2H-l,3-benzodiazepin-2-one
Step A: 3-fl-(4-Nitrophenvl)piperidin-4-vl]-l,3,4.5-tetrahydro-2H-l,3-benzodiazepin-2-one
A stirred mixture of 4-fluoronitrobenzene (30 mg; 0.213 mmol), 3-(piperidin-4-yl)- l,3,4,5-tetrahydro-2tf-l,3-benzodiazepin-2-one (US 2006/0019946} (52 mg, 0.213 mmol), and DIEA (0.108 mL, 0.638 mmol) in DMF (1 mL) was heated at 90 °C for 18 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was triturated with ether and the resulting solid was isolated by filtration and dried to give the title compound in sufficient purity for use in the next step.
MS: m/z = 367.3 (M + 1).
Step B: 3-[l-(4-Aminophenvl)piperidin-4-vll-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
A mixture of 3-[l-(4-nitrophenyl)piperidin-4-yl]-l,3,4,5-tetrahydro-2H-l,3- benzodiazepin-2-one (78 mg, 0.213 mmol) and 10% Pd/C (45 mg, 0.042 mmol) in EtOH (10 mL) and DMF (2 mL) was stirred at 40 °C under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The resulting mixture was cooled to ambient temperature, filtered through Celite", washing with EtOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 337.3 (M + 1).
INTERMEDIATE 6
56
Figure imgf000058_0001
l-(4-Aminophenvl¾-l',4'-dihvdro-3'H-spiro[piperidine-4,2'-quinoxalin1-3'-one
Step A: l',4'-Dihydro-3'H-spirofpiperidine-4,2'-quinoxalin1-3'-one
A suspension of 2-bromoaniline (172 mg, 1.0 mmol), 4-amino-l-(iert- butoxycarbonyl)piperidine-4-carboxylic acid (488 mg, 2.0 mmol), cesium carbonate (489 mg, 2.0 mmol) and Cul (19 mg, 0.1 mmol) in DMSO (1 mL) was deoxygenated with nitrogen gas. The reaction mixture was stirred at 125 °C under nitrogen for 5 h, then cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, then brine, then dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was dissolved in TFA (5 mL) and the solution was stirred at ambient temperature for 2 h, and then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 218.2 ( + 1).
Step B: l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiroipiperidine-4,2'-quinoxalinl-3'-one
Essentially following the procedures described in Intermediate 5, but using ,4'- dihydro-3'H-spiro[piperidine-4,2'-quinoxalin]-3'-one in place of 3-(piperidin-4-yl)-l,3,4,5- tetrahydro-2H-l,3-benzodiazepin-2-one, the title compound was obtained. MS: m/z = 309.3 (M + 1).
INTERMEDIATE 7
Figure imgf000058_0002
57 l-(4-Aminophenvl)spirorpiperidine-4,2'-pvridof3,2-fc1[l,41oxazinl-3'(4'H)-one
Step A: 1-terf-Butvl 4-methyl 4-f(2-nitropvridin-3-vl)oxvlpiperidine-l,4-dicarboxylate
To a mixture of 3-fluoro-2-nitropyridine (142 mg, 1.0 mmol) and 1-rert-butyl 4-methyl 4- hydroxypiperidine-l,4-dicarboxylate (260 mg, 1.00 mmol) in THF (10 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol) followed by the addition of 15- crown-5 (2 drops). The stirred mixture was warmed to ambient temperature and heated at 45 °C for 18 h. The reaction mixture was diluted with saturated aqueous NH4CI and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 60:40, to give the title compound. MS: m/z = 281.2 (M + I - CO2C4H9).
Step B: ferf-Butyl 3'-oxo-3',4'-dihvdro-lH-spirorpiperidine-4,2'-pyridof3,2-b1fl,4loxazinel-l- carboxvlate
To a stirred solution of 1-fert-butyl 4-methyl 4-[(2-nitropyridin-3-yl)oxy]piperidine-l,4- dicarboxylate (333 mg, 0.87 mmol) in AcOH (5 mL) was added iron powder (244 mg, 4.35 mmol). The resulting mixture was stirred at 50 °C for 3 h and cooled to ambient temperature. EtOAc (20 mL) was added followed by saturated aqueous sodium bicarbonate and the mixture was filtered through Celite* and extracted with EtOAc (3x). The combined organic extracts were dried over a2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 40:60, to give the title compound. MS: m/z = 320.3 (M + 1).
Step C: Spirofpiperidine-4,2'-pyridoi3.2-foiri.41oxazin1-3'(4'H)-one
To a solution of terf-butyl 3'-oxo-3^4'-dihydro-l/-/-spiro[piperidine-4,2'-pyrido[3,2- i ][l,4]oxazine]-l-carboxylate (636 mg, 2.0 mmol) in CH2CI2 (4 mL) was added TFA (8 mL). The resulting mixture was stirred at ambient temperature for 18 h and concentrated to dryness in vacuo to give the title compound in sufficient purity for use in the next step.
Step D: l-(4-Aminophenvl)spirofpiperidine-4,2'-pyrido[3,2-falfl,41oxazin1-3'(4'H)-one 58 Essentially following the procedures described in Intermediate 5, but using
spiro[piperidine-4,2'-pyridot3/2-ib][l,4]oxazin]-3'(4'H)-one in place of 3-(piperidin-4-y!)-l,3,4,5- tetrahydro-2H-l,3-benzodiazepin-2-one, the title compound was obtained. MS: m/z - 311.2 (M + 1).
INTERMEDIATE 8
Figure imgf000060_0001
l'-(4-Aminophenyl)spiro[l,4-benzoxazine-2,4'-piperidin1-3(4H)-one
Essentially following the procedures described in Intermediate 7, but using l-fluoro-2- nitrobenzene in place of 3-fluoro-2-nitropyridine, the title compound was obtained. MS: m/z = 310.2 (M + l).
INTERMEDIATE 9
Figure imgf000060_0002
l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiro[piperidine-4,2'-pyridof2.3-fc1pvrazin]-3'-one
Step A: 1-tert-Butyl 4-methyl 4-f(2-nitropvridin-3-vl)aminolpiperidine-l,4-dicarboxylate
A stirred mixture of 3-fluoro-2-nitropyridine (300 mg, 2.1 mmol), l-feri-butyl 4-methyl 4-aminopiperidine-l,4-dicarboxylate (654 mg, 2.5 mmol), and DIEA (819 mg, 6.3 mmol) in DMF
59 (7 mL) was heated at 70 °C for 72 h. The reaction mixture was poured into EtOAc and the organic layer was washed with water, then brine, then dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 50:50, to give the title compound. MS: m/z = 325.2 (M + I - C4H9).
Step B: ferf-Butyl 3'-oxo-3',4'-dihvdro-lH,l'H-spiro[piperidine-4,2'-pyrido[2,3-fc1pvrazine]-l- carboxylate
A stirred mixture of 1-teri-butyl 4-methyl 4-[(2-nitropyridin-3-yl)amino]piperidine-l,4- dicarboxylate (232 mg, 0.609 mmol) and iron powder (340 mg, 6.09 mmol) in AcOH (5 mL) was heated at 60 °C for 2 h. After cooling to ambient temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with EtOAc (3x). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z - 319.3 (M + 1).
Step C: l',4'-Dihvdro-3'H-spirofpiperidine-4,2'-pvridoi2,3-fe1pyrazin1-3'-one
To a solution of iert-butyl 3'-oxo-3',4'-dihydro-lH,l'H-spiro[piperidine-4,2'-pyrido[2,3- £>]pyrazine]-l-carboxylate (160 mg, 0.503 mmol) in CH2CI2 (5 mL) was added TFA (5 mL). The resulting mixture was stirred at ambient temperature for 4 h and concentrated in vacuo. The crude residue was dissolved in CH2CI2 (5 mL) and HCI (1 M in diethyl ether, 3 mL, 3 mmol) was added and the resulting mixture was stirred for 15 min. The solid was collected by filtration, washing with diethyl ether and dried to give the title compound in sufficient purity for use in the next step. MS: m/z = 219.1 (M + 1).
Step D: l-(4-Aminophenvl)-l',4'-dihvdro-3'H-spiro[piperidine-4,2'-pyridof2,3-ib1Pvrazin1-3'-one
Essentially following the procedures described in Intermediate 5, but using ,4'- dihydro-3'H-spiro[piperidine-4,2'-pyrido[2,3-fa]pyrazin]-3'-one in place of 3-(piperidin-4-yl)- l,3,4,5-tetrahydro-2/-/-l,3-benzodiazepin-2-one, the title compound was obtained. MS: m/z = 310.2 (M + l).
INTERMEDIATE 10
60
Figure imgf000062_0001
l-(4-Aminophenvl)-5'-methoxv-l'-{i2-(trimethvlsilvl)ethoxy]methvl}spiro[piperidine-4,3'- Pvrrolof2,3-b1Pvridin]-2'(rH¾-one
Step A: 5-Methoxv-l-f[2-(trimethvlsilvl)ethoxvlmethvl)-lH-pyrrolo[2,3-blPvridine
To a solution of 5-methoxy-lH-pyrrolo[2,3-jfc>]pyridine (1.00 g, 6.75 mmol) in DMF (10 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 324 mg, 8.10 mmol) portionwise and the mixture was stirred for 1 h. To the resulting mixture was slowly added 2- (trimethylsily)ethoxymethyl chloride (1.43 mL, 8.10 mmol) and the reaction mixture was stirred for an additional 1 h, then quenched with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step.
Step B: 3,3-Dibromo-5-methoxv-l-{[2-(trimethvlsilvl)ethoxy]methvl}-l,3-dihvdro-2H-
Pvrrolof2,3-fo1pyridin-2-one
A solution of 5-methoxy-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[2,3-fa]pyridine (1.88 g, 6.75 mmol) in 1,4-dioxane (5 mL) was added dropwise to a stirred suspension of pyridine hydrobromide perbromide (10.8 g, 33.7 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at ambient temperature for 1 h then quenched with water and extracted with EtOAc (3x). The combined organic extracts were washed with water, then brine, then dried over Na2S04, filtered, and concentrated in vacuo. The crude product was immediately dissolved in CH2CI2 and filtered through a plug of silica gel, eluting with CH2CI2. The filtrate was washed with saturated aqueous Sodium bicarbonate, then brine, then dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z = 453.0 (M + 1).
Step C: 5-Methoxv-l-{[2-(trimethvlsilvl)ethoxv1methvl}-l,3-dihvdro-2H-pyrrolor2,3-blPVridin-2- one To a solution of 3 -dibromo-5-methoxy-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3- dihydro-2H-pyrrolo[2,3-jb]pyridin-2-one (3.00 g, 6.75 mmol) in THF (44 mL) and saturated aqueous NH4CI (11 mL) was added zinc (4.4 g, 67 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was filtered through Celite®, washing with EtOAc. The organic layer of the filtrate was separated and the aqueous phase was extracted further with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 60:40, to give the title compound. 1H NMR (500 MHz, CDCI3) δ 7.90 (d, 1H, J = 2.7 Hz), 7.20 (dt, 1H, J = 2.7, 1.2 Hz), 5.24 (s, 2H), 3.85 (s, 3H), 3.72-3.65 (m, 2H), 3.59 (t, 2H, J = 1.0 Hz), 1.02-0.95 (m, 2H), 0.08 (s, 9H).
Step D: f(4-Nitrophenyl)imino1diethane-2,l-diyl dimethanesulfonate
To a stirred solution of 4-[/V,/V-bis(2-hydroxyethyl)amino]nitrobenzene (5.00 g, 22.1 mmol) and triethylamine (9.24 mL, 66.3 mmol) in CH2CI2 (50 mL) at 0 °C was added dropwise methanesulfonyl chloride (5.15 mL, 66.3 mmol). The resulting mixture was stirred for 1 h at 0 °C, diluted with CH2CI2 (200 mL) and washed with saturated aqueous sodium bicarbonate, then water, then brine, then dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. 1H NMR (500 MHz, CDCI3) δ 8.17 (d, 2H, J = 8.0 Hz), 6.73 (d, 2H, J = 8.0 Hz), 4.42 (t, 4H, J = 5.7 Hz), 3.90 (t, 4H, J = 5.8 Hz), 3.02 (s, 6H).
Step E: /V,A/-5/s(2-iodoethvl)-4-nitroaniline
A mixture of [(4-nitrophenyl)imino]diethane-2,l-diyl dimethanesulfonate
(8.40 g, 22.0 mmol) and sodium iodide (26.3 g, 176 mmol) in CH3CN (400 mL) was heated at reflux for 1 h. The mixture was cooled to ambient temperature, diluted with EtOAc (500 mL) and filtered through Celite®, washing with EtOAc. The combined organic extracts were washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 70:30, to give the title compound. 1H NMR (500 MHz, CDCI3) δ 8.16 (d, 2H, J = 8.0 Hz), 6.63 (d, 2H, J = 8.0 Hz), 3.85 (t, 4H, J = 7.9 Hz), 3.25 (t, 4H, J = 7.9 Hz).
Step F: 5'-Methoxv-l-(4-nitrophenvl)-l'-{f2-(trimethvlsilvl)ethoxv1methvl}spiroipiperidine-4,3'- pyrrolor2,3-b1pvridinl-2'(l'H)-one
To a stirred solution of 5-methoxy-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H- pyrrolo[2,3-ib]pyridin-2-one (295 mg, 1.00 mmol) in DMF (10 mL) was added cesium carbonate 62 (979 mg, 3.00 mmol). The resulting mixture was stirred at ambient temperature for 5 min then /V,/V-b/s(2-iodoethyl)-4-nitroaniline (447 mg, 1.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 h then poured into EtOAc (200 mL). The mixture was washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:EtOAc - 100:0 to 50:50, to give the title compound. MS: m/z = 485.3 (M + 1).
Step G: l-(4-Aminophenvl)-5'-methoxv-l'-{[2-(trimethvlsilvl)ethoxvlmethvl)spirofpiperidine-
4.3'-Pvrrolor2.3-frlPvridinl-2'(l'H)-one
A mixture of 5'-methoxy-l-(4-nitrophenyl)-l'-{[2-
(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-i)]pyridin]-2'(l'H)-one (322 mg, 0.66 mmol) and 10% Pd/C (70 mg, 0.066 mmol) in EtOAc (50 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The resulting mixture was filtered through Celite*", washing with EtOAc, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 455.3 (M + 1).
INTERMEDIATE 11
Figure imgf000064_0001
Methyl l-(4-aminophenvl)-2'-oxo-l'-{f2-(trimethvlsilvl)ethoxvlmethyl}-l',2'- dihvdrospirofpiperidine-4,3'-pyrrolo[2,3-iblpvridinel-5'-carboxvlate
Essentially following the procedures described in Intermediate 10, but using methyl 1H- pyrrolo[2,3-b]pyridine-5-carboxylate in place of 5-methoxy-lH-pyrrolo[2,3-ib]pyridine, the title compound was obtained. MS: m/z - 483.3 (M + 1).
INTERMEDIATE 12 63
Figure imgf000065_0001
l-(4-Aminophenvl)-5'-methoxv-lMf2-(trimethvlsilyl)ethoxy1me
PVrrolof2,3-b1Pvridin1-2'(rH)-one
Step A: l-(4-nitrophenvl)-l'-{f2-(trimethvlsilvl)ethoxv1methvl)spirofpiperidine-4.3'-pyrrolo[2,3- b1pvridinl-2'(l'H)-one
Essentially following the procedures described in Intermediate 10, but using 7-azaindole in place of 5-methoxy-lH-pyrrolo[2,3-/b]pyridine, the title compound was obtained. MS: m/z = 455.3 (M + l).
Step B: l-(4-Aminophenvl)-5'-methoxv-l'-{f2-(trimethvlsilvl)ethoxvlmethyl}spiro[piperidine-
4,3'-Pvrrolo[2.3-61pvridinl-2'(l'H)-one
Essentially following the procedures described in Intermediate 10, but using l-(4- nitrophenyl)-l'-{[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-i)]pyridin]- 2'(l'H)-one in place of 5'-methoxy-l-(4-nitrophenyl)-l'-{[2-
(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3--5]pyridin]-2'(l'H)-one, the title compound was obtained. MS: m/z = 425.4 (M + 1).
Figure imgf000065_0002
l-(4-Amino-2-bromophenvn-l'-{[2-(trimethvlsilvl¾ethoxvlmethvl)spirofpiperidine-4,3'- pyrrolo[2,3-b1Pvridin1-2'(l'H)-one 64 Step A: l-(2-Bromo-4-nitrophenvl)-l'-{r2-(trimethvlsilvl)ethoxvlmethvl)spiro[piperidine-4,3'-
Pvrrolof2,3--7]pyridin1-2'(l'W)-one
To a solution of l-(4-nitrophenyl)-l'-{[2-(trimethylsilyl)ethoxy]rnethyl}spiro[piperidine- 4,3'-pyrrolo[2,3-6]pyridin]-2'(l'H)-one (described in Intermediate 12) (500 mg, 1.1 mmol) in DMF (10 mL) was added /v-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at ambient temperature for 2 h; diluted with EtOAc (200 mL) and washed with saturated aqueous sodium bicarbonate (3x), then brine, then dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z = 533.2 (M + 1).
Step B: l-(4-Amino-2-bromophenvl)-l'-{[2-(trimethvlsilvnethoxvlmethyl}spirofpiperidine-4,3'-
Pvrrolor2,3-b1Pvridinl-2'(l'H)-one
To a solution of l-(2-bromo-4-nitrophenyl)-l'-{[2- (trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one (587 mg, 1.1 mmol) in AcOH (10 mL) was added iron powder (614 mg, 11 mmol). The resulting mixture was stirred at 50 °C for 3 h, then the AcOH was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and EtOAc and filtered through Celite*, washing with EtOAc. The organic layer was separated and the aqueous layer was extracted further with EtOAc (2x). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel
chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 50:50, to give the title compound. MS: m/z = 503.2 (M + 1).
INTERMEDIATE 14
Figure imgf000066_0001
l-(4-Aminophenvl)-5'-bromo-l'-{[2-(trimethvlsilvl)ethoxvlmethvl}spiro[piperidine-4.3'- pyrrolof2,3-fe1PVridinl-2'(l'H)-one 65 Step A: 5-Bromo-l-{f2-(trimethvlsilvl)ethoxvlmethvl}-l,3-clihvdro-2H-pvrrolof2,3-fc1Pvridin-2- one
To a solution of l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one (Stump et al. (2009) Bioorg. Med. Chem. Lett. 19, 214-217) (1.32 g, 4.99 mmol) in DMF (10 mL) was added W-bromosuccinimide (890 mg, 4.99 mmol). The resulting mixture was stirred at ambient temperature for 18 h then diluted with EtOAc (250 mL), washed with saturated aqueous sodium bicarbonate (3x), then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 80:20, to give the title compound. MS: m/z = 343.1 (M + 1).
Step B: 5'-Bromo-l-(4-nitrophenvl)-l'-{f2-(trimethylsilvl)ethoxv1methvl}spiro[piperidine-4,3'- pyrrolof2,3-i 1pvridin1-2'(l'H)-one
Essentially following the procedures described in Intermediate 10, but using 5-bromo-l- {[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-pyrrolo[2,3- 3]pyridin-2-one in place of 5- methoxy-l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, the title compound was obtained. MS: m/z - 533.2 (M + 1).
Step C: l-(4-Aminophenvl)-5'-bromo-l'-{f2-(trimethvlsilvl¾ethoxvlmethvl}spiro[piperidine-4,3'- pyrrolo[2,3-i 1pvridinl-2'(l' V)-one
Essentially following the procedures described in Intermediate 13, but using S'-bromo-l- (4-nitrophenyl)-l'-{[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]- 2'(l'H)-one in place of l-(2-bromo-4-nitrophenyl)-l'-{[2-
(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-fa]pyridin]-2'(l'H)-one, the title compound was obtained. MS: m/z - 503.1 (M + 1).
INTERMEDIATE 15
Figure imgf000067_0001
4-Chloro-2,6,8-trimethvlquinolin-7-amine Step A: Ethyl (2Z)-3-{[3-(acetvlamino)-2,4-dimethylphenvnaminojbut-2-enoate
A stirred mixture of A/-(3-amino-2,6-dimethylphenyl)acetamide (1.50 g, 8.40 mmol) and ethyl acetoacetate (1.30 g, 9.99 mol) in EtOH (30 mL) was heated at reflux for 20 h. The reaction mixture was concentrated in vacuo to afford the title compound in sufficient purity for use in the next step.
Step B: M-(4-Hvdroxv-2.6,8-trimethvlquinolin-7-vl)acetamide
Ethyl (2Z)-3-{[3-(acetylamino)-2;4-dimethylphenyl]amino}but-2-enoate (2.00 g, 6.90 mmol) was suspended in diphenyl ether (30 mL) and the mixture was stirred at 250 °C for 1 h then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washing with petroleum ether, and dried to give the title compound. MS: m/z = 245.0 (M + 1).
Step C: A/-(4-Chloro-2,6.8-trimethylquinolin-7-vl)acetamide
A mixture of A/-(4-hydroxy-2,6,8-trimethylquinolin-7-yl)acetamide (600 mg, 2.50 mmol) and POCI3 (20 mL) was stirred at 110 °C for 10 h. Most of the POCI3 was removed under reduced pressure and the residual mixture was poured onto ice-water slowly with stirring. The mixture was adjusted to pH = 8 by addition of saturated aqueous sodium bicarbonate, and the resulting precipitate was isolated by filtration, washing with water, and dried to afford the title compound. MS: m/z = 262.8 (M + 1).
Step D: 4-Chloro-2,6,8-trimethylquinolin-7-amine
To a solution of /V-(4-chloro-2,6,8-trimethylquinolin-7-yl)acetamide (420 mg, 1.60 mmol) in EtOH (10 mL) was added aqueous HCI (4 M, 4 mL, 16 mmol). The reaction mixture was stirred at 100 °C for 20 h, then cooled to ambient temperature and adjusted to pH = 8 by addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with EtOAc (3 x 8 mL), and the combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with petroleum ether:EtOAc - 5:1, to give the title compound. MS: m/z = 220.9 (M + 1); 1H NM (400 MHz, CD3OD) δ 7.72 (s, 1H), 7.15 (s, 1H), 2.61 (s, 3H), 2.53 (s, 3H), 2.38 (s, 3H).
INTERMEDIATE 16
Figure imgf000069_0001
4-Chloro-2.8-dimethyiquinolin-6-amine
Step A: 2,2,2-Trifluoro-/\/-(2-met vl-4-nitrophenvnacetamicle
To a stirred mixture of 2-methyl-4-nitroaniline (5.00 g, 32.9 mmol) in CH2CI2 (50 mL) and triethylamine (7.04 mL, 65.7 mmol) at 0 °C was added trifluoroacetic anhydride (10.4 g, 49.3 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 1 h, then washed with water (3 x 60 mL), dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z = 248.9 (M + 1).
Step B: A/-(4-Amino-2-methvlphenyl)-2,2.2-trifluoroacetamide
A mixture of 2,2,2-trifluoro-A/-(2-methyl-4-nitrophenyl)acetamide (8.00 g, 32.2 mmol) and 10% Pd/C (800 mg, 0.75 mmol) in MeOH (80 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 1 h. The resulting mixture was filtered through Celite*, washing with MeOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 219.0 (M + 1).
Step C: A/-f4-(Acetvlamino)-2-methylphenvn-2,2,2-trifluoroacetamide To a stirred mixture of /V-(4-amino-2-methylphenyl)-2,2,2-trifluoroacetamide (7.12 g,
32.6 mmol) in CH2CI2 (50 mL) and triethylamine (6.75 mL, 65.3 mmol) at 0 °C was added acetyl chloride (2.78 mL, 39.2 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 2 h, then washed with water (3 x 60 mL), dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z = 261.1 (M + 1).
Step D: A/-(4-Amino-3-methylphenyl)acetamide
A mixture of A/-[4-(acetylamino)-2-methylphenyl]-2,2,2-trifluoroacetamide (2.90 g, 11.2 mmol) and potassium carbonate (9.24 g, 66.9 mmol) in MeOH (30 mL) and water (30 mL) was stirred at ambient temperature for 14 h. The mixture was concentrated in vacuo to removed MeOH, then extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z = 165.1 (M + 1).
Step E: 4-Chloro-2,8-dimethylquinolin-6-amine
Essentially following the procedures described in Intermediate 15, but using Λ/-(4- amino-3-methylphenyl)acetamide in place of /V-(3-amino-2,6-dimethylphenyl)acetamide, the title compound was obtained. MS: m/z = 207.0 (M + 1); 1H NMR (400 MHz, CDCI3) δ 7.19 (s, 1H), 7.04 (d, 1H, J = 2.4 Hz), 6.94 (d, 1H, J = 1.2 Hz), 4.01 (br s, 1H), 2.63 (s, 3H), 2.57 (s, 3H).
INTERMEDIATE 17
Figure imgf000070_0001
2-(4-Chloro-2,8-dimethylquinolin-6-vl)propan-2-ol
To a stirred mixture of methyl 4-chloro-2,8-dimethylquinoline-6-carboxylate (60 mg, 0.24 mmol) in THF (5 mL) was added methylmagnesium bromide (3.0 M in diethyl ether, 0.23 mL, 0.69 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was treated with additional methylmagnesium bromide (3.0 M in diethyl ether, 0.23 mL, 0.69 mmol), stirred for 18 h and then concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eiuting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 250.1 (M + 1).
INTERMEDIATE 18
Figure imgf000071_0001
4-Chloro-7-ethoxv-2,6,8-trimethylquinoline
To a stirred mixture of 4-chloro-2,6,8-trimethylquinolin-7-oI (50 mg, 0.226 mmol) and cesium carbonate (220 mg, 0.677 mmol) in DMF at ambient temperature was added iodoethane (246 mg, 1.58 mmol). The mixture was heated at 60 °C for 1 h, cooled to ambient temperature, diluted with water, and the resulting solid was isolated by filtration. The crude product was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 250.1 (M + 1).
