WO2019014427A1 - Antagonists of the muscarinic acetylcholine receptor m4 - Google Patents

Antagonists of the muscarinic acetylcholine receptor m4 Download PDF

Info

Publication number
WO2019014427A1
WO2019014427A1 PCT/US2018/041783 US2018041783W WO2019014427A1 WO 2019014427 A1 WO2019014427 A1 WO 2019014427A1 US 2018041783 W US2018041783 W US 2018041783W WO 2019014427 A1 WO2019014427 A1 WO 2019014427A1
Authority
WO
WIPO (PCT)
Prior art keywords
azaspiro
methyl
octan
amine
pyridazin
Prior art date
Application number
PCT/US2018/041783
Other languages
French (fr)
Inventor
Craig W. Lindsley
Thomas M. Bridges
P. Jeffrey Conn
Aaron M. BENDER
Darren W. Engers
Original Assignee
Vanderbilt University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanderbilt University filed Critical Vanderbilt University
Priority to EP18831342.3A priority Critical patent/EP3651762B1/en
Priority to AU2018300980A priority patent/AU2018300980A1/en
Priority to KR1020207003737A priority patent/KR20200027992A/en
Priority to US16/629,491 priority patent/US20220048913A1/en
Priority to JP2020501337A priority patent/JP2020526557A/en
Priority to CN201880045391.5A priority patent/CN110891569A/en
Priority to CA3068842A priority patent/CA3068842A1/en
Publication of WO2019014427A1 publication Critical patent/WO2019014427A1/en
Priority to IL271805A priority patent/IL271805A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure relates to compounds, compositions, and methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction.
  • Parkinson's disease is the second most common neurodegenerative disease with an increasing prevalence as a function of age. Moreover, early-onset PD is also increasing. A hallmark of PD is the progressive degeneration and loss of dopaminergic neurons in the substantia nigra (SN) and basal ganglia (BG), leading to pronounced motor symptoms including bradykinesia, tremor, rigidity, gait dysfunction and postural instability.
  • SN substantia nigra
  • BG basal ganglia
  • L- DOPA levodopa
  • LID L-DOPA induced dyskinesia
  • mAChRs muscarinic acetylcholine receptors
  • DA dopamine
  • mAChR agonists inhibit DA release, and inhibit multiple behavioral effects of drugs that increase DA levels and signaling.
  • mAChR muscarinic acetylcholine receptor
  • the mAChRs include five subtypes, termed M3 ⁇ 4 - M 5 .
  • Available mAChR antagonists, such as scopolamine, are nonselective across these subtypes, and many of their adverse effects are likely mediated by mAChR subtypes that are not involved in the antiparkinsonian activity.
  • compounds possessing a more selective profile for individual mAChRs may offer an advantage in PD, as well as related disorders such as dystonia.
  • some studies indicate that the M 4 m AChR subtype may play a dominant role in m AChR regulation of basal ganglia motor function.
  • A is a five- or six-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 9- to 10-rnembered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, C1-C4 alkyl, and C 1 -C 4 haloafkyl;
  • Q is selected from NR 3 , O, and CR b R c ;
  • G is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocvcle, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 2 and R 3 are independently selected from hydrogen, C C 4 aikyl, and halo, or ⁇ R 2 and R' are taken together to form an oxo group;
  • each R 4 is independently selected from halo, C1 -C4 alkyl, and -QR S ;
  • R 5 and R 6 are independently selected from hydrogen, Ci-Cs aikyl, and -(CR'R ) r ,-Y ; each Y 1 is independently selected from optionally substituted cycloalkyl, optionally- substituted cycloalkenyl, optionally substituted heterocvcle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R a , R b , R c , R a , R e , R 1 , and R 8 is independently selected from hydrogen, C1-C4 alkyl, and aryl;
  • n 0, 1 or 2;
  • n 0, 1 or 2.
  • the invention provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method of antagonizing mAChR M 4 in a subject, comprising a step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
  • the invention provides a method of treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M 4 , comprising a step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
  • the invention provides a method of treating motor sy mptoms in a subject, comprising a step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
  • kits comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.
  • the invention provides compounds of formula (I), or a
  • the invention provides the use of compounds of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for antagonizing mAChR Mi, for the treatment of a disorder ameliorated by mAChR M4 antagonism, or for the treatment of motor symptoms.
  • FIG. 1 shows the structure of compound O (Example 5) obtained by X-ray erystallographic analysis.
  • mAChR M$ muscarinic acetylcholine receptor M 4
  • methods of making the compounds pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and pharmaceutical compositions.
  • the compounds include functionalized cyclopropylpiperidine compounds.
  • the modifier "about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
  • the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4" also discloses the range “from 2 to 4.”
  • the term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 1 1%, and “about 1 " may mean from 0.9-1.1. Other meanings of "about” may be apparent from the context, such as rounding off, so, for example "about 1” may also mean from 0.5 to 1.4.
  • alkoxy refers to an alky] group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy.
  • alkyl means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms.
  • lower alky l or “Ci.CValkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • C-.-CV alkyl means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, .sec-butyl, /.sobutyl, teri-butyl, w-pentyl, isopentyl, neopentyl, H-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yl, w-heptyl, w-octyl, w-nonyl, and n-decyl.
  • alkenyl means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond and from 2 to 10 carbon atoms.
  • alkoxyaikyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyfluoroalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • alkylene refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, for example, of 2 to 5 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 ⁇ , -CH 2 CH(CH L CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • alkylamino means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein.
  • amide means -C(0)NR- or -N C(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl.
  • aminoalkyl means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein.
  • amino means -NR x R y , wherein R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl.
  • R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl.
  • ammo may be -NR X -, wherein R x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl.
  • aryl refers to a phenyl group, or a bicyclic fused ring system.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein.
  • Representative examples of aryl include, but are not limited to, indol-4-yl, naphthyl, phenyl, benzodioxol-5-yl, and
  • cyanoalkyl means at least one -CN group, is appended to the parent molecular moiety through an alkylene group, as defined herein.
  • cyanofluoroalkyl means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • cycloalkoxy refers to a cycloalkvl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • cycloalkyl refers to a carbocyciic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds.
  • the cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic.
  • Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyciobutyi, cyclopentyl, cyciohexyl, cyclolieptyi, eye ooctyl, cycloiioiiyl, cvclodecvl, adamantyl, and bicyclo[l. l .
  • Cycloalkyl also includes carbocyciic ring systems in which a cycloalkyl group is appended to the parent molecular moiety and is fused to an aryl group as defined herein (e.g., a phenyl group), a heteroaryl group as defined herein, or a heterocycle as defined herein.
  • cycloalkyl groups include, but are not limited to, 2,3-dihydro- IH-indenyl (e.g., 2,3- dihydro-lH-inden-l-yl and 2,3-dihydro- lH-inden-2-yl), 6,7-dihydro-5H-cyclopenta[0]pyridinyl (e.g., 6,7-dihydro-5H-cyclopenta[i]pyridin-6-yl), oxaspiro[3.3]heptanyl (e.g., 2- oxaspiro[3.3]heptan-6-yl), and 5,6,7,8-tetrahydroquinolinyl (e.g., 5,6,7,8-tetrahydroquinolin-5- yi)-
  • 2,3-dihydro- IH-indenyl e.g., 2,3- dihydro-lH-inden-l-yl and 2,3-d
  • cycloaikenyl means a non-aromatic monocyclic or multicyclic (e.g., bridged) ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • exemplary monocyclic cycloaikenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • An exemplary bridged bicyclic ring system is bicyclo[2.2.1 ]hept-2-enyl.
  • fluoroalkyl means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine.
  • Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifiuoroethyl, trifluoromethvl, difluoromethyl, pentafluoroethyi, and trifluoropropyl such as 3,3, 3 - trifl uor opropy 1.
  • fluoroalkoxy means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • fluoroalkoxy examples include, but are not limited to, difluoromethoxy , trifl uoromethoxy and 2,2,2-trifiuoroethoxy.
  • halogen or "halo,” as used herein, means CI, Br, I, or F.
  • haloalkyl means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.
  • haioalkoxy means at least one haioalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • haiocycloalkyl means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen.
  • heteroalkyl means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N.
  • Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.
  • heteroaryl refers to an aromatic monocyclic ring or an aromatic bicyclic ring system.
  • the aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g. 1 , 2, 3, or 4 heteroatoms independently selected from O, S, and N).
  • the five membered aromatic monocyclic rings have two double bonds and the six membered six membered aromatic monocyclic rings have three double bonds.
  • the bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalky] group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • heteroaryl include, but are not limited to, indolyl, pyridmyl
  • heterocycle or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle.
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the six- member ed ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1,3-dithiolanyl, 1 ,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
  • oxadiazolidinvl oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,
  • tetrahydropyranyl tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2- thiazinanyl, 1 ,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1 ,1 - dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic
  • cycloalkenyl or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1 , 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3- dihydrobenzofuranyl, 2,3 -dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3 ]heptan- 2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2- azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3. 1.0]hexan-3-yl), 2,3-dihydro-lH-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a
  • tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[&]furan, hexahydro-lH-l,4-methanocyclopenta[c]furan, aza-adamantane (1 - azatrieyelo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane).
  • the monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • hydroxyl or "hydroxy,” as used herein, means an - ⁇ group.
  • hydroxyalkyl means at least one - ⁇ group, is appended to the parent molecular moiety through an alkyiene group, as defined herein.
  • hydroxyfluoroalkyl means at least one - ⁇ group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y -", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y - the number of carbon atoms in the substituent.
  • “CrC alkyl” refers to an alkyl substituent containing from 1 to 3 carbon atoms.
  • sulfonamide means -S(0) 2 NR- or -NRS(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
  • substituted refers to a group “substituted” on an aryl, heteroaryl, phenyl or pyridinyl group at any atom of that group. Any atom can be substituted.
  • substituted refers to a group that may be further substituted with one or more non-hydrogen substituent groups.
  • fluoroalkyl alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroaikyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,
  • heteroarylalkyl arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfmyl, -COOH, ketone, amide, carbamate, and acyl.
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • mAChR M 4 receptor antagonist refers to any exogenously administered compound or agent that directly or indirectly antagonizes mAChR M 4 , for example in an animal, in particular a mammal (e.g., a human).
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6. 1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • A is a five- or six-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;
  • Q is selected from NR a , O, and CR R ;
  • R ! is selected from hydrogen, halo, -QR d , C 1 -C4 alkyl, optionally substituted cycloalkyi, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 2 and R 5 are independently selected from hydrogen, C 1 -C4 alkyl, and halo, or R 2 and R 5 are taken together to form an oxo group;
  • each R 4 is independently selected from halo, C 1 -C 4 alkyl, and -OR e ;
  • R 5 and R 6 are independently selected from hydrogen, Cj-Cg alkyl, and -(CR'R ⁇ -Y 1 ; each Y 1 is independently selected from optionally substituted cycloalkyi, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R d , R , R L , R", R c , R 1 , and R g is independently selected from hydrogen, C 1 -C4 alkyl, and aryl;
  • n 0, 1 or 2;
  • n 0, 1 or 2.
  • Q is NR d , In some embodiments, R a is hydrogen or C 1 -C4 alkyl. In some embodiments, R d is hydrogen,
  • R 3 ⁇ 4 is hydrogen, phenyl, naphthyl (e.g., 2- naphthyl), benzodioxolyl (e.g., benzodioxol-5-yl), pyrazoiyl (e.g., pyrazol-3-yl, pyrazol-4-yl), isoxazolyl (e.g., isoxazol-4-yl), thienyl (e.g., 2-thienyl), pyridinyl (e.g., pyridin-3-yl), quinolinyl (e.g., quiiiolm-6-yl), isoquinoimyl (e.g., isoquinolin-7-yl), piperidinyl (e.g., piperidin-l-yl), pyrrolidinyl (e.g., pyrrolidin-l-yl), morpholinyl (e.g., morpholinyl (e
  • G is phenyl substituted with
  • R 1 is selected from: halo; aryl; and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C 1 -C4 alkyl, halo, cyano, C 1 -C 4 haloalkyl, C C 4 alkoxy, C haioalkoxy, and -NHCOR', wherein R' is Ci-C 4 alkyl.
  • R 1 is halo (e.g., chloro).
  • phenyl is selected from phenyl, pyrazoiyl, thiophene, quinolyl, benzodioxolyl, naphthyl, pyridyl, and isoxazolyl, each of which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from Cj . -C 4 alkyl, halo, cyano, Cj-C 4 haloalkyi, C1-C 4 alkoxy, C 1 -C 4 haloalkoxv, and -NHCOR', wherein R' is C1-C 4 alkyl.
  • R 1 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifiuoromethyi, trifluoromethoxy, methoxy, and cyano.
  • R ! is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifiuoromethyi, trifluoromethoxy, methoxy, and cyano.
  • Cj-C 4 alkyl e.g., methyl
  • halo e.g., fluoro or chloro
  • cyano Ci-C 4 haloalkyi (e.g., trifiuoromethyi)
  • C1-C4 alkoxy e.g., methoxy
  • Ci-C 4 haloalkoxv e.g., trifluoromethoxy
  • -NHCOR' wherein R' is Cj-C 4 alkyl (e.g., -NHCOCH 3 ).
  • R 1 is pyrazolyl that is substituted with 1 or 2 substituents independently selected from Cj-C 4 alkyl (e.g., methyl) and Cj-C 4 haloalkyi (e.g., trifiuoromethyi).
  • R ! is
  • R " is hydrogen and R J is hydrogen.
  • K z and R' are taken together to form an oxo group.
  • m is 0.
  • R 5 is hydrogen
  • R 6 is selected from Cj-Cg alkyl and -(CR ⁇ Y 1 .
  • R 0 is selected from Ci-Cg alkyl and -(CR f R g ) n - Y ! ;
  • R' is hydrogen;
  • R g is selected from hydrogen, C 1 -C4 alkyl and phenyl;
  • n is 0 or 1;
  • Y 1 is selected from: CVCjo-eycloalkyi;
  • the cycloaikyi, cycloalkenyi, phenyl, heteroaiyi and heterocyclyl are unsubstituted or substituted with I or 2 substituents independently selected from C 1 -C 4 alkyl, halo, and C1-C 4 hal
  • R° is Ci-Cg alkyl (e.g., methyl, ethyl, isopropyl, sec-butyl, neopentyl, sec-pentyl, 4,4-dimethylpentan-2-yl).
  • R 6 is -(CR ⁇ n -Y 1 , n is 0 or 1
  • R f is hydrogen
  • R s is hydrogen
  • Y 1 is selected from Cj-Cio-cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyL adamantyl), Cs-Cio-cycloalkenyl (e.g., bicyclo[2.2.1 ]hept-5-en-2-yl), phenyl, a 5- to 8-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S (e.g., tetrahydrofuranyl, tetrahydropyranyl, 7-oxabicyclo[2.2.1 jheptanyl), and a 5- to 6-membered heteroaiyi having 1 , 2 or 3 heteroatoms independently selected from N, O and S (e.g., pyrid
  • A is a five-membered heteroaiyi having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from N, O and S, a six-membered heteroaryi having 1 -2 nitrogen atoms, a phthalazinyl, an imidazofl ,2-b]pyridazinyl, or a
  • [l,2,4]tnazolo[4,3-b]pyridazinyi wherein A is optionally substituted with 1-4 substituents independently selected from halo, C1-C4 alkyl, and C 1 -C 4 haloalkyl.
  • A is a thiazol-2,5-diyl, pyridazin-3,6-diyl, pyrazin-2,5-diyl, pyridin-2,5-diyl, phthalazin-l,4-diyl, imidazo[l,2-b]pyridazin-6-yl, or [l,2,4]triazolo[4,3-b]pyridazin-6-yl, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, Ci-C 4 alkyl, and Cj -C 4 haloalkyl.
  • A is selected from: wherein T is selected from O, S and NH; and U, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 1 - A is or , (i .e., the R 1 of formula (I) is hydrogen 007 ⁇ :
  • the compound of formula (I) is a compound of formula (la):
  • W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
  • 1 or 2 of W, X, Y and Z are N. In some embodiments, W and X are N and Y and Z are CH. In some embodiments, W, Y and Z are CH and X is N. In some embodiments, X and Y are N, and W and Z are CH.
  • the compound of formula (I) is a compound of formula (lb):
  • Representative compounds of formula (I) include, but are not limited to:
  • the experimental section also refers to the compounds listed below by the name generated from the structure using the ChemDraw® software.
  • the compound may exist as a stereoisomer wherein asymmetric or chirai centers are present.
  • the stereoisomer is "i?" or "5"' depending on the configuration of substituents around the chirai carbon atom.
  • the terms "i?" and “S” used herein are configurations as defined in iUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appi. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chirai centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chirai auxiliary, separation of the resulting mixture of diastereomers by recry stall ization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or
  • the present disclosure also includes an isotopicaliy-labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to 2 H, 3 ⁇ 4 i3 C, i4 C, 15 N, 18 0, 1 ⁇ , 3I P, 32 P, 35 S, 18 F, and 36 C1, respectively. Substitution with heavier isotopes such as deuterium, i.e.
  • the compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors.
  • positron- emitting isotopes that can be incorporated in compounds of formula (I) are n C, lj N, and l8 F.
  • isotopicaliy-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopicaliy-labeled reagent in place of non- isotopically-labeled reagent.
  • the disclosed compounds may exist as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use.
  • the salts may be prepared during the final isolation and purification of the compounds or separately by reacting an ammo group of the compounds with a suitable acid.
  • a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid.
  • the resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure.
  • salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
  • glycerophosphate hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like.
  • amino groups of the compounds may also be quaternized with aikyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
  • Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • Quaternary amine salts can be prepared, such as those derived from methyl amine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamme, 1-ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanol amine, piperidine, piperazme, and the like,
  • Compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • compound A can be reacted with compound B to produce compound C, winch is coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound D.
  • Boc deprotection produces compound E.
  • This process can be used to prepare precursors to compounds of formula (I), for example, wherein R 2 and R 3 are hydrogen, m is 0, and wherein W is CH, X is N and Z is CH, or wherein W is CH, X is CH and Z is N (i.e. compounds of formula (lb)).
  • compound E can be reacted with a suitable aldehyde and sodium triacetoxyborohydride to produce compound F.
  • This process can be used to prepare compounds of formula (I), for example, wherein R 2 , R", and R 5 are hydrogen, m is 0, and wherein W is CH, X is N and Z is CH, or wherein W is CH, X is CH and Z is N (i.e. compounds of formula (lb)).
  • a suitable heteroaryi compound G (where A is, as defined herein, a five- or six-membered heteroaryi, and R ! is as defined herein) that is functional ized with a halo group (e.g., F or CI) can be coupled to compound A to produce compound H, which can be deprotected and coupled as described herein or according to other known methods.
  • This process can be used to prepare precursors to compounds of formula (I) in
  • R " and R are hydrogen, m is 0, and A is as described herein (e.g., wherein A is pyridyl or thiazolyl).
  • compound C (corresponding to compound C in which W is CH, X is CH and Z is N) can be deprotected and then reacted with 3,3- dimethyibutyraldehyde and sodium triacetoxyborohydride to produce compound I, which can be coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound J.
  • This process can be used to prepare certain compounds of formula (I), e.g., compounds of formula (lb) in which R 2 and R J are hydrogen, R 5 is hydrogen, and R 6 is
  • a specific compound can be prepared from compound K (prepared according to General Scheme A), by reacting compound K with rac-(lR,2S,4S)-7- oxabicy clo[2.2.1 ]heptane-2-carboxylic acid, in the presence of HATU and DIPEA, to generate compound L, which can be reduced using lithium aluminum hydride to generate compound M.
  • certain compounds of formula (I) can be prepared by reacting compound Q with 3-amino-6-chloropyridazine with PyCIU to form compound R, which can be coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound S. Deprotection and reaction with a suitable aldehyde and sodium
  • the compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis.
  • Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by
  • a disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt.
  • a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling.
  • acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandeiic, atrolactic,
  • the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
  • M 4 is the most highly expressed mAChR subtype in the striatum and its expression is similar in rodents and primates. Due to a lack of selective M 4 antagonists, mechanistic understanding of the role of M 4 has been guided by biochemical and genetic studies, as well as the use of highly selective M 4 positive allosteric modulators (PAMs). Highly selective M 4 PAMs induce robust decreases in behavioral responses to psychomotor stimulants that act by increasing striatal DA levels.
  • PAMs highly selective M 4 positive allosteric modulators
  • M 4 increases exploratory locomotor activity, potentiates locomotor responses to amphetamine and other stimulants, and eliminates effects of M 4 PAM.S on locomotor activity and these effects are also observed with selective deletion of M 4 from striatal spiny projection neurons that express the Dl subtype of DA receptor (Dl -SPNs).
  • Dl -SPNs Dl subtype of DA receptor
  • In vivo microdiaiysis studies reveal that administration of M 4 PAMs reduces amphetamine-induced DA release in the dorsal and ventral striatum and fMRI studies show that M4 PAMs reverse amphetamine- induced increases in cerebral blood flow (CBV) in striatum and other basal ganglia nuclei.
  • CBV cerebral blood flow
  • M4 PAMs act, at least in part, by inhibition of DA release from presynaptic DA terminals in the striatum through release of an endocannabinoid from striatal spiny projection neurons (SPNs) and activation of CB2 cannabinoid receptors on DA terminals.
  • SPNs striatal spiny projection neurons
  • M 4 is heavily expressed in a subset of SPNs that also express the Dj subtype of DA receptor (D]DR), which form the direct pathway (Dl-SPNs) sending inhibitory projections to the substantia nigra pars reticulata (SNr).
  • D Dj subtype of DA receptor
  • Dl-SPNs Dj subtype of DA receptor
  • SNr pars reticulata
  • DiDRs activate a unique GTP-binding protein in Dl-SPNs, termed G KO i f that couples DjRs to activation of adenylyi cyclase, formation of cAMP, and activation of protein kinase A (PKA).
  • M 4 PAMs may directly inhibit DIR-mediated signaling in Dj-SPNs by direct inhibition of cAMP formation and this could also contribute to the powerful inhibitory effect of selective M 4 activation of DA signaling in the basal ganglia. Consistent with this, M 4 PAMs inhibit locomotor-stimulating effects of a direct acting Di agonist.
  • M4 is the dominant mAChR subtype involved in the antiparkinsonian effects of non-selective mAChR antagonists and provide support for discover and development of selective M 4 antagonists for treatment of neurodegenerative disease such as PD, dystonia, tardive dyskinesia and other movement disorders.
  • the disclosed compounds are antagonists of mAChR M 4 .
  • Such activity can be demonstrated by methodology known in the art.
  • antagonism of mAChR M 4 activity can be determined by measurement of calcium flux in response to agonist, e.g. acetylcholine, in cells loaded with a Ca" ' -sensitive fluorescent dye (e.g., Fluo-4) and co- expression of a chimeric or promiscuous G protein.
  • the calcium flux can be measured as an increase in fluorescent static ratio.
  • antagonist activity can be analyzed as a concentration-dependent increase in the ECso acetylcholine response (i.e. the response of mAChR M4 at a concentration of acetylcholine that yields 80% of the maximal response).
  • the disclosed compounds antagonize mAChR M4 as a decrease in calcium fluorescence in mAChR M 4 -transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound.
  • a disclosed compound antagonizes the mAChR Mj response with an IC50 of less than about 10 ⁇ , less than about 5 ⁇ , less than about 1 ⁇ , less than about 500 nM, of less than about 100 nM, or less than about 50 nM.
  • the mAChR Mr transfected CHO-Kl cells are transfected with human mAChR M 4 .
  • the mAChR Mrtransfected CHO-Kl cells are transfected with rat mAChR M 4 . In some embodiments, the mAChR Mrtransfected CHO-Kl cells are transfected with mAChR M 4 from dog or cynomolgus monkey.
  • the disclosed compounds may antagonize mAChR M4 response in mAChR M4 - transfected CHO-Kl cells with an IC 50 less than the IC 50 for one or more of mAChR Mi , M 2 , M 3 or M 5 -transfected CHO-Kl ceils. That is, a disclosed compound can have selectivity for the mAChR M4 receptor vis-a-vis one or more of the mAChR M !? M 2 , M3 or M 5 receptors.
  • a disclosed compound can antagonize mAChR M 4 response with an IC 50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Mi .
  • a disclosed compound can antagonize m AChR M4 response with an IC 50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200- fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Mfe. In some embodiments, a disclosed compound can antagonize mACh .
  • a disclosed compound can antagonize mAChR M 4 response with an IC 50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400- fold less, or greater than about 500-fold less than that for mAChR M 3 .
  • a disclosed compound can antagonize mAChR M 4 response with an IC 50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M3 ⁇ 4.
  • a disclosed compound can antagonize mAChR M4 response with an IC 50 of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M 2 -M 5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for the mAChR Mi, M 2 , M 3 , or M 5 receptors.
  • the disclosed compounds may antagonize mAChR M4 response in Mrtransfected CHO-Kl cells with an IC 50 of less than about 10 ⁇ and exhibit a selectivity for the M4 receptor vis-a-vis one or more of the mAChR Mi, M2, M 3 , or M5 receptors.
  • the compound can have an IC50 of less than about 10 ⁇ , of less than about 5 ⁇ , of less than about 1 ⁇ , of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an IC 50 of about 5-fold less, 10-fold less, 20-fold less, 30-fold less, 50-fold less, 100-fold less, 200-fold less, 300- fold less, 400-fold less, or greater than about 500-fold less than that for mAChR Mj.
  • the compound can have an IC50 of less than about 10 ⁇ , of less than about 5 ⁇ . ⁇ , of less than about 1 ⁇ , of less than about 500 nM, of less than about 100 M, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M 2 .
  • the compound can have an IC 50 of less than about 10 ⁇ , of less than about 5 ⁇ , of less than about 1 ⁇ , of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mACh M4 response with an IC 50 of about 5-fold less, about 10-fold less, about 20- fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M3.
  • the compound can have an IC50 of less than about 10 ⁇ , of less than about 5 ⁇ , of less than about 1 ⁇ , of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR Mi response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M 5 .
  • the compound can have an IC 50 of less than about 10 ⁇ , of less than about 5 ⁇ , of less than about 1 ⁇ . ⁇ , of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M 4 response with IC 50 of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M 2 -M 5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, M 2 , M 3 , or M 5 receptors, or greater than about 500-fold less than that for the mAChR ⁇ ,, M 2 , M 3 , or M 5 receptors.
  • in vivo efficacy for disclosed compounds in models that predict antiparkinsonian activity can be measured in a number of preclinical rat models.
  • disclosed compounds may reverse deficits in motor function induced by the dopamine receptor antagonist in mice or rats.
  • these compounds may reverse deficits in motor function that are observed with other manipulations that reduce dopaminergic signaling, such as selective lesions of dopamine neurons.
  • it is possible that these compounds will have efficacy in animal models of dystonia and may increase attention, cognitive function, and measures of motivation in animal models.
  • the disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human).
  • a subject such as a patient, which may be a human or non-human.
  • the disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.
  • the pharmaceutical compositions and formulations may include a "therapeutically effective amount” or a “prophylactic-ally effective amount” of the agent.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I)) are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • a therapeutically effective amount of a compound of formula (I) may ⁇ be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about 550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about 450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about 350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about 250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about 150 mg/kg, and about 90 mg/kg
  • compositions and formulations may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • sugars such as, but not limited to, lactose, glucose and sucrose: starches such as, but not limited to, corn starch and potato starch: cellulose and its derivatives such as, but not limited to, sodium carboxymethyi cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic s
  • starches such as, but not limited to,
  • the compounds and their physiologically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration.
  • Techniques and formulations may generally be found in "Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.).
  • Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.
  • compositions may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).
  • systemic administration e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral
  • topical administration e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis.
  • Carriers for systemic administration typically include at least one of diluents, lubncants, binders, dismtegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.
  • Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitoi; and sorbitol.
  • the amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.
  • Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma.
  • the amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.
  • Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate;
  • starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose.
  • the amount of binder(s) in a systemic composition is typically about 5 to about 50%.
  • Suitable disintegrants include agar, algimc acid and the sodium salt thereof!, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins.
  • the amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.
  • Suitable colorants include a colorant such as an FD&C dye.
  • the amount of colorant in a sy stemic or topical composition is typically about 0.005 to about 0.1 %.
  • Suitable flavors include menthol, peppermint, and fruit flavors.
  • the amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.
  • Suitable sweeteners include aspartame and saccharin.
  • the amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.
  • Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • vitamin E vitamin E.
  • the amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.
  • Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about
  • Suitable glidants include silicon dioxide.
  • the amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.
  • Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxy lated castor oils, alcohols such as ethanol, and phosphate buffer solutions.
  • the amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.
  • Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate.
  • the amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.
  • Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware.
  • Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592;
  • the amount of surfactant(s) in the systemic or topical composition is typically about 0.1 % to about 5%.
  • systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or more carriers.
  • Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.
  • compositions for oral administration can have various dosage forms.
  • solid forms include tablets, capsules, granules, and bulk powders.
  • These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives.
  • the oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.
  • Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed.
  • Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof.
  • Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.
  • Specific binders include starch, gelatin, and sucrose.
  • Specific dismtegrants include alginic acid and croscarmeliose.
  • Specific lubricants include magnesium stearate, stearic acid, and talc.
  • Specific colorants are the FD&C dyes, which can be added for appearance.
  • Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination
  • Capsules typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin.
  • Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics.
  • Implants can be of the biodegradable or the non-biodegradable type.
  • ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.
  • Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action.
  • the coatings typically include one or more components selected from the group consisting of cellulose acetate phthaiate, polyvinyl acetate phthaiate, hydroxypropyl methyl cellulose phthaiate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik industries of Essen, Germany), waxes and shellac.
  • compositions for oral administration can have liquid forms.
  • suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like.
  • Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants.
  • Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.
  • compositions useful for attaining systemic deliver ⁇ ' of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose.
  • Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.
  • Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.
  • Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), and a carrier.
  • the carrier of the topical composition preferably aids penetration of the compounds into the skin.
  • the carrier may further include one or more optional components.
  • the amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practi cal quantity of composition for administration per unit dose of the compound.
  • Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al, Pharmaceutical Dosage Forms: Tablets ( 981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
  • a carrier may include a single ingredient or a combination of two or more ingredients, in the topical compositions, the earner includes a topical carrier.
  • Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like.
  • carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.
  • the carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, ail of which are optional.
  • Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-dioi, butane-l ,3-diol, mink oil, cetyl alcohol, isopropyi isostearate, stearic acid, isobutyi paimitate, isocetyl stearate, oleyl alcohol, isopropyi iaurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols
  • Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.
  • the amount of propellant(s) in a topical composition is typically about 0% to about 95%.
  • Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof.
  • Specific solvents include ethyl alcohol and homotopic alcohols.
  • the amount of solvent(s) in a topical composition is typically about 0% to about 95%.
  • Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, di butyl phthaiate, gelatin, and combinations thereof.
  • Specific humectants include glycerin.
  • the amount of humectant(s) in a topical composition is typically 0% to 95%.
  • the amount of thickener (s) in a topical composition is typically about 0% to about 95%.
  • Suitable powders include beta-cyclodextrins, hydrox -propyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyi cellulose, ethylene glycol monostearate, and combinations thereof.
  • the amount of powder(s) in a topical composition is typically 0% to 95%.
  • the amount of fragrance in a topical composition is ty pically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.
  • Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.
  • the pharmaceutical composition or formulation may antagonize mAChR M 4 with an IC 50 of less than about 10 ⁇ , less than about 5 ⁇ , less than about 1 ⁇ , less than about 500 nM, or less than about 100 nM.
  • the pharmaceutical composition or formulation may antagonize mAChR M4 with an IC 50 of between about 10 ⁇ and about 1 nM, about 1 ⁇ and about 1 nM, about 100 nM and about 1 nM, or between about 10 nM and about 1 nM.
  • the disclosed compounds may be formulated as a spray-dried dispersion (SDD).
  • SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution with the compound molecularly "dissolved” in a solid matrix. SDDs are obtained by dissolving drug and a polymer in an organic solvent and then spray-drying the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility of Biopharmaceutics Classification System (BCS) class II (high
  • SDDs have demonstrated long- term stability and manufaeturability. For example, shelf lives of more than 2 years have been demonstrated with SDDs.
  • Advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable and scalable manufacturing process and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.
  • the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I).
  • the disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as neurological and/or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction.
  • the disclosed compounds and pharmaceutical compositions may also be used in methods for decreasing muscarinic acetylcholine receptor activity in a mammal.
  • the methods further include cotherapeutic methods for improving treatment outcomes.
  • additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions.
  • the disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treating, preventing, ameliorating, controlling, reducing, or reducing the risk of a variety of disorders, or symptoms of the disorders, in which a patient would benefit from antagonism of mAChR M4.
  • the disorder may be a neurodegenerative disorder, a movement disorder, or a brain disorder.
  • the methods may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a
  • disorders in which a patient would benefit from antagonism of mAChR M4 may include neurodegenerative disorders and movement disorders.
  • exemplary disorders may include Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias (e.g., tardive dyskinesia or levodopa-induced dyskinesia), schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness (e.g., narcolepsy), attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea (e.g., chorea associated with Huntington's disease), cerebral palsy, and progressive supranuclear palsy.
  • Parkinson's disease drug-induced Parkinsonism
  • dystonia dystonia
  • Tourette's syndrome dyskinesias
  • schizophrenia cognitive deficits associated with schizophrenia
  • excessive daytime sleepiness e.g., narcolepsy
  • attention deficit hyperactivity disorder e.g., Huntington's disease
  • chorea
  • the disclosure provides a method for treating motor symptoms in a subject having Parkinson's disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the motor symptoms are selected from bradykinesia, tremor, rigidity, gait dysfunction, and postural instability.
  • the method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject.
  • the disclosure provides a method for treating motor symptoms in a subject having dystonia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject. For example, treatment may reduce muscle contractions or spasms in a subject having dystonia.
  • the disclosure provides a method for treating motor symptoms in a subject having tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject. For example, treatment may reduce involuntary movements in a subject having tardive dyskinesia.
  • the disclosure provides a method of preventing or delaying tardive dyskinesia in a subject at risk of developing tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a
  • the subject may be a subject being treated with a neuroleptic medication (e.g., a typical antipsychotic or an atypical antipsychotic), a dopamine antagonist, or an antiemetic.
  • a neuroleptic medication e.g., a typical antipsychotic or an atypical antipsychotic
  • a dopamine antagonist e.g., a dopamine antagonist
  • an antiemetic e.g., a typical antipsychotic or an atypical antipsychotic
  • the disclosure provides a method of treating catalepsy in a subject suffering from schizophrenia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the subject suffering from schizophrenia may have catalepsy induced by a neuroleptic agent (e.g., a typical antipsychotic or an atypical antipsychotic).
  • the disclosure provides a method of treating a brain disorder characterized by altered dopamine and cholinergic signaling that could benefit from antagonism of mAChR 4, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the treatment may increase motivation or goal-directed behavior in patients suffering from disorders characterized by reduced motivation for goal-directed behavior, such as schizophrenia and other brain disorders.
  • the disclosure provides a method for increasing wakefulness and/or reducing excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the subject is a subject suffering from narcolepsy.
  • the disclosure provides a method of increasing attention in a subject (e.g., a subject suffering from an attention deficit disorder such as ADHD) in a subject in need thereof!, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a subject e.g., a subject suffering from an attention deficit disorder such as ADHD
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method for treating motor symptoms in a subject having a drug-induced movement disorder, comprising administering the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the drug-induced movement disorder is selected from drug-induced parkinsonism, tardive dyskinesia, tardive dystonia, akathisia, myoclonus, and tremor.
  • the method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject.
  • the compounds and compositions 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 compounds and compositions 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.
  • an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level may be about 0.1 to about 250 mg/kg per day, or about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level can 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 can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response.
  • the disclosure relates to a method for antagonizing the mAChR Mj receptor in at least one cell, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one product of a disclosed method in an amount effective to antagonize mAChR. M 4 in the at least one cell.
  • the cell is mammalian, for example, human.
  • the cell has been isolated from a subject prior to the contacting step.
  • contacting is via administration to a subject.
  • the invention relates to a method for antagonizing the mAChR M 4 receptor in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to antagonize the mAChR. M4 receptor in the subject.
  • the subject is mammalian, for example, human.
  • the mammal has been diagnosed with a need for mAChR M 4 antagonism prior to the administering step.
  • the mammal has been diagnosed with a need for mAChR M 4 antagonism prior to the
  • the method further comprises the step of identifying a subject in need of mAChR M4 antagonism.
  • the disclosure relates to a method for antagonizing mAChR M4 in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.
  • antagonism of the muscarinic acetylcholine receptor decreases muscarinic acetylcholine receptor activity.
  • the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for reduction of muscarinic acetylcholine receptor activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of reducing muscarinic acetylcholine receptor activity, in some embodiments, the antagonism of the muscarinic acetylcholine receptor treats a disorder associated with muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.
  • antagonism of the muscarinic acetylcholine receptor in a mammal is associated with the treatment of a disorder associated with a muscarinic receptor dysfunction, such as a disorder disclosed herein.
  • the muscarinic receptor is mAChR M 4 .
  • the disclosure provides a method for antagonizing the muscarinic acetylcholine receptor in a cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof.
  • the cell is mammalian (e.g., human).
  • the ceil has been isolated from a mammal prior to the contacting step.
  • contacting is via administration to a mammal.
  • the present disclosure is further directed to administration of a mAChR M 4 antagonist, such as a selective mAChR M4 antagonist, for improving treatment outcomes. That is, in some embodiments, the disclosure relates to a cotherapeutic method comprising a step of administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
  • administration improves treatment outcomes in the context of cognitive or behavioral therapy.
  • Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and/or after therapy.
  • cognitive or behavioral therapy can be provided within 1 , 2, 3, 4, 5, 6, 7 days before or after administration of the compound.
  • cognitive or behavioral therapy can be provided withm 1, 2, 3, or 4 weeks before or after administration of the compound.
  • cognitive or behavioral therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.
  • administration may improve treatment outcomes in the context of physical or occupational therapy.
  • Administration in connection with physical or occupational therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and/or after therapy.
  • physical or occupational therapy- can be provided within 1 , 2, 3, 4, 5, 6, 7 days before or after administration of the compound.
  • physical or occupational therapy can be provided within 1 , 2, 3, or 4 weeks before or after administration of the compound.
  • physical or occupational therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.
  • additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I).
  • 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.
  • the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • the other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound may be used.
  • the combination therapy can also be administered on overlapping schedules.
  • the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.
  • the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.
  • compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • the above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds.
  • disclosed compounds can 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 disclosed compounds are useful.
  • Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred.
  • the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of a disclosed compound to the second active ingredient can 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 a disclosed compound to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably 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.
  • a disclosed compound and other active agents can be administered separately or in conjunction.
  • the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds.
  • the subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.
  • the compound can be employed in combination with any other agent that is used to treat a disorder described herein, such as a standard of care therapy for a disorder that would benefit from mAChR 4 antagonism, such as a disorder described herein.
  • the compound can be employed in combination with a Parkinsonian drug (e.g., L-DOPA, or carbidopa/levodopa) an mGlu4 positive allostenc modulator, an niGiu negative ailosteric modulator, an A 2 A inhibitor, a T-type calcium channel antagonist, a VMAT2 inhibitor, a muscle relaxant (e.g., baclofen), an anticholinergic agent, an antiemetic, a typical or atypical neuroleptic agent (e.g., risperidone, ziprasidone, haloperidol, pimozide, fluphenazine), an antihypertensive agent (e.g., clonidine or guanfacine), a tricyclic antidepressant (e.g., amitriptyline, butriptyline, clomipramine, desipramme, dosulepin, doxepm, imipramm
  • lisdexamfetamine an agent for treating excessive daytime sleepiness (e.g., sodium ox bate or a wakefulness-promoting agent such as armodafinil or modafinil), and a norepinephrine reuptake inhibitor (including selective NRIs, e.g., atomoxetine, and non-selective NRIs, e.g., bupropion).
  • an agent for treating excessive daytime sleepiness e.g., sodium ox bate or a wakefulness-promoting agent such as armodafinil or modafinil
  • a norepinephrine reuptake inhibitor including selective NRIs, e.g., atomoxetine, and non-selective NRIs, e.g., bupropion.
  • Methods of treatment may include any number of modes of administering a disclosed composition.
  • Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders.
  • the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g.
  • the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.
  • the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • a physiologically acceptable diluent such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.
  • the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
  • parenteraliy refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. 5. Kits
  • the disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof and one or more of:
  • kits can also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components.
  • a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for deliver ⁇ ' to a patient.
  • kits can be employed in connection with disclosed methods of use.
  • kits may further comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans).
  • the information and instructions may be in the form of words, pictures, or both, and the like.
  • the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).
  • Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, CI 8 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters.
  • the gradient conditions were 5% to 95% acetonitriie with the aqueous phase 0.1% TFA in water over 1.4 minutes.
  • Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 ⁇ , 1.0 x 50 mm) at 0.5 mL/min, with column and solvent temperatures maintained at 55 °C.
  • the DAD was set to scan from 190 to 300 nni, and the signals used were 220 nm and 254 nm (both with a band width of 4nm).
  • the MS detector was configured with an electrosprav ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles/second, and peak width of 0.008 minutes.
  • the drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi.
  • the capillar ⁇ ' needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.
  • RuPhos-Pd-G3 methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1 , 1 '-biphenyl)(2'-amino- 1 , i -biphenyl-2-yi)pailadium( (CAS No. 1445085-77-7)
  • N-((6- Azaspiro[2.5]octan-l-yi)methyl)-6-(2-chioro-5-fluorophenyi)pyridazm-3-aniine hydrochloride salt (11 mg, 0.028 mmol) was suspended in DCM (1 raL) and 3-(trifluoromethyl)pyridine-2- carbaldehyde (24 mg, 0.14 mmol) was added and allowed to stir at r.t. for 5 min, after which time sodium triacetoxyborohydride (30 mg, 0.14 mmol) was added. The resulting solution was stirred at r.t. overnight, after which time the reaction mixture was quenched with sat.
  • 6-Chloro-N-((6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-l-yl)methyl)pyridazin-3-amine (20 mg, 0.06 mmol), K 2 C0 3 (25 mg, 0.18 mmol), 4-fluorophenylboronic acid (10 mg, 0.07 mmol) and uPhos-Pd-G3 (5 mg, 0,006 mmol) were combined in a sealed vial, and a solution of 5; 1 1 ,4-dioxanes H 2 0 (1 .2 mL, degassed) was then added via syringe.
  • N-((6- Azaspiro[2.5] octan- 1 -yl)methyl)-6-( 1 ,3-dimethyl- lH-pyrazol-4-yl)pyridazin-3 -amine dihydrochloride (33 nig, 0.086 mmol) was dissolved in DMF (1 mL) and rac- ⁇ R,2SAS)-l- oxabicyclo[2.2.1]heptane-2-carboxylic acid (18 nig, 0.13 mmol) was then added, followed by DIPEA (0.045 mL, 0.26 mmol) and HATU (49 mg, 0.13 mmol). The resulting solution was stirred at r.t.
  • N-((6-Azaspiro[2.5]octan- l-yl)me4hyl)-6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-amine dihydrochloride (12 mg, 0.031 mmol) was suspended in DCM (1 inL) and 2-(2-bromoethyl)oxolane (11 mg, 0.062 mmol) was added, followed by K 2 C0 3 (8.7 mg, 0.062 mmol). The resulting suspension was stirred at r.t. for 4 h, after which time the reaction was quenched with sat. NaHC0 3 , and aqueous layer was extracted with 3: 1 chloroform/EPA.
  • the resulting suspension was heated to 110 °C with microwave irradiation for 20 mm, after which time the reaction was cooled to r.t., and diluted with DCM and H 2 0.
  • the aqueous layer was extracted with DCM, and organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a white solid (61 mg, 43%).
  • N-((6-Azaspiro[2.5]octan-l - yl)methyl)-5-(l ,3-dimethyl-l H-pyrazol-4-yl)pyridin-2-amine dihydrochloride (1 5 mg, 0.039 mmol) was suspended in DCM (1 mL) and 3,3-dimethylbutyraldehyde (19 mg, 0.1 9 mmol) was then added, followed by sodium triacetoxyborohydride (41 mg, 0.19 mmol). The resulting suspension was stirred at r.t. for 5 h, after which time the reaction was quenched with sat.
  • EXAMPLE 10 l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)oxy)methyl)-6-
  • tert-butyl l-(((6-ch!oropyridazin-3-yl)oxy)methyl)-6-azaspiro[2.5]octane-6- carboxylate tert-Butyl l-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (466 mg, 1.93 mmol) was dissolved in THF (10 mL) and Natl (93 mg, 3.86 mmol, 60% dispersion in mineral oil) was added at 0 °C. After stirring for 5 mins, 3,6-dichloropyridazine (432 mg, 2.90 mmol) was added. The resulting solution was warmed to r.t.
  • HC1 salt was suspended in DCM (1 mL) and 3,3-dimethylbutyraldehyde (27 nig, 0.27 mmol) was added, followed by sodium triacetoxyborohydride (57 mg, 0.27 mmol). After stirring overnight at r.t., the reaction mixture was quenched with sat. NaHC03, and the aqueous layer was extracted with 3: 1 chloroform/EPA. Combined organic extracts were filtered through a phase separator and concentrated, and crude residue was purified by KP-HPLC.
  • Compound master plates were formatted in a 10 point concentration-response curve (CRC) format (1 :3 dilutions) in 100% DMSO with a starting concentration of 10 or 1 mM using a BRAVO liquid handler (Agilent).
  • Test compound CRCs were then transferred to daughter plates (240 nL) using the Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA) and then diluted into assay buffer (40 ⁇ ) to a 2x stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).
  • Positive ailosteric modulator activity was analyzed as a concentration-dependent increase in the EC 20 acetylcholine response.
  • Antagonist activity was analyzed as a concentration-dependent decrease in the EC 80 acetylcholine response; for the purposes of the tables herein, an IC50 (inhibitory concentration 50) was calculated as a concentration-dependent decrease of the response elicited by an EC ⁇ o concentration of acetylcholine.
  • Concentration- response curves were generated using a four-parameter logistical equation in XLFit curve fitting software (IDBS, Bridgewater, NX) for Excel (Microsoft, Redmond, WA) or Prism (GraphPad Software, Inc., San Diego, CA) or the Dotmatics software platform (Dotmatics, Bishop's Stortford, UK).
  • the above described assay was also operated in a second mode where an appropriate fixed concentration of the present compounds were added to the cells after establishment of a fluorescence baseline for about 3 seconds, and the response in cells was measured. 140 s later, a full concentration-response range consisting of increasing concentrations of agonist was added and the calcium response (maximum-local minima response) was measured.
  • the EC 50 values for the agonist in the presence or absence of test compound were determined by nonlinear curve fitting. A decrease in the EC 50 value of the agonist with increasing concentrations of the present compounds (a leftward shift of the agonist concentration-response curve) is an indication of the degree of muscarinic positive allosteric modulation at a given concentration of the present compound.
  • An increase in the EC 50 value of the agonist with increasing concentrations of the present compounds is an indication of the degree of muscarinic antagonism at a given concentrati on of the present compound.
  • the second mode also indicates whether the present compounds also affect the maximum response of the muscarinic receptor to agonists.
  • A is a five- or six-membered heteroaryl having 1 , 2 or 3 heteroatoms independently selected from N, O and S, or a 9- to 10-membered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1-4 substituents independently selected from halo, C]-C 4 alkyl, and C1-C4 haloaikyl;
  • Q is selected from NR 3 , O, and CR R c ;
  • R 1 is selected from hydrogen, halo, -OR d , M R") .
  • d-C 4 alkyl, -CE CH-C1-C4 alkyl, optionally substituted cycioalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and -CH CH-G;
  • G is optionally substituted cycioalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 2 and R 5 are independently selected from hydrogen, C 1 -C 4 alkyl, and halo, or R 2 and R 5 are taken together to form an oxo group;
  • each R 4 is independently selected from halo, C1 alkyl, and -OR c ;
  • R 3 and R 6 are independently selected from hydrogen, Cj-C 8 alkyl, and -(CR I R g ) n -Y 1 ; each Y 1 is independently selected from optionally substituted cycioalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R d , R , IT, R", R c , R 1 , and R g is independently selected from hydrogen, C1-C4 alkyl, and aryl;
  • n 0, 1 or 2;
  • A is a five- or six-membered heteroaiyl having 1, 2 or 3 heteroatoms independently selected from N, O and S;
  • R 1 is selected from hydrogen, halo, -OR 0 , C 1 -C 4 alkyl, optionally substituted cycloalkyl, optionally substituted lieterocycle, optionally substituted aryl, and optionally substituted heteroaryi.
  • R a is hydrogen or Ci-C 4 alkyl.
  • R d is hydrogen
  • E5. The compound of any of E1-E4, or a pharmaceutically acceptable salt thereof, wherein:
  • G is a 6- to 12-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 4 alkyl, halo, cyano, C 1 -C 4 haloalkyl, C 1 -C4 alkoxy, -C4 haioalkoxy, and -NHCOR'; and
  • R' at each occurrence, is independently C 1 -C4 alkyl.
  • E6 The compound of E5, or a pharmaceutically acceptable salt thereof, wherein
  • G is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C C 4 alkyl, halo, cyano, Cj-C haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherein R' is C1-C4 alkyl.
  • R 1 is selected from halo, aryl, and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherei R' is C3 ⁇ 4- C 4 alkyl,
  • R 1 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 2 and R 3 are taken together to form an oxo group.
  • E12 The compound of any one of El-El 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
  • E13 The compound of any one of E1-E12, or a pharmaceutically acceptable salt thereof, wherein
  • R 0 is selected from Ci -Cg alkyi and ⁇ (CR f R g ) n - Y ! ;
  • R' is hydrogen
  • R g is selected from hydrogen, C 1 -C4 alkyi and phenyl
  • n 0 or 1 ;
  • Y 1 is selected from: C3-C 1 o-cy cloalkyl; Cs-Cio-cycloalkenyl; phenyl; a 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatorns independently selected from N, O and S; and a 5- to 8- membered heterocyclyl having 1 or 2 heteroatorns independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaiyl and heterocyclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from Ci-C 4 alkyi, halo, and C 1 -C 4 haloalkyl.
  • E14 The compound of any of E1-E13, or a pharmaceutically acceptable salt thereof!, wherein:
  • A is a five-membered heteroaryl having 1 nitrogen atom and optionally 1 -2 additional heteroatorns independently selected from N, O and S, a six-membered heteroaiyl having 1-2 nitrogen atoms, a phthalazinyl, an imidazo[! ,2-b]pyndazmyl, or a [l,2,4]triazolo[4,3- bjpyridazinyl, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, C 1 -C 4 alkyi, and C 1 -C 4 haloalkyl.
  • E15 The compound of E14, or a pharmaceutically acceptable salt thereof, wherein:
  • A is a thiazol-2,5-diyi, pyridazin-3,6-diyl, pyrazin-2,5-diyl, pyridin-2,5-diyi, phthalazin- 1,4-diyl, imidazo[l,2-b]pyridazin-6-yl, or [l,2,4]triazolo[4,3-b]pyridazin-6-yL wherein A is optionally substituted with 1-4 substituents independently selected from halo, C 1 -C 4 alkyi, and C1-C4 haloalkyl.
  • E16 The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein
  • A is selected from:
  • T is selected from O, S and NH;
  • U, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
  • E17 The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein
  • A is selected from
  • E19 The compound of any of E1-E13, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (la):
  • W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
  • E22 The compound of any one of E19-E21, or a pharmaceutically acceptable salt thereof, wherein
  • R ! is selected from: halo; aryi; and a 5- to 6-membered monocyclic heteroaiyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaiyl are uiisubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloaikyl, C1 -C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherein R' is Ci -
  • E23 The compound of any one of E19-E22, or a pharmaceutically acceptable salt thereof, wherein
  • R 2 is hydrogen
  • R 3 is hydrogen
  • E24 The compound of any one of E19-E22, or a pharmaceutically acceptable salt thereof, wherein
  • R 2 and R J are taken together to form an oxo group
  • R 5 is hydrogen.
  • E26 The compound of any one of El 9-E25, or a pharmaceutically acceptable salt thereof, wherein
  • R 6 is selected from Q-Cg alkyl and -(CR f R g ) n -Y l ;
  • R 1 is hydrogen
  • R g is selected from hydrogen, -C4 alkyl and phenyl
  • n 0 or 1 ;
  • Y ! is selected from: CrCio-cycloalkyl; Cs-Cjo-cycloalkenyl; phenyl; a 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; and a 5- to 8- membered heterocvclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocvclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from C 1 -C4 alkyl, halo, and C 1 -C4 haloalkyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Disclosed herein are cyclopropylpiperidme compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M4 (niAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.

Description

ANTAGONISTS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 62/531 ,818, filed July 12, 2017, which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to compounds, compositions, and methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction.
BACKGROUND
[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease with an increasing prevalence as a function of age. Moreover, early-onset PD is also increasing. A hallmark of PD is the progressive degeneration and loss of dopaminergic neurons in the substantia nigra (SN) and basal ganglia (BG), leading to pronounced motor symptoms including bradykinesia, tremor, rigidity, gait dysfunction and postural instability. At present, levodopa (L- DOPA) is the standard of care for treating the motor symptoms, but it is not curative, and prolonged use can engender L-DOPA induced dyskinesia (LID).
[0004] Prior to L-DOPA, compounds with anticholinergic activity represented the preferred mode of PD treatment. Cholinergic neurons provide important neuromodulatory control of the BG motor circuit. While the actions of cholinergic pathways on basal ganglia pathways are complex, activation of muscarinic acetylcholine receptors (mAChRs) generally have actions that oppose dopamine (DA) signaling. For instance, mAChR agonists inhibit DA release, and inhibit multiple behavioral effects of drugs that increase DA levels and signaling. Interestingly, muscarinic acetylcholine receptor (mAChR) antagonists were the first available treatments for PD and are still widely used for treatment of this disorder. While many studies of the actions of mAChR antagonists were carried out before randomized controlled trials were introduced, recent well controlled double-blind cross-over design studies demonstrate significant improvement in multiple aspects of motor function in patients receiving mAChR antagonists. Unfortunately, m AChR antagonists have a number of dose-limiting adverse effects that severely limit their clinical utility, including multiple peripheral adverse effects, as well as confusion and severe cognitive disturbances. [0005] Because adverse effects associated with mAChR antagonists limit the doses that can be tolerated, previous clinical studies may underestimate the efficacy that could be achieved if doses of mAChR antagonists could be increased to achieve more complete blockade of specific mAChR subtypes responsible for the antiparkinsonian effects of these agents. The mAChRs include five subtypes, termed M¾ - M5. Available mAChR antagonists, such as scopolamine, are nonselective across these subtypes, and many of their adverse effects are likely mediated by mAChR subtypes that are not involved in the antiparkinsonian activity. Thus, compounds possessing a more selective profile for individual mAChRs may offer an advantage in PD, as well as related disorders such as dystonia. For example, some studies indicate that the M4 m AChR subtype may play a dominant role in m AChR regulation of basal ganglia motor function.
SUMMARY
[0006] Disclosed are compounds, pharmaceutical compositions comprising the compounds, methods of making the compounds, kits compri sing the compounds, and methods of using the compounds, compositions and kits for treatment of disorders, such as neurological and/or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction in a mammal.
[00Θ7] In one aspect, disclosed are com ounds of formula (I),
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof!, wherein:
A is a five- or six-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 9- to 10-rnembered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, C1-C4 alkyl, and C1-C4 haloafkyl;
Q is selected from NR3, O, and CRbRc;
R1 is selected from hydrogen, halo, -ORd, -N(Rd)2j C1-C4 alkyl, -CH-CH-Ci-C4 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocvcle, optionally substituted aryl, optionally substituted heteroaryl, and -CH=CH-G;
G is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocvcle, optionally substituted aryl, or optionally substituted heteroaryl;
R2 and R3 are independently selected from hydrogen, C C4 aikyl, and halo, or ~R2 and R' are taken together to form an oxo group;
each R4 is independently selected from halo, C1 -C4 alkyl, and -QRS;
R5 and R6 are independently selected from hydrogen, Ci-Cs aikyl, and -(CR'R )r,-Y ; each Y1 is independently selected from optionally substituted cycloalkyl, optionally- substituted cycloalkenyl, optionally substituted heterocvcle, optionally substituted aryl, and optionally substituted heteroaryl;
each Ra, Rb, Rc, Ra, Re, R1, and R8 is independently selected from hydrogen, C1-C4 alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2.
[0008] In another aspect, the invention provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0009] In another aspect, the invention provides a method of antagonizing mAChR M4 in a subject, comprising a step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
[0010] In another aspect, the invention provides a method of treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M4, comprising a step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
[0011] In another aspect, the invention provides a method of treating motor sy mptoms in a subject, comprising a step of administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
[0012] In another aspect, the invention provides kits comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.
[0013] In another aspect, the invention provides compounds of formula (I), or a
pharmaceutically acceptable salt or composition thereof, for use in antagonizing mAChR M4, for the treatment of a disorder ameliorated by mAChR 4 antagonism, or for the treatment of motor symptoms.
[0014] In another aspect, the invention provides the use of compounds of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for antagonizing mAChR Mi, for the treatment of a disorder ameliorated by mAChR M4 antagonism, or for the treatment of motor symptoms.
DETAILED DESCRIPTION OF THE FIGURE
[0015] FIG. 1 shows the structure of compound O (Example 5) obtained by X-ray erystallographic analysis.
DETAILED DESCRIPTION
[0016] Disclosed herein are compounds that are antagonists of the muscarinic acetylcholine receptor M4 (mAChR M$), methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and pharmaceutical compositions. The compounds include functionalized cyclopropylpiperidine compounds.
1, Defisiitiosis
[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict the present document, including definitions, will control Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.
[0018] The terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments "comprising," "consisting of and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not. [0019] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." The term "about" may refer to plus or minus 10% of the indicated number. For example, "about 10%" may indicate a range of 9% to 1 1%, and "about 1 " may mean from 0.9-1.1. Other meanings of "about" may be apparent from the context, such as rounding off, so, for example "about 1" may also mean from 0.5 to 1.4.
[002Θ] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 75ta Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001 ; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3ld Edition, Cambridge Universit ' Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.
[0021] The term "alkoxy," as used herein, refers to an alky] group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy.
[0022] The term "alkyl," as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms. The term "lower alky l" or "Ci.CValkyl" means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term "C-.-CV alkyl" means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, .sec-butyl, /.sobutyl, teri-butyl, w-pentyl, isopentyl, neopentyl, H-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yl, w-heptyl, w-octyl, w-nonyl, and n-decyl.
[0023] The term "alkenyl," as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond and from 2 to 10 carbon atoms.
[0024] The term "alkoxyaikyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
[0025] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
[0026] The term "alkylene," as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, for example, of 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2CH2-, -CH2CH2CH2-, - CH2CH(CH3)CH2-, -CH2CH2CH2CH2~, -CH2CH(CHL CH2CH2-, and -CH2CH2CH2CH2CH2-.
[0027] The term "alkylamino," as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein.
[0028] The term "amide," as used herein, means -C(0)NR- or -N C(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl.
[0029] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein.
[0030] The term "amino," as used herein, means -NRxRy, wherein Rx and Ry may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl. In the case of an aminoalkyl group or any other moiety where ammo appends together two other moieties, ammo may be -NRX-, wherein Rx may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroaikyl.
[0031] The term "aryl," as used herein, refers to a phenyl group, or a bicyclic fused ring system. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Representative examples of aryl include, but are not limited to, indol-4-yl, naphthyl, phenyl, benzodioxol-5-yl, and
tetrahydroqumolin-6-yi.
[0032] The term "cyanoalkyl," as used herein, means at least one -CN group, is appended to the parent molecular moiety through an alkylene group, as defined herein. [0033] The term "cyanofluoroalkyl," as used herein, means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
[0034] The term "cycloalkoxy," as used herein, refers to a cycloalkvl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
[0035] The term "cycloalkyl," as used herein, refers to a carbocyciic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyciobutyi, cyclopentyl, cyciohexyl, cyclolieptyi, eye ooctyl, cycloiioiiyl, cvclodecvl, adamantyl, and bicyclo[l. l . l]pentanyl. "Cycloalkyl" also includes carbocyciic ring systems in which a cycloalkyl group is appended to the parent molecular moiety and is fused to an aryl group as defined herein (e.g., a phenyl group), a heteroaryl group as defined herein, or a heterocycle as defined herein. Representative examples of such cycloalkyl groups include, but are not limited to, 2,3-dihydro- IH-indenyl (e.g., 2,3- dihydro-lH-inden-l-yl and 2,3-dihydro- lH-inden-2-yl), 6,7-dihydro-5H-cyclopenta[0]pyridinyl (e.g., 6,7-dihydro-5H-cyclopenta[i]pyridin-6-yl), oxaspiro[3.3]heptanyl (e.g., 2- oxaspiro[3.3]heptan-6-yl), and 5,6,7,8-tetrahydroquinolinyl (e.g., 5,6,7,8-tetrahydroquinolin-5- yi)-
[0036] The term "cycloaikenyl," as used herein, means a non-aromatic monocyclic or multicyclic (e.g., bridged) ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloaikenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary bridged bicyclic ring system is bicyclo[2.2.1 ]hept-2-enyl.
[0037] The term "fluoroalkyl," as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifiuoroethyl, trifluoromethvl, difluoromethyl, pentafluoroethyi, and trifluoropropyl such as 3,3, 3 - trifl uor opropy 1.
[0038] The term "fluoroalkoxy," as used herein, means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy , trifl uoromethoxy and 2,2,2-trifiuoroethoxy. |Ό039] The term "halogen" or "halo," as used herein, means CI, Br, I, or F.
[0040] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.
[0041] The term "haioalkoxy," as used herein, means at least one haioalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
[0042] The term "haiocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen.
[0043] The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.
[0044] The term "heteroaryl," as used herein, refers to an aromatic monocyclic ring or an aromatic bicyclic ring system. The aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g. 1 , 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalky] group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
Representative examples of heteroaryl include, but are not limited to, indolyl, pyridmyl
(including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1 ,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl, benzothiazoiyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, punnyl, isoindolyl, quinoxalinyl, mdazolyl, quinazolinyl, 1 ,2,4- triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, 6,7-dihydro-l ,3-benzothiazolyl, imidazo[l,2- jpyridinyl, naphthyridinyl, pyridoimidazolyl, thiazolo[5,4- »]pyridin-2-yl, thiazolo 5,4- i |pyrimidin-2-yl, [l,2,4]triazolo[4,3-b]pyridazinyl, imidazo[l ,2-b]pyridazinyl, phthalazinyl.
[0045] The term "heterocycle" or "heterocyclic," as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six- member ed ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1,3-dithiolanyl, 1 ,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl,
oxadiazolidinvl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2- thiazinanyl, 1 ,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1 ,1 - dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic
cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1 , 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3- dihydrobenzofuranyl, 2,3 -dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3 ]heptan- 2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2- azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3. 1.0]hexan-3-yl), 2,3-dihydro-lH-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,
octahydropyrrolopyridinyl, and tetrahydroisoqumolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a
monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkyiene bridge of 1 , 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[&]furan, hexahydro-lH-l,4-methanocyclopenta[c]furan, aza-adamantane (1 - azatrieyelo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
[0046] The term "hydroxyl" or "hydroxy," as used herein, means an -ΟΗ group.
[0047] The term "hydroxyalkyl," as used herein, means at least one -ΟΗ group, is appended to the parent molecular moiety through an alkyiene group, as defined herein.
[0048] The term "hydroxyfluoroalkyl," as used herein, means at least one -ΟΗ group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
[0049] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl or cycloalkyl) is indicated by the prefix "Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "CrC alkyl" refers to an alkyl substituent containing from 1 to 3 carbon atoms.
[0050] The term "sulfonamide," as used herein, means -S(0)2NR- or -NRS(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
[0051] The term "substituents" refers to a group "substituted" on an aryl, heteroaryl, phenyl or pyridinyl group at any atom of that group. Any atom can be substituted.
[0052] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (oxo), ---§ (thioxo), cyano, nitro, fluoroalkyl, alkoxyfiuoroalkyl, fiuoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenvl, aryl, heteroaryl, heterocycle, cycioalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, aikoxy, alkoxyalkyl, alkyiene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyi, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, aiyisulfonyi, aminosulfonyl, sulfinyi, -COOH, ketone, amide, carbamate, and acyl. For example, if a group is described as being "optionally substituted" (such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroaikyl, heterocycle or other group such as an R group), it may have 0, 1, 2, 3, 4 or 5 substituents independently selected from halogen, ==0 (oxo), =;:S (thioxo), cyano, mtro,
fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroaikyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,
heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfmyl, -COOH, ketone, amide, carbamate, and acyl.
[0053] The term "— " designates a single bond (— ) or a double bond (= ).
[0054] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
[0055] The term "mAChR M4 receptor antagonist" as used herein refers to any exogenously administered compound or agent that directly or indirectly antagonizes mAChR M4, for example in an animal, in particular a mammal (e.g., a human).
[0056] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6. 1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
2. Compounds
[0057] Compounds of the invention have formula (I), wherein Rs, R , R3, R4, R3, R6, A, Q, and m are as defined herein, including any combinations of these variables or their subvariables, (e.g., Y1, G, etc.).
[0058] In one aspect, disclosed is a com ound of formula (I):
Figure imgf000013_0001
A is a five- or six-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;
Q is selected from NRa, O, and CR R ;
R! is selected from hydrogen, halo, -QRd, C1 -C4 alkyl, optionally substituted cycloalkyi, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
R2 and R5 are independently selected from hydrogen, C1-C4 alkyl, and halo, or R2 and R5 are taken together to form an oxo group;
each R4 is independently selected from halo, C1-C4 alkyl, and -ORe;
R5 and R6 are independently selected from hydrogen, Cj-Cg alkyl, and -(CR'R^-Y1; each Y1 is independently selected from optionally substituted cycloalkyi, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each Rd, R , RL, R", Rc, R1, and Rg is independently selected from hydrogen, C1 -C4 alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2.
[0059] In some embodiments, Q is NRd, In some embodiments, Ra is hydrogen or C1-C4 alkyl. In some embodiments, Rd is hydrogen,
[0060] In some embodiments, R is selected from hydrogen, halo (e.g., chloro), -CH=CH- C1-C4 alkyl, CH=CH-G, C5-C8 cycloalkenyl, a 4- to 8-membered monocyclic heterocvclyl, a 6- to 12-membered aryl, and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the cycloalkenyl, heterocvclyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C]-C4 alkoxy, C1-C4 haloalkoxy, and - NHCOR'; G is a 6- to 12-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, -C4 haloalkoxy, and -NHCOR'; and R', at each occurrence, is independently C1-C4 alkyl. In further embodiments, R1 is selected from halo, -CH=CH-C1-C4 alkyl, -CH=CH-G, C¾-C8 cycloalkenyl, a 4- to 8-membered monocyclic heterocvclyl, a 6- to 12-membered aryl, and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the cycloalkenyl, heterocyclyl, aryi and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from Ci -C4 alkyl, halo, cyano, Ci-C4 haloalkyl, Q- C4 alkoxy, Ci-C4 haloalkoxv, and -NHCOR'; G is a 6- to 12-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from Cj-C4 alkyl, halo, cyano, Cj- Ci haloalkyl, Ci-C4 alkoxy, Cj-C4 haioalkoxy, and -NHCOR' ; and R', at each occurrence, is independently Cj-C4 alkyl. In further embodiments, R¾ is hydrogen, phenyl, naphthyl (e.g., 2- naphthyl), benzodioxolyl (e.g., benzodioxol-5-yl), pyrazoiyl (e.g., pyrazol-3-yl, pyrazol-4-yl), isoxazolyl (e.g., isoxazol-4-yl), thienyl (e.g., 2-thienyl), pyridinyl (e.g., pyridin-3-yl), quinolinyl (e.g., quiiiolm-6-yl), isoquinoimyl (e.g., isoquinolin-7-yl), piperidinyl (e.g., piperidin-l-yl), pyrrolidinyl (e.g., pyrrolidin-l-yl), morpholinyl (e.g., morpholin-4-yl), cyclopentenyl (e.g., cyclopenten- 1 -y 1), or -CH=CH-G, wherein the phenyl, naphthyl, benzodioxolyl, pyrazoiyl, isoxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, and cyclopentenyl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluorom ethyl, trifiuoromethoxy, methoxy, and cyano; and G is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from Cj-C4 alkyl, halo, cyano, Cj-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haioalkoxy, and -NHCOR', wherein R' is CpC4 alkyl. In further embodiments, R1 is phenyl, pyrazoiyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenyl, or -CH=CH-G, wherein the phenyl, pyrazoiyl, piperidinyl, and pyrrolidinyl are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluorom ethyl, trifiuoromethoxy, methoxy, and cyano; and G is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, CrC4 haloalkyl, C1-C4 alkoxy, C1-C4 haioalkoxy, and -NHCOR', wherein R' is C1-C4 alkyl. In still further embodiments, G is phenyl substituted with Ci-C4 alkyl.
|0061] In some embodiments, R1 is selected from: halo; aryl; and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C C4 alkoxy, C haioalkoxy, and -NHCOR', wherein R' is Ci-C4 alkyl. In some embodiments, R1 is halo (e.g., chloro). In some embodiments, R! is selected from phenyl, pyrazoiyl, thiophene, quinolyl, benzodioxolyl, naphthyl, pyridyl, and isoxazolyl, each of which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from Cj.-C4 alkyl, halo, cyano, Cj-C4 haloalkyi, C1-C4 alkoxy, C1-C4 haloalkoxv, and -NHCOR', wherein R' is C1-C4 alkyl. In some embodiments, R1 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifiuoromethyi, trifluoromethoxy, methoxy, and cyano. In some embodiments, R! is phenyl that is unsubstituted or substituted with 1 or 2 substituents independently selected from Cj-C4 alkyl (e.g., methyl), halo (e.g., fluoro or chloro), cyano, Ci-C4 haloalkyi (e.g., trifiuoromethyi), C1-C4 alkoxy (e.g., methoxy), Ci-C4 haloalkoxv (e.g., trifluoromethoxy), and -NHCOR' wherein R' is Cj-C4 alkyl (e.g., -NHCOCH3). In some embodiments, R1 is pyrazolyl that is substituted with 1 or 2 substituents independently selected from Cj-C4 alkyl (e.g., methyl) and Cj-C4 haloalkyi (e.g., trifiuoromethyi).
In some embodiments, R! is
Figure imgf000016_0001
HC(0)C C4alkyl
Figure imgf000016_0003
rC4aikyi
Figure imgf000016_0004
Figure imgf000016_0005
Figure imgf000017_0001
[0063] In some embodiments, R" is hydrogen and RJ is hydrogen. In some embodiments, Kz and R' are taken together to form an oxo group.
[0064] In some embodiments, m is 0.
[0065] In some embodiments, R5 is hydrogen.
[0066] In some embodiments, R6 is selected from Cj-Cg alkyl and -(CR^ Y1.
[0067] In some embodiments: R0 is selected from Ci-Cg alkyl and -(CRfRg)n- Y! ; R' is hydrogen; Rg is selected from hydrogen, C1-C4 alkyl and phenyl; n is 0 or 1; and Y1 is selected from: CVCjo-eycloalkyi; C5-Cio-cycloalkenyl; phenyl; a 5- to 6-membered heteroaiyi having 1, 2 or 3 heteroatoms independently selected from N, O and S; and a 5- to 8-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloaikyi, cycloalkenyi, phenyl, heteroaiyi and heterocyclyl are unsubstituted or substituted with I or 2 substituents independently selected from C1-C4 alkyl, halo, and C1-C4 haloalkyl. In some embodiments, R° is Ci-Cg alkyl (e.g., methyl, ethyl, isopropyl, sec-butyl, neopentyl, sec-pentyl, 4,4-dimethylpentan-2-yl). In some embodiments, R6 is -(CR^^n-Y1, n is 0 or 1, Rf is hydrogen, Rs is hydrogen, and Y1 is selected from Cj-Cio-cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyL adamantyl), Cs-Cio-cycloalkenyl (e.g., bicyclo[2.2.1 ]hept-5-en-2-yl), phenyl, a 5- to 8-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S (e.g., tetrahydrofuranyl, tetrahydropyranyl, 7-oxabicyclo[2.2.1 jheptanyl), and a 5- to 6-membered heteroaiyi having 1 , 2 or 3 heteroatoms independently selected from N, O and S (e.g., pyridyi), wherein the cycloaikyi, cycloalkenyi, phenyl, heteroaiyi and heterocyclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, halo, and C1-C4 haloalkyl
[0068] In some embodiments, A is a five-membered heteroaiyi having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from N, O and S, a six-membered heteroaryi having 1 -2 nitrogen atoms, a phthalazinyl, an imidazofl ,2-b]pyridazinyl, or a
[l,2,4]tnazolo[4,3-b]pyridazinyi, wherein A is optionally substituted with 1-4 substituents independently selected from halo, C1-C4 alkyl, and C1-C4 haloalkyl. In further embodiments, A is a thiazol-2,5-diyl, pyridazin-3,6-diyl, pyrazin-2,5-diyl, pyridin-2,5-diyl, phthalazin-l,4-diyl, imidazo[l,2-b]pyridazin-6-yl, or [l,2,4]triazolo[4,3-b]pyridazin-6-yl, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, Ci-C4 alkyl, and Cj -C4 haloalkyl.
In some embodiments, A is selected from:
Figure imgf000018_0001
wherein T is selected from O, S and NH; and U, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
[007Θ]
Figure imgf000018_0002
[0071] In some embodiments, A is
Figure imgf000018_0003
embodiments, R1- A is
Figure imgf000018_0004
or , (i .e., the R1 of formula (I) is hydrogen 007 Ί: In some embodiments, the compound of formula (I) is a compound of formula (la):
Figure imgf000019_0001
(la)
wherein W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
[0073] In some embodiments, 1 or 2 of W, X, Y and Z are N. In some embodiments, W and X are N and Y and Z are CH. In some embodiments, W, Y and Z are CH and X is N. In some embodiments, X and Y are N, and W and Z are CH.
[0074] In some embodiments, the compound of formula (I) is a compound of formula (lb):
Figure imgf000019_0002
(lb).
[0075] Representative compounds of formula (I) include, but are not limited to:
6-(2-chloro-5-fluorophenyl)-iV-[[6-[[3-(trifluoromethyl)-2-pyridyl]methyl]-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(4- f!uorophenyl)pyridazm~3 -amine;
N-((6-(((li?,2i?,4A -7-oxabicyck>[2.2.1]heptan-2-yl)methyl)-6-azaspi
y l)methyl)-6-( 1 , 3 -dimethyl- 1H -pyrazol-4 ~yl)pyridazm~3 -amine;
N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-6-(2,3,3-trimethylbutyl)-6- azaspiro[2.5]octane-2-carboxamide;
N-(6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-yl)-6-(3,3-dirnethylbutyl)-6- azaspiro[2, 5] octane- 1 -carboxarnide;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3-dimethylpyrazol-4- yl)pyridin-2-amine;
6-(5 -bi cy cl o[2.2.1 ] hept-2-enylmethy 1 )-N- [6-(2,4-dimethy lpyrazol-3 -yl)pyridazin-3 -yl] -6- azaspiro [2, 5 ] octane-2-carboxamide;
N-[[6-(5-bicyclo[2.2. l ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3- dimethylpyrazol-4-yl)pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
AL[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]niethyl]-6-(2- chloro-5-fluoro-phenyl)pyridazin-3-amine;
6-(2-cliloro-5-fluoro-phenyl)-A?-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-cliloro-5-fluoro-phenyl)-A?-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine; compound 14
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-3-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine; compound 15
N-[[6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- phenyl)pyridazin-3 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(2,2-diphenylethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-N-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]-6- azaspiro[2.5]octane-2-carboxamide;
N-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]-6-(2,3,3-trimethylbutyl)-6- azaspiro[2.5]octane-2-carboxamide;
6-chloro-N-[[6-(3,3-dimethylbutyl)-6-azaspiro^
N-[[6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-6-azaspirof2.5]octan-2-yl]methyl]-5-(l,3- dimethylpyrazol-4-yl)pyrazin-2-amine;
5- (l,3-dimethylpyrazol-4-yl)-N-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyrazin-2-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspirof2.5]octan-2-yl]methyl]-5-(l,3-diniethylpyrazol-4- yl)pyrazin-2-amine;
6- (2-chloro-4-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl] methyl]pyridazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(4-methyl-3- pyridy i)pyndazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2- fluoropheny l)pyridazin- 3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3- fluoropheny l)pyridazin- 3 -amine;
6-(2,4-difluorophenyi)-A/-[[6-(3,3-dimethylbt3tyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(5-fluoro-2-methyl- phenyi)pyridazin-3-amine;
6-(2, 5-difliioropheny l)-N- [ [6-(3 , 3 -dimethy lbutyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbut\'l)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(5-fluoro-2-methoxy- phenyl)pyridazin-3-amine;
6-(3 ,4-difliioropheny l)-N- [ [6-(3 , 3 -dimethy lbutyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-(3 , 5-difliioropheny l)-iV- [ [6-(3 , 3 -dimethy lbutyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-phenyl-pyridazin-3- arnine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2,4-dimethylpyrazol-3- yl)pyridazin-3-amine;
iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3,5-trimethylpyrazol-4- yl)pyridazin-3 -amine;
iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3,5-dimethylisoxazol-4- yl)pyridazin-3-amine;
iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-methylpyrazol-3- yl)pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-[2-methyl-5- (trifluoromethyl)pyrazol-3-yl]pyridazin-3-amine;
N-[4-[6-[[[6-(3,3-dimemylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]amino]pyridazin-3- yl]phenyl]acetamide; 6-(2-chloro-3-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3-methyl-2- thienyl)pyridazin- 3 -amine;