INTERMEDIATE 19
Figure imgf000071_0002
Step A: 5-Bromo-2,8-dimethvlquinoline
A mixture of 2-methyl-5-bromoaniline (802 mg, 4.31 mmol) and (2 )-but-2-enal (1.5 mL) in concentrated HCI (10 mL) and AcOH (10 mL) was heated at reflux for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with 2 N aqueous sodium bicarbonate (50 mL) and extracted with CH2CI2 (2 χ 20 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with petroleum ether:EtOAc - 200:1, to afford the title compound. 1H NMR (400 MHz, CDCI3) δ 8.38 (d, 1H, J = 8.4 Hz), 7.62 (d, 1H, J = 7.6 Hz), 7.38- 7.34 (m, 2H), 2.77 (s, 3H), 2.74 (s, 3H).
INTERMEDIATE 20 70
Figure imgf000072_0001
8-Bromo-2,4,6-trimethylquinoline
A mixture of 2-bromo-4-methylariiline (1.50 g, 8.06 mmol) and (3£)-pent-3-en-2-one (1.6 mL, 9.67 mmol, 60%) in concentrated HCI (20 mL) was heated at reflux for 18 h. The reaction mixture was concentrated in vacuo and the residue was treated with 2 N aqueous sodium bicarbonate (60 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with petroleum ether:EtOAc - 100:1, to afford the title compound. 1H NMR (400 MHz, CDCI3) δ 7.86 (d, 1H, J = 2.0 Hz), 7.66 (s, 1H), 7.13 (s, 1H), 2.73 (s, 3H), 2.63 (s, 3H), 2.51 (s, 3H).
INTERMEDIATE 21
Figure imgf000072_0002
4-[(2,6,8-Trimethylquinolin-4-vl)aminolbenzoic acid
Step A: Methyl 4-[(2,6,8-trimethylquinolin-4-vl)aminolbenzoate
Essentially following the procedures described in Example 1, but using methyl 4- aminobenzoate in place of l-(4-aminophenyl)spiro[piperidine-4,3'-pyrrolo[2,3-i)]pyridin]- 2'(l'H)-one, the title compound was obtained. MS: m/z = 321.3 (M + 1).
Step B: 4-[(2,6,8-Trimethvlquinolin-4-yl)amino1benzoic acid 71 To a stirred solution of methyl 4-[(2,6,8-trimethylquinolin-4-yl)amino]benzoate (1.30 g, 4.06 mmol) in THF (60 mL) and MeOH (20 mL) was added a solution of lithium hydroxide (389 mg; 16.2 mmol) in water (20 mL). The resulting mixture was heated at 50 °C and stirred for 4 h. After cooling to ambient temperature, the organic solvent was removed under reduced pressure and the mixture was adjusted to pH = 4-5. The resulting precipitate was collected by filtration and dried to afford the title compound. MS: m/z = 307.2 (M + 1). 1H NMR (400 MHz, DMSO-d5) δ 12.57 (br s, 1H), 9.03 (br s, 1H), 7.91 (d, 2H, J = 8.7 Hz), 7.88 (s, 1H), 7.40 (s, 1H), 7.37 (d, 2H, J = 8.7 Hz), 7.15 (s, 1H), 2.63 (s, 3H), 2.53 (s, 3H), 2.46 (s, 3H).
INTERMEDIATE 22
Figure imgf000073_0001
l-(4-Aminophenvl)-7'-fert-butylspiro[piperidine-4,5'-pvrrolo[2,3-ci1pvrimidinl-6'(7'/-/)-one
Step A: Diethyl 2-formylbutanedioate
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 23.0 g, 0.574 mol) in THF (300 mL) was added EtOH (33.5 mL, 0.574 mol) dropwise. The resulting mixture was stirred at ambient temperature for 1 h then cooled to 10 "C and a solution of diethyl succinate (96 mL, 0.574 mol) in THF (100 mL) was added dropwise, followed by a solution of ethyl formate (46.2 mL, 0.574 mol) in THF (100 mL) dropwise. The reaction mixture was stirred at ambient temperature for 18 h, then diluted with water (500 mL) and extracted with diethyl ether (2 x 250 mL), and these organic extracts were discarded. The aqueous layer was acidified to pH = 3-4 by addition of 50% aqueous sulfuric acid and extracted with diethyl ether (2 x 250 mL). The combined organic layers were washed with brine, dried over a2S04, filtered, and concentrated in vacuo. The residue was purified by vacuum distillation to afford the title compound (b.p. 90-92 °C at 2 mm Hg). MS: m/z = 203.0 (M + 1).
Step B: Ethyl f4-hvdroxv-2-(methylsulfanvl)pvrimidin-5-vllacetate 72 To a stirred mixture of diethyl 2-formy!butanedioate (50.0 g, 0.247 moi) and S- methylthiourea semisulfate (34.4 g, 0.247 mol) in water (220 mL) was added a solution of sodium hydroxide (14.8 g, 0.37 mol) in water (55 mL). The resulting mixture was stirred at 100 °C for 90 min, cooled to ambient temperature, and acetic acid (21.2 mL, 0.37 mol) was added slowly. The resulting mixture was stirred at ambient temperature for 18 h and the solid was isolated by filtration, washing with water, and drying under reduced pressure to provide the title compound. MS: m/z = 229.1 (M + 1).
Step C: Ethyl [4-chloro-2-(methylsulfanvl)pvrimidin-5-vnacetate
A stirred suspension of ethyl [4-hydroxy-2-(methylsulfanyl)pyrimidin-5-yl]acetate (15.0 g, 65.7 mmol) in POCI3 (123 mL) was heated at reflux for 2 h, then concentrated in vacuo. The residue was twice resuspended in benzene (50 mL) and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 25:75, to give the title compound. MS: m/z = 247.0 (M + 1).
Step D: Ethyl [4-(ferf-butvlamino)-2-(methvlsulfanyl)pvrimidin-5-vl1acetate
A stirred solution of ethyl [4-chloro-2-(methylsulfanyl)pyrimidin-5-yl]acetate (10.0 g, 40.5 mmol) in ferr-butylamine (200 mL) in a sealed vessel was heated at 90 °C for 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 25:75, to give the title compound. MS: m/z = 284.2 (M + 1).
Step E: 7-tert-Butvl-2-(methvlsulfanvl)-5,7-dihvdro-6H-pvrrolof2,3-cflpyrimidin-6-one
To a stirred solution of ethyl [4-(tert-butylamino)-2-(methylsulfanyl)pyrimidin-5- yl]acetate (2.20 g, 7.76 mmol) in THF (25 mL) was added 1 N aqueous sodium hydroxide (8.54 mL, 8.54 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 90 min and then concentrated in vacuo. To a stirred solution of the residue in DMF (75 mL) were added HOBT (1.78 g, 11.6 mmol), EDC (2.23 g, 11.6 mmol), and DIEA (1.36 mL, 7.76 mmol), and the resulting mixture was stirred at ambient temperature for 18 h. Most of the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), washed with saturated aqueous sodium bicarbonate (75 mL), then brine (75 mL), then 10% aqueous citric acid (75 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes-.EtOAc - 100:0 to 20:80, to give the title compound. MS: m/z = 238.1 (M + 1). Step F: Benzyl 7'-ferf-butvl-2'-(methvlsulfanvl)-6'-oxo-6',7'-dihydro-lH-spiro[piperidine-4,5'-
Pvrrolof2,3-cflpvrimidinel-l-carboxylate
Argon was bubbled through a stirred mixture of 7-rert-butyl-2-(methylsulfanyl)-5,7- dihydro-6W-pyrrolo[2,3- /]pyrimidin-6-one (0.90 g, 3.79 mmol) and benzyl bis(2- chloroethyl)carbamate (1.05 g, 3.79 mmol) in NMP (15 mL) for 2 min. To the resulting mixture was added cesium carbonate (4.94 g, 15.2 mmol) and argon was bubbled through the mixture for an additional 2 min. The reaction mixture was stirred at ambient temperature for 2 h, then at 60 °C for 18 h, and then partitioned between water (40 mL) and EtOAc (75 mL). The aqueous layer was extracted further with EtOAc (50 mL) and the combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 35:65, to give the title compound. MS: m/z = 441.2 (M + 1).
Step G: 7'-tert-Butvlspiro[piperidine-4,5'-pvrrolo[2,3-d1pvrimidin1-6'(7'/- )-one To a solution of benzyl 7'-iert-butyl-2'-(methylsulfanyl)-6'-oxo-6',7,-dihydro-lH- spiro[piperidine-4,5'-pyrrolo[2,3--/]pyrimidine]-l-carboxylate (1.10 g, 2.50 mmol) in EtOH (20 mL) was added aney¾ Nickel (slurry in water, ca. 3 g) and the resulting mixture was stirred for 18 h under an atmosphere of hydrogen {ca. 1 atm). The resulting mixture was filtered through Celite^, washing with EtOH, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH OH - 100:0 to 70:30:3, to give the title compound. MS: m/z = 261.1 (M + 1).
Step H: 7'-ferf-Butvl-l-(4-nitrophenyl)spiroipiperidine-4,5'-pvrrolo[2,3-c/lpvrimidin1-6'(7'H)-one
A stirred mixture of 4-fluoronitrobenzene (65 mg, 0.461 mmol), T-tert- butylspiro[piperidine-4,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (120 mg, 0.461 mmol), and DIEA (0.24 mL, 1.38 mmol) in DMF (2 mL) was heated at 90 °C for 5 h. After cooling to ambient temperature, the solid was isolated by filtration, washing with cold Et20, and dried to give the title compound. MS: m/z = 382.1 (M + 1).
Step I: l-(4-Aminophenvl)-7'-fert-butvlspirofpiperidine-4,5'-pvrrolo[2,3-- lPvrimidinl-6'(7'H)- one
To a stirred suspension of 7'-ieri-butyl-l-(4-nitrophenyl)spiro[piperidine-4,5'- pyrrolo[2,3-cf]pyrimidin]-6'(7'H)-one (80 mg, 0.210 mmol) in EtOAc (15 mL) and MeOH (3 mL) was added 10% Pd/C (22 mg, 0.021 mmol) and the resulting mixture was stirred at ambient temperature under an atmosphere of hydrogen [ca. 1 atm) for 1 h. The reaction mixture was 74 filtered through Celite , washing with MeOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z - 352.2 (M + 1). 1H NMR (500 MHz, CDCIs) δ 8.78 (s, 1H), 8.55 (s, 1H), 6.90 (d, 2H, J = 8.8 Hz), 6.68 (d, 2H, J = 8.8 Hz), 3.54 (m, 2H), 3.47 (br s, 2H), 3.13 (m, 2H), 2.21 (m, 2H), 1.80 (m, 2H), 1.77 (s, 9H).
INTERMEDIATE 23
Figure imgf000076_0001
3-[l-(4-Aminophenvnpiperidin-4-vll-2-oxo-2,3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
Step A: 2-(2-Bromo-6-nitrophenvl)ethanol
To a stirred solution of l-bromo-2-methyl-3-nitrobenzene (20.0 g, 92.6 mmol) in DMA (200 mL) were added paraformaldehyde (3.30 g, 110 mmol of monomer) and potassium hydroxide (5.20 g, 92.6 mmol) and the resulting mixture was stirred at 30 °C for 18 h. The reaction mixture was diluted with EtOAc (500 mL) and washed with water (3 x 300 mL), then brine (300 mL). The organic layer was dried over Na2S0 , filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of petroleum ethenEtOAc - 95:5 to 80:20, to give the title compound.
Step B: 2-(2-Bromo-6-nitrophenvl)ethyl methanesulfonate
To a stirred solution of 2-(2-bromo-6-nitrophenyl)ethanol (11.0 g, 89.4 mmol) and triethylamine (12.5 mL, 89.4 mmol) in CH2CI2 (100 mL) at 0 °C was added methanesulfonyl chloride (7.68 g, 67.1 mmol) dropwise and the resulting mixture was stirred at 10 °C for 1 h. The reaction mixture was diluted with CH2CI2 (100 mL) and washed with water (2 x 100 mL), then brine (100 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z = 323.9 (M + l). Step C: l-Bromo-2-ethenyl-3-nitrobenzene
To a stirred solution of 2-(2-bromo-6-nitrophenyl)ethyl methanesulfonate (13.0 g, 40.1 mmol) in DMA (130 mL) was added l,4-diazabicyclo[2.2.2]octane (9.0 g, 80.2 mmol) and the resulting mixture was heated at 90 °C for 3 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with water (3 x 100 mL), then 0.5 N hydrochloric acid (100 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step.
Step D: ferf-Butyl 4-{r2-(2-bromo-6-nitrophenyl)ethvllamino}piperidine-l-carboxvlate
A stirred mixture of l-bromo-2-ethenyl-3-nitrobenzene (8.80 g, 38.6 mmol) and 4- amino-l-Boc-piperidine (19.3 g, 96.5 mmol) was heated at 90 °C for 18 h. The cooled reaction mixture was purified by silica gel chromatography, eluting with a gradient of petroleum ether:EtOAc - 90:10 to 50:50, to give the title compound. MS: m/z = 427.9 (M + 1).
Step E: ferf-Butyl 4-(r2-(2-amino-6-bromophenvl)ethyllamino}piperidine-l-carboxvlate
A stirred mixture of terf-butyl 4-{[2-(2-bromo-6-nitrophenyl)ethyl]amino}piperidine-l- carboxylate (11.0 g, 25.7 mmol), ammonium chloride (6.87 g, 128 mmol), and iron powder (7.20 g, 128 mmol) in EtOH (80 mL) and water (30 mL) was heated at 50 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was resuspended in EtOAc (200 mL) and washed with water (80 mL), then brine (80 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z - 397.9 (M + 1).
Step F: ferf-Butyl 4-(6-bromo-2-oxo-1.2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl)piperidine-l- carboxvlate
To a stirred solution of terf-butyl 4-{[2-(2-amino-6- bromophenyl)ethyl]amino}piperidine-l-carboxylate (5.0 g, 12.6 mmol) and triethylamine (5.27 mL, 37.8 mmol) in CH3CN (50 mL) at ambient temperature was added l,l'-carbonyldiimidazole (4.9 g, 30.2 mmol) and the resulting mixture was stirred at 30 °C for 18 h. The reaction mixture was diluted with EtOAc (15 mL) and water (50 mL), and the resulting precipitate was isolated by filtration and dried to give the title compound. MS: m/z = 424.1 (M + 1). Step G: tert-Butyl 4-(6-cvano-2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidine-l- carboxylate
A mixture of fe/t-butyl 4-(6-bromo-2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-3- yl)piperidine-l-carboxylate (1.00 g, 2.36 mmol), zinc (307 mg, 4.73 mmol), zinc cyanide (553 mg, 4.73 mmol), ir/s(dibenzylideneacetone)dipalladium(0) (216 mg, 0.236 mmol), and 1,1'- fo/s(diphenylphosphino)ferrocene (130 mg, 0.236 mmol) in DMA (12 mL) was heated in a microwave reactor at 130 °C for 30 min. The reaction mixture was filtered and the filtrate was diluted with EtOAc (20 mL) and washed with water (3 x 10 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of petroleum ethenEtOAc - 85:15 to 0:100, to give the title compound. MS: m/z = 371.2 (M + 1).
Step H: 2-Oxo-3-(piperidin-4-yl)-2,3,4,5-tetrahvdro-lH-l,3-benzodiazepine-6-carbonitrile
To a stirred solution of teri-butyl 4-(6-cyano-2-oxo-l,2,4,5-tetrahydro-3/-/-l,3- benzodiazepin-3-yl)piperidine-l-carboxylate (1.30 g, 3.50 mmol) in CH2CI2 (40 mL) and CH3CN (10 mL) was added TFA (4.1 mL, 55 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z - 271.1 (M + 1).
Step I: 3-[l-(4-Nitrophenvl)piperidin-4-vll-2-oxo-2,3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
A stirred mixture of 4-fluoronitrobenzene (359 mg, 2.60 mmol), 2-oxo-3-(piperidin-4-yl)- 2,3,4,5-tetrahydro-lH-l,3-benzodiazepine-6-carbonitrile (460 mg, 1.70 mmol), and DIEA (0.59 mL, 3.40 mmol) in DMF (5 mL) was heated at 90 °C for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with water (1 mL) and the solid was isolated by filtration and dried to give the title compound. MS: m/z = 392.2 (M + 1).
Step J: 3-[l-(4-Aminophenvl)piperidin-4-vll-2-oxo-2J3.4,5-tetrahydro-lH-l,3-benzodiazepine-6- carbonitrile
A stirred mixture of 3-[l-(4-nitrophenyl)piperidin-4-yl]-2-oxo-2,3,4,5-tetrahydro-lH-l,3- benzodiazepine-6-carbonitrile (225 mg, 0.58 mmol), ammonium chloride (157 mg, 2.88 mmol), and iron powder (161 mg, 2.88 mmol) in EtOH (3 mL) and water (1 mL) was heated at 50 °C for 18 h. The reaction mixture was diluted with EtOAc (10 mL), filtered and the filtrate was washed with water (5 mL), then brine (5 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound. MS: m/z = 362.2 (M + 1). 1H R (400
77 MHz, CD3OD) δ 7.35-7.31 (m, 1H), 7.30-7.25 (m, 2H), 6.95-6.86 (m, 2H), 6.80-6.72 (m, 2H), 4.30- 4.21 (m, 1H), 3.68-3.64 (m, 2H), 3.58-3.50 (m, 2H), 3.27-3.21 (m, 2H), 2.80-2.71 (m, 2H), 2.08- 1.95 (m, 2H), 1.89-1.82 (m, 2H).
INTERMEDIATE 24
Figure imgf000079_0001
4-lodo-A/,6-dimethvlpyridin-2-amine A stirred mixture of 2-fluoro-4-iodo-6-methylpyridine (0.30 g, 1.3 mmol), triethylamine
(0.53 mL, 3.8 mmol) and methylamine (2 M in THF, 2 mL, 4.0 mmol) in NMP (3 mL) was heated at 160 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 249.0 (M + 1). 1H NMR (400 MHz, DMSO) δ 7.22 (s, 1H), 7.06 (s, 1H), 2.89 (s, 3H), 2.54 (s, 1H), 2.35 (s, 3H).
INTERMEDIATE 25
Figure imgf000079_0002
4-lodo-2-methvl-6-(propan-2-vloxv)pyridine
A mixture of 2-f!uoro-4-iodo-6-methylpyridine (0.20 g, 0.84 mmol), isopropanol (0.20 mL, 2.6 mmol) and sodium hydride (95%, 100 mg, 4.0 mmol) in diethyl ether (5 mL) was stirred at 23 °C for 16 h. The reaction mixture was filtered through a plug of silica gel, eluting with diethyl ether, and the solvent was allowed to evaporate at atmospheric pressure to give the 78 title compound. MS: m/z = 278.2 (M + 1). 1H NMR (400 MHz, DMSO) 6 7.20 (dd, 1H, J = 1.2, 0.7 Hz), 6.96 (dd, 1H, J = 1.3, 0.7 Hz), 5.26-5.15 (m, 1H), 2.32 (s, 3H), 1.25 (d, 6H, J = 6.2 Hz).
INTERMEDIATE 26
Figure imgf000080_0001
A/-(4-Bromophenyl)-/\/,2,6-trinriethvlpvridiri-4-amine
Step A: A/-(4-Bromophenvl)-2,6-dimethvlpyridin-4-amine
To a deoxygenated mixture of l-bromo-4-iodobenzene (8.0 g, 28 mmol), 2,6- dimethylpyridin-4-amine (3.4 g, 28 mmol), 4,5-b/s(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (1.6 g, 2.8 mmol), and sodium tert-butoxide (4.1 g, 42 mmol) in toluene (220 mL) was added ir/s(dibenzylideneacetone)dipalladium(0) (1.3 g, 1.4 mmol) and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was allowed to cool to ambient
temperature and was filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH - 100:0 to 90:10, to give the title compound. MS: m/z = 277.1 (M + 1).
Step B: A/-(4-Bromophenvl)-A/,2,6-trimethvlpyridin-4-amine
To a solution of A/-(4-bromophenyl)-2,6-dimethylpyridin-4-amine (720 mg, 2.6 mmol) in DMF (10 mL) was added sodium hydride (95%, 180 mg, 6.8 mmol) and the reaction was stirred for 10 min at ambient temperature, lodomethane (0.21 mL, 3.4 mmol) was then added and the resulting mixture was stirred at ambient temperature for an additional 1 h. The reaction mixture was quenched with water (1 mL) and the solution was partitioned between EtOAc (150 mL) and water (100 mL). The organic layer was separated, washed with water (2 x 100 mL), then brine (50 mL), dried over Na2S04, filtered, and concentrated to give the title compound. MS: m/z = 291.1 (M + 1). 1H NMR (400 MHz, DMSO) δ 7.62-7.58 (m, 2H), 7.22-7.18 (m, 2H), 6.35 (s, 2H), 3.24 (s, 3H), 2.25 (s, 6H). 79 INTERMEDIATE 27
Figure imgf000081_0001
l-(4-Amino-3-phenoxvphenvl)spiro[piperidine-4,3'-Pvrrolor2,3-ib1Pvridinl-2'(l ¾-one
Step A: 5-Bromo-2-nitrophenyl phenyl ether
To a stirred solution of 4-bromo-2-fluoro-l-nitrobenzene (300 mg, 1.36 mmol) in DMF (6.8 mL) was added cesium carbonate (1.33 g, 4.09 mmol). Stirring was continued at ambient temperature for 5 min, and to this mixture was added phenol (0.12 mL, 1.36 mmol). The reaction mixture was stirred at ambient temperature for 48 h, then partitioned between saturated aqueous sodium bicarbonate (100 mL) and EtOAc (100 mL). The aqueous layer was extracted further with EtOAc (2 x 100 mL) and the combined organic extracts were washed with water (3 x), then brine, then dried over a2S04, filtered, and concentrated in vacuo, to give the title compound in sufficient purity for use in the next step.
Step B: l-(4-Nitro-3-phenoxvphenvl)spirofpiperidine-4,3'-Pvrrolo[2,3-felPvridin1-2'(l'H)-one
A deoxygenated mixture of 5-bromo-2-nitrophenyl phenyl ether (120 mg, 0.408 mmol), spiro[piperidine-4,3'-pyrrolo[2,3-fo]pyridin]-2'(l'H)-one trifluoroacetate (Burgey et al. (2009) Bioorg. Med. Chem. Lett. 19, 6368-6372) (129 mg, 0.408 mmol), (2-dicyclohexylphosphino- 2',4',6'-triisopropoxybiphenyl)[2-(2-aminoethylphenyl)]palladium(ll) chloride (XPhos precatalyst) (30 mg, 0.041 mmol) in 1,4-dioxane (2.7 mL) was treated with lithium
b/s(trimethylsilyl)amide (1.0 M in THF, 1.63 mL, 1.63 mmol) and the resulting mixture was heated at 70 °C for 45 min. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between saturated aqueous sodium bicarbonate (30 mL) and EtOAc (30 mL). The aqueous layer was extracted further with EtOAc (2 x 30 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a 80 gradient of H20:CH3CN:TFA - 80:20:0.1 to 40:60:0.1, to give the title compound. MS: m/z = 417.1 (M + l).
Step C: l-(4-Amino-3-phenoxvphenvl)spirofpiperidine-4,3'-pyrrolo[2,3--?lpvridinl-2'(l'H)-one A mixture of l-(4-nitro-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-Jb]pyridin]-
2'(l'H)-one (54 mg, 0.13 mmol) and 10% Pd/C (27.6 mg, 0.026 mmol) in EtOAc (3.2 mL) and MeOH (3.2 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The reaction mixture was filtered through Celite", washing with MeOH:CH2CI2 - 1:9, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 387.1 (M + 1).
INTERMEDIATE 28
Figure imgf000082_0001
3-[l-(2,3-Dihvdro-lH-indol-5-vl)piperidin-4-vn-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
Step A: tert-Butyl 5-bromo-2,3-dihvdro-lH-indole-l-carboxylate
To a stirred solution of 5-bromoindoline (320 mg, 1.62 mmol) in THF (8 mL) was added di-tert-butyl dicarbonate (529 mg, 2.42 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 90:10, to give the title compound.
Step B: fe/t-Butyl 5-i4-(2-oxo-l,2,4,5-tetrahvdro-3W-l,3-benzodiazepin-3-yl)piperidin-l-vn-2,3- dihvdro-lH-indole-l-carboxylate A deoxygenated mixture of terf-butyl 5-bromo-2,3-dihydro-lH-indole-l-carboxylate (116 mg, 0.390 mmoi), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (100 mg, 0.355 mmol), (2-dicyclohexylphosphino-2',4',6'- triisopropoxybiphenyl)[2-(2-aminoethylphenyl)]palladium(ll) chloride (XPhos precatalyst) (39 mg, 0.053 mmol) in 1,4-dioxane (3.5 mL) was treated with lithium £> s(trimethylsilyl)amide (1.0 M in THF, 1.77 mL, 1.77 mmol) and the resulting mixture was heated at 80 °C for 1 h. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between saturated aqueous sodium bicarbonate (30 mL) and EtOAc (30 mL). The aqueous layer was extracted further with EtOAc (2 x 30 mL) and the combined organic extracts were washed with brine, then dried over Na2S04/ filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH - 100:0 to 90:10, to give the title compound. MS: m/z = 463.2 (M + 1).