2-[6-[[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]amino]pyridazin-3-yl]-4- fluoro-benzonitrile;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]oclan-2-yl]methyl]-6-(7-isoquinolyl)pyridazin-
3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(6-quinolyl)pyridazin-3- amine;
6-(l,3~benzodioxol~5~yl)-A ~[[6~(3,3-dimethylbutyl)-6-azaspiro[2.5]oc†an~2~
y 1 ] methyl ] pyr idazin - 3 -ami ne;
N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2.5 ] octan-2-yl]methyl] -6-(2-naphthy l)pyri dazin-3 - amine;
N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro[2.5] octan-2-yl] methyl] ~6~ [2- (trifluoromethoxy)phenyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-[4-(trifluoromethyl)-3- pyridyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3-dimethylpyrazol-4- yl)pyridazin-3-amine;
6-( 1 , 3 -dimethylpyrazol-4-y 1)-/V- [ [6-(2-methylbuty l)-6-azaspiro [2, 5 ] octan-2- y 1 ] methy i ] pyr idazin - 3 -ami ne;
6-(l,3-dimethylpyrazol-4-yl)-iV-ff6-(2-methylpentyl)-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyr idazin -3 -ami ne;
6-(l,3-dimethylpyrazol-4-yl)-iV-f(6-ethyl-6-azaspiro[2.5]octan-2-yl)methyl]pyridazin-3- amine;
6-(l,3-dimethylpyrazol-4-yl)-iV-f(6-propyl-6-azaspiro[2.5]octan-2-yl)methyl]pyridazin-3- amine;
N-[[6-(cyclopropylmemyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3-dimethylpyrazol-4- yl)pyridazin-3-amine;
N-[[6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3-dimethylpyrazol-4^ yl)pyridazin-3 -amine;
AL[(6-benzyl-6-azaspiro[2.5]octan-2-yl)methyl]-6-(l ,3-dimetliylpyrazoi-4-yl)pyndazm-3- amine;
6-(l ,3-dimethylpyrazol-4-yl)-iV-[[6-(2,2-diphenylethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-iV-[[6-(tetrahydropyran-3-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-( 1 ,3 -dimethy lpyrazol -4-y \)-N- [ [6-(tetrahydropyran-4-y lmethyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-[(3-methyl-2-pyridyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-[[3-(trifluoromethyl)-2-pyridyl]methyl]-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- yi]methyi]pyndazm-3-amme;
(S)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
(S)-6-(2-chloro-5-fluoro-phenyl)-Ai-[ [6-(cyclohexylmethyi)-6-azaspiro[2.5 ]octan-2- yl]methyl]pyridazin-3-amine;
iV-ff6-(5-bicyclof2.2.1]hept-2-enylmethyl)-6-azaspiro[2.51octan-2-yllmethyll-5-(2- chloro-5-fluoro-phenyl)pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridin-2-amine;
iV-ff6-(5-bicyclof2.2.1]hept-2-enylmethyl)-6-azaspiro[2.51octan-2-yllmethyll-5-(l,3- dimethylpyrazol-4-yl)pyridin-2-amine;
6- (2,4-dimethylpyrazol-3-yl)-N-[[6-(2-tetrahydrofuran-2-ylethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine; Ar-ff6-(5-bicyclof2.2.11hept-2-enylmethyl)-6-azaspiro[2.51octan-2-yl]methyll-5-phenyl- thiazol-2-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-phenyl-thiazol-2-amine;
5- phenyl-Ar-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]thiazol-
2- amine;
6- (2,4-dimethylpyrazol-3-yl)-iV-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(3,3-difluoropyrrolidin-l-yl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2,4-dimethylpyrazol-3- yl)-N-methyl-pyridazin-3-amine;
2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]ox\'methyl]-6-(3,3-dimethylbut\'l)-6- azaspiro[2.5]octane;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l-piperidyl)pyridazin-3- amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-morpholino-pyridazin-3- amine;
6-(4,4-difluoro-l-piperidyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octe^
3- amine;
N-[[6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-6-azaspirof2.5]octan-2-yl]methyl]-6- morpholino-pyridazin-3-amine;
N-[[6-(cyclohe ylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-mo holino-pyridazin-3- amine;
N-[[6-(l-adamaniylmethyl)-6-azaspiro 2 ]octen-2-yl]methyl]-6-morphoiino-pyndazin- 3 -amine;
6-morpholino-N-[ [6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3- yl] oxymethyl] -6-azaspiro [2.5] octane; 2-ff6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]ox>'methyl]-6-(cyclohex>4methyl)-6- azaspiro[2.5]octane;
N-[(6-benzyl-6-azaspiro[2.5]octan-2-yl)methyl]-4-(l,3-dimethylpyrazol-4-yl)phthalazin-
1 -amine;
N-[[6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l,3-dimethylpyrazol-4- yl)phthalazin- 1 -amine;
6-(cyclopenten- 1 -yi)-N- [ [6-(3 ,3 -dimethylbutyl)-6-azaspiro [2.5 ] octan-2- yl]methyl]pyridazin-3-amine;
6-[(E)-3,3-dimethylbut-l -enyl]-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-[(E)-2-(p- tolyl)vinyl]pyridazin-3-amine;
4-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]phthalazin- 1 -amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3-dimethylpyrazol-4- yl)phthalazin- -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3-dimethylpyrazol-4- yl)phthalazin- 1 -amine;
N-[[6-(5-bicyc3o[2.2 ]hept-2-enylmethyl)-6-azaspiro[2,5]octan-2-yl]methy3]-4-(l ,3- dimethylpyrazol-4-yl)phthalazin- 1 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-[(3-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyr idazin - 3 -ami ne;
2-[[2-ff[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]amino]methyl]-6-azaspirof2.5]octan- 6-yl]methyl jbenzonitrile;
6-(2-chloro-5-fluoro-phenyl)-N-ff6-[(4-fluorophenyl)methyl]-6-azaspirof2.5]octan-2- y 1 ] methy i ] pyr idazin -3 -ami ne;
6-(2-chloro-5-fluoro-phenyl)-N-ff6-[(2-fluorophenyl)methyl]-6-azaspirof2.5]octan-2- y 1 ] methy i ] pyr idazin -3 -ami ne;
N-[(6-benzyl-6-azaspiro[2.5]octan-2-yl)methyl]-6-(2-chloro-5-fluoro-phenyl)pyridazin- 3 -amine;
N-[[6-(3,3-dimemylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]imidazo[l,2-b]pyridazin-6- amine;
N-ff6-(5-bicyclof2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]- [l,2,4]triazolo[4,3-b]pyridazin-6-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-[l,2,4]triazolo[4,3- b]pyridazin-6-amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-[l,2,4]triazolo[4,3- b]pyridazin-6-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-3-ylmethyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-(((lR)-6-(bicyclo[2.2. l]hept-5-en-2-ylmethyl)-6-azaspiro[2.5]octan-l -yl)methyl)-6-(2- chloro-5-fluorophenyl)pyridazin-3-amine;
(R)-6-(2-chloro-5-fluorophenyl)-N-((6-(cycloheptylmethyl)-6-azaspiro[2.5]octan-l- yl)methyl)pyridazin-3-amine;
N-(((lR)-6-((7-oxabicyclo[2.2.1]heptan-2-yl)methyl)-6-azaspiro[2.5]octan-l-yl)methyl)- 6-(2-chloro-5-fluorophenyl)pyridazin-3-amine;
N-[4-[6-[[(2R)-6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[[(2R)-6-benzyl-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- phenyl)pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[(2R)-6-(2-pyridylmethyl)-6-azaspirof2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-ff(2R)-6-f(3-methyl-2-pyridyl)methyl]-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-[[(2R)-6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- pheny l)py ridazin-3 -amine;
N-[4-[6-[[6-(3,3-dimethylbu1yl)-6-azaspiror2.5]o(rtan-2-yl]methylamino]-4,5-dimethyl- pyridazin-3-yl]phenyl]acetamide;
N- [4- [6- [ [6-(cyclohexylmethyl)-6-azaspiro [2.5] octan-2-yi ]methylamino] -4, 5-dimethyl- pyridazin-3-yl]phenyl]acetamide; N-[4-[6-[[(2R)-6-(cyclohexylme4hyl)-6-azaspirof2.5]octan-2-yl]methylamino]pyridazin- 3 -y 1] pheny 1 ] acetamide;
N-[4-[6-[[(2R)-6-(cycloheptylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-[(3-methyl-2-pyridyl)methyl]-6-azaspiro[2.5]octan-2- y 1 ] methy lami no] pyri dazi n- 3 -y 1 ] phenyl] acetamide;
N-[4-[6-[[(2R)-6-[(4-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- y 1 ] methy lami no] pyri dazi n- 3 -y 1 ] pheny 1] acetamide;
N-[4-[6-[[(2S)-6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyri 3 -y 1] pheny 1] acetam ide;
N-[4-[6-[[(2S)-6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3 -y 1] pheny 1] acetam ide;
N-[4-[6-[[(2S)-6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
or a pharmaceutically acceptable salt thereof.
[0076] The experimental section also refers to the compounds listed below by the name generated from the structure using the ChemDraw® software.
Compound
Compound name ChemDraw name
No.
6-(2-chloro-5-fluorophenyl)-iV-[[6- 6-(2-chloro-5-fluorophenyl)-N-((6-((3-
[[3-(trifluoromethyl)-2- (trifluoromethyl)pyridin-2-yl)methyl)-6-
1 pyri dyl]methyl] -6- azaspiro[2.5]octan- 1 - azaspiro[2.5]octan-2- yl)methyl)pyridazin-3-amine
yl]methyl]pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- JV-((6-(3,3-Dimethylbutyl)-6-
2 azaspiro [2, 5 ] octan-2-y 1 ] methy 1] -6- azaspiro[2.5]octan-l.-yl)methyl)-6-(4- (4-fluorophenyl)pyridazin-3-amine f! uoropheny l)pyn dazin-3 -am ine 6-(2, 4-dimethy lpyrazol -3 -y 1)-N- [ [6- 6-( 1 ,4-dimethyl- 1 H-pyrazol-5-yl)-N-((6- ( 2-tetrahy dr ofuran-2-y 1 ethy 1 ) -6- (2-(tetrahydrofuran-2-yl)ethyl)-6-
4
azaspiro[2.5]octan-2- azaspiro[2.5]octan- 1 - yl]methyl]pyridazin-3-amine yl)methyl)pyri dazin-3 -amine
6-(3 , 3 -difluoropyrrolidin- 1 -yl)-N- 6-(3,3-difluoropyrrolidm-l-yl)-N-((6- [[6-(3,3-dimethylbutyl)-6- (3, 3 -dimethylbuty l)-6-azaspiro [2.5] octan-
75
azaspiro[2.5]octan-2- 1 -yl)methyi)pyri dazin-3 -amine yl]methyl]pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- 6-(l, 4-dimethy l-lH-pyrazol-5-yl)-N-((6- azaspiro [2.5] octan-2-yl] methyl] -6- (3 , 3 -dimethylbuty l)-6-azaspiro [2.5 ] octan-
76
(2,4-dimethylpyrazol-3-yl)-N- l-yl)methyl)-N-methylpyridazin-3-amine methyl-pyridazin-3-amine
2-[[6-(2-chloro-5-fluoro- l-(((6-(2-chloro-5- pheny l)py ridazin- 3 -y 1] oxym ethyl ] - fluorophenyl)pyridazin-3-
77
6-(3 , 3 -dimethylbuty l)-6- yl)oxy)methyl)-6-(3,3-dimethylbutyl)-6- azaspiro[2.5] octane azaspir o [2.5 ] octane
[0077] The compound may exist as a stereoisomer wherein asymmetric or chirai centers are present. The stereoisomer is "i?" or "5"' depending on the configuration of substituents around the chirai carbon atom. The terms "i?" and "S" used herein are configurations as defined in iUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appi. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chirai centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chirai auxiliary, separation of the resulting mixture of diastereomers by recry stall ization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or
(2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or
(3) fractional recrystallization methods.
[0078] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.
[0079] The present disclosure also includes an isotopicaliy-labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to 2H, ¾ i3C, i4C, 15N, 180, 1 Ό, 3IP, 32P, 35S, 18F, and 36C1, respectively. Substitution with heavier isotopes such as deuterium, i.e. Ή, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron- emitting isotopes that can be incorporated in compounds of formula (I) are nC, ljN, and l8F. isotopicaliy-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopicaliy-labeled reagent in place of non- isotopically-labeled reagent.
Ά. Pharmaceutically Acceptable Salts
[0080] The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an ammo group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with aikyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
[0081] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methyl amine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamme, 1-ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanol amine, piperidine, piperazme, and the like,
b. General Synthesis
[0082] Compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.
[0083] Abbreviations which have been used in the descriptions of the Schemes that follow are:
[0084] AcOH acetic acid
[0085] BrettPhos-Pd-G3 methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy- 2,,4',6'-tri-i-propyl-l , 1 '-biphenyl)(2'-amino- 1 , 1 '-biphenyl-2-y l)palladium(II) (CAS No. 1470372- 59-8)
[0086] DCE 1,2-dichloroethane
[0087] DCM dichioromethaiie DIPEA N,N-diisopropylethylamine
DMF N,iV-dimethylformamide
HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-
6]pyridmium 3-oxid hexafluorophosphate
lithium aluminum hydride
NaBH(OAc)3 sodium triacetoxyborohydnde
NMP iV-methyl-2-pyrrolidone
Py CIU 1 -(chloro- 1 -pyrrolidinylmethylene)pyrrolidinium
hexafluorophosphate
[0095] RuPhos-Pd-G3 methanesulfonato(2-dicyclohexylphosphino-2',6'-di~i-propoxy~ 1 , 1 *-biphenyl)(2,-amino- 1 , 1 !-biphenyl-2-yl)palladium(II) (CAS No. 1445085-77-7)
[0096] SFC supercritical fluid chromatography
[0097] THF tetrahydrofuran
[0098] Compounds of formula (I) can be synthesized as shown in the following schemes. General Scheme A
Figure imgf000031_0001
1 ,4-dioxane/H20
120 °C, microwave
As shown in General Scheme A, compound A can be reacted with compound B to produce compound C, winch is coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound D. Boc deprotection produces compound E. This process can be used to prepare precursors to compounds of formula (I), for example, wherein R2 and R3 are hydrogen, m is 0, and wherein W is CH, X is N and Z is CH, or wherein W is CH, X is CH and Z is N (i.e. compounds of formula (lb)). I S
Figure imgf000032_0001
As shown in General Scheme B, compound E can be reacted with a suitable aldehyde and sodium triacetoxyborohydride to produce compound F. This process can be used to prepare compounds of formula (I), for example, wherein R2, R", and R5 are hydrogen, m is 0, and wherein W is CH, X is N and Z is CH, or wherein W is CH, X is CH and Z is N (i.e. compounds of formula (lb)).
General Scheme C
Figure imgf000032_0002
As shown in General Scheme C, a suitable heteroaryi compound G (where A is, as defined herein, a five- or six-membered heteroaryi, and R! is as defined herein) that is functional ized with a halo group (e.g., F or CI) can be coupled to compound A to produce compound H, which can be deprotected and coupled as described herein or according to other known methods. This process can be used to prepare precursors to compounds of formula (I) in
,y ^
which R" and R are hydrogen, m is 0, and A is as described herein (e.g., wherein A is pyridyl or thiazolyl).
sieral Scheme D
Figure imgf000033_0001
[00102] As shown in General Scheme D, compound C (corresponding to compound C in which W is CH, X is CH and Z is N) can be deprotected and then reacted with 3,3- dimethyibutyraldehyde and sodium triacetoxyborohydride to produce compound I, which can be coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound J. This process can be used to prepare certain compounds of formula (I), e.g., compounds of formula (lb) in which R2 and RJ are hydrogen, R5 is hydrogen, and R6 is
neopentyl.
Scheme E
Figure imgf000033_0002
LAH
THF, 0 °C
Figure imgf000033_0003
[00103] As shown in Scheme E, a specific compound can be prepared from compound K (prepared according to General Scheme A), by reacting compound K with rac-(lR,2S,4S)-7- oxabicy clo[2.2.1 ]heptane-2-carboxylic acid, in the presence of HATU and DIPEA, to generate compound L, which can be reduced using lithium aluminum hydride to generate compound M.
Figure imgf000034_0001
As shown in Scheme F, another specific compound can be prepared from compound K. Reaction with 2-(2-bromoethyl)oxolane generates compound N.
General Scheme G
Figure imgf000034_0002
)5] As shown in General Scheme G, compounds such as compound C can be subjected to chiral separation to separate enantiomers, if desired.
General Scheme H
Figure imgf000034_0003
As shown in General Scheme H, certain compounds of formula (I) can be prepared by reacting compound Q with 3-amino-6-chloropyridazine with PyCIU to form compound R, which can be coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound S. Deprotection and reaction with a suitable aldehyde and sodium
triacetoxyborohydride produces compound T. This procedure can be used to prepare certain compounds of formula (I), such as compounds of formula (lb) wherein R2 and R' are taken together to form an oxo group, and R3 is hydrogen.
C I S
Figure imgf000035_0001
As shown in General Scheme L compounds of formula (I), where R! is an amine- containing group attached through nitrogen may be prepared by reacting a suitable amine with chloropyridazine in the presence of base, in an organic solvent, and heating. Microwave irradiation may facilitate the reaction. In Scheme I, L is O, N, S, or a methylene group and R'a the optional substituent on R1, as defined herein. Although illustrated in Scheme I for cyclic amine R1 groups, the methodology may also be applied to acyclic amines -N(Rd)2.
General Scheme J
Figure imgf000035_0002
Figure imgf000035_0003
[00108] General Scheme J illustrates a preparative sequence analogous to Schemes A and B to prepare compounds of formula (I), wherein Q is NRa, and Ra is an alkyl group. The Suzuki, Boc deprotection, and reductive amination steps are generally analogous to those described elsewhere herein.
Gesieral Scheme
Figure imgf000036_0001
Figure imgf000036_0002
39] General Scheme K illustrates a sequence to prepare compounds of formula (I), wherein Q is O. The Suzuki, Boc deprotection, and reductive amination steps are generally analogous to those described elsewhere herein.
[00110] The compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by
recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific &
Technical, Essex CM20 2JE, England.
[00111] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandeiic, atrolactic,
methanesulfonic, ethanesuifonic, toluenesulfonic, naphthaienesulfonic, benzenesuifonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.
[00112] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the
conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
[00113] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirely'. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.
[00114] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material
(prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
[00115] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or
intermediates using a standard procedure such as chromatographic separation.
[00116] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.
c. Muscarinic Acetylcholine Receptor M4 Activity
[00 7] M4 is the most highly expressed mAChR subtype in the striatum and its expression is similar in rodents and primates. Due to a lack of selective M4 antagonists, mechanistic understanding of the role of M4 has been guided by biochemical and genetic studies, as well as the use of highly selective M4 positive allosteric modulators (PAMs). Highly selective M4 PAMs induce robust decreases in behavioral responses to psychomotor stimulants that act by increasing striatal DA levels. Furthermore, genetic deletion of M4 increases exploratory locomotor activity, potentiates locomotor responses to amphetamine and other stimulants, and eliminates effects of M4 PAM.S on locomotor activity and these effects are also observed with selective deletion of M4 from striatal spiny projection neurons that express the Dl subtype of DA receptor (Dl -SPNs). In vivo microdiaiysis studies reveal that administration of M4 PAMs reduces amphetamine-induced DA release in the dorsal and ventral striatum and fMRI studies show that M4 PAMs reverse amphetamine- induced increases in cerebral blood flow (CBV) in striatum and other basal ganglia nuclei. More recently, fast-scanning cyclic voltammetry (FSCV) and genetic studies, demonstrated that M4 PAMs act, at least in part, by inhibition of DA release from presynaptic DA terminals in the striatum through release of an endocannabinoid from striatal spiny projection neurons (SPNs) and activation of CB2 cannabinoid receptors on DA terminals.
[00118] M4 is heavily expressed in a subset of SPNs that also express the Dj subtype of DA receptor (D]DR), which form the direct pathway (Dl-SPNs) sending inhibitory projections to the substantia nigra pars reticulata (SNr). Interestingly, DiDRs activate a unique GTP-binding protein in Dl-SPNs, termed GKOif that couples DjRs to activation of adenylyi cyclase, formation of cAMP, and activation of protein kinase A (PKA). This signaling pathway is critical for many of the behavioral actions of DA-mediated activation of motor activity Interestingly, Mi couples to Ga,/o G proteins, which inhibit adenylyi cyclase and have the potential to directly counteract inhibit D¾ receptor signaling and effects on motor function. These studies raise the possibility that, in addition to inhibition of DA release, M4 PAMs may directly inhibit DIR-mediated signaling in Dj-SPNs by direct inhibition of cAMP formation and this could also contribute to the powerful inhibitory effect of selective M4 activation of DA signaling in the basal ganglia. Consistent with this, M4 PAMs inhibit locomotor-stimulating effects of a direct acting Di agonist. Furthermore, a series of pharmacological, genetic, and molecular/cellular studies reveal that this response is mediated by inhibition of DiDR signaling in Dl -SPNs. Thus, the primary action of Mj. PAMs on DjDR signaling is not in the striatum, but on GABAergic terminals of DpSPNs in the SNr, where activation of DiDRs induces a robust increase in GABA release. This challenges the widespread view that cholinergic regulation of striatal function is almost exclusively mediated through ACh released from tomcally active, striatal cholinergic interneurons (Chls) and raises the possibility that cholinergic innervation of the SNr from cholinergic projections from the pedunculopontine nucleus may also play a critical role in regulating motor activity and other functions of the basal ganglia direct pathway. Together, these data suggest that in addition to inhibiting DA release, M4 activation also acts postsynaptically in Di-expressmg SPNs to inhibit motor function.
[00119] Consistent with a prominent role of M4 as the primary mAChR subtype involved in regulating motor function, multiple reports indicate that the locomotor-activating effects of the mAChR antagonist scopolamine are dramatically reduced in M4 knockout mice, but not the other four mAChR subtypes (M 3 5). Furthermore, halopendol-induced catalepsy, a model of parkinsonian motor disability, is reduced in M4 knockout mice as compared to wild-type controls. Evaluation of the anti-parkinsonian effects of scopolamine, by assessing effects of this compound on catalepsy induced by the DA receptor antagonist haloperidol, display robust catalepsy that was completely reversed by scopolamine in WT mice. The reversal by scopolamine was uncommonly robust and more pronounced than we observe with agents targeting a number of other targets being evaluated for potential antiparkinsonian effects, including metabotropic glutamate (mGlu) receptors mGlu4 or mGlus, A2A adenosine receptors, and NMD A receptors. Importantly, scopolamine was ineffective in reducing catalepsy in M4 KO mice, suggesting that the anti-cataleptic effect of scopolamine requires actions on mAChR M4. Taken together with the extensive studies of M4 modulation of basal ganglia and motor function, these studies provide compelling evidence that M4 is the dominant mAChR subtype involved in the antiparkinsonian effects of non-selective mAChR antagonists and provide support for discover and development of selective M4 antagonists for treatment of neurodegenerative disease such as PD, dystonia, tardive dyskinesia and other movement disorders.
[00120] Despite advances in mAChR research, there is still a scarcity of compounds that are potent, efficacious and selective antagonists of the M4 mAChR, Highly selective M4 antagonists represent a new therapeutic approach for the treatment of neurodegenerative diseases including PD, dystonia, tardive dyskinesia and other movement disorders and may offer the clinical benefit of scopolamine, without the adverse effects mediated by pan-m AChR inhibition.
[00121] In some embodiments, the disclosed compounds are antagonists of mAChR M4. Such activity can be demonstrated by methodology known in the art. For example, antagonism of mAChR M4 activity can be determined by measurement of calcium flux in response to agonist, e.g. acetylcholine, in cells loaded with a Ca" ' -sensitive fluorescent dye (e.g., Fluo-4) and co- expression of a chimeric or promiscuous G protein. In some embodiments, the calcium flux can be measured as an increase in fluorescent static ratio. In some embodiments, antagonist activity can be analyzed as a concentration-dependent increase in the ECso acetylcholine response (i.e. the response of mAChR M4 at a concentration of acetylcholine that yields 80% of the maximal response).
[00122] In some embodiments, the disclosed compounds antagonize mAChR M4 as a decrease in calcium fluorescence in mAChR M4-transfected CHO-K1 cells in the presence of the compound, compared to the response of equivalent CHO-K1 cells in the absence of the compound. In some embodiments, a disclosed compound antagonizes the mAChR Mj response with an IC50 of less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, of less than about 100 nM, or less than about 50 nM. In some embodiments, the mAChR Mr transfected CHO-Kl cells are transfected with human mAChR M4. In some embodiments, the mAChR Mrtransfected CHO-Kl cells are transfected with rat mAChR M4. In some embodiments, the mAChR Mrtransfected CHO-Kl cells are transfected with mAChR M4 from dog or cynomolgus monkey.
[00123] The disclosed compounds may antagonize mAChR M4 response in mAChR M4 - transfected CHO-Kl cells with an IC50 less than the IC50 for one or more of mAChR Mi , M2, M3 or M5-transfected CHO-Kl ceils. That is, a disclosed compound can have selectivity for the mAChR M4 receptor vis-a-vis one or more of the mAChR M!? M2, M3 or M5 receptors. For example, in some embodiments, a disclosed compound can antagonize mAChR M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Mi . In some embodiments, a disclosed compound can antagonize m AChR M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200- fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Mfe. In some embodiments, a disclosed compound can antagonize mACh . M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400- fold less, or greater than about 500-fold less than that for mAChR M3. In some embodiments, a disclosed compound can antagonize mAChR M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M¾. In some embodiments, a disclosed compound can antagonize mAChR M4 response with an IC50 of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-M5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for the mAChR Mi, M2, M3, or M5 receptors.
[00124] The disclosed compounds may antagonize mAChR M4 response in Mrtransfected CHO-Kl cells with an IC50 of less than about 10 μΜ and exhibit a selectivity for the M4 receptor vis-a-vis one or more of the mAChR Mi, M2, M3, or M5 receptors. For example, in some embodiments, the compound can have an IC50 of less than about 10 μΜ, of less than about 5 μΜ, of less than about 1 μΜ, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an IC50 of about 5-fold less, 10-fold less, 20-fold less, 30-fold less, 50-fold less, 100-fold less, 200-fold less, 300- fold less, 400-fold less, or greater than about 500-fold less than that for mAChR Mj. In some embodiments, the compound can have an IC50 of less than about 10 μΜ, of less than about 5 μ.Μ, of less than about 1 μΜ, of less than about 500 nM, of less than about 100 M, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M2. In some embodiments, the compound can have an IC50 of less than about 10 μΜ, of less than about 5 μΜ, of less than about 1 μΜ, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mACh M4 response with an IC50 of about 5-fold less, about 10-fold less, about 20- fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M3. In some embodiments, the compound can have an IC50 of less than about 10 μΜ, of less than about 5 μΜ, of less than about 1 μΜ, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR Mi response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M5. In some embodiments, the compound can have an IC50 of less than about 10 μΜ, of less than about 5 μΜ, of less than about 1 μ.Μ, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also antagonize mAChR M4 response with IC50 of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-M5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, M2, M3, or M5 receptors, or greater than about 500-fold less than that for the mAChR Μ·,, M2, M3, or M5 receptors.