Step C: 3-fl-(2,3-Dihvdro-lH-indol-5-vl)piperidin-4-vn-l,3,4,5-tetrahydro-2 -/-l,3- benzodiazepin-2-one
To a stirred solution of tert-butyl 5-[4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin- 3-yl)piperidin-l-yl]-2,3-dihydro-lH-indole-l-carboxylate (80 mg, 0.17 mmol) in CH2CI2 (1 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and CH2CI2 (30 mL). The aqueous layer was extracted further with CH2CI2 (2 x 30 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 363.2 (M + 1). *H NMR (500 MHz, CDCI3) δ 7.15-7.05 (m, 2H), 6.91 (t, 2H, J = 7.2 Hz), 6.71 (d, 2H, J = 8.2 Hz), 6.61 (d, 1H, J = 8.3 Hz), 6.39 (s, 1H), 4.39 (t, 1H, J
(m, 6H), 3.05-2.99 (m, 4H), 2.81 (t, 2H, J = 11.8 Hz), 1.97 (s, 2H), 1.86 (d,
Figure imgf000083_0001
7-Chloro-5-methyl-2-(propan-2-vl)-3H-imidazof4,5-fclPvridine
A mixture of 5-methyl-2-(propan-2-yl)-3H-imidazo[4,5-6]pyridin-7-ol (Katagiri ef al. (1983) Chem. Pharm. Bull. 31, 2288-2295) (170 mg, 0.89 mmol) and POCI3 (1 mL) was heated at 100 °C for 2 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the POCI3 and the residue was poured onto ice with stirring, then extracted with CH2CI2 (3 χ 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 210.0 (M 1); XH NMR (500 MHz, DMSO-d6) δ 7.19 (s, 1H), 3.16 (s, 3H), 3.15-3.10 (m, 1H), 1.34 (d, 6H, J 7.0 Hz).
INTERMEDIATE 30
Figure imgf000084_0001
4-Chloro-2,6-diethvlpyridine A mixture of 2,6-diethylpyridin-4-ol (Malamas et al. (2010) Bioorg. Med. Chem. Lett. 18,
630-639) (500 mg, 3.31 mmol) and POCI3 (3 mL) was heated at 100 °C for 1 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the POCI3 and the residue was poured onto a mixture of ice and saturated aqueous sodium bicarbonate with stirring. The resulting mixture was adjusted to pH = 9-10 by addition of 1 N aqueous sodium hydroxide and then extracted with CH2CI2 (3 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 170.0 (M + 1); :H NMR (500 MHz, CDCI3) δ 7.01 (s, 2H), 2.79 (q, 4H, J = 7.6 Hz), 1.30 (t, 6H, J = 7.6 Hz).
INTERMEDIATE 31
Figure imgf000084_0002
5-Chloro-/V-(2,6-dimethvlpvridin-4-vl)pyridin-2-amine A deoxygenated mixture of 2-bromo-5-chloropyridine (473 mg, 2.46 mmol), 2,6- dimethylpyridin-4-amine (300 mg, 2.46 mmol), 4,5-£>/s(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) (142 mg, 0.246 mmol), palladium(ll) acetate (55 mg, 0.246 mmol) and cesium carbonate (1.60 g, 4.91 mmol) in 1,4-dioxane (12 mL) was heated at 150 °C for 1 h in a microwave reactor. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between saturated aqueous sodium bicarbonate (100 mL) and EtOAc (100 mL). The aqueous layer was extracted further with EtOAc (2 x 100 mL) and the combined organic extracts were washed with brine, then dried over Na2S0 , filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 50:50:0.1, to give the title compound. MS: m/z = 234.0 (M + 1). 1H IMM (400 MHz, CDCI3) δ 8.25 (dd, 1H, J = 2.6, 0.7 Hz), 7.55 (dd, 1H, J = 8.8, 2.6 Hz), 7.00 (s, 2H), 6.87 (dd, 1H, J = 8.8, 0.7 Hz), 6.70 (s, 1H), 2.48 (s, 6H).
INTERMEDIATE 32
Figure imgf000085_0001
l-(6-Chloropvridazin-3-vl)-l'-{r2-(trimethvlsilyl)ethoxvlmethvl}spirofpiperidine-4,3'-pvrrolof2,3- ib]pvridin1-2'(rH)-one
Step A: Benzyl 2'-oxo-l'-{r2-(trimethvlsilvl)ethoxv1methvl)-l',2'-dihvdro-lH-spirorpiperidine-
4,3'-Pvrrolo[2,3-fa1Pvridine1-l-carboxylate To a stirred solution of l-{[2-(trimethylsilyl)ethoxy]methyl}-l,3-dihydro-2H-pyrrolo[2,3-
6]pyridin-2-one (5.0 g, 18.9 mmol) in DMF (20 mL) were added cesium carbonate (18.5 g, 57 mmol) and sodium iodide (1.42 g, 9.45 mmol). The mixture was stirred at ambient temperature for 5 min and benzyl fo/s(2-chloroethyl)carbamate (7.8 g, 28.4 mmol) was added. The resulting mixture was stirred at 60 °C for 18 h, cooled to ambient temperature, and diluted with EtOAc (200 mL). The organic layer was washed with water, then brine, then dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 70:30, to afford the title compound. MS: m/z = 468.3 (M + l).
Step B: l'-{[2-(Trimethvlsilvl)ethoxv1methvl)spirofpiperidine-4,3'-Pvrrolor2,3-fe1pyridin1-2'(l'H)- one A mixture of benzyl Z'-oxo-l'-iia-itrimethylsilylJethoxyJmethylJ-l'^'-dihydro-lH- spiro[piperidine-4,3'-pyrrolo[2,3-ib]pyridine]-l-carboxylate (5.50 g, 11.8 mmol) and 10% Pd/C (1.00 g, 0.94 mmol) in EtOAc (30 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The resulting mixture was filtered through Celite®, washing with MeOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 334.2 (M + 1).
Step C: l-(6-Chloropvridazin-3-vl)-l'-(f2-(trimethvlsilvl)ethoxvlmethyl)spirofpiperidine-4,3'- pvrrolo[2,3-blpvridin]-2'(l'H)-one To a mixture of l'-{[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3- b]pyridin]-2'(l'H)-one (167 mg, 0.50 mmol) and 3,6-dichloropyridazine (75 mg, 0.50 mmol) in DMF (2 mL) was added DIEA (0.26 mL, 1.50 mmol). The resulting mixture was stirred at 80 °C for 18 h, cooled to ambient temperature, and diluted with EtOAc (20 mL). The organic layer was washed with water, then brine, then dried over a2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 40:60, to afford the title compound. MS: m/z = 446.2 (M + 1).
INTERMEDIATE 33
Figure imgf000086_0001
/\/-(5-Bromopvridin-2-vl)-2,6,8-trimethylquinolin-4-amine
A solution of 2,6,8-trimethyl-4-chloroquinoline (238 mg, 1.16 mmol) and 2-amino-5- bromopyridine (200 mg, 1.16 mmol) in DMF (6 mL) was treated with sodium hydride (60% dispersion in mineral oil, 92 mg, 2.31 mmol), then heated at 135 °C for 18 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to afford the title compound. MS: m/z = 343.0 (M + 1). 85 INTERMEDIATE 34
Figure imgf000087_0001
A/-(5-Chloropvrimidin-2-vl)-2,6,8-trimethylquinolin-4-arriine
A deoxygenated mixture of 4-amino-2,6,8-trimethylquinoline (50 mg, 0.268 mmol), 2,5- dichloropyrimidine (40 mg, 0.268 mmol), cesium carbonate (175 mg, 0.54 mmol), palladium(ll) acetate (6.0 mg, 0.027 mmol) and 4,5-b/s(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos) (15 mg, 0.027 mmol) in 1,4-dioxane (1.3 mL) was heated at 150 °C in a microwave reactor for 20 min. The reaction mixture was allowed to cool to ambient temperature and was filtered and then purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 299.1 (M + 1).
INTERMEDIATE 35
Figure imgf000087_0002
4-(4-Bromophenoxy)-2,6,8-trimethvlquinoline
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 120 mg, 3.0 mmol) in DMF (2 mL) was added 4-bromophenol (519 mg, 1.0 mmol). The mixture was stirred at ambient temperature for 10 min, followed by addition of 4-chloro-2,4,6-trimethylquinoline (206 mg, 1.0 mmol). The resulting mixture was heated at 135 °C and stirred for 5 h. The reaction mixture was cooled to ambient temperature, poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water, then brine, dried over a2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 90:10, to afford the title compound. MS: m/z - 342.1 (M + 1).
INTERMEDIATE 36
Figure imgf000088_0001
3- l-(5-Aminopvridin-2-yl)piperidin-4-vl]-l,8-naphthvridin-2(lH¾-one
Step A: /V-(3-Formvlpyridin-2-vl)pivalamide
To a stirred solution of 2-aminonicotinaldehyde (4.45 g, 36.4 mmol) and triethylamine (7.62 mL, 54.7 mmol) in CH2CI2 (100 mL) at 0 °C was added pivaloyl chloride (5.39 mL, 43.7 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 64 h. The resulting mixture was washed with water (2 x 50 mL), then brine, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 80:20 to 0:100, to afford the title compound. MS: m/z = 207.1 (M + l).
Step B: 3-(Piperidin-4-vl)-l,8-naphthyridin-2(lH)-one hydrochloride
To a stirred solution of lithium diisopropylamide (2 M, 3.20 mL, 6.40 mmol) in THF (25 mL) at -78 °C was added a solution of terf-butyl 4-(2-ethoxy-2-oxoethyl)piperidine-l- carboxylate (1.59 g, 5.87 mmol) in THF (6 mL), and the reaction mixture was stirred at -78 °C for 1.5 h. In a separate flask, to a stirred suspension of sodium hydride (60%, 0.256 g, 6.40 mmol) in THF (12 mL) at 0 °C was added a solution of W-(3-formylpyridin-2-yl)pivalamide (1.10 g, 5.33 mmol) in THF (6 mL) dropwise, and the reaction mixture was stirred at 0 °C for 2 h, and then added to the solution of lithium enolate (described above) dropwise. The resulting mixture was stirred at -78 °C for 2 h then slowly warmed to ambient temperature and stirred at ambient temperature for 18 h. The reaction was quenched by addition of 1 M aqueous ammonium chloride, and extracted with EtOAc (3 x). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo. To the residue was added 3 M aqueous hydrochloric acid (20 mL) and the resulting mixture was heated at 100 °C for 18 h, then concentrated to dryness in vacuo. Crystallization from EtOH afforded the title compound. MS: m/z = 230.1 (M + 1). H NMR (500 MHz, DMSO-d6) δ 12.2 (s, 1H), 9.01 (br, 1H), 8.87 (br, 1H), 8.47 (dd, 1H, J = 4.7, 1.6 Hz), 8.14 (dd, 1H, J = 7.7, 1.5 Hz), 7.72 (s, 1H), 7.24 (dd, 1H, J = 7.7, 4.7 Hz), 3.52-3.34 (m, 3H), 3.02 (m, 2H), 2.00 (m, 2H), 1.78 (ddd, 2H, J = 25.9, 13.2, 3.5 Hz).
Ste C: 3-fl-(5-Nitropvridin-2-vl)piperidin-4-vn-l,8-naphthvridin-2(lH)-one
To a stirred mixture of 2-chloro-5-nitropyridine (53.2 mg, 0.336 mmol) and 3-(piperidin- 4-yl)-l,8-naphthyridin-2(lH)-one hydrochloride (85.0 mg, 0.320 mmol) in DMF (1.5 mL) was added W,/\/-diisopropylethylamine (0.223 mL, 1.279 mmol) and the reaction mixture was stirred at 65 °C for 18 h then cooled to ambient temperature. The solid was isolated by filtration, washed with CH2CI2, to afford the title compound, which was used for the next step without purification. MS: m/z = 351.1 (M + 1).
Step D: 3-[l-(5-Aminopvridin-2-vl)piperidin-4-vll-l,8-naphthyridin-2(lti)-one
To a stirred solution of 3-[l-(5-nitropyridin-2-yl)piperidin-4-yl]-l,8-naphthyridin-2(lH)- one (56.0 mg, 0.159 mmol) in EtOH (10 mL) and water (5 mL) was added sodium hydrosulfite (139 mg, 0.797 mmol). The reaction mixture was stirred at 45 °C for 4 h, then more sodium hydrosulfite (60 mg, 0.344 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. The organic solvent was removed in vacuo and a few drops of 5 M aqueous sodium hydroxide were added to adjust the mixture to the pH = 8-9. The resulting mixture was extracted with EtOAc (3 x), and the combined organic layers were dried over
NaS04, filtered and concentrated in vacuo to afford the title compound. MS: m/z = 322.1 (M + 1).
INTERMEDIATE 37
Figure imgf000089_0001
4-[l-(5-Aminopvridin-2-vl)piperidin-4-vn-lH-l,2,4-triazol-5(4H)-one
Step A: Methyl 2-(ethoxymethvlene)hvdrazinecarboxvlate
A mixture of methyl hydrazinecarboxylate (2.50 g, 27.8 mmol) and triethyl orthoformate
(40 mL) was heated at 88 °C for 64 h and then concentrated in vacuo. Crystallization from EtOAc afforded the title compound.
Step B: fe/t-Butyl 4-f5-oxo-lH-l,2,4-triazol-4(5H)-vnpiperidine-l-carboxylate To a solution of methyl 2-(ethoxymethylene)hydrazinecarboxylate (0.438 g, 3.00 mmol) in EtOH (2 mL) was added ieri-butyl 4-aminopiperidine-l-carboxylate (0.12 g, 0.60 mmol) and the reaction mixture was heated at 50 °C for 64 h. To the resulting mixture was added MeOH (2 mL), followed by sodium methoxide (0.324 g, 6.00 mmol). The reaction mixture was stirred at 80 °C for 5 h then quenched with 1 M aqueous ammonium chloride (5 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH - 100:0 to 95:5, to afford the title compound. MS: m/z = 291.0 (M + 23).
Step C: 4-(Piperidin-4-yl)-l /-1.2,4-triazol-5(4H)-one trifluoracetate
To a solution of tert-butyl 4-[5-oxo-lH-l,2,4-triazol-4(5H)-yl]piperidine-l-carboxylate
(88 mg, 0.33 mmol) in CH2CI2 (1.5 mL) was added TFA (0.75 mL). The reaction mixture was stirred at ambient temperature for 1.5 h, then the volatile solvent was removed under reduced pressure and lyophillization afforded the title compound, which was used in the next step without purification. MS: m/z = 169.0 (M + 1).
Step D: 4-ri-(5-Nitropyridin-2-vl)piperidin-4-vll-lH-l,2,4-triazol-5(4fV)-one
To a stirred mixture of 2-chloro-5-nitropyridine (46.3 mg, 0.292 mmol) and 4-(piperidin- 4-yl)-lH-l,2,4-triazol-5(4H)-one trifluoroacetate (75.0 mg, 0.266 mmol) in DMF (1 mL) was added Λ/,/V-diisopropylethylamine (0.185 mL, 1.06 mmol). The reaction mixture was stirred at 65 °C for 18 h. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:HC02H - 95:5:0.1 to 10:90:0.1, to give the title compound. MS: m/z = 291.1 (M + l). Step E: 4-ri-(5-Aminopyridin-2-vl)piperidin-4-vn-lH-l,2,4-triazol-5(4H)-one
A mixture of 4-[l-(5-nitropyridin-2-yl)piperidin-4-yl]-lH-l,2,4-tnazol-5(4H)-one (14 mg; 0.048 mmol) and 10% Pd/C (7 mg, 0.0066 mmol) in DMF (1 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 5 h. The resulting mixture was filtered through Celite8, washing with CH2CI2, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 261.2 (M + 1).
INTERMEDIATE 38
Figure imgf000091_0001
l-fl-(5-Aminopvridin-2-vl)azetidin-3-vn-lH-imidazor4,5-b1pyridin-2(3/-/)-one
Step A: fe/t-Buty) 3-[(2-aminopvridin-3-yl)aminolazetidine-l-carboxvlate
To a stirred solution of 2,3-diaminopyridine (1.60 g, 14.7 mmol) in THF (30 mL) at ambient temperature were added trifluoroacetic acid (3.37 mL, 44.0 mmol), teri-butyl 3- oxoazetidine-l-carboxylate (2.89 g, 16.7 mmol), and sodium triacetoxyborohydride (4.35 g, 20.5 mmol). The reaction mixture was stirred at 55 °C for 2 h, then 1 M aqueous sodium hydroxide (35 mL) was added and the resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH - 100:0 to 95:5 to give the title compound. MS: m/z = 265.1 (M + 1).
Step B: fert-Butyl 3-(2-oxo-2,3-dihvdro-lH-imidazof4,5-b1pyridin-l-vl)azetidine-l-carboxvlate To a stirred solution of te/t-butyl 3-[(2-aminopyridin-3-yl)amino]azetidine-l-carboxylate
(3.20 g, 12.1 mmol) in DMF (20 mL) at ambient temperature was added 1,1 '- carbonyldiimidazole (2.16 g, 13.3 mmol). The reaction mixture was stirred at 120 °C for 18 h, then concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to afford the title compound. MS: m/z = 291.0 (M + 1).
Step C: l-(Azetidin-3-yl)-lW-imidazof4,5-blpvridin-2(3H)-one hydrochloride
A mixture of terf-butyl S-f -oxo- ^-dihydro-lH-imidazot^B-bJpyridin-l-y azetidine-l- carboxylate (2.60 g, 8.96 mmol), hydrogen chloride (4.0 M in dioxane, 27 mL, 108 mmol), and water (3 mL) was stirred at ambient temperature for 2 h and then concentrated in vacuo to give the title compound. MS: m/z = 190.0 (M + 1).
Step D: l-fl-(5-Aminopvridin-2-vl)azetidin-3-vn-lH-imidazor4,5-b1pyridin-2(3H)-one
Essentially following the procedures described in Intermediate 37, but using l-(azetidin- 3-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride in place of 4-(piperidin-4-yl)-lH-l,2,4- triazol-5(4H)-one trifluoroacetate, the title compound was obtained. MS: m/z = 283.1 (M + 1).
INTERMEDIATE 39
Figure imgf000092_0001
5'-Amino-l-methvl-2'-f4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl)piperidin-l-vn- 3,4'-bipyridin-6(lH)-one
Step A: 2'-Chloro-l-methvl-5'-nitro-3,4'-bipyridin-6(lH)-one
To a stirred mixture of 4-bromo-2-chloro-5-nitropyridine (200 mg, 0.842 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (218 mg, 0.927 mmol), and dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(ll) dichloromethane adduct (68.8 mg, 0.084 mmol) in deoxygenated l,4-dioxane:water - 5:l (6 mL) was added Na2C03 (179 mg, 1.69 mmol) and the resultant mixture was heated at 80 °C for 30 min in a sealed tube. The reaction mixture was then diluted with EtOAc and washed with water and brine. The organic layer was dried over a2S04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 5:95, to give the title compound. MS: m/z = 266.0 (M + 1).
Step B: l-Methvl-5'-nitro-2'-r4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-vl¾piperidin- l-vll-3.4'-bipyridin-6(l/V)-one
A mixture of 2'-chloro-l-methyl-5'-nitro-3,4'-bipyridin-6(lW)-one (109 mg, 0.410 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2W-l,3-benzodiazepin-2-one hydrochloride (US
2006/0019946) (139 mg, 0.492 mmol), and triethylamine (0.172 mL, 1.23 mmol) in DMSO (5 mL) was heated at 90 °C in a sealed tube for 2 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water (3x) and then brine. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound, which was used directly without further purification. MS: m/z = 474.2 (M + 1).
Step C: 5'-Amino-l-methvl-2'-f4-(2-oxo-l,2,4.5-tetrahydro-3H-l,3-benzodiazepin-3- vl)piperidin-l-vn-3,4'-bipyridin-6(lH)-one
To a stirred solution of l-methyl-5'-nitro-2'-[4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3- benzodiazepin-3-yl)piperidin-l-yl]-3,4'-bipyridin-6(lH)-one (183 mg, 0.386 mmol) in AcOH (4 mL) was added Zn (76 mg, 1.16 mmol) and ammonium chloride (61.9 mg, 1.16 mmol). The reaction mixture was stirred for 3 h at ambient temperature and then poured into a solution of saturated sodium bicarbonate. To the resulting mixture was added brine and the aqueous solution was extracted with CH2CI2 (3x). The organic layer was dried over MgS0 , filtered, and concentrated in vacuo. The crude material was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN: NH4OH - 95:5:0.05 to 5:95:0.05, to give the title compound. MS: m/z = 445.3 (M + 1).
INTERMEDIATE 40
Figure imgf000093_0001
4-(Piperidin-4-vl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one
Step A: Methyl /V-(2-nitrobenzvl)glycinate
A mixture of 2-nitrobenzyl bromide (5.0 g, 23 mmol), glycine methyl ester hydrochloride (4.4 g, 35 mmol) and DIEA (12 mL, 69 mmol) in DMF (50 mL) was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water (250 mL) and the product was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 225.1 (M + l).
Step B: Methyl /V-(ferf-butoxvcarbonvl)-A/-(2-nitrobenzyl)glvcinate
A mixture of methyl /V-(2-nitrobenzyl)glycinate (4.9 g, 22 mmol) and di-terf-butyl dicarbonate (7.2 g, 33 mmol) in CH2CI2 (120 mL) was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:50, to give the title compound. MS: m/z = 225.2 (M + l - C02C4H9).
Step C: Methyl N-(2-aminobenzyl)-/V-(½rr-butoxvcarbonvl)glvcinate
A mixture of methyl A/-(teri-butoxycarbonyl)-/\/-(2-nitrobenzyl)glycinate (7.1 g, 22 mmol) and 10% Pd/C (1.55 g, 1.4 mmol) in MeOH (150 mL) was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 5 h. The resulting mixture was filtered and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 295.4 (M + 1).
Step D: ferr-Butyl 2-oxo-l,2.3.5-tetrahydro-4H-l,4-benzodiazepine-4-carboxvlate
A mixture of methyl /V-(2-aminobenzyl)-A/-(tert-butoxycarbonyl)glycinate (5.71 g, 19.4 mmol) and HOBT (1.78 g, 11.6 mmol) in toluene (200 mL) was heated at 100 °C for 18 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 207.1 (M + l - C4H9).
Step E: l,3,4,5-Tetrahydro-2H-l,4-benzodiazepin-2-one A stirred mixture of ie/t-butyl 2-oxo-l,2,3,5-tetrahydro-4H-l,4-benzodiazepine-4- carboxylate (3.1 g, 12 mmol), and trifluoroacetic acid (7.0 mL, 91 mmol) in CH2CI2 (100 mL) was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo, the residue was triturated with ether and the resulting solid was isolated by filtration and dried in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z = 163.1 (M + l).
Step F: te/t-Butvl 4-(2-oxo-1.2,3,5-tetrahvdro-4H-l,4-benzodiazepin-4-yl)piperidine-l- carboxylate
To a stirred solution of l^AS-tetrahydro^H-l^-benzodiazepin-^-one (1.4 g, 5.1 mmol) and terf-butyl-4-oxopiperidine-l-carboxylate (1.0 g, 5.1 mmol) in THF (45 mL) at ambient temperature was added acetic acid (0.29 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 45 min, then sodium triacetoxyborohydride (5.4 g, 25 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:35:0.1, to give the title compound. MS: m/z = 346.3 (M + l).
Step G: 4-(Piperidin-4-yl)-l,3,4,5-tetrahvdro-2H-l,4-benzodiazepin-2-one To a stirred solution of tert-butyl 4-(2-oxo-l,2,3,5-tetrahydro-4W-l,4-benzodiazepin-4- yl)piperidine-l-carboxylate (1.8 g, 5.2 mmol) in CH2CI2 (50 mL) was added TFA (10 mL, 25 mmol) and the resulting mixture was stirred at ambient temperature for 4 h and then concentrated in vacuo to give the title compound as the trifluoroacetate salt. MS: m/z - 246.2 (M + 1); 1H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H); 8.77 (br s, 1H); 8.50 (br s, 1H); 7.46-7.53 (m, 2H); 7.25 (t, 1H, J = 7.5 Hz); 7.15 (d, 1H, J = 7.9 Hz); 4.31 (s, 2H); 3.67 (s, 2H); 3.44 (d, 3H, J = 12.8 Hz); 2.93- 2.99 (m, 2H); 2.28 (d, 2H, J = 13.0 Hz); 1.82-1.91 (m, 2H).
INTERMEDIATE 41
Figure imgf000095_0001
94 3-(l-{4-Amino-3-f6-(trifluoromethvl)pyridin-3-vnph
l,3-benzodiazepin-2-one
Step A: 5-(5-Fluoro-2-nitrophenvl)-2-(trifluoromethyl)pvridine
A deoxygenated mixture of 2-bromo-4-fluoro-l-nitrobenzene (500 mg, 2.3 mmol), (6- (trifluoromethyl)pyridin-3-yl)boronic acid (440 mg, 2.3 mmol), 2 M aqueous sodium carbonate solution (1.7 mL, 3.4 mmol) and dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(ll) dichloromethane adduct (90 mg, 0.11 mmol) in 1,4-dioxane (20 mL) was heated at 85 °C for 18 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2CI2 (30 mL) washed with water and brine, dried over sodium sulfate and purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 287.2 (M + 1).
Step B: 3-(l-{4-Nitro-3-i6-(trifluoromethvl)pvridin-3-vllphenvl}piperidin-4-vl)-l,3,4,5- tetrahydro-2H-l,3-benzodiazepin-2-one
A mixture of 5-(5-fluoro-2-nitrophenyl)-2-(trifluoromethyl)pyridine (290 mg, 1.0 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (US 2006/0019946) (200 mg, 1.0 mmol), and DIEA (0.70 mL, 4.0 mmol) in DMF (6.5 mL) was heated at 100 °C for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with water (20 mL) and the solid was collected by filtration and washed with water to give the title compound. MS: m/z = 512.3 (M + l).
Step C: 3-(l-{4-Amino-3-r6-(trifluoromethvl)pvridin-3-vnphenyl)piperidin-4-vl)-l.3.4,5- tetrahydro-2tf-l,3-benzodiazepin-2-one
A mixture of 3-(l-{4-nitro-3-[6-(trifluoromethyl)pyridin-3-yl]phenyl}piperidin-4-yl)- l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (450 mg, 0.88 mmol), 1,4-cyclohexadiene (3.0 mL, 32 mmol) and 10% Pd/C (50 mg, 0.047 mmol) in EtOH (10 mL) and EtOAc (10 mL) was stirred at 80 °C in a sealed tube for 18 h. The resulting mixture was cooled to ambient temperature, filtered, washed with MeOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 482.3 (M + 1).
INTERMEDIATE 42
Figure imgf000097_0001
6-Chloro-A/-(2,6-dimethvlpvridin-4-vl)-4 4-(methvlsulfonvl)phenvnpyridin-3-amine
Step A: 5-Bromo-2-chloro-4-f4-(methvlsulfonyl)phenvnpvridine
A deoxygenated mixture of 5-bromo-2-chloro-4-iodopyridine (6.01 g, 18.9 mmol), (4- (methylsulfonyl)phenyl)boronic acid (3.78 g, 18.9 mmol), 2 M aqueous sodium carbonate solution (14.2 mL, 28.3 mmol) and dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(ll) dichloromethane adduct (1.08 g, 1.32 mmol) in 1,4-dioxane (150 mL) was heated at 85 °C for 18 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2CI2 (60 mL) and filtered. The filtrate was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 346.0 (M + 1).
Step B: 6-Chloro-A/-(2,6-dimethvlpvridin-4-vl)-4-[4-(methylsulfonvl)phenvllpvridin-3-amine
A deoxygenated mixture of 5-bromo-2-chloro-4-[4-(methylsulfonyl)phenyl]pyridine (500 mg, 1.4 mmol), 4-amino-2,6-dimethylpyridine (260 mg, 2.1 mmol) and chloro(2- dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2-aminoethylphenyl)]palladium(ll)- methyl-ferr-butyl ether adduct ( uPhos precatalyst) (120 mg, 0.14 mmol) in 1,4-dioxane (15 mL) was treated with sodium iert-butoxide (2.0 M in THF, 1.4 mL, 2.9 mmol) and the resulting mixture was heated at 40 °C for 18 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2CI2 (30 mL) washed with water and brine, dried over sodium sulfate and purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc:MeOH:Et3N - 100:0:0:0 to 0:80:10:10, to give the title compound. MS: m/z = 388.2 (M + 1).
INTERMEDIATE 43 96
Figure imgf000098_0001
4-(l 5-Bromo-4-f4-(methylsulfonvl)phenvn^
l,4-benzodiazepin-2-one
A stirred solution of 5-bromo-2-chloro-4-[4-(methylsulfonyl)phenyl]pyridine (described in Intermediate 42) (160 mg, 0.462 mmol), 4-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,4- benzodiazepin-2-one trifluoroacetate (described in Intermediate 40) (170 mg, 0.692 mmol) and K2C03 (255 mg, 1.85 mmol) in DMSO (5 mL) was heated at 120 °C for 16 h in a sealed tube and then cooled to ambient temperature. The reaction mixture was then diluted with EtOAc (30 mL) and washed with water (3x) and then brine. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C- 18 column, eluting with a gradient of H20:CH3CN: NH4OH - 95:5:0.05 to 5:95:0.05, to give the title compound. MS: m/z = 556.1 (M + 1).
INTERMEDIATE 44
Figure imgf000098_0002
4-{l-r5-Bromo-4-(4-fluorophenvl)pyridin-2-vnpiperidin-4-vl)-l,3.4,5-tetrahvdro-2H-l,4- benzodiazepin-2-one
Step A: 5-Bromo-2-chloro-4-(4-fluorophenvl)pyridine To a mixture of 5-bromo-2-chloro-4-iodopyridine (2.0 g, 6.3 mmol), (4- fluorophenyl)boronic acid (0.92 g, 6.9 mmoi), tris-(3-suifonatophenyl)phosphine-hydrate sodium salt (0.30 g, 0.47 mmol), and pailadium(ll) acetate (35 mg, 0.16 mmol) in DMF (24 mL) and water (7.9 mL) was added diisopropylamine (2.7 mL, 19 mmol). The resulting solution was stirred at 70 °C for 2 h, then more water was added and the mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washing with water, and dried in vacuo to give the title compound. MS: m/z = 286.1 (M +1).
Step B: 4-{l-f5-Bromo-4-(4-fluorophenvl)pvridin-2-yllpiperidin-4-vl)-l,3,4,5-tetrahvdro-2H-l,4- benzodiazepin-2-one
To a mixture of 5-bromo-2-chloro-4-(4-fluorophenyl)pyridine (200 mg, 0.70 mmol) and 4-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one (described in Intermediate 40) dihydrochloride (270 mg, 0.84 mmol) in DMSO (3.5 mL) was added potassium carbonate (390 mg, 2.8 mmol). The resulting mixture was heated at 120 °C for 18 h. The reaction mixture was cooled to room temperature and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN: TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 495.1 (M + 1).
INTERMEDIATE 45
Figure imgf000099_0001
4,6-Dimethyl-2,3-dihvdro-l/- -pvrrolo[3,2-c1pyridine
Step A: A/-(2,6-Dimethylpvridin-4-vl)-2,2-dimethvlpropanamide
To a stirred solution of 4-amino-2,6-dimethylpyridine (3.00 g, 24.6 mmol) in CH2CI2 (100 mL) were added triethylamine (4.45 mL, 31.9 mmol) and trimethylacetyl chloride (3.63 mL, 29.5 mmol)._The resulting mixture was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous sodium bicarbonate (75 mL) and CH2CI2 (100 mL). The aqueous layer was extracted further with CH2CI2 (75 mL) and the combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH4OH - 100:0:0 to 80:20:2, to afford the title compound. MS: m/z = 207.2 (M + 1).
Step B: A/-(3-Bromo-2,6-dimethvlpvridin-4-vl)-2,2-dimethylpropanamide
To a stirred solution of /V-(2,6-dimethylpyridin-4-yl)-2,2-dimethylpropanamide.(4.50 g,
21.8 mmol) in CH3CN (80 mL) was added /v-bromosuccinimide (3.88 g, 21.8 mmol)._The resulting mixture was heated at 60 °C for 18 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate (150 mL) and CH2CI2 (250 mL). The aqueous layer was extracted further with CH2CI2 (100 mL) and the combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:EtOAc - 100:0 to 0:100, to afford the title compound. MS: m/z = 287.1 (M + 1).
Step C: /\/-{3-[(£)-2-Ethoxvethenvn-2,6-dimethvlpvridin-4-vl}-2,2-dimethylpropanamide
A deoxygenated mixture of W-(3-bromo-2,6-dimethylpyridin-4-yl)-2,2- dimethylpropanamide (3.00 g, 10.5 mmol), (£)-l-ethoxyethene-2-boronic acid pinacol ester (4.17 g, 21.0 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl (432 mg, 1.05 mmol), palladium(ll) acetate (118 mg, 0.53 mmol) and potassium phosphate tribasic (4.47 g, 21.0 mmol) in CH3CIM (30 mL) and water (20 mL) was heated at reflux for 1 h. The resulting mixture was allowed to cool to ambient temperature, then partitioned between water (30 mL) and CH2CI2 (50 mL). The aqueous layer was extracted further with CH2CI2 (2 x 50 mL) and the combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of
CH2CI2:MeOH :NH4OH - 100:0:0 to 80:20:2, to afford the title compound. MS: m/z = 277.2 (M + 1).
Step D: 4,6-Dimethvl-l/-7-pvrrolo[3,2-c1pyridine
A solution of N-{3-[(E )-2-ethoxyethenyl]-2,6-dimethylpyridin-4-yl}-2,2- dimethylpropanamide (2.20 g, 7.96 mmol) in 3 N aqueous hydrochloric acid (40 mL) was heated at 60 °C for 18 h. The resulting mixture was allowed to cool to ambient temperature and was washed with EtOAc (75 mL) and the organic layer was discarded. The aqueous layer was adjusted to pH = 10 by addition of 10 N aqueous sodium hydroxide, then extracted with EtOAc (3 x 100 mL) and the combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4OH - 100:0:0 to 70:30:3, to afford the title compound. MS: m/z = 147.1 (M + 1). Step E: 4,6-Dimethvl-2,3-dihvdro-lH-pvrrolof3,2-clpyridine
To a stirred solution of 4,6-dimethyl-lH-pyrrolo[3,2-c]pyridine (710 mg, 4.86 mmol) in EtOH (50 mL) was added aney Ni (1.43 g, 24.3 mmol) and the resulting mixture was stirred at ambient temperature under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The reaction mixture was filtered through Celite®, washing with EtOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 149.1 (M + 1). 1H NMR (500 MHz, CD3OD) δ 6.18 (s, 1H), 3.59 (t, 2H, J = 8.7 Hz), 2.92 (t, 2H, J = 8.7 Hz), 2.27 (s, 3H), 2.24 (s, 3H).
INTERMEDIATE 46
Figure imgf000101_0001
3-{l-f5-Amino-4-(l,l-dioxidothiomorpholin-4-vl¾pvridin-2-vnpiperidin-4-yl)-l,3.4,5-tetrahvdro- 2H-1.3-benzodiazepin-2-one
Step A: 4-(2-Chloro-5-nitropyridin-4-vl)thiomorpholine 1,1-dioxide
To a stirred solution of 2,4-dichloro-5-nitropyridine (500 mg, 2.59 mmol) and thiomorpholine 1,1-dioxide (368 mg, 2.72 mmol) in DMF (5 mL) at 0 °C was added DIEA (1.35 mL, 7.77 mmol) and the resulting mixture was warmed to ambient temperature and stirred for 3 h. Water (10 mL) was added and the resulting precipitate was isolated by filtration, washing with water, and the solid was dried to give the title compound, which was used without further purification. MS: m/z = 292.0 (M + 1).
Step B: 3-{l-r4-(l,l-Dioxidothiomorpholin-4-vl)-5-nitropyridin-2-vnpiperidin-4-vl}-l,3,4.5- tetrahydro-2H-l,3-benzodiazepin-2-one A mixture of 4-(2-chloro-5-nitropyridin-4-yl)thiomorpholine 1,1-dioxide (450 mg, 1.54 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (435 mg, 1.54 mmol), and DIEA (0.81 mL, 4.63 mmol) in DMF (4 mL) was heated at 70 °C for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with water (5 mL) and the solid was collected by filtration and washed with water. The solid was concentrated to dryness from acetonitrile (2 x 10 mL) to give the title compound. MS: m/z = 501.2 (M + 1).
Step C: 3-{l-f5-Amino-4-(l,l-dioxidothiomorpholin-4-vl)pyridin-2-vnpiperidin-4-vl)-l, 3.4.5- tetrahydro-2H-1.3-benzodiazepin-2-one
To a stirred solution of 3-{l-[4-(l,l-dioxidothiomorpholin-4-yl)-5-nitropyridin-2- yl]piperidin-4-yl}-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (200 mg, 0.400 mmol) in AcOH (1.67 mL) and EtOH (0.33 mL) was added zinc dust (104 mg, 1.60 mmol) and ammonium chloride (85 mg, 1.60 mmol). The resulting mixture was stirred at ambient temperature for 3 h, then partitioned between saturated aqueous sodium bicarbonate (30 mL) and CH2CI2 (30 mL). The aqueous layer was extracted further with CH2CI2 (2 x 30 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 471.2 (M + 1).
INTERMEDIATE 47
Figure imgf000102_0001
5-Amino-2-[4-(2-oxo-1.2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-vl)piperidin-l-vl]pyridine-4- carbonitrile
Step A: 5-Nitro-2-f4-(2-oxo-l,2,4,5-tetrahvdro-3H-1.3-benzodiazepin-3-yl)piperidin-l-
101 A mixture of 2-chloro-5-nitropyridine-4-carbonitrile (WO 2010/007114) (60 mg, 0.33 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (92 mg, 0.33 mmol), and DIEA (0.23 mL, 1.31 mmol) in DMF (1.6 mL) was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (3 mL) and the resulting precipitate was isolated by filtration, washed with water and then EtOAc, and dried to give the title compound. MS: m/z = 393.1 (M + 1).
Step B: 5-Amino-2-f4-(2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidin-l- vnpyridine-4-carbonitrile
To a stirred suspension of 5-nitro-2-[4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-
3-yl)piperidin-l-yl]pyridine-4-carbonitrile (102 mg, 0.260 mmol) in EtOAc (6.5 mL) and EtOH (6.5 mL) was added 10% Pd/C (83 mg, 0.078 mmol) and the resulting mixture was stirred at ambient temperature under an atmosphere of hydrogen {ca. 1 atm) for 4 h. The reaction mixture was filtered through Celite\ washing with CH2CI2:MeOH - 9:1, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z =
363.1 (M + 1). XH NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.93 (s, 1H), 7.00-7.03 (m, 3H), 6.94 (s, 1H), 6.77-6.80 (m, 1H), 4.22 (t, 1H, J = 11.6 Hz), 4.13 (d, 2H, J = 12.7 Hz), 3.33-3.35 (m, 2H), 2.86-2.88 (m, 2H), 2.69 (t, 2H, V = 12.2 Hz), 1.66-1.71 (m, 2H), 1.61-1.63 (m, 2H).
INTERMEDIATE 48
Figure imgf000103_0001
l-(4-lodo-3-phenoxvphenvl)spiro[piperidine-4,3'-Pvrrolo[2,3-blpyridin1-2'(l'H)-one
To a stirred solution of l-(4-amino-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-
£>]pyridin]-2'(l'W)-one (described in Intermediate 27) (193 mg, 0.499 mmol) in CH3CN (4 mL) at 0 °C were added tert-butyl nitrite (0.108 mL, 0.899 mmol) and tetrafluoroboric acid (0.103 mL, 0.749 mmol). Stirring was continued at 0 °C for 30 min, then a solution of potassium iodide (1.66 g, 10 mmol) in water (2.5 mL) was added, and the resulting mixture was stirred at 0 °C for 5 min and then allowed to warm to ambient temperature. The reaction mixture was stirred for 18 h then it was poured into saturated aqueous sodium bicarbonate (8 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc - 100:0 to 60:40, to afford the title compound. MS: m/z = 498.1 (M + l).
INTERMEDIATE 49
Figure imgf000104_0001
l-{5-i(2,6-Dimethvlpvridin-4-vnamino1-2'-(trifluoromethvl¾-4,4'-bipvridin-2-vl)piperidin-4-one
Step A: 4-(4,4,5,5-Tetramethvl-l,3,2-dioxaborolan-2-vl)-2-(trifluoromethvl)pyridine
A mixture of 4-bromo-2-(trifluoromethyl)pyridine (4.5 g, 19.91 mmol), B2Pin2 (5.56 g, 21.90 mmol), Pd(dppf)Cl2 (1.626 g, 1.991 mmol), and CH3C02 (3.91 g, 39.8 mmol) in DMSO (40 mL) was degassed and refilled with nitrogen 3 times. The mixture was stirred at 100 °C for 18 h, and then concentrated under reduced pressure. The residue was diluted with EtOAc (40 mL) and washed with H20 (40 mL). The organic phase was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with PE:EtOAc - 20:1, to afford the title compound. XH NMR (400 MHz, CDCI3) 6 8.73 (d, 1H, J = 4.4 Hz), 8.02 (s, 1H), 7.81 (d, 1H, J = 4.4 Hz), 1.36 (s, 12H).
Step B: 2-Chloro-5-nitro-2'-(trifluoromethvl)-4.4'-bipyridine
A mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (4 g, 14.65 mmol), 2,4-dichloro-5-nitropyridine (3.39 g, 17.58 mmol), K2C03 (4.05 g, 29.3 mmol) and PdCI2(dppf) (1.072 g, 1.465 mmol) in THF (240 mL) and H20 (60 mL) was degassed and refilled with nitrogen 3 times. The mixture was stirred at 55 °C for 18 h, and then concentrated under reduced pressure to remove the THF. The aqueous residue was extracted with EtOAc (3 103 x 50 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of PE:EtOAc - 100:1 to 5:1, to afford the title compound. XH NMR (400 MHz, CDCI3) δ 9.15 (s, 1H), 8.88 (d, 1H, J = 4.8 Hz), 7.64 (s, 1H), 7.43 (d, 1H, J = 4.8 Hz), 7.42 (s, 1H).
Step C: 2-(l,4-Dioxa-8-azaspirof4.51dec-8-vl)-5-nitro-2'-(trifluoromethyl)-4,4'-bipvridine
To a solution of 2-chloro-5-nitro-2'-(trifluoromethyl)-4,4'-bipyridine (1 g, 3.29 mmol) in DMF (15 mL) was added l,4-dioxa-8-azaspiro[4.5]decane (472 mg, 3.29 mmol) and DIEA (1.15 mL, 6.59 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (3 mL) and the resulting precipitate was isolated by filtration, washed with water and then EtOAc, and dried to give the title compound. MS: /z - 411.0 (M + 1).
Step D: 6-(l,4-Dioxa-8-azaspiroi4.5ldec-8-vl)-2'-(trifluoromethvl)-4,4'-bipvridin-3-amine
To a stirred suspension of 2-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-5-nitro-2'- (trifluoromethyl)-4,4'-bipyridine (1.30 g, 3.17 mmol) in DMF (20 mL) was added 10% Pd/C (337 mg, 0.302 mmol) and the resulting mixture was stirred at ambient temperature under an atmosphere of hydrogen {ca. 1 atm) for 2 h. The reaction mixture was filtered through Celite", washing MeOH, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 381.0 (M + 1).
Step E: /\/-(2,6-Dimethvlpvridin-4-vl)-6-(l,4-dioxa-8-azaspiro[4.51dec-8-vl)-2'-(trifluoromethyl)-
4,4'-bipyridin-3-amine
A deoxygenated mixture of 6-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2'-(trifluoromethyl)- 4,4'-bipyridin-3-amine (1.0 g, 2.63 mmol), 4-bromo-2,6-dimethylpyridine (1.05 g, 3.94 mmol), sodium tert-butoxide (758 mg, 7.89 mmol), and chloro[2-(dicyclohexylphosphino)-3,6- dimethoxy-2',4',6'-triisopropyl-l,l'-biphenyl] [2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (210 mg, 0.263 mmol) in 2-methyl-2-butanol (10 mL) was heated at 70 "C for 16 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CHaC^MeOH - 100:1 to 10:1, to give the title compound. MS: m/z = 486.2 (M + 1).
Step F: l-{5-f(2,6-Dimethvlpvridin-4-vl)amino)-2'-(trifluoromethvl)-4,4'-bipvridin-2-yl}piperidin- 4-one To a stirred solution of Λ/-(2,6-εΙΪΓηθΐΗνΙρνπάϊη-4-νΙ)-6-(1,4-οΙϊοχ3-8-3Ζ35ρίΓθ[4.5]άθ€-8- yi)-2'-(trifluoromethyl)-4,4'-bipyridin-3-amine (260 mg, 0.536 mmol) in THF (3 mL) and H20 (1 mL) was added cone. HCI (0.44 mL, 5.36 mmol). The resulting mixture was stirred at 50 °C for 18 h, then partitioned between saturated aqueous sodium bicarbonate (10 mL) and CH2CI2 (10 mL). The aqueous layer was extracted further with CH2CI2 (2 x 10 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 442.1 (M + 1). XH NMR (400 MHz, CDCI3) δ 8.70 (d, 1H, J = 5.2 Hz), 8.24 (s, 1H), 7.70 (s, 1H), 7.57 (d, 1H, J = 4.4 Hz), 6.71 (s, 1H), 6.29 (s, 2H), 4.02-3.99 (m, 4H), 2.61-2.58 (m, 4H), 2.40 (s, 6H).
INTERMEDIATE 50
Figure imgf000106_0001
9-r5-Bromo-4-(4-fluorophenvl)pyridin-2-vn-l,9-diazaspirof5.5lundecan-2-one
To a mixture of 5-bromo-2-chloro-4-(4-fluorophenyl)pyridine (described in Intermediate 44) (350 mg, 1.22 mmol) and l,9-diazaspiro[5.5]undecan-2-one (206 mg, 1.22 mmol) in DMSO (8 mL) was added potassium carbonate (675 mg, 4.89 mmol). The resulting mixture was heated at 120 °C for 18 h. The reaction mixture was cooled to room temperature and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN: TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 420.3 (M + 1).
INTERMEDIATE 51
Figure imgf000106_0002
4-Chloro-2-(fluoromethvl)-6-methvlpyridine hydrochloride
Step A: 2-(Bromomethvl)-4-chloro-6-methylpvridine
A stirred mixture of 4-chloro-2,6-dimethvlpyridine (1.00 g, 7.06 mmol), NBS (628 mg, 3.53 mmol) and A1BN (115 mg, 0.71 mmol) in CCU (150 ml) was heated at reflux for 18 h. The resulting mixture was allowed to cool to ambient temperature and was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography, eluting with PE:EtOAc - 5:1, to afford the title compound. MS: m/z = 222.0 (M + 1).
Step B: 4-Chloro-2-(fluoromethvl)-6-methylpvridine hydrochloride
A stirred mixture of 2-(bromomethyl)-4-chloro-6-methylpyridine (230 mg, 1.04 mmol) and cesium fluoride (1.60 g, 10.4 mmol) in CH3CN (3 mL) was heated at reflux for 6 h, then partitioned between water (5 mL) and CH2CI2 (10 mL). The aqueous layer was extracted further with CH2CI2 (2 x 10 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, treated with excess HCI in EtOAc, and then concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z - 160.2 (M + 1). H NM (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.08 (s, 1H), 5.79 (d, 2H, J = 46 Hz), 2.83 (s, 3H).
INTERMEDIATE 52
Figure imgf000107_0001
l-(5-[(2,6-Dimethvlpvridin-4-vl)(methvl)aminol-2'-fl-(trifluoromethvl)cyclopropvn-4,4'- bipvridin-2-yl}piperidin-4-one
Step A: (lZ,4g)-l-Hvdroxv-5-methoxv-l-fl-(trifluoromethvl)cvclopropvnpenta-l,4-dien-3-one
106 To a solution of (£)-4-methoxybut-3-en-2-one (14.96 g, 149 mmol) in THF (400 mL) was added LiHMDS (149 mL, 149 mmol) dropwise at -70 °C. The mixture was stirred at -70 °C for 30 min and then l-(trifluoromethyl)cyclopropanecarbonyl chloride (25 mL, 35.9 mmol) was added dropwise over 4 h, keeping the reaction temperature at -70 °C. The resulting mixture was allowed to warm to 15 °C over 2 h. The reaction mixture was quenched with saturated NH4CI (20 mL), concentrated under reduced pressure to remove THF and the residue was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S0 , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of PE:EtOAc - 100:0 to 50:1, to give the title compound. H NMR (400 MHz, CDCI3): δ 7.57 (d, 1H, J = 12.4 Hz), 5.70 (s, 1H), 5.24 (d, 1H, J = 12.4 Hz), 3.68 (s, 3H), 1.43-1.41 (m, 2H), 1.26-1.23 (m, 2H).
Step B: 2-fl-(Trifluoromethyl)cvclopropvll-4H-pvran-4-one
To a solution of (lZ,4f)-l-hydroxy-5-methoxy-l-(l-(trifluoromethyl)cyclopropyl)penta- l,4-dien-3-one (2.4 g, 12.2 mmol) in CH2CI2 (20 mL) was added trifluoroacetic acid (2.79 g, 24.47 mmol) and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of PE:EtOAc - 10:1 to 3:1, to give the title compound. H NMR (400 MHz, CDCI3): δ 7.76 (d, 1H, J = 5.6 Hz), 6.55 (d, 1H, J = 2.4 Hz), 6.39 (dd, 1H, J = 5.6, 2.4 Hz), 1.54- 1.51 (m, 2H), 1.38-1.34 (m, 2H).
Step C: 2-ri-(Trifluoromethvl)cvclopropyl]pvridin-4(l/Tf)-one
A stirred solution of 2-(l-(trifluoromethyl)cyclopropyl)-4H-pyran-4-one (1.2 g, 5.88 mmol) in NH4OH (15 mL, 28%) was heated at reflux for 1 h. The mixture was concentrated and the residue was triturated with PE to give the title compound in sufficient purity for use in the next step. H NMR (400 MHz, CDCI3): δ 7.64 (d, 1H, J = 7.2 Hz), 6.62 (d, 1H, J = 1.2 Hz), 6.44 (dd, 1H, J = 7.2, 1.2 Hz), 1.37-1.33 (m, 2H), 1.19-1.16 (m, 2H).
Step D: 4-Bromo-2-Fl-(trifluoromethyl)cvclopropvnpvridine
To a stirred solution of 2-(l-(trifluoromethyl)cyclopropyl)pyridin-4(lH)-one (1.10 g, 5.41 mmol) in DCE (20 mL) was added phosphoryl tribromide (3.10 g, 10.83 mmol) and the resulting mixture was heated at 80 °C for 2 h. The reaction mixture was carefully quenched with saturated aqueous NaHC03 (5 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of PE:EtOAc - 100:0 to 100:1, to give the title compound. XH NMR (400 MHz, CDCI3): δ 8.34 (d, 1H, J = 5.2 Hz), 7.72 (s, 1H), 7.36 (d, 1H, J = 4.0 Hz), 1.44-1.43 (m, 4H).
Step E: A/-(2,6-Dimethvlpyridin-4-vl)-6-(l,4-dioxa-8-azaspirof4.51dec-8-vl)-2'-fl- (trifluoromethvl)cyclopropvll-4,4'-bipvridin-3-amine
Essentially following the procedures described in Intermediate 49, but using 4-bromo-2- [l-(trifluoromethyl)cyclopropyl]pyridine in place of 4-bromo-2-(trifluoromethyl)pyridine, the title compound was obtained. MS: m/z = 526.1 (M + 1).