[00125] In vivo efficacy for disclosed compounds in models that predict antiparkinsonian activity can be measured in a number of preclinical rat models. For example, disclosed compounds may reverse deficits in motor function induced by the dopamine receptor antagonist in mice or rats. Also, these compounds may reverse deficits in motor function that are observed with other manipulations that reduce dopaminergic signaling, such as selective lesions of dopamine neurons. In addition, it is possible that these compounds will have efficacy in animal models of dystonia and may increase attention, cognitive function, and measures of motivation in animal models.
3. Pharmaceutical Compositions and Formulations
[00126] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.
[00127] The pharmaceutical compositions and formulations may include a "therapeutically effective amount" or a "prophylactic-ally effective amount" of the agent. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I)) are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
[00128] For example, a therapeutically effective amount of a compound of formula (I), may¬ be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about 550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about 450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about 350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about 250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about 150 mg/kg, and about 90 mg/kg to about 100 mg/kg.
[00129] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier," as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose: starches such as, but not limited to, corn starch and potato starch: cellulose and its derivatives such as, but not limited to, sodium carboxymethyi cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
[00130] Thus, the compounds and their physiologically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.
[00131] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). [00132] Carriers for systemic administration typically include at least one of diluents, lubncants, binders, dismtegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.
[00133] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitoi; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.
[00134] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.
[00135] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate;
starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.
[00136] Suitable disintegrants include agar, algimc acid and the sodium salt thereof!, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.
[00137] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a sy stemic or topical composition is typically about 0.005 to about 0.1 %.
[00138] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.
[00139] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.
[00140] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%. [00141] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about
0.01 to about 5%.
[00142] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.
[00143] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxy lated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.
[00144] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.
[00145] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592;
Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume
1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1 % to about 5%.
[00146] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.
[00147] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.
[00148] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific dismtegrants include alginic acid and croscarmeliose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.
[00149] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.
[00150] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.
[00151] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthaiate, polyvinyl acetate phthaiate, hydroxypropyl methyl cellulose phthaiate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik industries of Essen, Germany), waxes and shellac.
[00152] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.
[00153] Other compositions useful for attaining systemic deliver}' of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.
[00154] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.
[00155] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practi cal quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al, Pharmaceutical Dosage Forms: Tablets ( 981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
[00156] A carrier may include a single ingredient or a combination of two or more ingredients, in the topical compositions, the earner includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.
[00157] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, ail of which are optional.
[00158] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-dioi, butane-l ,3-diol, mink oil, cetyl alcohol, isopropyi isostearate, stearic acid, isobutyi paimitate, isocetyl stearate, oleyl alcohol, isopropyi iaurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyi lactate, decyl oleate, myristyi myristate, and combinations thereof. Specific emollients for skm include stearyl alcohol and polydimethylsiloxane. The amount of emoilient(s) in a skin-based topical composition is typically about 5% to about 95%.
[00159] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.
[00160] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.
[00161] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, di butyl phthaiate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.
[00162] The amount of thickener (s) in a topical composition is typically about 0% to about 95%.
[00163] Suitable powders include beta-cyclodextrins, hydrox -propyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyi cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.
[00164] The amount of fragrance in a topical composition is ty pically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.
[00165] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. [00166] The pharmaceutical composition or formulation may antagonize mAChR M4 with an IC50 of less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, or less than about 100 nM. The pharmaceutical composition or formulation may antagonize mAChR M4 with an IC50 of between about 10 μΜ and about 1 nM, about 1 μΜ and about 1 nM, about 100 nM and about 1 nM, or between about 10 nM and about 1 nM.
a. Spray-Dried Dispersion Formulations
[00167] The disclosed compounds may be formulated as a spray-dried dispersion (SDD). An SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution with the compound molecularly "dissolved" in a solid matrix. SDDs are obtained by dissolving drug and a polymer in an organic solvent and then spray-drying the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility of Biopharmaceutics Classification System (BCS) class II (high
permeability, low solubility) and class IV (low permeability, low solubility) drugs. Formulation and process conditions are selected so that the solvent quickly evaporates from the droplets, thus allowing insufficient time for phase separation or crystallization. SDDs have demonstrated long- term stability and manufaeturability. For example, shelf lives of more than 2 years have been demonstrated with SDDs. Advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable and scalable manufacturing process and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.
[00168] Thus, in one embodiment, the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I).
4. Methods of Use
[00169] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as neurological and/or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions may also be used in methods for decreasing muscarinic acetylcholine receptor activity in a mammal. The methods further include cotherapeutic methods for improving treatment outcomes. In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions.
a. Treating disorders
[00170] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treating, preventing, ameliorating, controlling, reducing, or reducing the risk of a variety of disorders, or symptoms of the disorders, in which a patient would benefit from antagonism of mAChR M4. In some embodiments, the disorder may be a neurodegenerative disorder, a movement disorder, or a brain disorder. The methods may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[00171] Disorders in which a patient would benefit from antagonism of mAChR M4 may include neurodegenerative disorders and movement disorders. For example, exemplary disorders may include Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias (e.g., tardive dyskinesia or levodopa-induced dyskinesia), schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness (e.g., narcolepsy), attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea (e.g., chorea associated with Huntington's disease), cerebral palsy, and progressive supranuclear palsy.
[00172] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having Parkinson's disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the motor symptoms are selected from bradykinesia, tremor, rigidity, gait dysfunction, and postural instability. The method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject.
[00173] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having dystonia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject. For example, treatment may reduce muscle contractions or spasms in a subject having dystonia.
[00174] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject. For example, treatment may reduce involuntary movements in a subject having tardive dyskinesia.
[00175] In some embodiments, the disclosure provides a method of preventing or delaying tardive dyskinesia in a subject at risk of developing tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may be a subject being treated with a neuroleptic medication (e.g., a typical antipsychotic or an atypical antipsychotic), a dopamine antagonist, or an antiemetic.
[00176] In some embodiments, the disclosure provides a method of treating catalepsy in a subject suffering from schizophrenia, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject suffering from schizophrenia may have catalepsy induced by a neuroleptic agent (e.g., a typical antipsychotic or an atypical antipsychotic).
[00177] In some embodiments, the disclosure provides a method of treating a brain disorder characterized by altered dopamine and cholinergic signaling that could benefit from antagonism of mAChR 4, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the treatment may increase motivation or goal-directed behavior in patients suffering from disorders characterized by reduced motivation for goal-directed behavior, such as schizophrenia and other brain disorders.
[00178] In some embodiments, the disclosure provides a method for increasing wakefulness and/or reducing excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a subject suffering from narcolepsy.
[00179] In some embodiments, the disclosure provides a method of increasing attention in a subject (e.g., a subject suffering from an attention deficit disorder such as ADHD) in a subject in need thereof!, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[00180] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject having a drug-induced movement disorder, comprising administering the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the drug-induced movement disorder is selected from drug-induced parkinsonism, tardive dyskinesia, tardive dystonia, akathisia, myoclonus, and tremor. The method may treat the motor symptoms, control the motor symptoms, and/or reduce the motor symptoms in the subject.
[00181] The compounds and compositions 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 compounds and compositions 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.
[00182] In the treatment of conditions such as those that would benefit from antagonism of mAChR M4, an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. The dosage level may be about 0.1 to about 250 mg/kg per day, or about 0.5 to about 100 mg/kg per day. A suitable dosage level can 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 can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can 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 can 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.
[00183] Thus, in some embodiments, the disclosure relates to a method for antagonizing the mAChR Mj receptor in at least one cell, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one product of a disclosed method in an amount effective to antagonize mAChR. M4 in the at least one cell. In some embodiments, the cell is mammalian, for example, human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, contacting is via administration to a subject.
[00184] In some embodiments, the invention relates to a method for antagonizing the mAChR M4 receptor in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to antagonize the mAChR. M4 receptor in the subject. In some embodiments, the subject is mammalian, for example, human. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 antagonism prior to the administering step. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 antagonism prior to the
administering step. In some embodiments, the method further comprises the step of identifying a subject in need of mAChR M4 antagonism. b. Antagonism of the Muscarinic Acetylcholine Receptor
[00185] In some embodiments, the disclosure relates to a method for antagonizing mAChR M4 in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.
[00186] In some embodiments, antagonism of the muscarinic acetylcholine receptor decreases muscarinic acetylcholine receptor activity.
[00187] In some embodiments, the compound administered antagonizes mAChR M4 with an IC50 of less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, or less than about 100 nM. In some embodiments, the compound administered antagonizes m AChR M4 with an IC5 of between about 10 μΜ and about 1 nM, about 1 μΜ and about 1 nM, about 100 nM and about 1 nM, or about 10 nM and about 1 nM.
[00188] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for reduction of muscarinic acetylcholine receptor activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of reducing muscarinic acetylcholine receptor activity, in some embodiments, the antagonism of the muscarinic acetylcholine receptor treats a disorder associated with muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.
[00189] In some embodiments, antagonism of the muscarinic acetylcholine receptor in a mammal is associated with the treatment of a disorder associated with a muscarinic receptor dysfunction, such as a disorder disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.
[00190] In some embodiments, the disclosure provides a method for antagonizing the muscarinic acetylcholine receptor in a cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is mammalian (e.g., human). In some embodiments, the ceil has been isolated from a mammal prior to the contacting step. In some embodiments, contacting is via administration to a mammal. c. Cotherapeutic methods
[00191] The present disclosure is further directed to administration of a mAChR M4 antagonist, such as a selective mAChR M4 antagonist, for improving treatment outcomes. That is, in some embodiments, the disclosure relates to a cotherapeutic method comprising a step of administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
[00192] In some embodiments, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and/or after therapy. For example, cognitive or behavioral therapy can be provided within 1 , 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy can be provided withm 1, 2, 3, or 4 weeks before or after administration of the compound. As a still further example, cognitive or behavioral therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.
[00193] In some embodiments, administration may improve treatment outcomes in the context of physical or occupational therapy. Administration in connection with physical or occupational therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and/or after therapy. For example, physical or occupational therapy- can be provided within 1 , 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, physical or occupational therapy can be provided within 1 , 2, 3, or 4 weeks before or after administration of the compound. As a still further example, physical or occupational therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.
[00194] It is understood that the disclosed cotherapeutic methods can be used in connection with the disclosed compounds, compositions, kits, and uses.
. Combination Therapies
[00195] In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. 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). 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.
[00196] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound may be used. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.
[00197] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
[00198] The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds can 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 disclosed compounds are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, 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 a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
[00199] The weight ratio of a disclosed compound to the second active ingredient can 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 a disclosed compound to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably 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.
[00200] In such combinations a disclosed compound and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).
[00201] Accordingly, the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.
[00202] In some embodiments, the compound can be employed in combination with any other agent that is used to treat a disorder described herein, such as a standard of care therapy for a disorder that would benefit from mAChR 4 antagonism, such as a disorder described herein. For example, in some embodiments, the compound can be employed in combination with a Parkinsonian drug (e.g., L-DOPA, or carbidopa/levodopa) an mGlu4 positive allostenc modulator, an niGiu negative ailosteric modulator, an A2A inhibitor, a T-type calcium channel antagonist, a VMAT2 inhibitor, a muscle relaxant (e.g., baclofen), an anticholinergic agent, an antiemetic, a typical or atypical neuroleptic agent (e.g., risperidone, ziprasidone, haloperidol, pimozide, fluphenazine), an antihypertensive agent (e.g., clonidine or guanfacine), a tricyclic antidepressant (e.g., amitriptyline, butriptyline, clomipramine, desipramme, dosulepin, doxepm, imipramme, iprindole, lofepramine, nortriptyline, protriptyline, or trimipramine) an agent that increases extracellular dopamine levels (e.g., amphetamine, methylphenidate, or
lisdexamfetamine), an agent for treating excessive daytime sleepiness (e.g., sodium ox bate or a wakefulness-promoting agent such as armodafinil or modafinil), and a norepinephrine reuptake inhibitor (including selective NRIs, e.g., atomoxetine, and non-selective NRIs, e.g., bupropion). e, Modes of Administration
[00203] Methods of treatment may include any number of modes of administering a disclosed composition. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g. , mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or nonaqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire™). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.
[00204] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
[00205] The term "parenteraliy," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. 5. Kits
[00206] In one aspect, the disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof and one or more of:
(a) at least one agent known to increase mAChR M4 activity;
(b) at least one agent known to decrease mAChR M4 activity;
(c) at least one agent known to treat a disorder associated with mAChR M4, such as a disorder described herein; and
(d) instructions for administering the compound.
[00207] In some embodiments, the at least one disclosed compound and the at least one agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one agent are co-packaged. The kits can also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for deliver}' to a patient.
[00208] That the disclosed kits can be employed in connection with disclosed methods of use.
[00209] The kits may further comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).
[00210] The compounds and processes of the invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
6. Examples
[00211] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. !H chemical shifts are reported in δ values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq := AB quartet), coupling constant, integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, CI 8 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitriie with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 μηι, 1.0 x 50 mm) at 0.5 mL/min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nni, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrosprav ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles/second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi. The capillar}' needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.
[00212] Abbreviations used in the examples and reaction schemes that follow are:
[00213] AcOH acetic acid
[00214] BrettPhos-Pd-G3 Methanesulfonato(2-dicyclohexy3phosphino-3,6-dimethoxy- 2',4',6'-tri-i-propyl-lJ '-biphenyl)(2'-amino-l ,r-biphenyl-2-yi)pal3adium(II) (CAS No. 1470372
[00215] DCE 1 ,2-dichloroethane
[00216] DCM dichloromethane
[00217] DIPEA N, N-di isopr opy 1 ethy lamine
[00218] DMF iV,N-dimethylformamide
[00219] EtOAc ethyl acetate
[00220] h or hr hour
[00221] HATU l -[bis(dimethylamino)methyS
&]pyridini": um 3-oxid hexafluorophosphate
[00222] IPA isopropyl alcohol
[00223] LAH lithium aluminum hydride
[00224] MeOH methanol NaBH(OAc)3 Sodium triacetoxyborohydride
NMP N-methyl-2-pyrrolidone
PyClU 1 -(chloro- 1 -pyrrolidinylmethylene)pyrrolidinium
hexafluorophosphate
RP-HPLC reversed-phase high-performance liquid chromatography rt or r.t. room temperature
RuPhos-Pd-G3 methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1 , 1 '-biphenyl)(2'-amino- 1 , i -biphenyl-2-yi)pailadium( (CAS No. 1445085-77-7)
SFC supercritical fluid chromatography
THF tetrahydrofuran
Example 1. 6-(2-chloro-5-fluorophenyl)-iV-((6-((3-(trifluoromethyl)pyridin-2-yl)methyl)-6- azaspiro[2.5]octan-l-yl)methyl)pyridazin-3-amine (Compound 1)
Figure imgf000062_0001
[00233] Tert-butyl l-(((6-chloropyridazin-3-yl)amino)methyl)-6-azaspiro[2.5]octane-6- carboxylate. Tert-butyl 2-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (3.0 g, 12.5 mmol) was dissolved in t-BuOH (14 mL), and DIPEA (6.5 mL, 37.4 mmol) was added, followed by 3,6-dichloropyridazine (4.65 g, 31.2 mmol). The resulting suspension was heated to 100 °C overnight, after which time the reaction was cooled to r.t., and diluted with DCM and sat.
NaHCOj, The aqueous layer was extracted with DCM, and organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by RP-HPLC, and fractions containing product were extracted with DCM. Organic extracts were dried with MgSQ4, filtered and concentrated to give the title compound as a white, spongy solid. (1.86 g, 42%). H-NMR (400 MHz, CDC13) δ 7.16 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 9.3 Hz, 1H), 4.74 (br, 1H), 3.65 (br, 2H), 3.47 - 3.35 (ni, 2H), 3.26 - 3.20 (m, 2H), 1.69 - 1.62 (m, 1H), 1.57 - 1.51 (m, 1H), 1.46 (s, 9H), 1.40 - 1.35 (m, 1H), 1.17 - 1.13 (m, IH), 1.05 - 0.98 (m, IH), 0.63 (dd, J = 8.4, 4.7 Hz, 1H), 0.30 (t, J = 5.0 Hz, IH). ES-MS [M+H]+ = 353.2.
[00234] Tert-butyl l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)methyl)-6- azaspiro[2.5]octane-6-carboxylate. To a 5 mL microwave vial was added tert-butyl l-(((6- chloropyridazin-3-yl)amino)methyl)-6-azaspiro[2.5]octane-6-carboxylate (199 nig, 0.56 mmol), 2-chloro-5-fluorophenylboronic acid (147 mg, 0.85 mmol), K3CO3 (237 mg, 1.69 mmol) and RuPhos-Pd-G3 (24 mg, 0.03 mmol). A degassed mixture of 5: 1 1 ,4-dioxane H20 (2.5 mL) was then added, and the resulting suspension was stirred under microwave irradiation at 120 °C for 30 min, after which time the reaction mixture was cooled to r.t. and diluted with DCM and sat. NaHCOj, The aqueous layer was extracted with DCM, and organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (hex/EtOAc) to give the title compound as a colorless oi 1 (100 mg, 40%). ¾- MR (400 MHz, CDCI3) δ 7.61 (d, ,/ 9.2 Hz, I H), 7,47 i d. J ------- 9.1, 3 , 1 Hz, IH), 7.40 (dd, I 8.8, 5.0 Hz, IH),
7.06 - 7,01 (m, IH), 6.69 (d, ./ 9.3 Hz, IH), 4.93 (br, IH), 3.65 (br, 2H), 3 ,55 - 3.42 (m, 21 1 ). 3.28 - 3.21 (m, 2H), 1.71 - 1 .65 (m, I H), 1 ,58 - 1.52 (m, I H), 1 ,46 (s, 91 1 ). 1.43 - 1.38 (m, IH), 1.18 - 1.13 (m, IH), 1.10 - 1 ,03 (m, IH), 0.64 (dd, J= 8,4, 4.7 Hz, IH), 0.32 (t, J ------- 5.0 Hz, I H),
ES-MS [ M · H I = 447.2.
[00235] Ar-((6-Azaspiro[2.5]octan-l-yl)metbyl)-6-(2-ehloro-5-flisorophe yI)pyridaz8!5-3- amine. Tert-butyl l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)methyl)-6- azaspiro[2,5]octane-6-carboxylate (100 mg, 0.22 mmol) was dissolved in ,4-dioxanes (2 mL). 4M HC1 in 1,4-dioxane solution (2 mL) was then added dropwise. The resulting mixture was stirred at r.t. for 30 min, after which time solvents were removed under reduced pressure, and the resulting white solid was dried under vacuum and used without further purification as the title compound as the HC1 salt. ES-MS | M 1 1 1 = 347.0.
[00236] 6-(2-chloro-5-fluorophenyl)-iV-((6-((3-(trifluoromethyl)pyridin-2-yl)methyl)-6- azaspiro[2.5]octan-l-yl)methyl)pyridazin-3-amine (Compound 1). N-((6- Azaspiro[2.5]octan-l-yi)methyl)-6-(2-chioro-5-fluorophenyi)pyridazm-3-aniine hydrochloride salt (11 mg, 0.028 mmol) was suspended in DCM (1 raL) and 3-(trifluoromethyl)pyridine-2- carbaldehyde (24 mg, 0.14 mmol) was added and allowed to stir at r.t. for 5 min, after which time sodium triacetoxyborohydride (30 mg, 0.14 mmol) was added. The resulting solution was stirred at r.t. overnight, after which time the reaction mixture was quenched with sat. NaHCO-j, and extracted with 3: 1 chloroform/IP A. Organic extracts were filtered through a phase separator, and concentrated. Crude residue was purified by RP-HPLC, and fractions containing product were basified with sat. NaHCQs, and extracted with 3: 1 chloroform/IP A. Organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (6.2 mg, 44%). Ή-WJR (400 MHz, CDCI3) δ 8.80 (dd, J= 4.6, 0.8 Hz, 1H), 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7,61 (d, ./ 9.3 Hz, I I I). 7,48 (dd, J = 9:2, 3, 1 Hz, 1H), 7,41 (dd, ,/ 8.8, 5,0 Hz, 1 1 1). 7.31 (dd, J= 7.8, 4.8 Hz, 1H), 7,07 - 7.02 (m, 1 1 1). 6.68 (d, J= 9.3 Hz, H i). 4.83 (t, ./ 4.6 Hz, 1H), 3,83 (s, 2H), 3,52 - 3.41 (m, 2H), 2,67 - 2.62 (m, 2H), 2.50 - 2,45 (m, 21 1). 1.83 - 1,78 (m, 1H), 1,69 - 1.65 (m, I I I). 1 ,49 - 1 ,46 (m, 1 1 1). 1.25 - 1 ,20 (m, H i). 1.05 - 0,97 (m, IH), 0.61 (dd, J= 8.4, 4.6 Hz, IH), 0,28 (t, ,/ 4,9 Hz, H i), ES-MS [M+H]+ = 506.2,
Example 2, iV-((6-(3,3-Di™ethylbutyl)-6-azaspiro[2.5]octan-l-yl)methyl)-6-(4- fluorophenyl)pyridazin-3-amine (Compound 2)
1 ) HCi, dioxanes, r.t.
Figure imgf000064_0001
100 °C
[00237] 6-Chioro- i~((6~(3 -dimethyibutyl)~6~azaspiro[2,5]octan~l~yi)methyi)pyridazi!i~ 3-amine. Tert-butyl l-(((6-chloropyridazin-3-yl)amino)methyl)-6-azaspiro[2.5]octane-6- carboxylate (prepared as described in Example 1) (1.34 g, 3,80 mmol) was dissolved in 1 ,4- dioxanes ( 5 mL) and 4M HC1 in dioxanes solution (15 mL) was added dropwise. The resulting cloudy solution was stirred at r.t. for 30 mm, after which time solvents were concentrated to give a white solid that was dried under vacuum and used without further purification as the HCl salt. The previously mentioned HCl salt (1.10 g, 3.80 mmol) was suspended in DCM (20 niL) and 3,3-dimethylbutyraldehyde (1.14 g, 11.39 mmol) was then added dropwise, followed by sodium triacetoxyborohydride (2.41 g, 11.39 mmol). The resulting suspension was stirred at r.t. for 6 h, after which time the reaction was cooled to 0 °C, and quenched with sat. NaHC0 . The aqueous layer was extracted with DCM and 3 : 1 chloroform/IP A. Organic extracts were dried with MgS04, and solvents were filtered and concentrated to give the title compound as a yellow oil which was used directly without further purification (1.28 g, 100%). ' H-NMR (400 MHz, ΠΧΊ ;) δ 7.12 (d, ./ 9.3 Hz, i l l ). 6.68 (d, ./ 9,3 Hz, i l l ). 5.05 (br, I H ). 3.41 - 3.36 (m, 2H), 2.68 (br, 2H), 2.45 - 2.41 (m, 4H), 1.80 - 1.38 (m, 6H), 1.00 - 0.93 (m, 1H), 0.89 (s, 9H), 0,57 (dd, J = 8.4, 4.7 Hz, 1H), 0.24 (t, ./ 4,9 Hz, i l l ). ES-MS [M+Hf = 337.3.
[00238] iV-((6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-l-yl)methyl)-6-(4- fluorophenyl)pyridazin-3-amine (Compound 2). 6-Chloro-N-((6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-l-yl)methyl)pyridazin-3-amine (20 mg, 0.06 mmol), K2C03 (25 mg, 0.18 mmol), 4-fluorophenylboronic acid (10 mg, 0.07 mmol) and uPhos-Pd-G3 (5 mg, 0,006 mmol) were combined in a sealed vial, and a solution of 5; 1 1 ,4-dioxanes H20 (1 .2 mL, degassed) was then added via syringe. The resultmg suspension was stirred under an inert atmosphere at 100 °C for 2 h, after which time the reaction was cooled to r.t. and diluted with sat. NaHC03 and 3 : 1 chloroform/IP A. The aqueous layer was extracted with 3 : 1 chloroform/IP A, and organic extracts were filtered through a phase separator. Solvents were concentrated, and crude residue was purified by RP-HPLC. Fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/lPA. Solvents were filtered through a phase separator and concentrated to gi ve the title compound as a colorless oil (2.7 mg, 11%). 5 H-NMR (400 MHz, CDC13) δ 7.95 - 7.91 (m, 2H), 7.57 (d, ./ 9.3 Hz, IH), 7.18 - 7.12 (m, 2H), 6.74 (d, J = 9.3 Hz, l ! i ). 4.78 (t, J = 4.6 Hz, I I I ). 3.48 (t, J = 6.7 Hz, 2H), 2.67 (br, 2H), 2.45 - 2.40 (m, 4H), 1.81 1 .25 (m, 6H), 1.06 - 0.99 (m, IH), 0.91 (s, 9H), 0.61 (dd, J = 8.4, 4.6 Hz, IH), 0.29 (t, ./ 5.0 Hz, I H). ES-MS [ M i l l 397.4. Example 3.
Figure imgf000066_0001
azaspiro[2.5]octan-l-yl)methyl)-6-(l,3-dimethyl-lH-pyrazol-4-yl)pyridazin-3-amine (Compound 3)
Figure imgf000066_0002
[00239] Tert-butyl l-(((6-(l^-dimethyl-LH-pyrazol-4-yl)pyridazin-3-yl)amino)methyl)-6- azaspiro[2.5]octane-6-carboxylate. Tert-butyl l-(((6-chloropyridazin-3-yl)amino)methyl)-6- azaspiro[2.5]octane-6-carboxylate (prepared as described in Example 1 ) (68 mg, 0.19 mmol), 1,3 -dimethyl- lH-pyrazole-4-boronic acid pinacol ester (51 mg, 0.23 mmol), K2C03 (81 mg, 0.58 mmol) and RuPhos-Pd-G3 (8 mg, 0.010 mmol) were dissolved in 5: 1 1 ,4-dioxanes H20 (2.4 niL, degassed), and the resulting solution was heated in a sealed flask at 100 °C for 1 h, after winch time the reaction mixture was cooled to r.t and diluted with sat. NaHC03 and DCM. Aqueous layer was extracted with DCM (3x), and combined organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (12-100 % EtOAc/hexanes to 0-1 0% MeOH/EtOAc) to give the title compound as a colorless oil (35 mg, 45%). ES-MS [M-i-H]+ = 413,3.
[00240] iV-((6-azaspiro[2.5]octan-l-yI)methyl)-6-(l,3-diniethyl-lH-pyrazoI-4- yl)pyridazin-3-amine dihydrochloride. Tert-butyl 1 -(((6-(l,3-dimethyl-lH-pyrazol-4- yl)pyridazin-3-yl)amino)methyl)-6-azaspiro[2.5]octane-6-carboxylate (35 mg, 0.086 mmol) was dissolved in 1,4-dioxanes (1 mL) and 4M HC1 in dioxanes solution (1 mL) was added dropwise. The resulting solution was stirred at r.t. for 30 min, after which time solvents were concentrated to give a white solid that was dried under vacuum and used without further purification as the HC1 salt. ES-MS ! M - ! I ] = 313.3.
[00241] ((l ¾,2S,4S)-7-oxabicyclo[2.2 ]heptan-2-yl)(l-(((6-(l,3-dimethyl-li -pyrazol-4- yl)pyridazin-3-yl)amino)methyl)-6-azaspiro[2.5]octan-6-yl)methanone. N-((6- Azaspiro[2.5] octan- 1 -yl)methyl)-6-( 1 ,3-dimethyl- lH-pyrazol-4-yl)pyridazin-3 -amine dihydrochloride (33 nig, 0.086 mmol) was dissolved in DMF (1 mL) and rac-{\R,2SAS)-l- oxabicyclo[2.2.1]heptane-2-carboxylic acid (18 nig, 0.13 mmol) was then added, followed by DIPEA (0.045 mL, 0.26 mmol) and HATU (49 mg, 0.13 mmol). The resulting solution was stirred at r.t. for 4 h, after which time the reaction was quenched with sat, Xal ICO,, and the aqueous layer was extracted with 3: 1 chloroform/EPA. Solvents were filtered through a phase separator and concentrated, and crude residue was purified by RP-HPLC. Fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/EPA. Solvents were filtered through a phase separator and concentrated to give the title compound as a colorless oil (17.3 mg, 46%). ES-MS [M+Hf = 437.5.
[00242] Ar-((6-(((l/?,2/?,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)methyI)-6-azaspiro[2.5]octan- l-yl)methyl)-6-(l,3-dimethyl-lH-pyrazol-4-yl)pyridazin-3-amine (Compound 3).
((l ?,2,S',4i ,)-7-oxabicyclo[2.2.1]heptan-2-yi)(l -(((6-(l ,3-dimethyl-l.H-pyrazol-4-yl)pyridazin-3- yl)amino)methyl)-6-azaspiro[2.5]octan-6-yl)methanone (17.3 mg, 0.04 mmol) was dissolved in THF (1 mL) and cooled to 0 °C LAH (0,079 mL, 0.08 mmol, 1.0 M in TEEF) was then added dropwise, and the resulting solution was stirred at 0 °C for 30 mm. Reaction was quenched with the slow addition of sat. NaHC03, and the aqueous layer was extracted with DCM and 3: 1 chloroform/EPA. Organic extracts were filtered through a phase separator and concentrated, and crude residue was purified by RE'-HPLC. Fractions containing product were basified with sat. NaHCOj, and extracted with 3: 1 chloroform/EPA. Solvents were filtered through a phase separator and concentrated to give the title compound as a colorless oil that solidified on standing (1.0 mg, 6%). ES-MS | \i i i f 423.5. Example 4. 6-(l,4-dimethyl-lH-pyrazol-5-yl)- -((6-(2-(tetrahydrofuran-2-yl)ethyl)-6- e (
Figure imgf000068_0001
[00243] Tert-butyl l-(((6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-yl)amino)methyl)-6- azaspiro[2.5]octane~6~carboxylate. Tert-butyl l-(((6-chloropyridazin-3-yl)amino)methyl)-6- azaspiro[2,5]oetane-6-carboxylate (prepared as described in Example 1) (133 mg, 0,38 mmol), l,4-dimethylpyrazole-5-boronic acid pinacol ester (125 mg, 0,56 mmol), K2C03 (158 mg, 1.13 mmol) and RuPhos-Pd-G3 (16 mg, 0.019 mmol) were dissolved in 5: 1 l,4-dioxanes/H20 (3 mL, degassed), and the resulting solution was heated under microwave irradiation at 120 °C for 20 min, after which time the reaction mixture was cooled to r.t, and diluted with sat. NaHC03 and DCM. Aqueous layer was extracted with DCM (3x), and combined organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column
chromatography (12-100 % EtOAc/hexanes to 0-1.0% MeOH EtOAc) to give the title compound as a colorless oil (37 mg, 24%), ES-MS | M I I I - 413.2.
[00244] N-((6-Azaspiro[2.5]octan-l-yl)methyl)-6-(l,4-dimethyl-lH-pyrazol-5- yl)pyridazin-3-amine dihydrochloride. Tert-butyl l-(((6-(l ,4-dimethyl-l H-pyrazol-5- yl)pyridazin-3-yl)amino)methyl)-6-azaspiro[2.5]octane-6-carboxylate (64 mg, 0.16 mmol) was dissolved in 1 ,4-dioxanes (1 mL) and 4M HCl in dioxanes solution (1 mL) was added dropwise. The resulting solution was stirred at r.t. for 1 h, after which time solvents were concentrated to give a white solid that was dried under vacuum and used without further purification as the HCl salt. ES-MS [ M i l ! = 313.3
[00245] 6-(l,4-dimethyl-lH-pyrazol-5-yl)-N-((6-(2-(tetrahydrofuran-2-yl)ethyl)-6- azaspiro[2.5]octan-l-yl)methyl)pyridazin-3-amine (Compound 4). N-((6-Azaspiro[2.5]octan- l-yl)me4hyl)-6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-amine dihydrochloride (12 mg, 0.031 mmol) was suspended in DCM (1 inL) and 2-(2-bromoethyl)oxolane (11 mg, 0.062 mmol) was added, followed by K2C03 (8.7 mg, 0.062 mmol). The resulting suspension was stirred at r.t. for 4 h, after which time the reaction was quenched with sat. NaHC03, and aqueous layer was extracted with 3: 1 chloroform/EPA. Solvents were filtered through a phase separator and concentrated, and crude residue was purified by RP-HPLC. Fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/IP A. Solvents were filtered through a phase separator and concentrated to give the title compound as a white solid (2 mg, 16%). ES-MS m - ! i ] 411.4.
Example 5. Chiral Separation
Figure imgf000069_0001
|00246J Tert-butyl l-(((6-chloropyridazin-3-yl)amino)methyl)-6-azaspirof2.5]octane-6- carboxylate was separated into individual enantiomers via preparative SFC purification
(CHIRALPAK iC 20 x 250 mm column), 30% isocratic gradient with MeOH as co-solvent. Retention time of early eluting enantiomer O: 7.03 min (peak 1), retention time late eluting enantiomer P 7.65 min (peak 2). Peak 1 is the higher affinity enantiomer. X-ray crystallographic analysis showed that compound O has (R)-stereochemistry on the cy clopropane, as sho wn in the FIG. 1.
Example 6. JV-(6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-yl)-6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octasie-l-carboxaHiide. (Compound 5)
Figure imgf000069_0002
[00247] Tert-butyl l-((6-chloropyridazin-3-yI)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate. 6-Boc-6-azaspiro[2.5]octane-l-carboxylic acid (100 mg, 0.39 mmol) and 3-amino- 6-chloropyridazine (101 mg, 0.78 mmol) were dissolved in DCE (3 raL) and DIPEA (0.14 mL, 0.78 mmol) and PyClU (261 mg, 0.78 mmol) were added. The resulting suspension was heated to 110 °C with microwave irradiation for 20 mm, after which time the reaction was cooled to r.t., and diluted with DCM and H20. The aqueous layer was extracted with DCM, and organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a white solid (61 mg, 43%). 1H-NMR (400 MHz, CDC13) δ 10.4 (br, 1H), 8.60 (d, J = 9.4 Hz, 1H), 7.51 (d, J= 9.3 Hz, 1H), 3.58 - 3.48 (m, 2H), 3.42 - 3.35 (m, 1H), 3.25 - 3.19 (m, 1H), 2.18 (dd, J= 7.6, 5.6 Hz, 1H), 1.75 (t, ./ 5.7 Hz, 2H), 1.59 - 1.53 (m, 1H), 1.48 - 1.46 (m, 1H), 1.44 (s, 9H), 1.36 (t, J = 4.9 Hz, 1H), 1 ,08 (dd, ./ 7.6, 4.5 Hz, 1H). ES-MS [M+Hf = 367.2.
[00248] Tert- butyl l-((6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-yl)carbamoyl)-6- azaspiro[2.5]octane~6~carboxylate. Tert-butyl l-((6-chloropyridazin-3-yl)carbamoyl)-6- azaspiro[2,5]oetane-6-earboxylate (61 mg, 0.17 mmol), l,4-dimethylpyrazole-5-boronic acid pinacol ester (44 mg, 0,20 mmol), K2C03 (70 mg, 0.50 mmol) and RuPhos-Pd-G3 (7 mg, 0.008 mmol) were combined in a sealed vial, and 5: 1 l,4-dioxanes H20 solution (1.2 mL, degassed) was added. The resulting suspension was stirred at 100 °C under an inert atmosphere for 1 h, after which time the reaction mixture was cooled to r.t. and diluted with H20. Aqueous layer was extracted with DCM, and combined organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (hex/EtOAc) to give the title compound as a colorless oil (55 mg, 78%). ES-MS I M 1 11 = 427.2.
[00249] iV-(6-(l,4-dimethyI-lH-pyrazol-5-yl)pyridazin-3-yI)-6-(3,3-dimethylbutyl)-6- azaspiro|2.5]octasie-l-carboxai¾ide (Compound 5). Tert-butyl l -((6-(l,4-dimethyl-lH- pyrazol-5-yl)pyridazin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (55 mg, 0. 3 mmol) was dissolved in 1,4-dioxanes (1 mL). 4M HC1 in 1,4-dioxane solution (1 mL) was then added dropwise. The resulting mixture was stirred at r.t. for 1 h, after which time solvents were removed under reduced pressure, and the resulting white solid was dried under vacuum and used without further purification as the HC1 salt. The previously mentioned HC1 salt (17 mg, 0.043 mmol) was suspended in DCM (1 mL) and 3,3-dimethylbutyraldehyde (22 mg, 0.22 mmol) was added and allowed to stir at r.t. for 5 min, after which time sodium triacetoxyborohydride (46 mg, 0.22 mmol) was added. The resulting solution was stirred at r.t. overnight, after which time the reaction mixture was quenched with H20, and extracted with DCM. Organic extracts were filtered through a phase separator, and concentrated. Crude residue was purified by RP-HPLC, and fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/EPA. Organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (7.6 mg, 43%). ES-MS [M+HHf = 411.4.
Example 7. N- [ |'6-(3,3-dimethylbutyl)-6-azaspiro [2.5 ] octan-2-yI ] methyl] -5-(l ,3- dimethylpyrazol-4-yl)pyridin-2-amine (Compound 6)
Figure imgf000071_0001
[00250] Tert-butyl l-(((5-bromopyridin-2-yl)amino)methyl)-6-azaspiro|"2.5]octane-6- carboxylate. Tert-butyl l -(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (150 mg, 0.62 mmol) and 5-bromo-2-fluoropyridine (275 mg, 1.56 mmol) were dissolved in NMP (1.5 mL) in a 2 mL microwave vial. DIPEA (0.33 mL, 1.87 mmol) was then added, and the resulting solution was heated under microwave irradiation for 1 h at 180 °C, after which time the reaction mixture was purified directly by RP-HPLC and extracted with 3: 1 chloroform/IP A. Organic extracts were dried with MgS04, filtered and concentrated to give the title compound as a colorless oil (125 mg, 50%). ' i i- W!R (400 MHz, CDC13) δ 8.10 (d, ,/ 2.4 Hz, IH), 7,47 (dd, ./ 8.8, 2,5 Hz, IH), 6.29 (d, 8, 8 Hz, IH), 4.51 (br, i l l ). 3.64 (br, 2H), 3.27 - 3,21 (m, 4H), 1 .68 - 1.61 (m, 1 1 1 ). 1.56 - 1 ,49 (m, H i ). 1.46 (s, 9H), 1.39 - 1 ,35 (m, i l l ). 1.18 - 1.13 (m, i l l ). 1.01 - 0.94 (m, IH), 0.61 (dd, J= 8.4, 4.7 Hz, IH), 0.27 (t, J= 4.9 Hz, IH). ES-MS [M+H]+ = 396.4.
[00251] Tert-butyl l-(((5-(1 -dimethyl-lH-pyrazol-4-yl)pyridin-2-yl)amino)niethyl)-6- azaspiro[2.5]octane~6~carboxylate. Tert-butyl l -(((5-bromopyridin-2-yl)amino)methyl)-6- azaspiro[2.5]octane-6-carboxylate (51 mg, 0.13 mmol), l,3-dimethyl-lH-pyrazole-4-boronic acid pinacol ester (34 mg, 0.15 mmol), K2C03 (54 mg, 0.39 mmol) and RuPhos-Pd-G3 (5 mg, 0.006 mmol) were dissolved in 5: 1 1 ,4-dioxanes/H20 (2.4 mL, degassed), and the resulting solution was heated in a sealed flask at 100 °C for 1 h, after which time the reaction mixture was cooled to r.t. and diluted with sat. NaHC03 and DCM. Aqueous layer was extracted with DCM (3x), and combined organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (12-100 % EtOAc/hexanes to 0-10% MeOH/EtOAc) to give the title compound as a slightly brown oil (48 mg, 90%). ES-MS | M ! i j = 412.3.
[00252] A?~((6~Aiaspiro[2.5]octa!i-l-yl)methyl)~5~(l^~i!imethyl~lH-pyrazol~4-yl)pyrii!i!i- 2~amine dihydrochloride. Tert-butyl l-(((5-(l ,3-dimethyl-lH-pyrazol-4-yl)pyridin-2- yl)ammo)methyl)-6-azaspiro[2.5]octane-6-carboxylate (48 mg, 0.12 mmol) was dissolved in 1,4- dioxanes (1 mL) and 4M HC1 in dioxanes solution (1 mL) was added dropwise. The resulting solution was stirred at r.t. for 30 min, after which time solvents were concentrated to give a brown solid that was dried under vacuum and used without further purification as the HCl salt. ES-MS I \3 F I j 3 1 2.3.
[00253] iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3- dimethylpyrazol-4-yl)pyridin-2-amine (Compound 6). N-((6-Azaspiro[2.5]octan-l - yl)methyl)-5-(l ,3-dimethyl-l H-pyrazol-4-yl)pyridin-2-amine dihydrochloride (1 5 mg, 0.039 mmol) was suspended in DCM (1 mL) and 3,3-dimethylbutyraldehyde (19 mg, 0.1 9 mmol) was then added, followed by sodium triacetoxyborohydride (41 mg, 0.19 mmol). The resulting suspension was stirred at r.t. for 5 h, after which time the reaction was quenched with sat.
NaHC03. The aqueous layer was extracted with 3: 1 chloroform/IP A (3x). Organic extracts were filtered through a phase separator and concentrated, and crude residue was purified by RP- HPLC. Fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/IP A. Organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (3.4 mg, 22%). ES-MS [M- lLf = 396.6.
[00254] The compounds shown in Table 1 were prepared similarly to the compounds described above, with appropriate starting materials. In Table I , the "Scheme(s)" column indicates the general reaction scheme that was used to prepare the compound, where the schemes are shown in the Detailed Description section. Table 1
Figure imgf000073_0001
Cpd ES-MS
Name Structure Scheme(s)
No
6-(2-chloro-5-fluoro-phenyl)-
N-[[6-(tetrahydropyran-3-
IS ylmethyl)-6- A,B 445.2 azaspiro[2.5]octan-2- If
yljjm ethy 1 ]py rid azi n - 3 - am ine
N-j ] 6-( 1 -adamantylmethy 1)- 6-azaspiro[2.5Joctan-2-
16 y 1| methyl ] - 6 -(2 -ch loro -5 - A,B 495.3 fluoro-phenyl)pyridazin-3 - amine
6~(2 -ch! oro-5 -fluoro-phenyi)- N-[[6-(2,2-diphenylethyl)-6-
17 A,B 527.2 azaspiro[2.5]octari-2- yl]methyl]pyridazin-3-amine
6-(5-bicyclo[2.2.1]hept-2- enylmethyl)-N-f6-(2-chloro-
18 5 -fluoro-phenyl)pyridazin-3 - H 467.2 yl]-6-azaspiro[2.5]octane-2- carboxamide
N-[6-(2-chloro-5-fluoro- phenyl)pyridazin-3-yl]-6-
19 (2,3 ,3 -trimethy lbutyl)-6- H 459.4 azaspiro [2.5 Joctan e- 2 - carboxamide
6-chloro-N-[[6-(3,3- dimethylbutyl)-6-
20 D 337.3 azaspiro [2.5 ]octan-2- yl]methyl]pyridazin-3-amine
N-[[6-(5-bicyclo[2.2.1]hept- 2-enylmethyl)-6- azaspiro [2.5 ]octan-2-
21 A,B 419.3 y |methyl]-5-(l,3- dimethylpyrazol-4- yl)pyrazin-2 -amine
5 -(1 ,3 -dim ethylpyrazoi -4-yl)- N-[[6-(2,3,3-trimethylbutyl)-
22 A,B 411.4 6-azaspiro[2.5]octan-2- yl]methyl]pyrazin-2-amine
N-[[6-(3,3-dimethylbu1yl)-6- azaspiro [2.5 ]octan-2-
23 yl]methyl]-5-(l ,3- A,B 397.4 d im ethylpyrazoi -4- yl)pyrazin-2 -amine
Figure imgf000075_0001
Cpd ES-MS
Name Structure Scheme(s)
No
F
6 - (3 , 5 - d i fluoro ph eny 1) -N - f [6 - (3,3-dimethylbutyl)-6-
33 D 41 .3 azaspiro [2.5 ]octan-2- yl]methyl]pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-2-
34 D 379.4 yl]methyl]-6-phenyl- pyridazin-3 -amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro [2.5 ]octan-2-
35 yl]methyl]-6-(2,4- D 397.4 dimeth lpyrazol-3- yl)pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro [2.5 ]octan-2-
36 yl]methyl]-6-(l,3,5- D 411.4 trim ethy lpyrazol -4- yl)pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro [2.5 ]octan-2-
37 yl]methyl]-6-(3,5- D 398.3 dimeth lisoxazol-4- yl)pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro [2.5 ]octan-2-
38 yl]methyl]-6-(2- D 383.4 m ethy lpyrazol -3 - yl)pyridazin-3-atnine
N-[[6-(3,3-dimethylbu1yl)-6- azaspiro [2.5 joetan -2-
39 yl]methyl]-6-[2-methyl-5- D 451.3 (trifluoromethyl)pyrazol-3 - yl]pyridazin-3 -amine
N-[4-[6-[[[6-(3,3- dimethylbutyl)-6-
40 azaspiro [2.5 joetan -2- D 436.3 yl]meihyl amino]pyridazin-3- y 1 jplieny 1] acetamide H
6-(2-chloro-3-fluoro-phenyl)-
N-[[6-(3,3-dimethylbutyl)-6-
41 D 431.2 azaspiro [2.5 joetan -2- y 1] m ethy 1 ]py rid azi n - 3 - am ine Cpd ES-MS
Name Structure Scheme(s)
No
N-[[6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-2-
42 D 399.2 yl]methyl]-6-(3-methyl-2- tliienyl)pyridazin-3-amine
2 - [6 - [[[6-(3 ,3 -dimethylbuty 1)- 6-azaspiro[2.5]octan-2-
43 D 422.2 yl]methyl]amino]pyridazin-3- yl]-4-fluoro-benzonitrile
N-[[6-(3,3-dimethylbu1yl)-6- azaspiro [2.5 ]octan-2-
44 yl]methyl]-6-(7- D 430.3 isoquinolyl)pyridazin-3- amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-2-
45 D 430.3 yl]methyl]-6-(6- quinolyl)pyridazin-3-amine
6-(l ,3-benzodioxol-5-yl)-N- [[6-(3,3-dimethylbutyl)-6-
46 D 423.3 azaspiro [2.5 ]octan-2- yljmethy ljpyrid azin-3 -amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro [2.5 ]octan-2-
47 D 429.4 yl]methyl]-6-(2- naphthyl)pyridazin-3-amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro [2.5 ]octan-2-
48 yl|methyi]~6-[2- D 463.2 (trif!uoromethoxy )ph enyl] pyr
idazin-3 -amine
F
N-[[6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-2-
49 yl]methyl]-6-[4- D 448.2 (trifluoromethyl)-3 - pyridyl]pyridazin-3 -amine
N-[[6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-2-
50 yl]methyl]-6-(l,3- D 397.5 dimethylpyrazol-4- y l)pyridazin-3 -amine
Figure imgf000078_0001
Cpd ES-MS
Name Structure Scheme(s)
No
6-(l ,3-dimethylpyrazol-4-yl)- N-[[6-(2,2-di henylethyl)-6-
S9 A,B 493.5 azaspiro [2. Joctan-2- yl]methyl]pyridazin-3-amine
6-(l,3-dimethylpyrazol-4-yl)-
N-[[6-(tetrahydropyran-3-
60 ylmethyl)-6- A,B 411.5 azaspiro [2. Joetan-2- yllmethyl]pyridazin-3-amine
6-(l,3-dimethylpyrazol-4-yl)-
N-[[6-(tetrahydropyran-4-
61 ylmethyl)-6- A,B 411.5 azaspiro [2. Joetan-2- yllmethyl]pyridazin-3-amine
6-(l,3-dimethylpyrazol-4-yl)- N-[[6-[(3-methyl-2-
62 pyridy l)methy 1] -6- A,B 418.5 azaspiro [2. Joetan-2- yllmethyl]pyridazin-3-amine
6-(l,3-dimethylpyrazol-4-yl)- N-[ [6-[ [3 -(trifluoromethyl)-2-
63 pyridy 1 Jmethy 1] -6- A,B 472.4 azaspiro [2. Joetan-2- yllmethyl]pyridazin-3-amine '"JO"
(R)-6-(2-chloro-5-fluoro- phenyl)-N-[[6-(3,3-
64 dimethylbutyl)-6- A,G,B 431.5 azaspiro [2.5 ]octan-2- yl]methyl]pyridazin-3-amine
(R)-6-(2-chloro-5-fluoro- phenyl)-N-[[6-
65 (cyclohexylmethyl)-6- A,G,B 443.4 azaspiro [2. Joetan-2- yllmethyl]pyridazin-3-amine
(S)-6-(2-chloro-5-fluoro- phenyl)-N-[[6-(3,3-
66 dimethylbutyl)-6- A,G,B 431.4 azaspiro [2.5 ]octan-2- yi Jmethy ljpyrid azin-3 -amine
(S)-6-(2-chloro-5-fluoro- phenyl)-N-[[6-
67 (cyclohexylmethyl)-6- A,G,B 443.5 azaspiro [2.5 ]octan-2- yi Jmethy ljpyrid azin-3 -amine
Figure imgf000080_0001
[00255] EXAMPLE 8, 6-(3,3-difluoropyrrolidin-l-yl)-N-((6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-l-yl)methyl)pyridazin-3-amine (Compound 75)
Figure imgf000081_0001
[00256] 6-Chloro-N-((6-(3 ,3 -dimethylbutyl)-6-azaspiro[2.5]octan- 1 -y l)methyl)pyridazin-
3-amine (24 nig, 0.071 mmol) and 3,3-difluoropyrrolidine hydrochloride (51 mg, 0.36 mmol) were combined in a microwave vial, and NMP (1 mL) was added, followed by DIPEA (0.062 mL, 0.36 mmol). The reaction mixture was heated under microwave irradiation at 200 °C for 1 h, after which time the reaction mixture was purified directly by RP-HPLC. Fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/IP A. Combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a slightly orange oil (12.3 mg, 42%). ιΉ NMR (400 MHz. CDC13) δ 6.67 - 6,61 (nr. 2H), 4.13 (t, J ------- 4.8 Hz, I I I ). 2.84 (t, ,/ 13.3 Hz, 2H), 3,66 (t, I 7.2 Hz, 2H), 3,40 - 3.36
(m, 2H), 2,67 (br, 2H), 2.53 - 2.42 (m, 6H), 1.80 - 1 .49 (m, 3H), 1.47 - 1.43 (m, 2H), 1 ,32 (br, ! ! i ). 1.03 - 0.96 (m, i l l ). 0.90 (s, 9H), 0.55 (dd, ./ 8.4, 4.6 Hz, ! ! i ). 0.23 (t, J = 4.9 Hz, I I I ). | M 1 1 j = 408.3.
[00257] EXAMPLE 9, 6-(l,4-dimethyl-l.H-pyrazol-5-yl)-N-((6-(3,3-dimethylbutyI)-6- azaspiro[2.5]octan-l-yl)methyI)-N-methylpyridazin-3-amine (Compound 76)
Figure imgf000082_0001
[00258] tert-Butyl l-(((6-chloropyridazin-3-yl)(methyl)amino)methyl)-6- azaspiro[2.5]oetarae~6-carboxylate. To a solution of tert-butyl l-(((6-chloropyridazin-3- yl)amino)methyl)-6-azaspiro[2.5]octane-6-carboxylate (58 mg, 0.16 mmol) in DMF (1 niL) was added sodium hydride (7.8 mg, 0.33 mmol, 60% dispersion in mineral oil) at 0 °C, and the resulting mixture was stirred for 5 min. lodomethane (3 p.L, 0.25 mmol) was then added, and the resulting solution was stirred at 0 °C for 1 h, after which time the reaction mixture was diluted with DCM and sat, NaHC03. The aqueous layer was extracted with DCM, and combined organic extracts were passed through a phase separator and concentrated under reduced pressure. Crude residue was purified by column chromatography (hex/EtOAc) to give the title compound (37 mg, 62%). [M+H]+ = 367,2.
[00259] tert-butyl l-(((6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3- yl)(methyl)amino)methyl)-6-azaspiro[2.5] octane-6-carboxylate. tert-Butyl 1 -(((6- chloropyridazin-3-yl)(methyl)amino)methyl)-6-azaspiro[2.5]octane-6-carboxylate (37 mg, 0.10 mmol), l,4-dimethylpyrazole-5-boronic acid pinacol ester (40 mg, 0.18 mmol), K2C03 (42 mg, 0.30 mmol) and BrettPhos-Pd-G3 (4.6 mg, 0.005 mmol) were combined in a microwave vial, and 5: 1 1 ,4-dioxanes/H20 solution (1 niL, degassed) was added under an inert atmosphere. The resulting mixture was heated under microwave irradiation at 20 °C for 20 min, after which time the reaction mixture was diluted with DCM and sat. NaHC03. The aqueous layer was extracted with DCM, and combined organic extracts were passed through a phase separator and concentrated under reduced pressure. Crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a yellow oil (32 nig, 74%). [M+H]+ = 427.4.
[00260] 6-(l,4-dimethyl-lH-pyrazol-5-yl)- -((6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octan-l-yl)methyl)-N-methylpyridazin-3-amine. tert-Butyl l-(((6-(l,4-dimethyl- lH-pyrazol-5-yl)pyridazin-3-yl)(methyl)amino)methyl)-6-azaspiro[2.5]octane-6-carboxylate (32 mg, 0.074 mmol) was dissolved in 1,4-dioxane (1 mL) and 4M HC1 in dioxanes solution (1 mL) was added dropwise. The resulting solution was stirred at r.t. for 1 h, after which time solvents were concentrated under reduced pressure to give the HC1 salt, which was used directly without further purification. The HC1 salt (30 mg, 0.074 mmol) was suspended in DCM (1 mL) and 3,3- dimethylbutyraldehyde (37 mg, 0.37 mmol) was added, followed by sodium
triacetoxyborohydride (79 mg, 0.37 mmol). After stirring overnight at r.t., the reaction mixture was heated to 55 °C and stirred overnight, followed by the addition of AcOH (3 drops) and overnight stirring. The reaction mixture was cooled to r.t. and diluted with 3: 1 chlorofoim/TPA and sat. NaHC03. The aqueous layer was extracted with 3: 1 chloroform/TP A. Combined organic extracts were filtered through a phase separator and concentrated, and crude residue was purified by RP-HPLC. Fractions containing product were basified with sat. NaHC03, and extracted with 3: 1 chloroform/IP A. Combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (9.3 mg, 30%). [M+H]+ = 41 1.5.
[00261] EXAMPLE 10. l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)oxy)methyl)-6-
(3,3-dimethylbutyl)-6-azaspiro [2.5] octane (Compound 77)
Figure imgf000084_0001
[00262] tert-butyl l-(((6-ch!oropyridazin-3-yl)oxy)methyl)-6-azaspiro[2.5]octane-6- carboxylate. tert-Butyl l-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (466 mg, 1.93 mmol) was dissolved in THF (10 mL) and Natl (93 mg, 3.86 mmol, 60% dispersion in mineral oil) was added at 0 °C. After stirring for 5 mins, 3,6-dichloropyridazine (432 mg, 2.90 mmol) was added. The resulting solution was warmed to r.t. and stirred overnight, after which time the reaction mixture was diluted with DCM and H20. The aqueous layer was extracted with DCM, and combined organic extracts were filtered through a phase separator and concentrated. Crude residue was purified by column chromatography (hex/EtOAc) to give the title compound as a white solid (541 mg, 79%). j \! ! !-Bocj = 254.4.
[00263] tert-butyl l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)oxy)methyl)-6- azaspiro[2.5]octane-6-carboxylate. tert-Butyl l-(((6-chloropyridazin-3-yl)oxy)methyl)-6- azaspiro[2.5]octaiie-6-carboxyiate (541 mg, 1.53 mmol), 2-chioro-5-fluorophenyiboronic acid (320 mg, 1.83 mmol), K2C03 (643 mg, 4.59 mmol) and RuPhos-Pd-G3 (128 mg, 0.15 mmol) were combined in a microwave vial, and 5: 1 l,4-dioxanes/H20 solution (12 mL, degassed) was added under an inert atmosphere. The resulting mixture was heated under microwave irradiation at 120 °C for 20 min, after winch time the reaction mixture was diluted with DCM and sat.
NaHCOj. The aqueous layer was extracted with DCM, and combined organic extracts were dried with MgS04. Solvents were filtered and concentrated under reduced pressure, and crude residue was purified by column chromatography (hex EtOAc) to give the title compound as a white foamy solid (290 mg, 42% (89% purity)). ( M l !-Boc] · = 348.2.
[00264] l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)oxy)methyl)-6-(3,3- dimethylbutyl)-6-azaspiro[2.5]octane. tert-Butyl l-(((6-(2-chloro-5-fluorophenyl)pyridazin-3- yl)oxy)methyl)-6-azaspiro[2.5]octane-6-carboxylate (290 mg, 0.65 mmol) was dissolved in 1,4- dioxane (5 mL) and 4M HC1 in dioxanes solution (4 mL) was added dropwise. The resulting solution was stirred at r.t. for 1 h, after which time solvents were concentrated under reduced pressure to give the HC1 salt, which was used directly without further purification. The HC1 salt was suspended in DCM (1 mL) and 3,3-dimethylbutyraldehyde (27 nig, 0.27 mmol) was added, followed by sodium triacetoxyborohydride (57 mg, 0.27 mmol). After stirring overnight at r.t., the reaction mixture was quenched with sat. NaHC03, and the aqueous layer was extracted with 3: 1 chloroform/EPA. Combined organic extracts were filtered through a phase separator and concentrated, and crude residue was purified by KP-HPLC. Fractions containing product were basified with sat. NaHCCh, and extracted with 3: 1 chloroform/IPA. Combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (4.2 mg, 18%). [M+H]+ = 432,4.
[00265] The compounds shown in Table 1.1 were prepared similarly to the compounds described above, with appropriate starting materials. In Table 1.1 , the "Schenie(s)" column indicates the general reaction scheme that was used to prepare the compound, where the schemes are shown in the Detailed Description section.
Table 1.1
Cpd ES-MS
Name Structure Scheme(s)
No [M+l]+
N-[[6-(3,3-dimethylbu1yl)-6- azaspiro[2.5]octan-2-
78 1 386.4 yl]methyl]-6-(l- piperidyl)pyridazin-3 -amine
N-[[6-(3,3-dimethylbu1yl)-6- azaspiro[2.5]octan-2- 388.4
79 1
y l]methy 1] -6 -morpholino - pyridazin-3 -amine
6-(4,4-difluoro-l-piperidyl)- N-[[6-(353-dimethylbutyl)-6-
80 1 422.3 azaspiro [2.5 ]octan-2- yl]methyl]pyridazin-3 -amine F
N-[[6-(3,3-dimethylbutyl)-6- azaspiro {?., .5 Joctan-2-
81 I 372.4 yl]metliyl]-6-pyrrolidin- 1 -yl- pyridazin-3-amine
N-[[6-(5-bicyclo[2.2.1]hept- 2-enylmethyl)-6-