Step F: A/-(2,6-Dimethylpvridin-4-vl)-6-(l,4-dioxa-8-azaspiror4.5ldec-8-yl)-/\/-methvl-2'-fl- (trifluoromethyl)cvclopropvll-4,4'-bipvridin-3-amine
To a solution of A/-(2,6-dimethylpyridin-4-yl)-6-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2'-[l- (trifluoromethyl)cyclopropyl]-4,4'-bipyridin-3-amine (180 mg, 0.342 mmol) in DMF (10 mL) at O °C was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1.03 mmol), and the resulting mixture was stirred at 0 °C for 1 h. lodomethane (146 mg, 1.03 mmol) was added ans the reaction mixture was allowed to warm to ambient temperature over 30 min. The reaction mixture was poured into saturated aqueous ammonium chloride (20 mL) and extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound, which was used without further purification. MS: m/z = 540.1 (M + 1).
Step G: l-{5-i(2,6-Dimethvlpvridin-4-vl)(methvl)aminol-2'-il-(trifluoromethvl)cyclopropvn-4,4'- bipyridin-2-vl}piperidin-4-one
To a stirred solution of A/-(2,6-dimethylpyridin-4-yl)-6-(l,4-dioxa-8-azaspiro[4.5]dec-8- yl)-/V-methyl-2'-[l-(trifluoromethyl)cyclopropyl]-4,4'-bipyridin-3-amine (170 mg, 0.315 mmol) in THF (3.2 mL) was added 2 M aqueous HCI (3.15 mL, 6.30 mmol). The resulting mixture was stirred at 30 °C for 18 h, then partitioned between saturated aqueous sodium bicarbonate (20 mL) and CH2CI2 (20 mL). The aqueous layer was extracted further with CH2CI2 (2 x 20 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z = 496.1 (M + 1). H NMR (400 MHz, CD3OD) δ 8.74 (d, 1H, J = 5.2 Hz), 8.09 (m, 1H), 7.45 (d, 1H, J = 9.2 Hz), 7.35 (m, 1H), 6.96 (m, 1H), 6.22 (br, s, 2H),
4.06-4.03 (m, 2H), 3.76-3.69 (m, 2H), 3.06 (s, 3H), 2.58-2.55 (m, 2H), 2.31 (s, 6H), 1.85-1.82 (m, 2H), 1.35-1.22 (m, 4H).
108 The intermediates appearing in the following tables were prepared by analogy to the above intermediates, 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. Straightforward protecting group strategies were applied in some routes.
Figure imgf000110_0001
Figure imgf000110_0002
109
Figure imgf000111_0001
Figure imgf000112_0002
TABLE I T-B
Figure imgf000112_0001
Figure imgf000112_0003
TABLE INT-C
Figure imgf000113_0001
Figure imgf000113_0003
TABLE INT-D
Figure imgf000113_0002
Figure imgf000113_0004
Figure imgf000114_0001
TABLE I T-E
Figure imgf000114_0002
Figure imgf000115_0001
TABLE I T-F
Figure imgf000115_0002
114
Figure imgf000116_0001
115
Figure imgf000117_0001
Figure imgf000118_0001
117
Figure imgf000119_0001
118
Figure imgf000120_0001
119
Figure imgf000121_0001
120
Figure imgf000122_0001
121
Figure imgf000123_0001
122
Figure imgf000124_0001
123
Figure imgf000125_0001
124
Figure imgf000126_0002
TABLE INT-G
Figure imgf000126_0001
125
Figure imgf000127_0002
Figure imgf000127_0001
126
Figure imgf000128_0001
EXAMPLE 1
127
Figure imgf000129_0001
l-{4 (2,6,8-Trimethvlquinolin-4-vl)ami^
2'(l'H)-one
A stirred mixture of 2/6,8-trimethyl-4-chloroquinoline (50 mg, 0.24 mmol) and l-(4- aminophenyl)spiro[piperidine-4 3,-pyrrolo[2,3-i'3pyridin]-2'(l'H)-one (described in Intermediate F2) (79 mg, 0.267 mmol) in AcOH (1.0 mL) was heated at 135 °C for 3 h. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of
H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 464.4 (M + 1). 1H NMR (500 MHz, CD3OD) δ 8.14 (d, 1H, J = 1.7 Hz), 8.10 (dd, 1H, J = 5.3, 1.5 Hz), 7.86 (dd, 1H, J = 8.0, 1.5 Hz), 7.68 (s, 1H), 7.32 (d, 2H, J = 8.9 Hz), 7.23 (d, 2H, J = 8.9 Hz), 7.04 (dd, 1H, J = 7.4, 5.3 Hz), 6.63 (s, 1H), 3.86-3.78 (m, 2H), 3.60-3.52 (m, 2H), 2.70 (s, 3H), 2.64 (s, 3 H), 2.56 (s, 3H), 2.18-2.10 (m, 2H), 2.02-1.94 (m, 2H).
EXAMPLE 2
Figure imgf000129_0002
128 3-(l-{4-f(6-Bromo-2.8-dimethvlquinolin-4-yl
2/-/-l,3-benzodiazepin-2-one
A stirred mixture of 6-bromo-2,8-dimethyl-4-chloroquinoline (40 mg, 0.148 mmol) and 3-[l-(4- aminopheny piperidin^-yO-l^^^-tetrahydro- H-l^-benzodiazepin- -one (described in Intermediate 5) (50 mg, 0.148 mmol) in AcOH (1.0 mL) was heated at 135 °C for 3 h. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95 :5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 570.2 (M + 1). 1H NMR (500 MHz, CD3OD) δ 8.61 (d, 1H, J = 2.1 Hz), 7.97 (t, 1H, J = 1.9 Hz), 7.43-7.33 (m, 4H), 7.08 (d, 2H, J = 7.6 Hz), 6.95-6.86 (m, 2H), 6.74 (s, 1H), 4.45-4.37 (m, 1H), 3.90 (d, 2H, J = 12.1 Hz), 3.57-3.53 (m, 2H), 3.15 (t, 2H, J = 12.2 Hz), 3.05- 3.01 (m, 2H), 2.73 (s, 3H), 2.66 (s, 3H), 2.16-2.05 (m, 2H), 1.93 (d, 2H, J = 12.3 Hz).
EXAMPLE 3
Figure imgf000130_0001
3-ri-(4-{r6-Cvano-2,8-dimethvlquinolin-4-vnamino}phenvl)piperidin-4-vll-l,3,4,5-tetrahydro- 2H-l,3-benzodiazepin-2-one
A stirred mixture of 6-cyano-2,8-dimethyl-4-chloroquinoline (14.2 mg, 0.065 mmol) (described in Intermediate A31) and 3-[l-(4-aminophenyl)piperidin-4-yl]-l,3,4,5-tetrahydro-2H-l,3- benzodiazepin-2-one (described in Intermediate 5) (20 mg, 0.065 mmol) in AcOH (1.0 mL) was heated at 135 °C for 3 h. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by reversed-phase HPLC on
129 a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 517.2 (M + 1). 1H NMR (500 MHz, CD s OD) δ 8.83 (d, 1H, J = 1.6 Hz), 8.07 (dd, 1H, J = 1.7, 1.0 Hz), 7.35 (d, 2H, J = 8.9 Hz), 7.25 (d, 2H, J = 8.9 Hz), 7.08 (d, 2H, J = 7.6 Hz), 6.96-6.86 (m, 2H), 6.77 (s, 1H), 4.4one to four.31 (m, 1H), 3.92 (d, 2H, J = 12.4 Hz), 3.57-3.52 (m, 2H), 3.07-2.95 (m, 4H), 2.77 (s, 3H), 2.68 (s, 3H), 2.09-1.96 (m, 2H), 1.88 (d, 2H, J = 12.3 Hz).
EXAMPLE 4
Figure imgf000131_0001
3-fl-(4-{[2,8-Dimethvl-6-(morpholin-4-vlmethvl)quinolin-4-vllamino}phenyl)piperidin-4-vn- l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
A mixture of 3-(l-{4-[(6-bromo-2,8-dimethylquinolin-4-yl)amino]phenyl}piperidin-4-yl)- l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (described in Example 2) (30 mg, 0.053 mmol), 2-(dicyclohexylphosphino)2',4',6'-triisopropylbiphenyl (5.0 mg, 0.010 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (32.7 mg, 0.158 mmol), cesium carbonate (68.5 mg, 0.21
130 mmol) and palladium(ll) acetate (1.1 mg, 0.005 mmol) in THF (0.5 mL) and water (0.05 mL) was irradiated at 140 °C in a microwave reactor for 1 h. The reaction mixture was cooled to ambient temperature, filtered, and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN :TFA - 95:5:0.1 to 5 :95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 591.4 (M + 1). 1H NMR (500 MHz, CD3OD) δ 8.52 (s, 1H), 7.98 (s, 1H), 7.94 (s, 1H), 7.40 (d, 2H, J = 8.9 Hz), 7.32 (d, 2H, J = 8.9 Hz), 7.09 (t, 2H, J = 7.5 Hz), 6.95- 6.87 (m, 2H), 6.76 (s, 1H), 4.53 (s, 2H), 3.92 (d, 4H, J = 13.1 Hz), 3.58-3.53 (m, 2H), 3.14-3.00 (m, 4H), 2.99 (s, 3H), 2.86 (d, 2H, J = 0.7 Hz), 2.77 (s, 3H), 2.69 (s, 2H), 2.15-2.00 (m, 2H), 1.92 (d, 2H, J = 12.7 Hz).
EXAMPLE 5
Figure imgf000132_0001
Methyl 2'-oxo-l-{4-[(2,6,8-trimethvlquinolin-4-vl)aminol phenvl}-l',2'-dihydrospirorpiperidine- 4,3'-pvrrolof2,3-felpyridinel-5'-carboxvlate
A stirred mixture of 2,6,8-trimethyl-4-chloroquinoline (100 mg, 0.486 mmol) and methyl l-(4- aminophenyl)-2,-oxo-l'-{[2-(trimethylsilyl)ethoxy]methyl}-l',2'-dihydrospiro[piperidine-4,3'- pyrrolo[2,3-i}] pyridine]-5'-carboxylate (described in Intermediate 11) (235 mg, 0.486 mmol) in AcOH (1.0 mL) was heated at 135 °C for 2 h. The reaction mixture was cooled to ambient temperature and TFA (1 mL) was added. The mixture was stirred at 60 °C for 3 h and cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by reversed-phase H PLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 522.3 (M + 1). 'H NMR (500 MHz, DMSO-d e ) δ 8.73 (d, 1H, J = 2.0 Hz), 8.31 (s, 1H), 8.20 (d, 1H, J = 2.0 Hz), 7.70 (s, 1H), 7.30 (d, 2H, J = 8.7 Hz), 7.20 (d, 2H, J = 8.8 Hz), 6.62 (s, 1H), 3.85 (s, 3H), 3.75- 3.66 (m, 2H), 3.61 (s, 3H), 3.54-3.46 (m, 2H), 2.70 (s, 3H), 2.63 (s, 3H), 2.05-1.96 (m, 4H).
EXAMPLE 6
Figure imgf000133_0001
2'-Oxo-l-{4-f(2,6,8-trimethvlquinolin-4-vl)aminolphenvl}-l',2'-dihydrospiro[piperidine-4,3'- pyrrolo[2,3-iblpvridine1-5'-carboxvlic acid
To a stirred solution of methyl 2l-oxo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}- l',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-5'-carboxylate (described in Example 5) (155 mg, 0.297 mmol) in MeOH (10 mL) and THF (10 mL) was added aqueous lithium
132 hydroxide (1 M , 1.5 mL, 1.5 mmol) and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (2 mL). The mixture was adjusted to pH = 7 with 1 N aqueous hydrochloric acid and the resulting precipitate was collected by filtration, washing with water, and dried to give the title compound. MS: m/z = 508.3 (M + 1). 1H NMR (500 MHz, DMSO-de ) δ 8.53 (d, 1H, J = 1.7 Hz), 8.47 (s, 1H), 8.14 (d, 1H, J = 1.7 Hz), 7.95 (s, 1H), 7.33 (s, 1H), 7.22 (d, 2H, J = 8.7 Hz), 7.12 (d, 2H, J = 8.7 Hz), 6.60 (s, 1H), 3.74-3.66 (m, 2H), 2.79 (s, 3H), 2.76 (s, 3H), 2.76-2.56 (m, 2H), 2.34- 2.31 (m, 2H), 2.05-1.97 (m, 2H).
EXAMPLE 7
Figure imgf000134_0001
A/-(2-Methoxvethvl)-2'-oxo-l-{4-r(2,6,8-trimethvlquinolin-4-yl)amino1phenvl}-l',2'- dihvdrospirorpiperidine-4,3'-Pvrrolor2,3-fc1pvridine1-5'-carboxamide
To a stirred mixture of 2'-oxo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-i)]pyridine]-5'-carboxylic acid (described in Example 6) (15 mg, 0.03 mmol), HOBT (9 mg, 0.6 mmol) and DIEA (0.015 mL, 0.09 mmol) in DMF (1 mL) was added EDC (11.3 mg, 0.59 mmol). The mixture was stirred at ambient temperature for 5 min, then 2-methoxyethylamine (12 mg, 0.15 mmol) was added and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 565.4 (M + 1). 1H NMR (500 MHz, CD3OD) δ 8.63 (d, 1H, J = 2.0 Hz), 8.29 (d, 1H, J = 1.9 Hz), 8.23 (d, 1H, J = 2.1 Hz), 8.15 (s, 1H), 7.69 (s, 1H), 7.36 (dd, 2H, J = 9.0, 2.8 Hz), 7.29 (dd, 2H, J = 9.0, 2.7 Hz), 6.66 (d, 1H, J = 4.3 Hz), 3.92-3.84 (m, 4H), 3.57-3.52 (m, 2H), 3.38 (s, 3H), 3.28 (t, 2H, J = 7.1 Hz), 2.71 (s, 3H), 2.65 (s, 3H), 2.57 (s, 6H), 2.35-2.31 (m, 2H), 2.07-2.01 (m, 2H).
EXAMPLE 8
133
Figure imgf000135_0001
5'-Amino-l-{4 (2,6,8-trimethylquinolin-4^
fe1pvridin1-2'(l' V)-one
Step A: ferf-Butyl (2'-oxo-l-{4-f(2,6,8-trimethvlquinolin-4-vl¾amino1phenyl}-l',2'- dihvdrospiro[piperidine-4,3'-pyrrolor2,3-ib]pvridin1-5'-vl)carbamate
To a solution of 2'-oxo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l';2'- dihydrospiro[piperidine-4,3'-pyri"olo[2,3-i']pyi'idine]-5'-carboxylic acid (described in Example 6) (15 mg, 0.03 rnmol) in i-BuOH (5 mL) were added triethylamine (0.041 mL, 0.3 mmol) and diphenyl phosphoryl azide (0.064 mL, 0.3 mmol) and the resulting mixture was heated at 85 °C with stirring for 18 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (50 mL), washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z = 579.4 (M + l).
Step B: 5'-Amino-l-{4-f(2,6,8-trimethylquinolin-4-vl)aminolphenvl}spirorpiperidine-4,3'- pyrrolor2.3-blpvridinl-2'(l'H)-one A solution of terf-butyl (2'-oxo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-fa]pyridin]-5'-yl)carbamate (17 mg, 0.03 mmol) in TFA (2 mL) was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 479.3 (M + 1). 1H NMR (500 MHz, CD3OD) 6 8.15 (s, 1H), 7.95 (d, 1H, J = 2.4 Hz), 7.73 (d, 1H, J = 2.4 Hz), 7.69 (s, 1H), 7.38 (d, 2H, J = 8.9 Hz), 7.19 (dd, 2H, J = 8.0, 1.2 Hz), 6.65 (s, 1H), 3.90-3.84 (m, 2H), 3.57-3.52 (m, 2H), 2.71 (s, 3H), 2.64 (s, 3H), 2.56 (s, 3H), 2.16-2.08 (m, 4H). 134 EXAMPLE 9
Figure imgf000136_0001
5'-(Hvdroxvmethvl)-l-{4-f(2,6,8-trimethylquinolin-4-vl)aminolp envl)spirofpiperidine pyrrolo[2,3-ib1pvridinl-2'(l'H)-one
Step A: Methyl 2'-oxo-l-{4-f(2,6,8-trimethylquinolin-4-vl)amino1phenvl}-l'-{r2- (trimethvlsilv^)ethoxvlmethvl}-1 2'-dihvdrospirofpi eridine-4,3'-pvrrolof2,3-b^pvr^dine^-5'- carboxylate
A stirred mixture of methyl l-(4-aminophenyl)-2'-oxo-l'-{[2- (trimethylsilyl)ethoxy]methyl}-l, 2'-dihydrospiro[piperidine-4,3'-pyrrolo[2/3-6]pyridine]-5'- carboxylate (described in Intermediate 11) (235 mg, 0.486 mmol) and 2,6,8-trimethyl-4-chloro- quinoline (100 mg, 0.486 mmol) in AcOH (3 mL) was heated at 90 °C for 3 h. The reaction mixture was concentrated to dryness in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic layer was dried over Na2S04/ filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 40:60, to afford the title compound. MS: m/z = 652.2 (M + l).
Step B: 2'-Oxo-l-{4-f(2.6,8-trimethvlquinolin-4-vl)amino1phenv -l'-{[2- (trimethvlsilvl)ethoxv1methvl}-l',2'-dihvdrospiro[piperidine-4,3'-Pvrrolo[2,3-b1pyridinel-5'- carboxylic acid To a stirred solution of methyl 2'-oxo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}- l'-{[2-(trimethylsilyl)ethoxy]methyl}-l',2'-dihydrospiro[piperidine-4,3,-pyrrolo[2,3-fa]pyridine]- 5'-carboxylate (238 mg, 0.365 mmol) in THF (10 mL) and MeOH (5 mL) was added 1 N aqueous LiOH (3.65 mL, 3.65 mmol) and the mixture was stirred at ambient temperature for 18 h. The
135 reaction mixture was concentrated in vacuo and the residue was dissolved in water. The mixture was adjusted to pH ~ 7 with 1 N aqueous HCI and the resulting precipitate was collected by filtration, washing with water, and dried to give the title compound. MS: m/z = 638.4 (M + 1).
Step C: 5'-(Hvdroxvmethvn-l-{4-[(2,6,8-trimethvlquinolin-4-vl)amino1phenyl}-l'-{[2- (trimethvlsilvl)ethoxvlmethvl}spirofpiperidine-4,3'-Pvrrolof2,3--7lpyridinl-2'(l'H)-one
To a solution of 2'-oxo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2- (trimethylsilylJethoxylmethylJ-l'^'-dihydrospirotpiperidine^S'-pyrrolo^^-falpyridinel-S1- carboxylic acid (100 mg, 0.16 mmol) in THF (10 mL) was carefully added BH3-THF (1 M in THF, 1.6 mL, 1.6 mmol) and the resulting mixture was stirred at 45 °C for 18 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate, then water, then brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z = 624.1 (M + l).
Step D: 5'-(Hvdroxvmethvl)-l-{4-[(2.6,8-trimethvlquinolin-4-vl)aminolphenyl}spirofpiperidine- 4,3'-Pvrrolor2,3--7lpyridinl-2'(l'H)-one
A stirred mixture of 5'-(hydroxymethyl)-l-{4-[(2,6,8-trimethylquinolin-4- yl)amino]phenyl}-l'-{[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3- i>]pyridin]-2'(l'H)-one (98 mg, 0.16 mmol) and cone. HCI (2 mL) in dioxane (10 mL) was heated at 45 °C for 3 h. Solvent was removed under reduced pressure and the residue was dissolved in MeOH (5 mL) and DIEA (3 mL) was added. The resulting mixture was stirred at 45 °C for 3 h then concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 494.3 (M + 1). "Ή NM (500 MHz, CD sOD): 8.19 (s, 1H), 8.13-8.12 (m, 1H), 8.03 (s, 1H), 7.83 (d, 2H, J = 8.2 Hz), 7.73 (s, 1H), 7.66 (d, 2H, J = 8.5 Hz), 6.85 (s, 1H), 4.66 (s, 2H), 4.30-4.25 (m, 2H), 3.82-3.75 (m, 2H), 2.73 (s, 3H), 2.71 (s, 3H), 2.58 (s, 3H), 2.58-2.55(m, 2H), 2.31 (m, 2H).
EXAMPLE 10
136
Figure imgf000138_0001
2'-Oxo-l-(4-f(2,6,8 rimethylquinolin-4-vl
pyrrolol S-j lpyridinel-S'-carbonitrile
Step A: 5'-Bromo-l-{4-r(2,6.8-trimethvlquinolin-4-yl¾amino1phenvl}-l'-{f2- (trimethvlsilvl¾ethoxv1methvl}spiro[piperidine-4 '-pyrrolo[23-fe1pyridin1-2'(l' /)-one
Essentially following the procedures described in Example 9, but using l-(4- aminophenyl)-5'-bromo- -{[2-(trimethylsilyl)eth^
fa]pyridin]-2'(l'H)-one (described in intermediate 14) in place of methyl l-(4-aminophenyl)-2'- oxo-l'-{[2-(trimethylsilyl)ethoxy]methyl}-l',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3- b]pyridine]-5'-carboxylate, the title compound was obtained. MS: m/z = 672.4 (M + 1).
Step B: 2'-Oxo-l-{4-ri2,6,8-trimethylquinolin-4-vl)aminolphenvl)-l'-{i2- (trimethvlsilvl)ethoxv1methvl}-l',2'-dihvdrospirorpiperidine-4i3'-pvrrolo[2,3-blpvridine1-5l- carbonitrile
To a stirred solution of 5'-bromo-l-{4-[(2;6,8-trimethylquinolin-4-yl)amino]phenyl}-l'- {[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4/3'-pyrrolo[2,3-/b]pyridin]-2'(l'H)-one (85 mg, 0.126 mmol) in DMF (2 mL), were added zinc cyanide (15 mg, 0.126 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and the resulting mixture was heated at 110 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, then brine, then dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 30:70, to afford the title compound. MS: m/z = 619.4 (M + l).
Step C: 2'-Oxo-l-{4-f(2,6,8-trimethvlquinolin-4-vl)aminoTphenvl}-l',2'-dihydrospirofpiperidine- 4,3'-Pvrrolo[2,3-felpyridine1-5'-carbonitrile 137 Essentially following the procedures described in Example 9, but using 2'-oxo-l-{4- [(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l' [2-(trimethylsilyl)ethoxy]meth
dihydrospiro[piperidine-4,3'-pyrrolo[2;3-b]pyridine]-5'-carbonitrile in place of 5'- (hydroxymethyl)-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2- (trimethylsilyl)ethoxy]rnethyl}spiro[piperidine-4,3'-pyrrolo[2,3-jb]pyridin]-2'(l'H)-one, the title compound was obtained as the trifluoroacetate salt. MS: m/z = 489.3 (M + 1). 1H NMR (500 MHz, CD a OD): 8.52 (d, 1H, J = 1.9 Hz), 8.15-8.10 (m, 2H), 7.68 (s, 1H), 7.34 (d, 2H, J = 8.9 Hz), 7.26 (d, 2H, J = 8.9 Hz), 6.64 (s, 1H), 3.84-3.75 (m, 2H), 3.63-3.55 (m, 2H), 2.70 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H), 2.18-2.01 (m, 4H).
EXAMPLE 11
Figure imgf000139_0001
5'-(Aminomethvl)-l-{4-f(2,6,8-trimethylquinolin-4-vl)aminolphenvl)spirofpiperidine-4,3'- Pvrrolof2,3-b1Pvridin1-2'(l'H)-one
Step A: 5'-(Aminomethvl)-l-{4-f(2,6.8-trimethvlquinolin-4-vl)aminolphenyl}-l'-{r2- (trimethvlsilvl)ethoxv1methvl}spiroipiperidine-4,3'-Pvrrolo[2,3-fc1pyridinl-2'(l'H)-one
To a stirred solution of 2'-oxo-l-{4-[(2/6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2-
(trimethylsilyl)ethoxy]methyl}-l',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-f)]pyridine]-5'- carbonitrile (23 mg, 0.037 mmol) in MeOH (2 mL) at ambient temperature was added nickel(ll) chloride hexahydrate (9 mg, 0.04 mmol), followed by sodium borohydride (4 mg, 0.1 mmol). After 5 min, the reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate, then water, then brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z = 623.5 (M + 1).
138 Step B: 5'-(Aminomethvl)-l-{4-f(2,6,8-trimethvlauinolin-4-yl)aminolphenvl}spiro[piperidine-
4,3'-Pvrrolof2.3-b1pvridin1-2'(l'H¾-one
Essentially following the procedures described in Example 9, but using 5'- (aminomethyl)-l-{4-[(2;6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2- (trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-fa]pyridin]-2'(l'H)-one in place of 5'-(hydroxymethyl)-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2- (trimethylsilyl)ethoxy]methyl}spiro[piperidine-4 '^yrrolo[2 -ib]pyridin]-2'(l,H)-one, the title compound was obtained as the trifluoroacetate salt. MS: m/z = 493.3 (M + 1). 1H NMR (500 MHz, CD s OD): 8.21 (d, 1H, J = 2.0 Hz), 8.14 (s, 1H), 7.97 (d, 1H, J = 2.1 Hz), 7.69 (s, 1H), 7.36 (d, 2H, J = 8.9 Hz), 7.28 (d, 2H, J = 8.9 Hz), 6.64 (s, 1H), 4.15 (s, 2 H), 3.89-3.81 (m, 2H), 3.64-3.56 (m, 2H), 2.71 (s, 3H), 2.66-2.64 (s, 3H), 2.57 (s, 3H), 2.20-2.13 (m, 2H), 2.11-2.02 (m, 2H).