82 azaspiro [2.5 ]octan-2- ί 410.5 y 1 j meth l] -6 -morpholino - pyridazin-3-amine
N - [ [6-(cyclohexy lm ethyl )-6 - azaspiro [2.5 joetan -2-
83 ί 400.6 y 1| methyl ] -6 -morphol ino - pyridazin-3-amine
N-[[6-( 1 -adamantylmethy 1)~
6-azaspiro[2.5]octan-2-
84 I 452.6 y 1 j meth l] -6 -morphol ino - pyridazin-3-amine
6-morpholino-N-[[6- (tetrahydropyran-4-ylmethyl)-
85 I 402.5 6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine
6-(5~bicyclo[2.2, l jhept-2- eny m ethyl)-2- [[6-(2 -chloro-
86 5 -fluoro-phenyl)pyridazin-3 - K 454.3 yl]oxymethyl]-6- G!
azaspiro [2.5 Joctane
Figure imgf000087_0001
Figure imgf000088_0001
Cpd ES-MS
Name Structure Scheme(s)
No
Figure imgf000089_0001
b]pyridazin-6-amine
N-[[6-(3,3-dimethylbu1yl)-6- azaspiro [2.5 ]octan-2-
104 yljniethyl]- C,B 343.4 [l,2,4]triazolo[4,3- b[pyridazin-6-amine
N-j [6-(cyclohexyimethyi)-6- azaspiro [2. Joctan -2-
105 yljmethy ]- C,B 355.4 [ ,2,4]triazolo[4,3- b jpyridazin-6-amine
( ) - 6 - (2 - chl oro - 5 -fluoro - H
phenyl)-N-[[6-
106 (tetrahydropyran-3-ylmethyl)- A,G,B 445.5
6-azaspiro[2.5]octan-2- y Ij in ethy IJpy r id azin -3 - amine
(R)-6-(2-chloro-5-fluoro- phenyl)-N-[[6-
107 (tetrahydropyraii-4-ylmethyl)- A,G,B 445.5
6-azaspiro[2.5]octan.-2- CI
yl]methyl]pyridazin-3-amine
N-(((l R)-6-
(b i cycio [2.2.1 Jhept-5 -en -2- ylmethyl)-6-
108 azaspiro [2.5 joctan- 1 - A,G,B 453.4 yl)methyl)-6-(2-chloro-5- fluorophenyl )py ridazi n -3 - amine
(R)-6-(2-chloro-5- fluorophenyl)-N-((6-
109 (cycloheptylmethyl)-6- A,G,B 457.4 azaspiro[2.5]octan-l- yl)meth l)pyridazin-3-amine
N-(((lR)-6-((7- oxabicyclo[2.2.1]heptan-2- yl)methyl)-6-
110 azaspiro [2.5 Joctan- 1 - A,G,B 457.3 yl)methyl)-6-(2-chloro-5- fluorophenyl)pyridazin-3 - amine
N-[4-[6-[[(2R)-6-(3,3- dimethylbutyl)-6-
111 azaspiro [2. Joctan -2- A,G,B 436.5 yl]methylamino]pyridazin-3- AX/
y 1 [phenyl J acetamide Cpd ES-MS
Name Structure Scheme(s)
No
N-[[(2R)-6-benzyl-6- azaspiro [2.5 ]octan-2-
112 yl]methyl]-6-(2-chloro-5- A,G,B 437.4 fluoro-phenyl)pyridazin-3-
Figure imgf000090_0001
aniine
6-(2 -chl oro-5 -fluoro-phenyl)-
N-[[(2R)-6-(2-
113 pyridyimethyl)-6- A,G,B 438.4 azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine
6-(2-chloro-5-fluoro-phenyl)- N-[[(2R)-6-[(3-methyl-2-
114 pyridyi)methyl]-6- A,G,B 452.4 azaspiro [2.5 ]octan-2- yllmethyl]pyridazin-3-amine
N-[[(2R)-6-(j - adatn antylmethyl)~6- azaspiro[2.5]octan-2-
115 A,G,B 495.4 yl]methyl]-6-(2-chloro-5- fluoro-phenyl)pyridazin-3 - amine
N-[4-[6-[[6-(3,3- dimethylbutyl)-6- azaspiro[2.5]octan-2-
116 A,B 464.6 y i jjm ethylam ino] -4,5 - dimethyl-pyridazin-3- y Ijpheny 1 ] acetamide
N-[4-[6-[[6-
(cy cl ohexy lm ethyl) - 6 - azaspiro [2.5 ]octan-2-
117 A,B 476.5 y 1 j methyl amino J -4,5 - dimethyl-pyridazin-3 - ylj phenyl jaeetam ide
N-[4-[6-[[(2R)-6- (cyclohexylmethyl)-6-
118 azaspiro [2.5 joetan -2- A,G,B 448.5 yl]methylamino]pyridazin-3- y Ijpheny 1 ] acetamide
N-[4-[6-[[(2R)-6- (cycloheptylmethyl)-6-
119 azaspiro [2. ]octan-2- A,G,B 462.5 yl]methylamino]pyridazin-3- y 1 ]phenyl ] acetamide
Figure imgf000091_0001
y 1 jplieny 1] acetamide
Example 11. Biological Activity
A. Cell Lines Expressing Muscarinic Acetylcholine Receptors
[00266] Human, rat, or mouse M4 cDN A, along with the chimeric G protein Gql5, were transfected into Chinese hamster ovaiy (CHO-Kl) cells purchased from the American Type Culture Collection using Lipofectamine2000. M4/Gq!5/CHO cells were grown in Ham's F-12 medium containing 10% heat- inactivated fetal bovine serum (FBS), 20mM HEPES, 500 μ§/ηιΙ, G418 sulfate, and 200 .ug/mL Hygromycin B.
B. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity [00267] For high throughput measurement of agonist-evoked increases in intracellular calcium, CHO-K1 ceils stably expressing muscarinic receptors were plated in growth medium lacking G418 and hygromycin at 15,000 cells/20
Figure imgf000092_0001
in Gremer 384-well black-walled, tissue culture (TC)-treated, clear-bottom plates (VWR). Cells were incubated overnight at 37 °C and 5% C02. The next day, cells were washed using an ELX 405 (BioTek) with assay buffer; the final volume was then aspirated to 20 μΕ. Next, 20 μΕ of a 2.3 μ.Μ stock of Fluo- 4/acetoxymethyl ester (Invitrogen, Carlsbad, CA), prepared as a 2.3 mM stock in DMSO and mixed in a 1 : 1 ratio with 10% (w/v) Pluronic F-127 and diluted in assay buffer, was added to the wells and the ceil plates were incubated for 50 min at 37 °C and 5% CO?.. Dye was removed by washing with the ELX 405 and the final volume was aspirated to 20 μί_. Compound master plates were formatted in a 10 point concentration-response curve (CRC) format (1 :3 dilutions) in 100% DMSO with a starting concentration of 10 or 1 mM using a BRAVO liquid handler (Agilent). Test compound CRCs were then transferred to daughter plates (240 nL) using the Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA) and then diluted into assay buffer (40 μΕ) to a 2x stock using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).
[00268] Calcium flux was measured using the Functional Drug Screening System (FDSS) 6000 or 7000 (Hamamatsu Corporation, Tokyo, Japan) as an increase in the fluorescent static ratio. Compounds were applied to cells (20 μΕ, 2X) using the automated system of the FDSS at 2 seconds into the protocol and the data were collected at 1 Hz. At 143 s, 10 μΕ of an EC2o concentration of the muscarinic receptor agonist acetylcholine was added (5X), followed by the addition of 12 Ε of an EC80 concentration of acetylcholine at the 268 s time point (5X). Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive ailosteric modulator activity was analyzed as a concentration- dependent increase in the EC20 acetylcholine response. Antagonist activity was analyzed as a concentration-dependent decrease in the EC80 acetylcholine response; for the purposes of the tables herein, an IC50 (inhibitory concentration 50) was calculated as a concentration-dependent decrease of the response elicited by an EC§o concentration of acetylcholine. Concentration- response curves were generated using a four-parameter logistical equation in XLFit curve fitting software (IDBS, Bridgewater, NX) for Excel (Microsoft, Redmond, WA) or Prism (GraphPad Software, Inc., San Diego, CA) or the Dotmatics software platform (Dotmatics, Bishop's Stortford, UK).
[00269] The above described assay was also operated in a second mode where an appropriate fixed concentration of the present compounds were added to the cells after establishment of a fluorescence baseline for about 3 seconds, and the response in cells was measured. 140 s later, a full concentration-response range consisting of increasing concentrations of agonist was added and the calcium response (maximum-local minima response) was measured. The EC50 values for the agonist in the presence or absence of test compound were determined by nonlinear curve fitting. A decrease in the EC50 value of the agonist with increasing concentrations of the present compounds (a leftward shift of the agonist concentration-response curve) is an indication of the degree of muscarinic positive allosteric modulation at a given concentration of the present compound. An increase in the EC50 value of the agonist with increasing concentrations of the present compounds (a rightward shift of the agonist concentrati on response curve) is an indication of the degree of muscarinic antagonism at a given concentrati on of the present compound. The second mode also indicates whether the present compounds also affect the maximum response of the muscarinic receptor to agonists.
C. Activity of Compounds in a mAChR M4 Cell-Based Assay
[00270] Compounds were synthesized as described above. Activity (IC50 an Emin) was determined in the mAChR M4 cell-based functional assay as described above and the data are shown in Table 2 and Table 3. The compound number corresponds to the compound numbers used in the examples and Tables 1 and 1.1.
Table 2.
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
* %ACh maximum at 30 μΜ,
ND = not determined
Table 3.
Figure imgf000096_0002
%ACh maximum at 30 μΜ.
itiosial Aspects and Embodiments of the Invention
A compound of formula (I):
Figure imgf000097_0001
(I)
or a pharmaceutically acceptable salt thereof, wherein;
A is a five- or six-membered heteroaryl having 1 , 2 or 3 heteroatoms independently selected from N, O and S, or a 9- to 10-membered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1-4 substituents independently selected from halo, C]-C4 alkyl, and C1-C4 haloaikyl;
Q is selected from NR3, O, and CR Rc;
R1 is selected from hydrogen, halo, -ORd, M R") . d-C4 alkyl, -CE CH-C1-C4 alkyl, optionally substituted cycioalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and -CH=CH-G;
G is optionally substituted cycioalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
R2 and R5 are independently selected from hydrogen, C1-C4 alkyl, and halo, or R2 and R5 are taken together to form an oxo group;
each R4 is independently selected from halo, C1 alkyl, and -ORc;
R3 and R6 are independently selected from hydrogen, Cj-C8 alkyl, and -(CRIRg)n-Y1; each Y1 is independently selected from optionally substituted cycioalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each Rd, R , IT, R", Rc, R1, and Rg is independently selected from hydrogen, C1-C4 alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2. [00273] E2. The compound of El , or a pharmaceutically acceptable salt thereof, wherein:
A is a five- or six-membered heteroaiyl having 1, 2 or 3 heteroatoms independently selected from N, O and S; and
R1 is selected from hydrogen, halo, -OR0, C1-C4 alkyl, optionally substituted cycloalkyl, optionally substituted lieterocycle, optionally substituted aryl, and optionally substituted heteroaryi.
[00274] E3. The compound of El or E2, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa; and
Ra is hydrogen or Ci-C4 alkyl.
[00275] E4. The compound of El or E2, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa; and
Rd is hydrogen.
[00276] E5. The compound of any of E1-E4, or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, halo, -CH=CH-C1-C4 alkyl, -CH=CH-G, Cs-Cg cycloaikenyl, a 4- to 8-membered monocyclic heterocyclyl, a 6- to 12-membered aryl, and a 5- to 6-rnembered monocyclic heteroaryi having 1 , 2, or 3 heteroatoms independently selected from N, O, and S; wherein the cycloaikenyl, heterocyclyl, aryl and heteroaiyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, Ci- C4 haloalkyl, C1-C4 alkoxy, C1-C4 haioalkoxy, and -NHCOR';
G is a 6- to 12-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, -C4 haioalkoxy, and -NHCOR'; and
R', at each occurrence, is independently C1-C4 alkyl.
[00277] E6. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen, phenyl, naphthyl, benzoclioxolyi, pyrazolyl, isoxazolyi, thienyl, pyridinyl, qumolinyl, isoquinoiinyi, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenvl, or -CH=CH-G, wherein the phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, and cyclopentenyl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano; and
G is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C C4 alkyl, halo, cyano, Cj-C haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherein R' is C1-C4 alkyl.
[00278] E7. The compound of any one of E1-E4, or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from halo, aryl, and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherei R' is C¾- C4 alkyl,
[00279] E8. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein
R1 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano.
[00280] E9. The compound of any one of El -E8, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen; and
R3 is hydrogen.
[00281] E10. The compound of any one of E1 -E8, or a pharmaceutically acceptable salt thereof, wherein
R2 and R3 are taken together to form an oxo group.
[00282] El l . The compound of any one of El-El 0, or a pharmaceutically acceptable salt thereof, wherein
m is 0.
[00283] E12. The compound of any one of El-El 1, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.
[00284] E13. The compound of any one of E1-E12, or a pharmaceutically acceptable salt thereof, wherein
R0 is selected from Ci -Cg alkyi and ~(CRfRg)n- Y! ;
R' is hydrogen;
Rg is selected from hydrogen, C1 -C4 alkyi and phenyl;
n is 0 or 1 ; and
Y1 is selected from: C3-C 1 o-cy cloalkyl; Cs-Cio-cycloalkenyl; phenyl; a 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatorns independently selected from N, O and S; and a 5- to 8- membered heterocyclyl having 1 or 2 heteroatorns independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaiyl and heterocyclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from Ci-C4 alkyi, halo, and C1-C4 haloalkyl.
[00285] E14. The compound of any of E1-E13, or a pharmaceutically acceptable salt thereof!, wherein:
A is a five-membered heteroaryl having 1 nitrogen atom and optionally 1 -2 additional heteroatorns independently selected from N, O and S, a six-membered heteroaiyl having 1-2 nitrogen atoms, a phthalazinyl, an imidazo[! ,2-b]pyndazmyl, or a [l,2,4]triazolo[4,3- bjpyridazinyl, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, C1-C4 alkyi, and C1-C4 haloalkyl.
[00286] E15. The compound of E14, or a pharmaceutically acceptable salt thereof, wherein:
A is a thiazol-2,5-diyi, pyridazin-3,6-diyl, pyrazin-2,5-diyl, pyridin-2,5-diyi, phthalazin- 1,4-diyl, imidazo[l,2-b]pyridazin-6-yl, or [l,2,4]triazolo[4,3-b]pyridazin-6-yL wherein A is optionally substituted with 1-4 substituents independently selected from halo, C1-C4 alkyi, and C1-C4 haloalkyl.
[00287] E16. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein
A is selected from:
Figure imgf000101_0001
wherein
T is selected from O, S and NH; and
U, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
[00288] E17. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein
A is selected from
Figure imgf000101_0002
£89] El 8. The compound of any of El -El 3, or a pharmaceutically acceptable
Figure imgf000101_0003
[00290] E19. The compound of any of E1-E13, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (la):
Figure imgf000101_0004
(la)
wherein. W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
[00291] E20. The compound of El 9, or a pharmaceutically acceptable salt thereof, wherein
1 or 2 of W, X, Y and Z are N.
[00292] E21. The compound of any of El -El 3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (lb):
Figure imgf000102_0001
[00293] E22. The compound of any one of E19-E21, or a pharmaceutically acceptable salt thereof, wherein
R! is selected from: halo; aryi; and a 5- to 6-membered monocyclic heteroaiyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaiyl are uiisubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloaikyl, C1 -C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherein R' is Ci -
C4 alkyl,
[00294] E23, The compound of any one of E19-E22, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen; and
R3 is hydrogen.
[00295] E24, The compound of any one of E19-E22, or a pharmaceutically acceptable salt thereof, wherein
R2 and RJ are taken together to form an oxo group,
[00296] E25. The compound of any one of El 9-E24, or a pharmaceutically acceptable salt thereof, wherein
R5 is hydrogen. 00297] E26. The compound of any one of El 9-E25, or a pharmaceutically acceptable salt thereof, wherein
R6 is selected from Q-Cg alkyl and -(CRfRg)n-Yl;
R1 is hydrogen:
Rg is selected from hydrogen, -C4 alkyl and phenyl;
n is 0 or 1 ; and
Y! is selected from: CrCio-cycloalkyl; Cs-Cjo-cycloalkenyl; phenyl; a 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; and a 5- to 8- membered heterocvclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocvclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, halo, and C1-C4 haloalkyl.
[00298] E27, The compound of El, wherein the compound is selected from:
6-(2-chloro-5-fluorophenyl)-N-[[6-[[3-(trifluoromethyl)-2-pyridyl]methyl]-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N- [ [6-(3 , 3 -dimethyl butyl)-6-azaspiro[2.5 ] octan-2-yl] methyl] -6-(4- fluoropheny l)pyri dazi n-3 -amine;
N-((6-(((l.i?,2i?,46)-7-oxabicyclo[2.2J ]heptan-2-yl)methyl)-6-azaspiro[2.5]octan-l - yl)methyl)-6-( 1 , 3 -dimethyl- 1 H -pyrazol-4-yl)py ri dazin-3 -amine;
N-[6-(2,4-dimemylpyrazol-3-yl)pyri(kzin-3-yl]-6-(2,3,3-trimethylbutyl)-6- azaspiro[2.5]octane-2-carboxamide;
N-(6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-yl)-6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octane-l -carboxamide;
Ar-[[6-(3,3-dimethylbut>4)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l ,3-dimethylpyrazol-4- yl)pyridin-2-amine;
6-(5-bicyclo[2.2^]hept-2-enylmethyl)-N-[6-(2,4-dirnethylpyrazol-3-yl)pyridazin-3-yl]-6- azaspiro[2.5]octane-2-carboxamide;
iV-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3- dimethyipyrazol-4-yi)pyridazin-3-aniine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyi]pyridazin-3-aniine; N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2- chloro-5-fluoro-phenyl)pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-3-ylmethyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
N-[[6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- pheny l)pyridazin-3 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(2,2-diphenylethyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
6-(5-bicydo[2.2 l]hept-2-enylmethyl)-N-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]-6- azaspiro [2.5 ] octane-2-carboxamide;
N-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]-6-(2,3,3-trimethylbut l)-6- azaspiro[2.5]octane-2-carboxamide;
6-chloro-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3- dimethylpyrazol-4-yl)pyrazin-2-amine;
5- (l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,3,3-1ximethylbutyl)-6-azaspiror2.5]octan-2- yl]methyl]pyrazin-2-amine;
N-ff6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3-dimethylpyrazol-4- yl)pyrazin-2-amine;
6- (2-chloro-4-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(4-methyl-3- pyridy l)pyridazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2- fluorophenyl)pyridazin-3-amine; N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3- fluoropheny l)pyri dazin-3 -amine;
6-(2,4-difluorophenyl)-iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(5-fluoro-2-methyl- pheny l)pyri dazin-3 -amine;
6-(2,5-difluoroplienyl)-N-[[6-(3,3-dimethyibutyl)-6-azaspiro[2.5]ocian-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(5-fluoro-2-methoxy- pheny l)pyri dazin-3 -amine;
6~(3 ,4-difl uoropheny l)~A- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2, 5 ] octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
6-(3 , 5-difl uoropheny \)-N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2, 5 ] octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2.5 ] octan-2-yl]methyl] -6-phenyl-pyridazin-3 - amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2,4-dimethylpyrazol-3- yl)pyri dazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3,5-trimethylpyrazoM yl)pyri dazin-3 -amine;
Ar-[[6-(3,3-dimethylbutyl)-6-azaspiro[2^]octan-2-yl]methyl]-6-(3,5-dimethy]isoxazol-4- yl)pyri dazin-3 -amine;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiror2.5]octan-2-yl]methyll-6-(2-methylpyrazol-3- yl)pyri dazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiror2.5]octan-2-yl]rnethyl]-6-[2-methyl-5- (trifluoromethyl)pyrazol-3-yl]pyridazin-3-amine;
N-[4-[6-fff6-(3,3-dimethylbutyl)-6-azaspirof2.5]octan-2-yl]methyl]amino]pyridazin-3- yl]phenyl]acetamide;
6-(2-chloro-3-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl] methyl] pyridazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3-methyl-2- thienyl)pyridazin-3-amine;
2-[6-ff[6-(3,3-dimethylbutyl)-6-azaspirof2.5]octan-2-yl]methyl]amino]pyridazin-3-yl]-4- fluoro-benzonitrile;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(7-isoquinolyl)pyridazin- 3 -amine;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(6-quinolyl)pyridazin-3- amine;
6-( 1 , 3 -benzodioxol- 5-yl)-N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro[2.5] octan-2- yl]methyl]pyridazin-3-amine;
N- [ [6-(3 , 3 -dimethyl butyl)-6-azaspiro [2.5] octan-2-yl] methyl] -6-(2-naphthyl)pyridazin-3 - amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]m.ethyl]-6-[2- ( rill uoromethoxy jpheny 1 ] py ridazin - 3 -ami ne;
N- [ [6-(3 , 3 -dimethyl butyl)-6-azaspiro [2.5] octan-2-yl] methyl] -6- [4-(trifluoromethyl)-3 - pyridyl]pyridazin-3 -amine;
N-[[6-(3,3-dimethylbut\'l)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
6-( 1 ,3 -dimethylpyrazol -4-y 1)-N- [ [6-(2-methy lbutyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2-methylpentyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[(6-ethyl-6-azaspiro[2.5]octan-2-yl)methyl]pyridazin-3- amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[(6-propyl-6-azaspirof2.5]octan-2-yl)methyl]pyridazin-3- amine;
iV-[[6-(cyclopropylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
iV-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
N- [ [6-( 1 -adamantylmethy l)-6-azaspiro[2.5] octan-2-y l]methyl] -6-( 1 , 3 -dimethylpyrazol-4- yl)pyridazin-3 -amine; N-[(6-benzyf-6-azaspiro[2.5"joctan-2-yf)m
amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,2-diphenylethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-( 1 ,3 -dimethy lpyrazol-4-yl)-N- [ [6-(tetrahydropyran-3 -y lmethyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-( 1 ,3 -dimethy lpyrazol-4-yl)-N- [ [6-(tetrahydropyran-4-y lmethyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-[(3-methyl-2-pyridyl)methyl]-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-[[3-(trifluoromethyl)-2-pyridyl]methyl]-6- azaspiro [2.5 ] octan-2-yl ]methy 1 ]pyridazin-3 -amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-iV- [ [6-(3 , 3 -dimethy lbutyl)-6-azaspiro [2.5] octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
(R)-6-(2-chloro-5-fluoro-phenyl)-iV-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
(S)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
(S)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(5-bicyclo[2.2. l ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(2- chloro-5-fluoro-phenyl)pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl)-iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl jmethyi ]pyridin-2-amine;
N-[[6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3- dimethy lpyrazol-4-yl)pyridin-2-amine;
6- (2,4-dimethylpyrazol-3-yl)-N-[[6-(2-te1xahydrofuran-2-ylethyl)-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyr idazin - 3 -ami ne;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-phenyl- thiazol-2-amine;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]memyl]-5-phenyl-thiazol-2-amine; 5- phenyl-N-ff6-(tetrahydropyran-4-ylmethyl)-6-azaspirof2.5]octan-2-yl]methyl]thiazol-
2- amine;
6- (2,4-dimethylpyrazol-3-yl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(3,3-difluoropyrrolidin-l-yl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2,4-dimethylpyrazol-3- yl)-N-methyl-pyridazin-3-amine;
2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-6-(3,3-dimethylbutyl)-6- azaspiro [2.5] octane;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l-piperidyl)pyridazin-3- amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-mo holino-pyΓidazin-3- amine;
6-(4,4-difluoro-l-piperidyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-pyrrolidin- l -yl-pyridazm^
3- amine;
N-[[6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6- rnorpholmo-pyndazin-3-arnine;
N-[[6-(cyck hexylmethy])-6-azaspiro[2.5]octan-2-y]]methyl]-6-morpholino-pyridazm-3- amine;
N-[[6-(l -ackman1ylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-morpholino-pyridazin-
3-amine;
6-morpholino-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyr idazin - 3 -ami ne;
6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3- y 1 ] oxymethy 1 ] -6-azaspiro [2.5] octane;
2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-6-(cyclohexylmethyl)-6- azaspiro [2.5] octane;
N-[(6-benzyl-6-azaspiro[2.5]octan-2-yl)methyl]-4-(l,3-dimethylpyrazol-4-yl)phthalazin- 1 -anwne;
N-ff6-(l -adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l,3-diniethylpyrazol-4- yl)phthalazin- 1 -amine;
6-(cy clopenten- 1 -yl)-N- [ [6-(3 ,3 -dimethylbutyl)-6-azaspiro [2.5 ] octan-2- yl]methyl]pyridazin-3-amine;
6-[(E)-3,3-dimethylbut-l -enyl]-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-[(E)-2-(p- tolyl)vinyl]pyridazin-3-amine;
4-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]phthalazin- 1 -amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3-dimethylpyrazol-4- yl)phthalazin- 1 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3-dimethylpyrazol-4- yl)phthalazin- 1 -amine;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3- dimethylpyrazol-4-yl)phthalazin- 1 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-[(3-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
2-[[2-[[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]amino]methyl]-6-azaspiro[2.5]octan- 6-yl]methyl]benzonitrile;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-f(4-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-[(2-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[(6-benz l-6-azaspiro[2.5]octan-2-yl)methyl]-6-(2-chloro-5-fluoro-phenyl)pyridazin- 3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]imi(Jazo[l,2-b]pyri(Jazm amine;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]- [l,2,4]triazolo[4,3-b]pyridazin-6-amine; N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-[l,2,4]triazolo[4,3- b]pyridazin-6-amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-[l,2,4]triazolo[4,3- b]pyridazin-6-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-3-ylmethyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-(((lR)-6-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-azaspiro[2.5]octan-l-yl)methyl)-6-(2- chloro- 5 -fluoropheny l)py ridazin- 3 -amine ;
(R)-6-(2-chloro-5-fluorophenyl)-N-((6-(cycloheptylmethyl)-6-azaspiro[2.5]octan-l- yl)methyl)pyridazin-3-amine;
N-(((lR)-6-((7-oxabicyclo[2.2^]heptan-2-yl)methyl)-6-azaspiro[2.5]octan-l-yl)methyl)- 6-(2-chloro-5-fluorophenyl)pyridazin-3-amine;
N-[4-[6-[[(2R)-6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[[(2R)-6-benzyl-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- phenyl)pyridazin-3 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[(2R.)-6-(2-pyridylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[(2R.)-6-[(3-methyl-2-pyridyl)methyl]-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-ff(2R)-6-(l-adamantylmethyl)-6-azaspirof2.5]o(rtan-2-yl]methyl]-6-(2-chloro-5-fluoro- phenyl)pyridazin-3 -amine;
N-[4-[6-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methylamino]-4,5-dimethyl- pyridazin-3-yl]phenyl]acetamide;
N-f4-f6-ff6-(cyclohex>4methyl)-6-azaspirof2.5]octan-2-yl]methylamino]-4,5-dimethyl- pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(cycloheptylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-[(3-methyl-2-pyridyl)methyl]-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-[(4-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N~[4~[6~[[(2S)-0-(3,3-dimethylbu
3-yl]phenyl]acetamide;
N-[4-[6-[[(2S)-6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2S)-6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;or a pharmaceutically acceptable salt thereof.
[00299] E28. The compound of any one of E1 -E27, or a pharmaceutically acceptable salt thereof!, wherein the compound is isotopically labeled,
[003ΘΘ] E29. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of El -E28, or a pharmaceutically acceptable salt thereof!, and a pharmaceutically acceptable carrier,
[00301] E30, A method for antagonizing mAChR M4 in a subject, comprising a step of administering to the subject a therapeutically effective amount of the compound of any one of El -E28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E29.
[00302] E31. A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mACh M4, comprising a step of administering to the mammal a therapeutically effective amount of the compound of any one of El -E28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E29.
[00303] E32. The method of E3 , wherein the disorder is a movement disorder.
[00304] E33. The method of E32, wherein the disorder is selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
[00305] E34. A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of E1-E28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E29.
[00306] E35. The method of E34, wherein the subject has a disorder selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
[003Θ7] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.
[00308] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

What is claimed is:
1. A compound of formula I):
Figure imgf000113_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is a five- or six-membered heteroaryl having 1 , 2 or 3 heteroatoms independently selected from N, O and S, or a 9- to 10-membered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1-4 substituents independently selected from halo, C]-C4 alkyl, and Ci-C4 haloalkyl;
Q is selected from \ R '. O, and CRbRL;
R1 is selected from hydrogen, halo, -ORd, -N(Rd)2, C1-C4 alkyl, -CH=CH-Ci-C4 alkyl, optionally substituted cycloalkyi, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and -CH=CH-G;
G is optionally substituted cycloalkyi, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
R2 and R3 are independently selected from hydrogen, C1-C4 alkyl, and halo, or R2 and R3 are taken together to form an oxo group;
each R4 is independently selected from halo, C1-C4 alkyl, and -OR*;
R5 and R6 are independently selected from hydrogen, Ci-Cs alkyl, and
Figure imgf000113_0002
each Y! is independently selected from optionally substituted cycloalkyi, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each R3, Rb, Rc, RQ, Re, R1, and Rg is independently selected from hydrogen, C1-C4 alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
A is a five- or six-membered heteroaiyl having 1,
2 or 3 heteroatoms independently selected from N, O and S; and
R1 is selected from hydrogen, halo, -OR0, Cj-C4 alkyl, optionally substituted cycloalkyl, optionally substituted lieterocycle, optionally substituted aryl, and optionally substituted heteroaiyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa; and
Ra is hydrogen or Ci-C4 alkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Q is NRa; and
Rd is hydrogen.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, halo, -CH=CH-C1-C4 alkyl, -CH=CH-G, Cs-Cg cycloalkenyl, a 4- to 8-membered monocyclic heterocyclyl, a 6- to 12-membered aryl, and a 5- to 6-rnembered monocyclic heteroaryl having 1 , 2, or 3 heteroatoms independently selected from N, O, and S; wherein the cycloalkenyl, heterocyclyl, aryl and heteroaiyl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, Ci- C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR';
G is a 6- to 12-membered aryl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, -C4 haloalkoxy, and -NHCOR'; and
R', at each occurrence, is independently C1-C4 alkyl.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen, phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, qumolinyl, isoquinolinyi, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenvl, or -CH=CH-G, wherein the phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, and cyclopentenyl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano; and
G is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C C4 alkyl, halo, cyano, Cj-C haloalkyl, -C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherein R' is C1-C4 alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from halo, aryl, and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, halo, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherei R' is C¾- C4 alkyl,
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein
R1 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen; and
R3 is hydrogen.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2 and R3 are taken together to form an oxo group.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
m is 0.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R0 is selected from Ci -Cg alkyi and ~(CRfRg)n- Y! ;
R' is hydrogen;
Rg is selected from hydrogen, C1 -C4 alkyi and phenyl;
n is 0 or 1 ; and
Y1 is selected from: C3-C 1 o-cy cloalkyl; Cs-Cio-cycloalkenyl; phenyl; a 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatorns independently selected from N, O and S; and a 5- to 8- membered heterocyclyl having 1 or 2 heteroatorns independently selected from N, O and S; wherein the cyeloalkyl, cycloalkenyl, phenyl, heteroaiyl and heterocyclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from Ci-C4 alkyi, halo, and C1-C4 haloalkyl.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
A is a five-membered heteroaryl having 1 nitrogen atom and optionally 1 -2 additional heteroatorns independently selected from N, O and S, a six-membered heteroaiyl having 1-2 nitrogen atoms, a phthalazinyl, an imidazo[l ,2-b]pyndaziny], or a [l,2,4]triazolo[4,3- bjpyridazinyl, wherein A is optionally substituted with 1 -4 substituents independently selected from halo, C1-C4 alkyi, and C1-C4 haloalkyl.
15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:
A is a thiazol-2,5-diyi, pyridazin-3,6-diyi, pyrazin-2,5-diyl, pyridin-2,5-diyi, phthalazin- 1,4-diyi, imidazo[l,2-b]pyridazin-6-yl, or [l,2,4]triazolo 4,3-b]pyridazin-6-yl, wherein A is optionally substituted with 1-4 substituents independently selected from halo, C1-C4 alkyi, and C1-C4 haloalkyl.
16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is selected from: wherein
T is selected from O, S and NH; and
U, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y. and Z are N.
17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is selected from
Figure imgf000117_0001
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (la): wherein:
W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
1 or 2 of W, X, Y and Z are N.
21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (lb):
Figure imgf000118_0001
22. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from: halo; aryl; and a 5- to 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from C1 -C4 alkyl, halo, cyano, C1 -C4 haloalkyl, Ci~C4 alkoxy, C1-C4 haloalkoxy, and -NHCOR', wherein R' is Ci~ C4 alkyl.
23. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen; and
R3 is hydrogen.
24. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R ' and are taken together to form an oxo group.
25. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
RJ is hydrogen.
26. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from C C8 alkyl and -(CRfRg)„- Y! ;
R1 is hydrogen;
Rg is selected from hydrogen, C1 -C4 alkyl and phenyl;
n is 0 or 1 ; and
Y{ is selected from: C3-C 1 o-cy cloalkyl; Cs-Cio-cycloalkenyl; phenyl; a 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; and a 5- to 8- membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the ey cloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from Cj-Gi alkyl, halo, and Q-C4 haloalkyl
27. The compound of claim 1 , wherein the compound is selected from:
6-(2-chloro-5-fluorophenyl)-iV~[[6~[[3-(trifluoromethyl)-2-pyridyl]methyl]-6~ azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N- [ [6-(3 , 3 -dimethyl butyl)-6-azaspiro[2.5 ] octan-2-yl] methyl] -6-(4- fluoropheny l)pyri dazi n-3 -amine;
A/-((6-(((li?,2A3,45)-7-oxabicyclo[2.2. l ]heptan-2-yl)methyl)-6-azaspiro[2.5]octan-l - yl)methyl)-6-( 1 , 3 -dimethyl- 1 H -pyrazol-4-yl)py ri dazin-3 -amine;
N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-6-(2,3,3-trimethylbutyl)-6- azaspiro[2.5]octane-2-carboxamide;
N-(6-(l,4-dimethyl-lH-pyrazol-5-yl)pyridazin-3-yl)-6-(3,3-dimethylbutyl)-6- azaspiro[2.5]octane-l -carboxamide;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l ,3-dimethylpyrazol-4- yl)pyridin-2-amine;
6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-6- azaspiro[2.5]octane-2-carboxamide;
iV-ff6-(5-bicyclof2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3- dimethylpyrazol-4-yl)pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine; N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2- chloro-5-fluoro-phenyl)pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(2,3,3-trimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-3-ylmethyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
N-[[6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- pheny l)pyridazin-3 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-(2,2-diphenylethyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
6-(5-bicydo[2.2 l]hept-2-enylmethyl)-N-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]-6- azaspiro [2.5 ] octane-2-carboxamide;
N-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]-6-(2,3,3-trimethylbut l)-6- azaspiro[2.5]octane-2-carboxamide;
6-chloro-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3- dimethylpyrazol-4-yl)pyrazin-2-amine;
5- (l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,3,3-1ximethylbutyl)-6-azaspiror2.5]octan-2- yl]methyl]pyrazin-2-amine;
N-ff6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3-dimethylpyrazol-4- yl)pyrazin-2-amine;
6- (2-chloro-4-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(4-methyl-3- pyridy l)pyridazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2- fluorophenyl)pyridazin-3-amine; N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3- fluoropheny l)pyri dazin-3 -amine;
6-(2,4-difluorophenyl)-iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(5-fluoro-2-methyl- pheny l)pyri dazin-3 -amine;
6-(2,5-difluoroplienyl)-N-[[6-(3,3-dimethyibutyl)-6-azaspiro[2.5]ocian-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(5-fluoro-2-methoxy- pheny l)pyri dazin-3 -amine;
6~(3 ,4-difl uoropheny l)~A- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2, 5 ] octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
6-(3 , 5-difl uoropheny \)-N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2, 5 ] octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro [2.5 ] octan-2-yl]methyl] -6-phenyl-pyridazin-3 - amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2,4-dimethylpyrazol-3- yl)pyri dazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3,5-trimethylpyrazoM yl)pyri dazin-3 -amine;
Ar-[[6-(3,3-dimethylbutyl)-6-azaspiro[2^]octan-2-yl]methyl]-6-(3,5-dimethy]isoxazol-4- yl)pyri dazin-3 -amine;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiror2.5]octan-2-yl]methyll-6-(2-methylpyrazol-3- yl)pyri dazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiror2.5]octan-2-yl]rnethyl]-6-[2-methyl-5- (trifluoromethyl)pyrazol-3-yl]pyridazin-3-amine;
N-[4-[6-fff6-(3,3-dimethylbutyl)-6-azaspirof2.5]octan-2-yl]methyl]amino]pyridazin-3- yl]phenyl]acetamide;
6-(2-chloro-3-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl] methyl] pyridazin-3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(3-methyl-2- thienyl)pyridazin-3-amine;
2-[6-ff[6-(3,3-dimethylbutyl)-6-azaspirof2.5]octan-2-yl]methyl]amino]pyridazin-3-yl]-4- fluoro-benzonitrile;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(7-isoquinolyl)pyridazin- 3 -amine;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(6-quinolyl)pyridazin-3- amine;
6-( 1 , 3 -benzodioxol- 5-yl)-N- [ [6-(3 , 3 -dimethylbutyl)-6-azaspiro[2.5] octan-2- yl]methyl]pyridazin-3-amine;
N- [ [6-(3 , 3 -dimethyl butyl)-6-azaspiro [2.5] octan-2-yl] methyl] -6-(2-naphthyl)pyridazin-3 - amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]m.ethyl]-6-[2- ( rill uoromethoxy jpheny 1 ] py ridazin - 3 -ami ne;
N- [ [6-(3 , 3 -dimethyl butyl)-6-azaspiro [2.5] octan-2-yl] methyl] -6- [4-(trifluoromethyl)-3 - pyridyl]pyridazin-3 -amine;
N-[[6-(3,3-dimethylbut\'l)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
6-( 1 ,3 -dimethylpyrazol -4-y 1)-N- [ [6-(2-methy lbutyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2-methylpentyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[(6-ethyl-6-azaspiro[2.5]octan-2-yl)methyl]pyridazin-3- amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[(6-propyl-6-azaspirof2.5]octan-2-yl)methyl]pyridazin-3- amine;
iV-[[6-(cyclopropylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l ,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
iV-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l,3-dimethylpyrazol-4- yl)pyridazin-3 -amine;
N- [ [6-( 1 -adamantylmethy l)-6-azaspiro[2.5] octan-2-y l]methyl] -6-( 1 , 3 -dimethylpyrazol-4- yl)pyridazin-3 -amine; N-[(6-benzyf-6-azaspiro[2.5"joctan-2-yf)m
amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(2,2-diphenylethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-( 1 ,3 -dimethy lpyrazol-4-yl)-N- [ [6-(tetrahydropyran-3 -y lmethyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-( 1 ,3 -dimethy lpyrazol-4-yl)-N- [ [6-(tetrahydropyran-4-y lmethyl)-6-azaspiro [2.5] octan-2- yl]methyl]pyridazin-3-amine;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-[(3-methyl-2-pyridyl)methyl]-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
6-(l ,3-dimethylpyrazol-4-yl)-N-[[6-[[3-(trifluoromethyl)-2-pyridyl]methyl]-6- azaspiro [2.5 ] octan-2-yl ]methy 1 ]pyridazin-3 -amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-iV- [ [6-(3 , 3 -dimethy lbutyl)-6-azaspiro [2.5] octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
(R)-6-(2-chloro-5-fluoro-phenyl)-iV-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin -3 -ami ne;
(S)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
(S)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(5-bicyclo[2.2. l ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(2- chloro-5-fluoro-phenyl)pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl)-iV-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl jmethyi ]pyridin-2-amine;
N-[[6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-(l,3- dimethy lpyrazol-4-yl)pyridin-2-amine;
6- (2,4-dimethylpyrazol-3-yl)-N-[[6-(2-te1xahydrofuran-2-ylethyl)-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyr idazin - 3 -ami ne;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-5-phenyl- thiazol-2-amine;
N-[[6-(3,3-dimethylbu1yl)-6-azaspiro[2.5]octan-2-yl]memyl]-5-phenyl-thiazol-2-amine; 5- phenyl-N-ff6-(tetrahydropyran-4-ylmethyl)-6-azaspirof2.5]octan-2-yl]methyl]thiazol-
2- amine;
6- (2,4-dimethylpyrazol-3-yl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(3,3-difluoropyrrolidin-l-yl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2,4-dimethylpyrazol-3- yl)-N-methyl-pyridazin-3-amine;
2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-6-(3,3-dimethylbutyl)-6- azaspiro [2.5] octane;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-(l-piperidyl)pyridazin-3- amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-mo holino-pyΓidazin-3- amine;
6-(4,4-difluoro-l-piperidyl)-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- y 1 ] methyl ] pyr idazin - 3 -ami ne;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-pyrrolidin- l -yl-pyridazm^
3- amine;
N-[[6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6- rnorpholmo-pyndazin-3-arnine;
N-[[6-(cyck hexylmethy])-6-azaspiro[2.5]octan-2-y]]methyl]-6-morpholino-pyridazm-3- amine;
N-[[6-(l -ackman1ylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-morpholino-pyridazin-
3-amine;
6-morpholino-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- y 1 ] methy i ] pyr idazin - 3 -ami ne;
6-(5-bicyclo[2.2.1 ]hept-2-enylmethyl)-2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3- y 1 ] oxymethy 1 ] -6-azaspiro [2.5] octane;
2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-6-(cyclohexylmethyl)-6- azaspiro [2.5] octane;
N-[(6-benzyl-6-azaspiro[2.5]octan-2-yl)methyl]-4-(l,3-dimethylpyrazol-4-yl)phthalazin- 1 -anwne;
N-ff6-(l -adamantylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l,3-diniethylpyrazol-4- yl)phthalazin- 1 -amine;
6-(cy clopenten- 1 -yl)-N- [ [6-(3 ,3 -dimethylbutyl)-6-azaspiro [2.5 ] octan-2- yl]methyl]pyridazin-3-amine;
6-[(E)-3,3-dimethylbut-l -enyl]-N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-6-[(E)-2-(p- tolyl)vinyl]pyridazin-3-amine;
4-(l ,3-dimethylpyrazol-4-yl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]phthalazin- 1 -amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3-dimethylpyrazol-4- yl)phthalazin- 1 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3-dimethylpyrazol-4- yl)phthalazin- 1 -amine;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-4-(l ,3- dimethylpyrazol-4-yl)phthalazin- 1 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-[(3-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
2-[[2-[[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]amino]methyl]-6-azaspiro[2.5]octan- 6-yl]methyl]benzonitrile;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-f(4-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[6-[(2-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
N-[(6-benz l-6-azaspiro[2.5]octan-2-yl)methyl]-6-(2-chloro-5-fluoro-phenyl)pyridazin- 3 -amine;
N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]imi(Jazo[l,2-b]pyri(Jazm amine;
N-[[6-(5-bicyclo[2.2.1]hept-2-enylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]- [l,2,4]triazolo[4,3-b]pyridazin-6-amine; N-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methyl]-[l,2,4]triazolo[4,3- b]pyridazin-6-amine;
N-[[6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methyl]-[l,2,4]triazolo[4,3- b]pyridazin-6-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-3-ylmethyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
(R)-6-(2-chloro-5-fluoro-phenyl)-N-[[6-(tetrahydropyran-4-ylmethyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-(((lR)-6-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-azaspiro[2.5]octan-l-yl)methyl)-6-(2- chloro- 5 -fluoropheny l)py ridazin- 3 -amine ;
(R)-6-(2-chloro-5-fluorophenyl)-N-((6-(cycloheptylmethyl)-6-azaspiro[2.5]octan-l- yl)methyl)pyridazin-3-amine;
N-(((lR)-6-((7-oxabicyclo[2.2^]heptan-2-yl)methyl)-6-azaspiro[2.5]octan-l-yl)methyl)- 6-(2-chloro-5-fluorophenyl)pyridazin-3-amine;
N-[4-[6-[[(2R)-6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[[(2R)-6-benzyl-6-azaspiro[2.5]octan-2-yl]methyl]-6-(2-chloro-5-fluoro- phenyl)pyridazin-3 -amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[(2R.)-6-(2-pyridylmethyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyridazin-3-amine;
6-(2-chloro-5-fluoro-phenyl)-N-[[(2R.)-6-[(3-methyl-2-pyridyl)methyl]-6- azaspiro[2.5]octan-2-yl]methyl]pyridazin-3-amine;
N-ff(2R)-6-(l-adamantylmethyl)-6-azaspirof2.5]o(rtan-2-yl]methyl]-6-(2-chloro-5-fluoro- phenyl)pyridazin-3 -amine;
N-[4-[6-[[6-(3,3-dimethylbutyl)-6-azaspiro[2.5]octan-2-yl]methylamino]-4,5-dimethyl- pyridazin-3-yl]phenyl]acetamide;
N-f4-f6-ff6-(cyclohex>4methyl)-6-azaspirof2.5]octan-2-yl]methylamino]-4,5-dimethyl- pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(cycloheptylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(l-adamantylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-[(3-methyl-2-pyridyl)methyl]-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2R)-6-[(4-fluorophenyl)methyl]-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;
N-[4-[6-[[(2S)-6-(3,3-dimethylbut\d)-6-azaspiro[2 ]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2S)-6-(cyclohexylmethyl)-6-azaspiro[2.5]octan-2-yl]methylamino]pyridazin- 3-yl]phenyl]acetamide;
N-[4-[6-[[(2S)-6-(tetrahydropyran-4-ylmethyl)-6-azaspiro[2.5]octan-2- yl]methylamino]pyridazin-3-yl]phenyl]acetamide;or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof!, and a pharmaceutically acceptable carrier.
30. A method for antagonizing mAChR M4 in a subject, comprising a step of administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
31. A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M4, comprising a step of administering to the mammal a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
32. The method of claim 31, wherein the disorder is a movement disorder.
33. The method of claim 32, wherein the disorder is selected from Parkinson's disease, drug- induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
34. A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound claim 1, or a pharmaceutically acceptable salt thereof.
35. The method of claim 34, wherein the subject has a disorder selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
PCT/US2018/041783 2017-07-12 2018-07-12 Antagonists of the muscarinic acetylcholine receptor m4 WO2019014427A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP18831342.3A EP3651762B1 (en) 2017-07-12 2018-07-12 Antagonists of the muscarinic acetylcholine receptor m4
AU2018300980A AU2018300980A1 (en) 2017-07-12 2018-07-12 Antagonists of the muscarinic acetylcholine receptor M4
KR1020207003737A KR20200027992A (en) 2017-07-12 2018-07-12 Antagonist of muscarinic acetylcholine receptor M4
US16/629,491 US20220048913A1 (en) 2017-07-12 2018-07-12 Antagonists of the muscarinic acetylcholine receptor m4
JP2020501337A JP2020526557A (en) 2017-07-12 2018-07-12 Antagonist of muscarinic acetylcholine receptor M4
CN201880045391.5A CN110891569A (en) 2017-07-12 2018-07-12 Antagonists of muscarinic acetylcholine receptor M4
CA3068842A CA3068842A1 (en) 2017-07-12 2018-07-12 Antagonists of the muscarinic acetylcholine receptor m4
IL271805A IL271805A (en) 2017-07-12 2020-01-02 Antagonists of the muscarinic acetylcholine receptor m4