EXAMPLE 12
Figure imgf000140_0001
5'-[(Dimethvlamino)methvll-l-{4-f(2,6,8-trimethvlquinolin-4-vl)aminolphenvl)spirorpiperidine- 4.3'-pvrrolof2.3-fc1pyridinl-2'(l'H)-one
Step A: 5'-f(Dimethvlamino)methvn-l-{4-r(2,6,8-trimethvlquinolin-4-vl)amino1phenyl)-l'-{[2- (trimethvlsilvl)ethoxvlmethvl}spirorpiperidine-4,3'-pyrrolof2.3-i-ilpvridin1-2'(l'H)-one
A deoxygenated mixture of 5'-bromo-l-{4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}- l'-{[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-fc]pyridin]-2'(l,H)-one (described in Example 10) (40 mg, 0.059 mmol), XPhos (6 mg, 0.012 mmol), palladium(ll) acetate (1.5 mg, 6 μητιοΙ), cesium carbonate (77 mg, 0.238 mmol), and potassium 1- trifluoroborato-W,N-dimethylmethanamine (40 mg, 0.18 mmol) in THF (0.5 mL) and water (0.05 mL) was heated at 140 °C in a microwave reactor for 1 h. The cooled reaction mixture was diluted with EtOAc and washed with water, then brine, dried over Na2S04, filtered, and 139 concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z = 651.5 (M + 1).
Step B: 5'-r(Dimethvlamino)methvll-l-|4-r(2,6,8-trimethylquinolin-4- vl)amino1phenyl)spirofpiperidine-4,3'-Pvrrolof2,3-ib1Pvridinl-2'il'H)-one
Essentially following the procedures described in Example 9, but using 5'- [(dimethylamino)methyl]-l-{4-[(2;6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2- (trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-fo]pyridin]-2'(l'W)-one in place of 5'-(hydroxymethyl)-l-{4-[(2/6,8-trimethylquinolin-4-yl)amino]phenyl}-l'-{[2- (trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(l,H)-one, the title compound was obtained as the trifluoroacetate salt. MS: m/z = 521.4 (M + 1). H NMR (500 MHz, CD a OD): 8.24 (d, 1H, J = 2.0 Hz), 8.14 (s, 1H), 8.01 (d, 1H, J = 2.0 Hz), 7.68 (s, 1H), 7.34 (d, 2H, J = 8.8 Hz), 7.25 (d, 2H, J = 8.9 Hz), 6.63 (s, 1H), 4.33 (s, 2H), 3.87-3.79 (m, 2H), 3.62-3.54 (m, 2H), 2.89 (s, 3H), 2.70 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H) 2.20-2.13 (m, 2H), 2.11-2.02 (m, 2H).
EXAMPLE 13
Figure imgf000141_0001
2-Oxo-3-(l-{4-r(2,618-trimethvlquinolin-4-vl)amino1phenvl)piperidin-4-vl)-2,3,4,5-tetrahydro- ltf-l,3-benzodiazepine-7-carbonitrile
Step A: 7-Bromo-3-(l-{4-[(2,6,8-trimethvlquinolin-4-vl)aminolphenvl}piperidin-4-yl)-l, 3,4,5- tetrahvdro-2#-l,3-benzodiazepin-2-one A stirred mixture of 3-[l-(4-aminophenyl)piperidin-4-yl]-7-bromo-l,3,4,5-tetrahydro-2H- l,3-benzodiazepin-2-one (described in Intermediate F22) (194 mg, 0.467 mmol) and 2,6,8- 140 trimethyl-4-chloroquinoline (80 mg, 0.389 mmoi) in HOAc (1 mL) was heated at 90 °C for 3 h then concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 584.3 (M + 1).
Step B: 2-Oxo-3-il-{4-f(2,6,8-trimethvlquinolin-4-vl)amino1phenyl}piperidin-4-vl¾-2,3.4.5- tetrahydro-lH-l,3-benzodiazepine-7-carbonitrile
Essentially following the procedures described in Example 10, but using 7-bromo-3-(l- {4-[(2,6,8-trimethylquinolin-4-yl)amino]phenyl}piperidin-4-yl)-l;3,4,5-tetrahydro-2H-l,3- benzodiazepin-2-one in place of 5'-bromo-l-{4-[(2,6 8-trimethylquinolin-4-yl)amino]phenyl}-l'- {[2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3,-pyrrolo[2,3-i3]pyridin]-2'(l'H)-one, the title compound was obtained as the trifluoroacetate salt. MS: m/z = 531.3 (M + 1). 1H NMR (500 MHz, CD s OD): 8.13 (s, 1H), 7.68 (s, 1H), 7.47 (d, 1H, J = 1.9 Hz), 7.44 (dd, 1H, J = 2.0, 8.0 Hz), 7.30 (d, 2H, J = 8.9 Hz), 7.21-7.15 (m, 2H), 7.09 (d, 1H, J = 8.1 Hz), 6.61 (s, 1H), 4.65-4.60 (m, 1H), 3.92-3.87 (m, 2H), 3.58-3.53 (m, 2H), 3.09-3.03 (m, 2H), 2.94-2.91 (m, 2H), 2.87 (m, 2H), 2.70 (s, 3H), 2.64 (s, 3H), 2.56 (s, 3H) 2.01 (d, 1H, J = 4.1 Hz), 1.89-1.85 (m, 2H).
EXAMPLE 14
Figure imgf000142_0001
2-Oxo-3-(l-f5-r(2,6,8-trimethvlquinolin-4-vl)amino1pyridin-2-vl}piperidin-4-vl)-2.3.4,5- tetrahydro-lH-l,3-benzodiazepine-7-carbonitrile
Essentially following the procedures described in Example 13, but using 3-[l-(5- aminopyridin-2-yl)piperidin-4-yl]-7-bromo-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (described in Intermediate F23) in place of 3-[l-(4-aminophenyl)piperidin-4-yl]-7-bromo- l,3,4,5-tetrahydro-2/-/-l,3-benzodiazepin-2-one, the title compound was obtained as the 141 trifluoroacetate salt. MS: m/z = 532.3 (M + 1). 1H NMR (500 MHz, CD3OD) δ 8.16 (d, 1H, J = 2.7 Hz), 8.12 (s, 1H), 7.70 (s, 1H), 7.64 (dd, 1H, J = 2.8, 8.4 Hz), 7.46-7.43 (m, 2H), 7.10-7.05 (m, 2H), 6.58 (s, 1H), 4.54 (t, 2H, J = 13.3 Hz), 3.54-3.49 (m, 2H), 3.27-3.23 (m, 1H), 3.09-3.01 (m, 4H), 2.71 (s, 3H), 2.67 (s, 3H), 2.57 (s, 3H), 1.90-1.84 (m, 4H).
EXAMPLE 15
Figure imgf000143_0001
7-(Aminomethvl)-3-(l-{4-[(2,6,8-trimethvlquinolin-4-vl)aminoTphenvl}piperidin-4-vl)-l, 3,4,5- tetrahvdro-2H-l,3-benzodiazepin-2-one
To a stirred solution of 2-oxo-3-(l-{4-[(2,6,8-trimethylquinolin-4- yl)amino]phenyl}piperidin-4-yl)-2,3,4,5-tetrahydro-lH-l,3-benzodiazepine-7-carbonitri (28 mg, 0.053 mmol) in MeOH (2 mL) at ambient temperature was added nickel(ll) chloride hexahydrate (13 mg, 0.055 mmol), followed by sodium borohydride (6 mg, 0.16 mmol). After 5 min, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z - 535.3 (M + 1). 1H NMR (500 MHz, CD3OD) 6 8.10 (s, 1H), 7.65 (s, 1H), 7.28 (d, 2H, J = 8.7 Hz), 7.21-7.12 (m, 4H), 6.99 (d, 1H, J = 8.2 Hz), 6.59 (s, 1H), 4.35-4.30 (m, 1H), 3.98 (s, 2H), 3.87 (d, 2H, J = 12.2 Hz), 3.56-3.51 (m, 2H),
3.06-3.00 (m, 2H), 2.91 (t, 2H, J = 12.1 Hz), 2.67 (s, 3H), 2.61 (s, 3H), 2.53 (s, 3 H), 2.03-1.97 (m, 2H), 1.85 {d, 2H, J = 12.1 Hz).
EXAMPLE 16
142
Figure imgf000144_0001
l-{6-f(2,6,8-Trimethvlquinolin-4-yl)amm^
b1pvridin1-2'(l'H)-one
Step A: l-{6-f(2,6,8-Trimethvlquinolin-4-yl)amino1pvridazin-3-vl}-l'-{[2- (trimethvlsilvl)ethoxv]methvl}spirofpiperidine-4,3'-pvrrolof23-fe1Pvridinl-2'(l'H)-one
A deoxygenated stirred mixture of 4-amino-2/6;8-trimethylquinoline (15 mg, 0.081 mmol), l-(6 hloropyridazin3-yl)-l'-{t2-(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'- pyrrolo[2,3-b]pyridin]-2'(l'H)-one (described in Intermediate 32) (36 mg, 0.081 mmol), cesium carbonate (79 mg, 0.24 mmol), in's(dibenzylideneacetone)dipalladium(0) (8 mg, 0.009 mmol) and 4,5-b/s(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (10 mg, 0.017 mmol) in 1,4- dioxane (1 mL) was heated at 100 °C for 6 h. The reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc. The organic layer was washed with water, then brine, then dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z = 596.4 (M + 1).
Step B: l-{6-f(2,6,8-Trimethvlquinolin-4-vl)aminolpyridazin-3-vl)spirofpiperidine-4.3'-
Pvrrolo[2,3-folPvridinl-2'(l'H)-one A solution of l-{6-[(2,6,8-trimethylquinolin-4-yl)amino]pyridazin-3-yl}-l'-{[2-
(trimethylsilyl)ethoxy]methyl}spiro[piperidine-4,3'-pyrrolo[2,3-i3]pyridin]-2'(l'W)-one (48 mg, 0.081 mmol) was dissolved in TFA (3 mL) and stirred at ambient temperature for 3 h. The reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in MeOH (1 mL) and to this solution was added triethylamine (1 mL). The resulting mixture was stirred at ambient temperature 3 h and concentrated in vacuo. The residue was purified by reversed- phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 466.3 (M + 1). 1H NMR (500 MHz, CD3OD) δ 8.24 (s, 2H), 8.06 (dd, 1H, J = 5.4, 1.5 Hz), 7.82-7.78 (m, 2H), 7.67 (d, 1H, J = 1.7 Hz), 7.62 (s, 1H), 7.00 (dd, 1H, J = 7.4, 5.4 Hz), 4.24-4.16 (m, 2H), 4.07-3.99 (m, 2H), 2.81 (s, 3H), 2.73 (s, 3H), 2.56 (s, 3H), 2.08-2.00 (m, 4H).
4 EXAMPLE 17
Figure imgf000145_0001
3-(l-{6-[(2,6,8-Trimethylquinolin-4-vl)ami
l,3-benzodiazepin-2-one
A deoxygenated mixture of /V-(5-bromopyridin-2-yl)-2,6,8-trimethylquinolin-4-amine (described in Intermediate 33) (22 mg, 0.064 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H- l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (19.9 mg, 0.071 mmol), chloro (2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl)[2-(2-aminoethylphenyl)]palladium(ll), methyl f-butyl ether adduct (5.25 mg, 0.0064 mmol) and 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos) (6.00 mg, 0.013 mmol) in 1,4-dioxane (O.lmL) was treated with lithium to/s(trimethylsiiyl)amide (1.0 M in THF, 0.27 mL, 0.27 mmol) and the resulting mixture was heated at 90 °C for 18 h. The reaction mixture was allowed to cool to ambient
temperature and was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN :TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the
trifluoroacetate salt. MS: m/z = 507.3 (M + 1). 1H NMR (500 MHz, CD s OD) δ 8.25 (d, 1H, J = 3.0 Hz), 8.22 (s, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 7.61 (dd, 1H, J = 8.9, 3.1 Hz), 7.38 (s, 1H), 7.08 (d, 2H, J = 7.8 Hz), 6.94 (s, 1H), 6.93-6.86 (m, 1H), 4.36 (t, 1H, J = 4.2 Hz), 3.94 (d, 2H, J = 12.5 Hz), 3.57- 3.52 (m, 2H), 3.07-2.96 (m, 3H), 2.96 (d, 1H, J = 2.6 Hz), 2.93 (d, 1H, J = 2.6 Hz), 2.76 (s, 3H), 2.74 (s, 3H), 2.58 (s, 3H), 2.04-1.98 (m, 2H), 1.88 (d, 2H, J = 12.2 Hz).
EXAMPLE 18
Figure imgf000146_0001
3-(l-{2-f(2,6,8-Trimethylquinolin-4-vl)amin^^
2H-l,3-benzodiazepin-2-one Essentially following the procedures described in Example 17, but using W-(5- chloropyrimidin-2-yl)-2,6,8-trimethylquinolin-4-amine (described in Intermediate 34) in place of W-(5-bromopyridin-2-yl)-2,6,8-trimethylquinolin-4-amine, the title compound was obtained as the trifluoroacetate salt. MS: m/z = 508.3 (M + 1). 'H NMR (500 MHz, CD 3 OD) δ 8.77 (s, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.73 (s, 1H), 7.08 (d, 2H, J = 7.9 Hz), 6.94 (s, 1H), 6.93-6.89 (m, 1H), 6.89-6.86 (m, 2H), 4.38-4.33 (m, 1H), 3.94 (d, 2H, J = 12.5 Hz), 3.57-3.52 (m, 2H), 3.05-2.95 (m, 4H), 2.94 (d, 1H, J = 2.7 Hz), 2.86 (s, 3H), 2.76 (s, 3H), 2.60 (s, 3H), 2.01-1.88 (m, 4H).
EXAMPLE 19
Figure imgf000146_0002
Methyl 2,8-dimethvl-4-({4-f4-(2-oxo-l,2,4.5-tetrahydro-3H-l,3-benzodiazepin-3-vl)piperidin-l- yll phenvl}amino)quinoline-6-carboxylate
A stirred mixture of methyl 4-chloro-2,8-dimethylquinoline-6-carboxylate 4 (50 mg, 0.2 mmol) and S-tl-i^aminopheny piperidin-^yn-l^AS-tetrahydro-ZH-l^- benzodiazepin-2-one (described in Intermediate 5) (67.4 mg, 0.2 mmol) in AcOH (1.0 mL) was heated at 135 °C for 3 h. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 550.3 (M + 1). 1H NMR (500 MHz, DMSO-d6) 6 9.11 (s, 1H), 8.34 (s, 1H), 7.30 (d, 2H, J = 8.5 Hz), 7.17 (d, 2H, J = 8.5 Hz), 7.09 (t, 2H, J = 7.8 Hz), 6.95-6.85 (m, 2H), 6.69 (s, 1H), 4.35 (t, 1 H, J = 4.4 Hz), 4.00 (s, 3H), 3.92 (d, 2H, J = 12.4 Hz), 3.57-3.52 (m, 2H), 3.05-3.00 (m, 2H), 2.77 (s, 3H), 2.68 (m, 5H), 2.04-1.96 (m, 2H), 1.89-1.86 (m, 2H).
EXAMPLE 20
Figure imgf000147_0001
2,8-Dimethyl-4-({4-r4-(2-oxo-l,2,4,5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidin-l- vnphenvl}amino)quinoline-6-carboxylic acid
A mixture of methyl 2,8-dimethyl-4-({4-[4-(2-oxo-l,2,4,5-tetrahydro-3tf-l,3- benzodiazepin-3-yl)piperidin-l-yl]phenyl}amino)quinoline-6-carboxylate (described in Example 19) (10 mg, 0.018 mmol) and lithium hydroxide (12 mg, 0.50 mmol) in MeOH (1 mL) was stirred at 60 °C for 18 h and then concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 536.3 (M + 1). 1H NMR (500 MHz, CD s OD) δ 9.06 (d, 1H, J = 1.6 Hz), 8.30 (s, 1H), 7.80 (d, 2H, J = 8.7 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 7.04 (d, 2H, J = 8.7 Hz), 6.89 (d, 2H, J = 8.0 Hz), 6.84 (s, 1H), 6.65 (s, 1H), 4.25-4.20 (m, 2H),
3.88-3.85 (m, 2H), 3.52-3.47 (m, 2H), 3.00-2.94 (m, 4H), 2.72 (s, 3H), 2.62 (s, 3H), 1.97-1.88 (m, 4H). EXAMPLE 21
Figure imgf000148_0001
2,8-Dimethvl-4-({4-f4-(2-oxo-l,2,4.5-tetrahvdro-3H-l,3-benzodiazepin-3-yl)piperidin-l- vnphenyl}amino)-/V-(2,2.2-trifluoroethvl)quinoline-6-carboxamide
To a stirred mixture of 2,8-dimethyl-4-({4-[4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3- benzodiazepin-3-yl)piperidin-l-yl]phenyl}amirio)quinoline-6-carboxylic acid (described in Example 20) (41 mg, 0.077 mmol), 2,2,2-trifluoroethylamine (15 mg, 0.153 mmol) and BOP (50.8 mg, 0.115 mmol) in DMF (0.77 mL) was added DIEA (0.040 mL, 0.23 mmol) and the resulting mixture was stirred at ambient temperature for 18 h and then concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 617.4 (M + 1). 'H NMR (500 MHz, CD s OD) δ 8.91 (d, 1H, J = 1.8 Hz), 8.19 (dd, 1H, J = 1.8, 1.0 Hz), 7.31 (d, 2H, J = 8.8 Hz), 7.18 (d, 2H, J = 8.9 Hz), 7.08 (d, 2H, J = 7.7 Hz), 6.94 (s, 1H), 6.92-6.87 (m, 2H), 6.71 (s, 1H), 4.34-4.30 (m, 1H), 4.2one to four.14 (m, 2H), 3.92 (d, 2H, J = 12.5 Hz), 3.57-3.52 (m, 2H), 3.05-3.00 (m, 2H), 2.93-2.85 (m, 2H), 2.79 (s, 3H), 2.67 (s, 3H), 2.00- 1.85 (m, 4H).
EXAMPLE 22
Figure imgf000149_0001
3-fl-(4-(f6-(HvdroxvmethvB-2,8-dimethvlquinolin-4-yl1am
tetrahydro-2H-l,3-benzodiazepin-2-one To a stirred mixture of methyl 2,8-dimethyl-4-({4-[4-(2-oxo-l,2,4,5-tetrahydro-3H-l,3- benzodiazepin-3-yl)piperidin-l-yl]phenyl}amino)quinoline-6-carboxylate (described in Example 19) (10 mg, 0.018 mmol) in 1,4-dioxane (0.18 mL), was added lithium triethylborohydride (1 M in THF, 0.036 mL, 0.036 mmol). The resulting mixture was stirred at ambient temperature for 18 h and then purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN :TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 522.3 (M + 1). 1H NMR (500 MHz, CDs OD) δ 8.31 (s, 1H), 7.82 (s, 1H), 7.35 (d, 2H, J = 8.8 Hz), 7.27 (d, 2H, J = 8.8 Hz), 7.08 (d, 2H, J = 7.6 Hz), 6.96-6.86 (m, 2H), 6.67 (s, 1H), 4.42-4.32 (m, 1H), 3.91 (d, 2H, J = 12.3 Hz), 3.57-3.52 (m, 2H), 3.02 (t, 4H, J = 9.4 Hz), 2.74 (s, 3H), 2.66 (s, 3H), 2.05 (qd, 2H, J = 12.3, 3.9 Hz), 1.89 (d, 2H, J = 12.3 Hz).
EXAMPLE 23
Figure imgf000149_0002
3-(l-{4-r(2,6,8-Trimethvlquinolin-4-vl)oxvlphenvljpiperidin-4-yl)-1.3.4,5-tetrahvdro-2H-l,3- benzodiazepin-2-one A deoxygenated stirred mixture 4-(4-bromophenoxy)-2;6,8-trimethylquinoline
(described in Intermediate 35) (15 mg, 0.044 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H- l,3-benzodiazepin-2-one hydrochloride (US 2006/0019946) (13.6 mg, 0.048 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.0 mg, 0.0044 mmol), and 2-dicyclohexylphosphino- 2'-(A/,A/-dimethylamino)biphenyl (DavePhos) (2.1 mg, 0.0053 mmol) in 1,4-dioxane (0.6 mL) was treated with lithium b/s(trimethylsilyl)amide (1.0 M in THF, 0.14 mL, 0.14 mmol) and the resulting mixture was heated at 65 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature and was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: /z = 507.2 (M + 1). 1H NMR (500 MHz, CD 3 OD) δ 8.25 (s, 1H), 7.85 (s, 1H), 7.35 (d, 2H, J = 8.8 Hz), 7.32-7.26 (m, 2H), 7.09 (d, 2H, J = 7.6 Hz), 6.95-6.86 (m, 3H), 4.42-4.34 (m, 1H), 3.90-3.85 (m, 2H), 3.58-3.53 (m, 2H), 3.1one to three.OO (m, 4H), 2.89 (s, 3H), 2.85 (s, 3H), 2.61 (s, 3H), 2.14-2.03 (m, 2H), 1.94-1.88 (m, 2H).
EXAMPLE 24
Figure imgf000150_0001
3-[l-({4-f(2,6.8-Trimethvlquinolin-4-yl)amino1phenvl)carbonvl)piperidin-4-vn-l13,4,5- tetrahvdro-2H-l,3-benzodiazepin-2-one To a stirred solution of 4-[(2,6,8-trimethylquinolin-4-yl)amino]benzoic acid (described in
Intermediate 21) (31 mg, 0.101 mmol) in DMF (2 mL) were added HATU (57.5 mg, 0.152 mmol), HOAt (21 mg, 0.152 mmol), 3-(piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (US 2006/0019946) (37 mg, 0.152 mmol) and DIEA (0.027 mL, 0.152 mmol). The resulting mixture was stirred at ambient temperature for 12 h, and then purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 534.4 (M + 1). 1H NMR (500 MHz, DMSO- d6) δ 10.54 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 7.73 (s, 1H), 7.64 (d, 2H, J = 8.3 Hz), 7.55 (d, 2H, J = 8.3 Hz), 7.06-7.02 (m, 3H), 6.91 (s, 1H), 6.83-6.78 (m, 1H), 4.37 (m, 1H), 3.46 (d, 2H, J = 6.8 Hz), 2.91 (t, 2H, J = 4.5 Hz), 2.70 (s, 3H), 2.68 (s, 3H), 2.53 (s, 3H), 2.53-2.49 (m, 4H), 1.88-1.76 (m, 4H). EXAMPLE 25
Figure imgf000151_0001
3-(l-{4-f(2,6-Dimethylpvridin-4-vl)amm^
benzodiazepin-2-one
A stirred mixture of 4-chloro-2,6-dimethylpyridine (84 mg, 0.594 mmol) and 3-[l-(4- aminophenyl)piperidin-4-yl]-1 ,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (described in Intermediate 5) (200 mg, 0.594 mmol) in t-BuOH (10 mL) and 1 N hydrochloric acid (0.297 mL, 0.297 mmol) was heated at 100 °C for 18 h. The reaction mixture was cooled to ambient temperature, carefully poured into saturated aqueous sodium bicarbonate (30 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was initially purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH4OH - 100:0:0 to 70:30:1. Further purification was achieved by silica gel chromatography, eluting with a gradient of EtOAc:MeOH:NH4OH - 100:0:0 to 70:30:1, to afford the title compound. MS: m/z = 442.4 (M + 1). H NMR (500 MHz, CD3OD) δ 7.84 (d, 2H, J = 9.0 Hz), 7.54 (d, 2H, J = 8.8 Hz), 7.12-7.08 (m, 2H), 6.95 (d, 1H, J = 8.6 Hz), 6.91 (t, 1H, J = 7.6 Hz), 6.89-6.87 (m, 2H), 4.56 (tt, 1H, J = 12.1, 4.0 Hz), 3.83-3.80 (m, 4H), 3.61 (m, 2H), 3.08 (m, 2H), 2.52 (s, 6H), 2.51 (m, 2H) 2.13 (d, 2H, J = 12.9 Hz).
EXAMPLE 26
Figure imgf000152_0001
l-{4-f(2,6-Dimethvlpvridin-4-yl)amino1phe^
6'(7'H¾-one
Step A: 7'-fe^Butvl-l-{4-[(2,6-dimethylpvridin-4-vl¾aminolphenvl)spirofpiperidine-4,5'- pyrrolo[2,3-cnPVnmidin1-6'(7'/-/)-one
A deoxygenated mixture of 4-chloro-2,6-dimethylpyridine (16 mg, 0.114 mmol), l-(4- aminophenyl)-7'-fe^butylspiro[pi eridine^ (described in Intermediate 22) (40 mg, 0.114 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy- 2',4',6'-triisopropylbiphenyl] [2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (9.1 mg, 0.011 mmol), and potassium tert-butoxide (38 mg, 0.341 mmol) in 2-methyl-2-butanol (0.5 mL) was stirred at 40 °C for 3 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (2 mL), and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH4OH - 100:0:0 to 70:30:1, to afford the title compound. MS: m/z = 457.2 (M +
1).
Step B: l-{4-[(2,6-Dimethvlpvridin-4-vl)amino1phenyl}spiro[piperidine-4,5'-pvrrolof2,3- c/1pvrimidinl-6'(7'H)-one
A solution of 7'-tert-butyl-l-{4-[(2,6-dimethylpyridin-4-yl)amino]phenyl}spiro[piperidine- 4,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (21 mg, 0.046 mmol), in methanesulfonic acid (0.15 mL) was stirred at 90 °C for 1 h. The reaction mixture was cooled to 0 °C and saturated aqueous sodium carbonate was added to adjust the mixture to pH = 10. The resulting aqueous mixture was extracted with CHCI3:EtOH - 4:1 (3 x 5 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was initially purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH OH - 100:0:0 to 70:30:1, to afford the title compound. MS: m/z = 401.2 (M + 1). *H NMR (500 MHz, CD3OD) δ 8.68 (s, 1H), 8.60 ( s, 1H), 7.14 (d, 2H, J = 8.8 Hz), 7.10 (d, 2H, J = 9.0 Hz), 3.72 (m, 2H), 3.33 (m, 2H), 2.32 (s, 6H), 2.21 (m, 2H) 1.93 (d, 2H, J = 14.6 Hz).
EXAMPLE 27
Figure imgf000153_0001
l-{4-f(2,6-Dimethylpvridin-4-vl)amino1phenyl)spirofpiper
6'(7'H¾-one
A deoxygenated mixture of 4-chloro-2,6-dimethylpyridine (200 mg, 1.41 mmol), l-(5- aminopyridin-2-yl)spiro[piperidine-4,3'-pyrrolo[2,3-£)]pyridin]-2,(l'/-/)-one (described in Intermediate F52) (500 mg, 1.69 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy- 2',4',6'-triisopropylbiphenyl][2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (113 mg, 0.141 mmol), and potassium re t-butoxide (475 mg, 4.24 mmol) in 2-methyl-2-butanol (5 mL) was stirred at 40 °C for 3 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (10 mL), and extracted with EtOAc (2 x 20 mL). The aqueous layer was extracted further with CHCl3:EtOH - 4:1 (20 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 60:40:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 401.2 (M + 1). X NMR (500 MHz, DMSO-d6) δ 8.10 (dd, 1H, J - 5.1, 1.5 Hz), 8.02 (m, 1H), 7.91 (dd, 1H, J = 7.3, 1.5 Hz), 7.44 (dd, 1H, J = 8.9, 2.8 Hz), 6.98-6.93 (m, 2H), 6.36 (s, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 2.24 (s, 6H), 1.89 (m, 2H), 1.74 (m, 2H).
EXAMPLE 28
Figure imgf000154_0001
3-fl-(5-{f2-Methvl-6-(methvlamino¾pvridin-4-vnamino}pyridin-2-vl)piperidin-4-vn
tetrahydro-2/-/-l,3-benzodiazepin-2-one To a deoxygenated mixture of 3-[l-(5-aminopyridin-2-yl)piperidin-4-yl]-l,3,4,5- tetrahydro-2W-l,3-benzodiazepin-2-one (described in Intermediate F19) (68 mg, 0.20 mmol), 4- iodo-/V,6-dimethylpyridin-2-amine (described in Intermediate 24) (50 mg, 0.20 mmol), Xantphos (12 mg, 0.020 mmol) and sodium ieri-butoxide (39 mg, 0.40 mmol) in toluene (2 mL) was added fr/s(dibenzylideneacetone)dipalladium(0) (9 mg, 0.010 mmol) and the reaction was heated at 95 °C for 16 h. The reaction mixture was allowed to cool to ambient temperature,
concentrated in vacuo and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, and product-containing fractions were combined and concentrated under reduced pressure. The residue was dissolved in 1 N aqueous hydrochloric acid and concentrated to dryness in vacuo (3 x) to afford the title compound as the hydrochloride salt. MS: m/z = 458.3 (M + 1). 1H NMR (400 MHz, CD3OD) δ 8.01 (d, 1H, J = 9.8 Hz), 7.92 (d, 1H, J = 2.3 Hz), 7.55 (d, 1H, J = 9.4 Hz), 7.12-7.03 (m, 2H), 6.95- 6.86 (m, 2H), 6.24 (s, 1H), 5.89 (s, 1H), 4.49 (m, 1H), 4.35 (d, 2H, J = 13.3 Hz), 3.54-3.02 (m, 6H), 2.92 (s, 3H), 2.39 (s, 3H), 2.08-1.95 (m, 4H).
EXAMPLE 29
Figure imgf000154_0002
153 l-(5-{f2-Methvl-6-(propan-2-vloxv)pvridin-4-vllamino}pyridin-2-vl)spiroipiperidine-4 pvrrolof2,3-fclPvridin1-2'(l'H)-one
A deoxygenated mixture of l-(5-aminopyridin-2-yl)spiro[piperidine-4,3'-pyrrolo[2,3- b]pyridin]-2'(l'H)-one (described in Intermediate F52) (35 mg, 0.12 mmol), 4-iodo-2-methyl-6- (propan-2-yloxy)pyridine (described in Intermediate 25) (43 mg, 0.15 mmol), chloro[2- (dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-l,l'-biphenyl][2-(2- aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst, 9.5 mg, 0.012 mmol) and potassium ferr-butoxide (1 M in THF, 0.36 mL, 0.36 mmol) in terf-amyl alcohol (1 mL) was heated at 40 °C for 16 h. The reaction mixture was concentrated in vacuo and purified by by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 445.2 (M + 1). 1H NMR (400 MHz, CD3OD) δ 8.12-8.07 (m, 2H), 7.84 (dd, 1H, J = 7.4, 1.5 Hz), 7.71 (dd, 1 , J = 9.3, 2.7 Hz), 7.22 (d, 1H, J = 9.4 Hz), 7.05 (dd, 1H, J = 7.4, 5.4 Hz), 6.44 (s, 1H), 6.21 (s, 1H), 4.86 (m, 1H), 4.2one to four.12 (m, 2H), 3.96 (m 2H), 2.39 (s, 3H), 2.11-1.92 (m, 4H), 1.43 (d, 6H, J = 6.1 Hz).
EXAMPLE 30
Figure imgf000155_0001
l-{4-f(2,6-Dimethvlpvridin-4-vl)(methvl)aminolphenvl}spirofpiperidine-4,3'-Pvrrolo[2,3-
61pvridin1-2'(l'H)-one
A deoxygenated mixture of spiro[piperidine-4,3'-pyrrolo[2,3-i7]pyridin]-2'(l'H)-one (Burgey et al. (2009) Bioorg. Med. Chem. Lett. 19, 6368-6372) (150 mg, 0.34 mmol), Λ/-(4- bromophenyl)-W,2,6-trimethylpyridin-4-amine (described in Intermediate 26) (100 mg, 0.34 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl)[2-(2- aminoethylphenyl)]palladium(ll) methyl-t-butylether adduct (SPhos precatalyst) (26 mg, 0.034 mmol) and potassium fert-butoxide (1 M in THF, 1.2 mL, 1.2 mmol) in teri-amyl alcohol (3 mL) was heated at 50 °C for 16 h. The resulting mixture was concentrated in vacuo and purified by 154 reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was dissolved in methanol saturated with HCI, and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: m/z = 414.3 (M + 1). 1H NMR (400 MHz, CD3OD) δ 8.27-8.16 (m, 2H), 8.01 (d, 2H, J = 7.6 Hz), 7.60 (d, 2H, J = 7.6 Hz), 7.42-7.35 (m, 1H), 6.66 (s, 2H), 4.42-4.29 (m, 2H), 3.87-3.79 (m, 2H), 3.51 (s, 3H), 3.01-2.66 (m, 2H), 2.48 (s, 6H), 2.36 (m, 2H).
EXAMPLE 31
Figure imgf000156_0001
l-{4-[(2,6-Dimethvlpvridin-4-vl)amino1-3-phenoxyphenvl}spirofpiperidine-4,3'-pyrrolof2,3- b1pyridin1-2'(l'H)-one
A deoxygenated mixture of 4-chloro-2,6-dimethylpyridine (18 mg, 0.13 mmol), l-(4- amino-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-i>]pyridin]-2'(l'H)-one (described in Intermediate 27) (50 mg, 0.13 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'- triisopropylbiphenyl] [2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (10.3 mg, 0.013 mmol), and potassium ie/t-butoxide (1 M in THF, 0.39 mL, 0.39 mmol) in 2-methyl-2- butanol (1.3 mL) was stirred at 40 °C for 3 h. The resulting mixture was concentrated in vacuo and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of
H20:CH3CN:TFA - 95:5:0.1 to 40:60:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 492.2 (M + 1). 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.08 (dd, 1H, J = 5.3, 1.5 Hz), 7.86 (dd, 1H, J = 7.4, 1.5 Hz), 7.29 (t, 2H, J = 3.9 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.03 (t, 1H, J = 7.4 Hz), 6.97-6.92 (m, 1H), 6.91-6.87 (m, 3H), 6.66 (d, 1H, J = 2.7 Hz), 6.33 (s, 2H), 3.60-3.53 (m, 2H), 3.36-3.30 (m, 2H), 2.23 (s, 6H), 1.95-1.88 (m, 2H), 1.82-1.76 (m, 2H).
155 EXAMPLE 32
Figure imgf000157_0001
l-{5 (2,6-Dimethylpvridin-4-vl)oxvlpvridin-2-y ^
2'(l'H¾-one
To a deoxygenated mixture of 4-chloro-2,6-dimethylpyridine (19 mg, 0.13 mmol), l-(5- hydroxypyridin-2-yl)spiro[piperidine-4,3'-pyrrolo[2;3-i)]pyridin]-2'(l'H)-one (described in intermediate F34) (30 mg, 0.10 mmol), 2;2,6,6-tetramethyl-3,5-heptanedione (10 mg, 0.056 mmol), and cesium carbonate (99 mg, 0.30 mmol) in NMP (0.5 mL) was added copper(l) chloride (11 mg, 0.11 mmol) and the resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between cold saturated aqueous ammonium chloride (20 mL) and EtOAc (20 mL). The aqueous layer was extracted further with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of
H20:CH3CN:TFA - 95:5:0.1 to 60:40:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 402.1 (M + 1). 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H),
8.09 (dd, 1H, J = 5.2, 1.5 Hz), 8.03 (d, 1H, J = 3.0 Hz), 7.92 (dd, 1H, J = 7.4, 1.5 Hz), 7.44 (dd, 1H, J = 9.1, 3.0 Hz), 7.01-6.94 (m, 2H), 6.56 (s, 2H), 4.06-3.99 (m, 2H), 3.76-3.69 (m, 2H), 2.35 (s, 6H), 1.92-1.85 (m, 2H), 1.79-1.72 (m, 2H).
EXAMPLE 33
156
Figure imgf000158_0001
3-[l-(5-{f2-Methyl-6-(methvlamino)pyridin^
tetrahydro-2H-l,3-benzodiazepin-2-one To a deoxygenated mixture of 3-[l-(5-aminopyridin-2-yl)piperidin-4-yl]-l,3,4,5- tetrahydro-2W-l,3-benzodiazepin-2-one (described in Intermediate F19) (68 mg, 0.20 mmol), 4- iodo-/V,6-dimethylpyridin-2-amine (described in Intermediate 24) (50 mg, 0.20 mmol), Xantphos (12 mg, 0.020 mmol) and sodium tert-butoxide (39 mg, 0.40 mmol) in toluene (2 mL) was added t 7s(dibenzylideneacetone)dipalladium(0) (9 mg, 0.010 mmol) and the reaction was heated at 95 °C for 16 h. The reaction mixture was allowed to cool to ambient temperature,
concentrated in vacuo and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, and product-containing fractions were combined and concentrated under reduced pressure. The residue was dissolved in 1 N aqueous hydrochloric acid and concentrated to dryness in vacuo (3 x) to afford the title compound as the hydrochloride salt. MS: m/z = 458.3 (M + 1). 1H NM (400 MHz, CD3OD) δ 8.01 (d, 1H, J = 9.8 Hz), 7.92 (d, 1H, J = 2.3 Hz), 7.55 (d, 1H, J = 9.4 Hz), 7.12-7.03 (m, 2H), 6.95- 6.86 (m, 2H), 6.24 (s, 1H), 5.89 (s, 1H), 4.49 (m, 1H), 4.35 (d, 2H, J = 13.3 Hz), 3.54-3.02 (m, 6H), 2.92 (s, 3H), 2.39 (s, 3H), 2.08-1.95 (m, 4H).
EXAMPLE 34
Figure imgf000158_0002
157 3-(l-{5-f(2,6-Dimethvlpvridin-4-vl¾amino1-4-[4-(methvlsulfonvl)phenvl1pvridin-2-yl|p'm yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
A mixture of 6-chloro-/V-(2,6-dimethylpyridin-4-yl)-4-[4-(methy
3-amine (described in Intermediate 42) (50 mg, 0.13 mmol), 3-(piperidin-4-yl)-l,3,4,5- tetrahydro-2W-l,3-benzodiazepin-2-one (US 2006/0019946) (36 mg, 1.3 mmol), and potassium carbonate (71 mg, 0.51 mmol) in NMP (2 mL) was heated at 200 °C in a microwave reactor for 8 h. The reaction mixture was allowed to cool to ambient temperature and was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 597.5 (M + 1); 1H NMR (400 MHz, DMSO-d6): δ 13.33 (s, 1H); 9.90 (s, 1H); 8.49 (s, 1H); 8.09 (s, 1H); 7.93 (d, 2H, J = 8.0 Hz); 7.69 (d, 2H, J = 8.1 Hz); 6.98-7.05 (m, 4H); 6.77 (s, 1H); 6.61 (br s, 1H); 6.32 (br s, 1H); 4.54 (d, 2H, J = 12.9 Hz); 4.33 (m, 1H); 3.35 (m, 2H); 3.21 (s, 3H); 2.80-3.07 (m, 4H); 2.51 (s, 6H); 1.70 (br s, 4H).
EXAMPLE 35
Figure imgf000159_0001
3-(l-(4-[(2,6-Dimethvlpvridin-4-vl)aminol-3-[6-(trifluoromethvl)pvridin-3-vnphenvl)piperidin-4- yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one
A deoxygenated mixture of 3-(l-{4-amino-3-[6-(trifluoromethyl)pyridin-3- yl]phenyl}piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (described in
Intermediate 41) (50 mg, 0.1 mmol), 4-bromo-2,6-dimethylpyridine (20 mg, 0.1 mmol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl) [2-(2- aminoethylphenyl)]palladium(ll)-methyl-iert-butyl ether adduct (SPhos precatalyst) (8 mg, 0.01 mmol) in THF (1 mL) was treated with lithium / /s(trimethylsilyl)amide (1.0 M in TH F, 0.4 mL, 0.4
158 mmol) and the resulting mixture was heated at 90 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature and was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 587.4 (M + 1) ; H NMR (400 MHz, CD3OD): δ 8.71 (d, J = 2.1 Hz, 1H); 8.05 (dd, 1H, J = 8.1, 2.1 Hz); 7.83 (d, 1H, J = 8.1 Hz); 7.28-7.36 (m, 2H); 7.23 (d, lH, V = 2.7 Hz); 7.07 (d, 2H, J = 7.7 Hz); 6.86-6.93 (m, 2H); 6.46 (s, 2H); 4.33-4.40 (m, 1H); 3.97 (d, 2H, V = 12.5 Hz); 3.53-3.55 (m, 2H); 3.03 (m, 4H); 2.40 (s, 6H); 1.89-2.10 (m, 4H).
Figure imgf000160_0001
4-(l-{5-f(2,6-Dimethvlpvridin-4-vl)aminol-4-f4-(methvlsulfonvl)phenvllpvridin-2-vl)piperidin-4- vl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one
To a deoxygenated mixture of 4-(l-{5-bromo-4-[4-(methylsulfonyl)phenyl]pyridin-2- yl}piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one (described in Intermediate 43) (50.0 mg, 0.090 mmol), 4-amino-2,6-dimethylpyridine (16.5 mg, 0.135 mmol), and chloro[2- (dicyclohexylphosphino)-3,6-dimethoxy-2',4,,6'-triisopropylbiphenyl] [2-(2- aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (7.19 mg, 9.00 umol) in THF (1.5 mL) was added sodium te/t-butoxide (2.0 M in THF, 0.135 mL, 0.270 mmol). The reaction mixture was heated to 55 °C for 3 h, then cooled to ambient temperature, filtered, and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 15:85:0.1, to give the title compound. MS: m/z = 597.3 (M + 1) ; *H NMR (500 MHz, CDCI3): 6 8.20 (s, 1H), 7.95 (d, 2H, J = 8.0 Hz), 7.53 (m, 3H), 7.27 (m, 1H), 7.15 (m, 1H), 6.91 (d, 1H, J = 7.8 Hz), 6.63 (s, 1H), 6.24 (s, 2H), 4.35 (m, 2H), 3.97 (s, 2H), 3.59 (m, 3H), 3.07 (s, 3H), 2.97 (m, 2H), 2.86 (m, 1H), 2.39 (s, 6H), 2.09 (m, 2H), 1.67 (m, 1H).
EXAMPLE 37 159
Figure imgf000161_0001
2-[(2.6-Dimethvlpvridin-4-vl)amino1-5-f4-(2-oxo-l,2,4.5-tetrahvdro-3H-l,3-benzodiazepin-3- vQpiperidiri-l-vnbenzoic acid
A deoxygenated mixture of ethyl 2-[(2,6-dimethylpyridin-4-yl)amino]-5-[4-(2-oxo- l,2,4,5-tetrahydro-3H-l,3-benzodiazepin-3-yl)piperidin-l-yl]benzoate
(described in Intermediate F51) (250 mg, 0.612 mmol), 4-chloro-2,6-dimethylpyridine (87 mg, 0.612 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl)[2-(2- aminoethylphenyl)]palladium(ll) methyl-t-butylether adduct (SPhos precatalyst) (47 mg, 0.061 mmol) and potassium te/t-butoxide (1 M in THF, 1.84 mL, 1.84 mmol) in terr-amyl alcohol (4 mL) was heated at 50 °C for 18 h. The resulting mixture was concentrated in vacuo and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 60:40:0.1, and product-containing fractions were combined and concentrated in vacuo to give the title compound as the trifluoroacetate salt. MS: m/z = 486.2 (M + 1). XH NM (500 MHz, CD3OD) δ 7.69 (d, 1H, J - 2.8 Hz), 7.31-7.37 (m, 2H), 7.07-7.11 (m, 2H), 6.94 (d, 1H, J = 7.9 Hz), 6.90 (t, 1H, J = 7.4 Hz), 6.70 (s, 2H), 4.36 (t, 1H, J = 12.1 Hz), 3.92 (d, 2H, J = 12.4 Hz), 3.54- 3.56 (m, 2H); 3.02-3.04 (m, 2H), 2.94 (t, 2H, J = 12.3 Hz), 2.47 (s, 6H), 1.95-2.02 (m, 2H), 1.87 (d, 2H, y = 12.1 Hz).
EXAMPLE 38
160
Figure imgf000162_0001
2-i(2,6-Dimethvlpvridin-4-vl)amino1-/V,/V-dimethyl-5-r4-(2-oxo-l,2,4.5-tetrahvdro-3H-l,3- benzodiazepin-3-vl)piperidin-l-vl1benzamide
To a stirred mixture of 2-[(2,6-dimethylpyridin-4-yl)amino]-5-[4-(2-oxo-l,2,4,5- tetrahydro-3H-l,3-benzodiazepin-3-yl)piperidin-l-yl]benzoic acid trifluoroacetate (described in Example 37) (50 mg, 0.070 mmol), dimethylamine (2 M in THF, 0.035 mL, 0.070 mmol), HOBT (9.6 mg, 0.070 mmol), and EDC (20 mg, 0.104 mmol) in DMF (0.7 mL) was added DIEA (0.023 mL, 0.14 mmol). The mixture was stirred at ambient temperature for 18 h. The reaction mixture was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 55:45:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 513.3 (M + 1). 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.91 (s, 1H), 7.13 (d, 1H, J = 8.8 Hz), 7.04 (t, 4H, J = 4.3 Hz), 6.83 (d, 1H, J = 2.8 Hz), 6.80 (t, 1H, J = 5.8 Hz), 6.33 (s, 2H), 4.21 (t, 1H, J = 11.9 Hz), 3.79 (d, 2H, J = 12.0 Hz), 3.40 (s, 2H), 2.91 (d, 2H, J = 6.9 Hz), 2.87 (s, 3H), 2.73-2.75 (m, 2H), 2.75 (s, 3H), 2.21 (s, 6H), 1.78-1.85 (m, 2H), 1.70 (d, 2H, J = 11.8 Hz).
EXAMPLE 39
Figure imgf000162_0002
161 l-f4-(4,6-Dimethvl-2,3-dihvdro-lH-pvrrolor3,2-c1pvridin-l-vl)-3- phenoxvphenvllspiroipiperidine-4,3'-Pvrrolof2,3-blpyridin1-2'(l'H)-one
A deoxygenated mixture of l-(4-iodo-3-phenoxyphenyl)spiro[piperidine-4,3'- pyrrolo[2,3-i>]pyridin]-2'(l'H)-one (described in Intermediate 48) (95 mg, 0.191 mmol), 4,6- dimethyl-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine (described in Intermediate 45) (30 mg, 0.202 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2- aminoethyl)phenyl]palladium(ll) chloride (XPhos precatalyst) (14 mg, 0.019 mmol) in 1,4- dioxane (1.9 mL) was treated with lithium b/s(trimethylsilyl)amide (1.0 M in THF, 0.86 imL, 0.86 mmol) and the resulting mixture was heated at 70 °C for 3 h. The reaction mixture was allowed to cool to ambient temperature and saturated aqueous ammonium chloride (20 mL) was added. The resulting mixture was extracted with EtOAc (3 x 30 mL) and the combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 50:50:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S0 , filtered, and concentrated in vacuo to give the title compound. MS: m/z = 518.3 (M + 1). *H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H); 8.08 (d, 1H, J = 5.2 Hz), 7.88 (d, 1H, J = 7.4 Hz), 7.26-7.30 (m, 3H), 7.01 (t, 1H, J = 7.4 Hz), 6.91- 6.97 (m, 2H), 6.84 (d, 2H, J = 8.0 Hz), 6.72 (s, 1H), 5.98 (s, 1H), 3.77 (t, 2H, J = 8.7 Hz), 3.60-3.62 (m, 2H), 3.37 (s, 2H), 2.81 (t, 2H, J = 8.7 Hz), 2.20 (s, 3H), 2.15 (s, 3H), 1.93 (t, 2H, J = 10.2 Hz), 1.79 (br s, 2H).
EXAMPLE 40
Figure imgf000163_0001
4-(l-{5-f(2,6-Dimethvlpvridin-4-vl)aminol-2'-(trifluoromethvl)-4,4'-bipvridin-2-yl}piperidin-4-vl)- l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one 162 To a stirred solution of l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one (described in Intermediate 40) (66.1 mg, 0.408 mmol) and l-{5-[(2,6-dimethylpyridin-4-yl)amino]-2'- (trifluoromethyl)-4;4'-bipyridin-2-yl}piperidin-4-one (described in Intermediate 49) (180 mg, 0.408 mmol) in DCE (4 mL) at ambient temperature was added acetic acid (24.5 mg, 0.408 mmol). The reaction mixture was stirred at 50 "C for 1 h, then sodium triacetoxyborohydride (216 mg, 1.02 mmol) was added. The reaction mixture was stirred at 50 °C for 16 h, cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (15 mL), and extracted with CH2CI2 (2 x 10 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C- 18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 588.2 (M + 1). H NMR (400 MHz, CD3OD) δ 8.81 (d, 1H, J = 4.8 Hz), 8.25 (s, 1H), 8.05 (s, 1H), 7.82 (d, 1H, J = 4.8 Hz), 7.71 (d, 1H, J = 7.6 Hz), 7.65 (s, 1H), 7.60-7.58 (m, 1H), 7.41-7.39 (m, 1H), 7.25 (d, 1H, J = 8.4 Hz), 6.69 (s, 2H), 4.69-4.61 (m, 4H), 4.00-3.93 (m, 3H), 3.51-3.44 (m, 2H); 2.56-2.54 (m, 2H), 2.46 (s, 1H), 2.26-2.20 (m, 2H).
EXAMPLE 41
Figure imgf000164_0001
4-ri-(4-{f2-(Fluoromethvl)-6-methvlpvridin-4-vllamino}-3-f6-(trifluoromethvl)pvridin-3- vllphenvl)piperidin-4-vll-l,3,4,5-tetrahydro-2/-/-l,4-benzodiazepin-2-one
To a deoxygenated mixture of 4-(l-{4-amino-3-[6-(trifluoromethyl)pyridin-3- yl]phenyl}piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one (described in
Intermediate F57) (50 mg, 0.10 mmol), 4-chloro-2-(fluoromethyl)-6-methylpyridine
hydrochloride (described in Intermediate 51) (41 mg, 0.20 mmol), and chioro[2- (dicyclohexylphosphino)-3,6-dimethoxy-2',4l,6'-triisopropylbiphenyl] [2-(2- aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (5.3 mg, 7.0 umol) in THF (1 mL) was added potassium teri-butoxide (23 mg, 0.20 mmol). The reaction mixture was heated to 50 °C for 18 h, then cooled to ambient temperature, filtered, and purified by reversed-phase HPLC on 163 a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 15:85:0.1, to give the title compound. MS: m/z = 605.2 (M + 1) ; JH NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 8.08 (d, 1H, J = 7.2 Hz), 7.84 (d, 1H, J = 7.6 Hz), 7.66-7.56 (m, 2H), 7.41-7.36 (m, 3H), 7.28-7.22 (m, 2H), 6.42 (br s, 2H), 5.41 (d, 2H, J = 46 Hz), 4.56 (s, 2H), 4.10 (d, 2H, J = 12 Hz), 3.88 (s, 2H), 3.75 (m, 1H), 3.09 (t, 2H, J = 12 Hz), 2.46-2.44 (m, 5H), 2.11 (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 EX-A
Figure imgf000165_0001
Figure imgf000165_0002
164
Figure imgf000166_0001
165
Figure imgf000167_0001
166
Figure imgf000168_0001
167
Figure imgf000169_0001
168
Figure imgf000170_0001
Figure imgf000171_0001
170
Figure imgf000172_0001
171
Figure imgf000173_0001
172
Figure imgf000174_0001
TABLE EX-B
173
Figure imgf000175_0001
Figure imgf000175_0002
174
Figure imgf000176_0001
175
Figure imgf000177_0001
176
Figure imgf000178_0001
Figure imgf000179_0001
178
Figure imgf000180_0001
Figure imgf000181_0001
180
Figure imgf000182_0001
Figure imgf000183_0001
182
Figure imgf000184_0001
183
Figure imgf000185_0001
Figure imgf000186_0001
185
Figure imgf000187_0001
186
Figure imgf000188_0001
187
Figure imgf000189_0002
TABLE EX-C
Figure imgf000189_0001
Figure imgf000189_0003
188
Figure imgf000190_0001
189
Figure imgf000191_0001
Figure imgf000192_0001
9
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0002
TABLE EX-D
Figure imgf000200_0001
Figure imgf000200_0003
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0002
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
204 TABLE EX-F
Figure imgf000206_0001
Figure imgf000206_0002
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
208
Figure imgf000210_0001
Figure imgf000211_0002
TABLE EX-G
Figure imgf000211_0001
Figure imgf000211_0003
210
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
TABLE EX-H
217
Figure imgf000219_0001
Figure imgf000219_0002
Figure imgf000220_0002
TABLE EX-I
Figure imgf000220_0001
Figure imgf000220_0003
Figure imgf000221_0002
TABLE EX-J
Figure imgf000221_0001
Figure imgf000221_0003
Pharmaceutical Composition
As a specific embodiment of this invention, 100 mg of l-i^tiZ^^-Trimethylquinolin^- yl)amino]phenyl}spiro[piperidine-4/3'-pyrrolo[2,3-0]pyridin]-2'(l'H)-one is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard- gelatin capsule.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula:
Figure imgf000223_0001
wherein A is benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, cinnolinyl, imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrimidinyl, pyrimidinyl, pyrimidyl, pyrrolopyridinyl, pyrrolopyrimidinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, or triazolyl, and A is optionally substituted with R1, R2, R3, R and R5;
X is NR9, 0, S(0)m, or CR6R7;
G1, G2, G3 and G4 are each independently selected from the group consisting of CRa and N;
B is a bond, (C=0) or CR6R7;
D1 and D4 are each CR6R7 or (C=0);
D2, D3, D5 and D6 are each independently selected from the group consisting of a bond and CR6R7;
W is selected from:
Figure imgf000224_0001
and Z is hydrogen or d-6 alkyl, wherein said alkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano and hydroxy;
or W and Z can be taken together with the carbon atom to which they are attached to form:
Figure imgf000224_0002
Each X1 is independently selected from the group consisting of CRcRd ; NRe, (C=0) and 0, Each X2 is independently selected from the group consisting of CRcRd and (OO), Each X3 is independently selected from the group consisting of CRb and N,
Each X4 is independently selected from the group consisting of CRb and N,
Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of CRb and N;
V1, V2, V3 and V4 are each independently selected from the group consisting of CR and N; u\ U2 ; U3 and U4 are each independently selected from the group consisting of CRb and N;
Q is NRe, 0, N(Re)CRcRd or CRcRd,
T1 is a bond or CRcRd,
T2 is a bond or CRcRd,
R , R , R , R4 and R are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR11R12, heterocyclyl and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR1XR12 and heterocyclyl;
(g) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NR R12,
(h) R10,
(i) OR10,
(j) (OO)R8,
(k) (C=0)OR8,
(I) (C=0)NRuR12,
(m) (C=0)R1U, (n) NR R , and
(o) S(0)mR9,
or R4and R5 can be taken together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) oxo,
(c) phenyl,
(d) OR8, and
(e) R8;
R6 and R7 are independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano, R10 and NRnR12,
(e) OR8,
(f) (C=0)OR8, and
(g) (C=0)NRuR12;
or R6 and R7 can be taken together with the carbon atom(s) to which they are attached to form a 3 to 7 membered carbocyclic or heterocyclic ring; R is hydrogen, Ci.6 alkyl, or C3-6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C3-6 cycloalkyl, phenyl and hydroxy;
R9 is selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12, (C=0)OR8, R10 and OR10,
(c) R10,
(d) (OO)R8,
(e) (C=0)OR8, and
(f) (C=0)NRnR12;
or R9 and Ra can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring, which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci-6 alkyl,
(c) OR8,
(d) oxo, and
(e) Ci-6 alkyl, which is optionally substituted with one to three halo;
or R9 and R1 can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring, which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci-6 alkyl,
(c) OR*, (d) oxo, and
(e) Ci-6 alkyl, which is optionally substituted with one to three halo;
R is heterocyclyl, C3.6 cycloalkyl, phenyl or heteroaryl, wherein said heterocylyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one to five substituents
independently selected from the group consisting of halo, cyano, OR8, S(0)mR8, (C=0)OR8, (C=0)NRX1R12, NR R12, and C1-6 alkyl, wherein said alkyl is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (C=0)OR8, NH(C=0)OR8, NH2, and aryl;
R11 and R12 are each independently selected from the group consisting of
(a) hydrogen,
(b) Ci_6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (C=0)OR8, NH(C=0)OR8,
NH2,'heterocyclyl, C3-6 cycloalkyl, phenyl and heteroaryl,
(c) (C=0)R8,
(d) (OO)OR8,
(e) heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(f) C3.6 cycloalkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(g) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8, and
(h) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8;
or R and R can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring optionally containing an additional heteroatom selected from N, 0, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is
optionallysubstituted with one to four substituents each independently selected from the group consisting of:
(a) halo, (b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci_6 alkyl,
(c) OR8, and
(d) Ci-6 alkyl, which is unsubstituted or substituted with one to three halo;
Each Ra is independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, S(0)mR9, (C=0)OR8, (C=0)N RnR12, NR R12, R10and OR10;
(f) OCx-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12 and R10;
(g) S(0)mR9,
(h) (C=0)OR8,
(i) (C=0)NRuR12,
(j) R10,
(k) OR10,
(I) (C=0)R8,
(m) (C=0)R10, and
(n) NR R12,
Each Rb is independently selected from the group consisting of
(a) hydrogen, (b) halo,
(c) cyano,
(d) hydroxyl,
(e) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12, R10 and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12 and heterocyclyl;
(g) R10,
(h) (C=0)R8,
(i) (C=0)OR8,
(j) (C=0)NR R12, and (k) N R R12,
Each Rc and Rd are each independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NRUR12,
(e) C3.6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8,
(f) OC1.6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NRUR12, and
(g) phenyl;
Each Re is independently selected from the group consisting of (a) hydrogen, (b) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, C3.6 cycloalkyl, phenyl, OR8 and NRnR12, and
m is independently an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 wherein wherein A is cinnolinyl, imidazopyridinyl, naphthyridinyl, pyrazolopyridinyl, pyridinyl, pyridopyrimidinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, quinazolinyl or quinolinyl, wherein A is optionally substituted with R1, R2, R3, R4 and R5, or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 2 wherein X is NR9, or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 3 of the formula:
Figure imgf000231_0001
wherein G1, G2, G3 and G4 are each independently selected from the group consisting of CRa and N;
B is a bond, (C=0) or CR6R7;
D1 and D4 are each CR6R7; D2, D3, D5 and D6 are each independently selected from the group consisting of a bond and CR6R7;
W is selected from:
Figure imgf000232_0001
and Z is hydrogen or d-6 alkyl, wherein said alkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano and hydroxy;
or W and Z can be taken together with the carbon atom to which they are attached to form:
Figure imgf000233_0001
Each X1 is independently selected from the group consisting of CRc d, NRe, (OO) and 0,
Each X2 is independently selected from the group consisting of CRcRd and (OO),
Each X3 is independently selected from the group consisting of CRb and IM,
Each X4 is independently selected from the group consisting of CRb and N,
Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of CRb and N;
V1, V2, V3 and V4 are each independently selected from the group consisting of CRb and N;
U1, U2, U3 and U4 are each independently selected from the group consisting of CR and N;
Q is NRe, 0, N(Re)CRcRd or CRcRd ;
T1 is a bond or CRcRd,
T2 is a bond or CRcRd,
R1, R2, R3 , R4 and R5 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano, (d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12, heterocyclyl and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NRUR12 and heterocyclyl;
(g) C2-6 ^kenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NR1:tR12,
(h) R10,
(i) OR10,
(j) (OO)R8,
(k) (C=0)OR8,
(I) (C=0)NRxlR12,
(m) (OO)R10,
(n) NRUR12, and
(o) S(0)mR9,
or R4 and R5 can be taken together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) oxo,
(c) phenyl,
(d) OR8, and
(e) R8;
R5 and R7 are independently selected from the group consisting of:
(a) hydrogen,
(b) halo, (c) cyano,
(d) QL-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano, R10 and NR R12,
(e) OR8,
(f) (C=0)OR8, and
(g) (O0)NR R12;
or R6 and R7 can be taken together with the carbon atom(s) to which they are attached to form a 3 to 7 membered carbocyclic or heterocyclic ring;
R8 is hydrogen, Ci_6 alkyl, or C3-6 cycloalkyl, wherein said aikyl or cycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C3_6 cycloalkyl, phenyl and hydroxy;
R9 is selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR11R12, (C=0)OR8, R10 and OR10,
(c) R10,
(d) (C=0)R8,
(e) (OO)OR8, and
(f) (C=0)NRnR12;
or R9 and Ra can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring, which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and C1-6 alkyl,
(c) OR8, (d) oxo, and
(e) Ci-6 alkyl, which is optionally substituted with one to three halo;
or R9 and R1 can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring, which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci-6 alkyl,
(c) OR8,
(d) oxo, and
(e) Ci-6 alkyl, which is optionally substituted with one to three halo;
R10 is heterocyclyl, C3.6 cycloalkyl, phenyl or heteroaryl, wherein said heterocylyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one to five substituents
independently selected from the group consisting of halo, cyano, OR8, S(0)mR8, (OO)OR8, (C=0)NR R12, NRnR12, and Ci-6 alkyl, wherein said alkyl is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (C=0)OR8, NH(C=0)0R8, NH2, and aryl;
R11 and R12 are each independently selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (OO)OR8, NH(C=0)OR8,
NH2,'heterocyclyl, C3-S cycloalkyl, phenyl and heteroaryl,
(c) (C=0)R8,
(d) (C=0)OR8,
(e) heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(f) C3-6 cycloalkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(g) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8, and (h) heteroaryi, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8;
or R and R can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring optionally containing an additional heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is
optionallysubstituted with one to four substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci-6 alkyl,
(c) OR8, and
(d) Ci-6 alkyl, which is unsubstituted or substituted with one to three halo;
Each Ra is independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, S(0)mR9, (C=0)OR8, (C=0)NRuR12, NR R12, R10 and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12 and R10;
(g) S(0)mR9,
(h) (OO)OR8,
(i) (O0)NR R12,
0) R10,
(k) OR10, (I) (OO)R8,
(m) (C=0)R , and
(n) NR R12,
Each RB is independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy!,
(e) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR11R12, R10 and OR10;
(f) OC1-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR11R12 and heterocyclyl;
(g) 10,
(h) (OO)R8,
(i) (C=0)OR8,
(j) (C=0)I\IR"R12, and
(k) NRNR12,
Each RC and RD are each independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NR R12;
(e) C3_6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8, (f) OCi-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NR R12, and
(g) phenyl;
Each Re is independently selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, C3.6 cycloalkyl, phenyl, OR8 and NRnR12, and
(c) R10;
m is independently an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
5. The compound of Claim 3 of the formula:
Figure imgf000239_0001
wherein G1, G2, G3 and G4 are each independently selected from the group consisting of CRa and
N;
B is a bond, (C=0) or CR6R7;
D1 and D4 are each CR6R7; D2, D3, D5 and D6 are each independently selected from the group consisting of a bond and CR6R7;
W is selected from:
Figure imgf000240_0001
and Z is hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano and hydroxy;
or W and Z can be taken together with the carbon atom to which they are attached to form:
Figure imgf000240_0002
Each X1 is independently selected from the group consisting of CRcRd, NRe, (C=0) and 0,
Each X2 is independently selected from the group consisting of CRcRd and (C=0);
Each X3 is independently selected from the group consisting of CRb and N,
Each X4 is independently selected from the group consisting of CR and N,
Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of CRb and N;
V1, V2, V3 and V4 are each independently selected from the group consisting of CRb and N;
U1, U2, U3 and U4 are each independently selected from the group consisting of CRb and N;
Q is NRe, O, N(Re)CRcRd or CRcRd ;
T1 is a bond or CRcRd,
T2 is a bond or CRcRd,
R1, R2, R3 and R4 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NR R12, heterocyclyl and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, NRUR12 and heterocyclyl;
(g) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano and NRnR12,
(j) (C=0)R8, (k) (O0)0R8,
(i) (O0)NR R12,
(m) (C=0)R10,
(n) NR R12, and
(o) S(0)mR9,
or R and R5 can be taken together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) oxo,
(c) phenyl,
(d) OR8, and
(e) R8;
R5 and R7 are independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, hydroxy, cyano, R and NR R ,
(e) OR8,
(f) (OO)OR8, and
(g) (C=0)NR R12;
or R6and R7can be taken together with the carbon atom(s) to which they are attached to form a 3 to 7 membered carbocyclic or heterocyclic ring; R is hydrogen, Ci-6 alkyl, or C3.6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C3-6 cycloalkyl, phenyl and hydroxy;
R9 is selected from the group consisting of
(a) hydrogen,
(b) Ci.6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12, (C=0)OR8, R10 and OR10,
(c) R10,
(d) (C=0)R8,
(e) (C=0)OR8, and
(f) (O0)NRuR12;
or R9 and Ra can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring, which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci_6 alkyl,
(c) OR8,
(d) oxo, and
(e) Ci-6 alkyl, which is optionally substituted with one to three halo;
or R9 and R1 can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring, which ring is optionally substituted with one to three substituents each independently selected from the group consisting of:
(a) halo,
(b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci-6 alkyl,
(c) OR , (d) oxo, and
(e) Ci-6 a!kyl, which is optionally substituted with one to three halo;
R is heterocyclyl, C3-6 cycloalkyl, phenyl or heteroaryl, wherein said heterocylyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with one to five substituents
independently selected from the group consisting of halo, cyano, OR8, S(0)mR8, (C=0)OR8, (C=0)NR R12, NR11R12, and Ci-6 alkyl, wherein said alkyl is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (C=0)OR8, NH(C=0)OR8, NH2, and aryl;
R11 and R12 are each independently selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR8, (C=0)OR8, NH(C=0)OR8,
NH2,'heterocyclyl, C3-6 cycloalkyl, phenyl and heteroaryl,
(c) (C=0)R8,
(d) (C=0)OR8,
(e) heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(f) C3-6 cycloalkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8,
(g) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8, and
(h) heteroaryl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R8 and OR8;
or R and R can be taken together with the atom(s) to which they are attached to form a 3 to 7 membered ring optionally containing an additional heteroatom selected from N, 0, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is
optionallysubstituted with one to four substituents each independently selected from the group consisting of:
(a) halo, (b) phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, OR8, CN, and Ci_6 alkyl,
(c) OR8, and
(d) Ci-6 alkyl, which is unsubstituted or substituted with one to three halo;
Each Ra is independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) hydroxy,
(e) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, S(0)mR9, (OO)OR8, (C=0)NRnR12, NR11R12, R10and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12 and R10;
(g) S(0)mR9,
(h) (C=0)OR8,
(i) (O0)NRuR12,
(k) OR10, (I) (C=0)R8,
(m) (C=0)R10, and
(n) NR R12,
Each Rb is independently selected from the group consisting of
(a) hydrogen,
(b) halo, (c) cyano,
(d) hydroxyl,
(e) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NR11R12, R10and OR10;
(f) OCi-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8, NRnR12 and heterocyclyl;
(g) R10,
(h) (OO)R8,
(i) (C=0)OR8,
(j) (C=0)NRuR12, and
(k) NR R12,
Each Rc and Rd are each independently selected from the group consisting of
(a) hydrogen,
(b) halo,
(c) cyano,
(d) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NR^R12;
(e) C3-6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8,
(f) OCi_6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, OR8 and NR1JR12, and
(g) phenyl;
Each Re is independently selected from the group consisting of
(a) hydrogen,
(b) Ci-6 alkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano, C3.6 cycloalkyl, phenyl, OR8 and NRnR12, and ndependently an integer from 0 to 2;
tarmaceutically acceptable salt thereof.
6. The compound of Claim 4 wherein G1, G2, G3 and G4 are CH; or a pharmaceutically acceptable salt thereof.
7. The compound of Claim 6 wherein B is a bond, or a pharmaceutically acceptable thereof.
8. The compound of Claim 7 wherein D1, D2, D4 and D6 are each CH2,
D5 and D6 are each a bond, or a pharmaceutically acceptable salt thereof.
9. The compound of Claim 8 wherein W is
Figure imgf000247_0001
or a pharmaceutically acceptable salt thereof.
10. The compound of Claim 8 wherein W and Z taken together as
Figure imgf000247_0002
or a pharmaceutically acceptable salt thereof. A compound of Formula la
Figure imgf000248_0001
or a pharmaceutically acceptable salt thereof, wherein:
"A" is: benzimidazolyl; benzisoxazolyl; benzothiazolyl; benzoxazolyl; benzopyrazolyl;
benzotriazolyl; cinnolinyl; imidazolyl; imidazopyridinyl; indolyl; indazolyl; isoquinolinyl;
isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl; oxadiazolyl; phthalazinyl; pyrazinyl;
pyrazolopyridinyl; pyrazolyl; pyridazinyl; pyridinyl; pyridopyrazinyl; pyridopyridazinyl;
pyridopyridinyl; pyridopyrimidinyl; pyrimidinyl; pyrimidyl; pyrrolopyridinyl; pyrrolopyrimidinyl; quinazolinyl; quinolinyl; quinoxalinyl; tetrazolyl; thiazolyl; or triazolyl, wherein A is optionally substituted with one or more of R1, R2, R3, R4 and R5;
"X" is: NR9; 0; S(0)m; or CR6R7;
"G1", "G2", " G3" and "G4" are independently: CRa; or N;
"B" is: a bond; (C=0); or CR6R7;
"D1" and "D4" are independently: CR6R7; or (C=0);
"Dz", "D3", "D5" and "D6" are independently: a bond; or CR6R7;
"W" is:
Figure imgf000248_0002
"Z" is: hydrogen; or Ci_6 alkyl, wherein said alkyl is optionally substituted with up to three substituents which are independently for each occurrence: halo; cyano; or hydroxy; or
"W" and "Z" together with the carbon atom to which they are attached form a moiety of the formula:
Figure imgf000249_0001
wherein:
wherein:
"X1" is independently for each occurrence: -CRcRd-, -NRe-, -(C=0)- and -0-,
"X2" is independently for each occurrence: -CRcRd-, -NRe-, -(C=0)-,
/^3// ityAu «γΐ// «γ2>/ //γ3// «γ4// // 1\ ·" "\ι^" " ^" "(J^" " 3« g jj "JJ^" 3f
independently sfor each occurrence: -CRb- and -N-;
"Q" is -NR% -0-, -N(Re)CRcRd- or -CRcRd-;
"T1" and "T2" are independently, for each occurrence: a bond; or -CRcRd-;
R1, R2, R3 , R4 and R5 are independently for each occurrence:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) hydroxy;
(e) Ci-6 alkyl, optionally substituted with up to three substitutents which are independently: halogen; -CN; -ORB; - R^R"; -heterocyclyl; or -OR ;
(f) O-Ci-6 alkyl, optionally substituted with up to three substitutents which are independently: halogen; -CN; -OR8; -NR R12; or -heterocyclyl;
(g) C2-6 alkenyl, optionally substituted with up to three substitutents which are independently: halogen; -OH; -CN, or -NR R12-; (i) OR10; (j) (C=0)R8;
(k) (C=0)OR8;
(I) (C=0)N RUR12; (m) (C=0) R10;
(n) NR"R12; or (o) S(0)MR9; or
R and R5 together with the atoms to which they are attached to form a 4 to 6 membered carbocyclic or heterocyclic ring, wherein said ring may contain from one to three unsaturated bonds, and wherein said ring is optionally substituted with up to three substituents which are independently: (a) halo; (b) oxo; (c) phenyl; (d) OR8; or (e) R8;
R6 and R7 are independently for each occurrance:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) Ci-6 alkyl, which is optionally substituted with up to three substituents which are independently: halo; hydroxy; cyano; R10; or NRUR12;
(e) OR8;
(f) (C=0)OR8; or
(g) (C=0)NR R12; or
R6 and R7, together with the carbon atom(s) to which they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring;
R8 is independently for each occurrence: hydrogen; Ci-6 alkyl; or C3_6 cycloalkyl, and when selected to be alkyl or cycloalkyl, said moiety is optionally substituted with up to three substituents which are independently: halo; cyano; C3-6-cycloalkyl; phenyl; or hydroxy;
R9 is independently for each occurrance:
(a) hydrogen, (b) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; C3.6 cycloalkyl; cyano; OR8; NRnR12; (C=0)OR8; R10; or OR10,
(c) C3-6 cycloalkyl, optionally substituted with up to three substituents which are
independently: halo; cyano; OR8; or R8;
(d) R10;
(e) (OO)R8;
(f) (OO)OR8; or
(g) (O0)NRnR12; or
R9 and Ra together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR8; CN; or Ci-6 alkyl; (c) OR8; (d) oxo; or (e) Ci.6 alkyl, which is optionally substituted with up to three halogen atoms; or
R9 and R1 together with the atom(s) to which they are attached form a 3 to 7 membered ring, optionally substituted with up to three substituents which are independently: (a) halo; (b) phenyl, optionally substituted with up to three substituents which are independently: halo; OR8; CN; or Ci_6 alkyl; (c) OR8; (d) oxo; or (e) C1-6 alkyl, which is optionally substituted with up to three halogen atoms;
R10 is: (i) heterocyclyl; (ii) C3.6 cycloalkyl; (iii) aryl; or (iv) heteroaryl, wherein said heterocylyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with up to five substituents which are independently for each occurrence:
(a) halo;
(b) cyano;
(c) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently: halo; C3.6 cycloalkyl; cyano; OR8; (C=0)OR8; NH(C=0)OR8; NH2; or aryl;
(d) C3.6 cycloalkyl, optionally substituted with up to three substitutents which are
independently: halo; cyano; -OR8; or R8;
(e) OR8;
(f) oxo;
(g) C2-6 alkynyl, which is optionally substituted with up to three substitutents which are independently: halo; hydroxy; cyano; or NRnR12; (h) C2-6 alkenyl, which is optionally substituted with up to three substitutents which are independently: halo; hydroxy; cyano; or NR1^12;
(i) (C=0)R8;
(j) (C=0)OR8;
(k) (C=0)NRuR12;
(I) NR R12; or
(m) S(0)mR8;
R11 and R12 are independently for each occurrence:
(a) hydrogen;
(b) Ci-s alkyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; (C=0)OR8; NH(C=0)OR8; NH2; heterocyclyl; C3-6 cycloalkyl; phenyl; or heteroaryl;
(c) (C=0)R8;
(d) (OO)OR8;
(e) heterocyclyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; or R8;
(f) C3-6 cycloalkyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; or R8;
(g) phenyl, optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; or R8; or
(h) heteroaryl, , optionally substituted with up to three substitutentswhich are independently for each occurrence: halo; cyano; OR8; or R8; or
Rn and R12 together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally when present, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionallysubstituted with up to four substituents which are independently:
(a) halo,
(b) phenyl, optionally substituted with up to three substituents which are independently halo; OR8; CN; or Ci.6 alkyl; (c) OR ; or
(d) Ci-6 alkyl, which is optionally substituted with one to three halo;
Ra is independently for each occurrence:
(a) hydrogen; (b) halo; (c) cyano; (d) hydroxy; (e) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; S(0)mR9;
(C=0)OR8; (C=0)NRuR12; NR R12; R10; or OR10; (f) Od.6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; S(0)mR9; NRnR12; or R10; (g) S(0)mR9; (h) (OO)OR8; (i) (C=0)NRnR12; (j) R10;(k) OR10; (I) (C=0)R8; (m) (C=0)R10; or (n) NR R12;
Rb is independently for each occurrence:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) hydroxy;
(e) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; NRnR12; R10or OR10;
(f) OCx.6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; NR1:1R12 or heterocyclyl;
(g) R10;
(h) (OO)R8;
(i) (C=0)OR8;
(j) (C=0)NRuR12; or
(k) NRnR12;
Rc and Rd are each independently for each occurrence:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) Ci_6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; or NR1:1R12; (e) C3.6 cycloalkyl, which is optionally substituted with one to five substitutents independently selected from the group consisting of halo, cyano and OR8,
(f) OC1.6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; or NRnR12; or
(g) phenyl; or
Rc and Rd together with the atom(s) to which they are attached form a 3- to 7-membered ring which may optionally comprise one or more heteroatoms selected independently from N, 0, or S, and wherein, when said 3- to 7-membered ring comprises one or more sulfur atoms, optionally, said sulfur atoms may be present in an oxidized form as a sulfone or sulfoxide moiety, and wherein said 3- to 7-membered ring is optionally substituted with up to four substituents which are independently:
(a) halo;
(b) phenyl, optionally substituted with up to three substituents which are independently: halo, OR8; CN; or C« alkyl;
(c) OR8; or
(d) Ci-6 alkyl, optionally substituted with up to three halogen substituents;
Re is independently for each occurrence:
(a) hydrogen;
(b) Ci-6 alkyl, optionally substituted with up to five substitutents which are independently for each occurrence: halo; cyano; OR8; or NR11R12; C3.6 cycloalkyl; or phenyl; or
(c) R10; and
m is independently an integer from 0 to 2.
12. A pharmaceutical composition comprising a compound of any of claims 1 to 11, and a pharmaceutically acceptable carrier.
13. Use of a pharmaceutical composition of any of Claims 1 to 12, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a migraine.
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