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762531818P 2017-07-12 2017-07-12
US62/531,818 2017-07-12

Publications (1)

Publication Number Publication Date
WO2019014427A1 true WO2019014427A1 (en) 2019-01-17

Family

ID=65002384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/041783 WO2019014427A1 (en) 2017-07-12 2018-07-12 Antagonists of the muscarinic acetylcholine receptor m4

Country Status (9)

Country Link
US (1) US20220048913A1 (en)
EP (1) EP3651762B1 (en)
JP (1) JP2020526557A (en)
KR (1) KR20200027992A (en)
CN (1) CN110891569A (en)
AU (1) AU2018300980A1 (en)
CA (1) CA3068842A1 (en)
IL (1) IL271805A (en)
WO (1) WO2019014427A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11149022B2 (en) 2017-10-17 2021-10-19 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11325896B2 (en) 2017-12-20 2022-05-10 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
WO2022152853A1 (en) * 2021-01-15 2022-07-21 Glaxosmithkline Intellectual Property Development Limited Antagonists of mrgx2
WO2023016447A1 (en) * 2021-08-09 2023-02-16 Sironax Ltd. Ferroptosis modulators, preparations, and uses thereof
WO2023141511A1 (en) * 2022-01-19 2023-07-27 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120157410A1 (en) * 2006-04-28 2012-06-21 U.S. Government Compositions and treatments using pyridazine compounds and cholinesterase inhibitors
WO2017083867A1 (en) * 2015-11-12 2017-05-18 Afasci, Inc. Ion channel inhibitory compounds, pharmaceutical formulations and uses

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012047703A2 (en) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-piperidines useful as sodium channel blockers
AU2018352828A1 (en) * 2017-10-17 2020-04-23 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120157410A1 (en) * 2006-04-28 2012-06-21 U.S. Government Compositions and treatments using pyridazine compounds and cholinesterase inhibitors
WO2017083867A1 (en) * 2015-11-12 2017-05-18 Afasci, Inc. Ion channel inhibitory compounds, pharmaceutical formulations and uses

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
"C.T.F.A. Cosmetic Ingredient Handbook", 1992, MEADE PUBLISHING CO., pages: 587 - 592
"Handbook of Chemistry and Physics", article "Periodic Table of the Elements"
"Modern Pharmaceutics", 1979
"Pure Appl. Chem.", vol. 45, 1976, article "IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry", pages: 13 - 30
"Remington's Pharmaceutical Sciences", 1975, pages: 335 - 337
ANSEL, INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS, 1976
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
CROY ET AL., EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 782, 2016, pages 70 - 76
CROY ET AL.: "Characterization of PCS1055, a Novel Muscarinic M4 Receptor Antagonist", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 782, 2016, pages 70 - 76, XP029532648 *
FURNISSHANNAFORDSMITHTATCHELL: "Vogel's Textbook of Practical Organic Chemistry", 1989, LONGMAN SCIENTIFIC & TECHNICAL
LIEBERMAN ET AL., PHARMACEUTICAL DOSAGE FORMS: TABLETS, 1981
MCCUTCHEON: "Emulsifiers & Detergents", vol. 1, 1994, pages: 236 - 239
PGM WUTSTW GREENE: "Greene's book titled Protective Groups in Organic Synthesis", 2006, JOHN WILEY & SONS
See also references of EP3651762A4
SMITHMARCH: "March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS, INC.
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11149022B2 (en) 2017-10-17 2021-10-19 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11325896B2 (en) 2017-12-20 2022-05-10 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
WO2022152853A1 (en) * 2021-01-15 2022-07-21 Glaxosmithkline Intellectual Property Development Limited Antagonists of mrgx2
WO2023016447A1 (en) * 2021-08-09 2023-02-16 Sironax Ltd. Ferroptosis modulators, preparations, and uses thereof
WO2023141511A1 (en) * 2022-01-19 2023-07-27 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Also Published As

Publication number Publication date
AU2018300980A1 (en) 2020-01-02
CN110891569A (en) 2020-03-17
EP3651762A4 (en) 2021-02-24
EP3651762A1 (en) 2020-05-20
EP3651762B1 (en) 2024-07-03
KR20200027992A (en) 2020-03-13
CA3068842A1 (en) 2019-01-17
US20220048913A1 (en) 2022-02-17
JP2020526557A (en) 2020-08-31
IL271805A (en) 2020-02-27

Similar Documents

Publication Publication Date Title
US11820757B2 (en) Antagonists of the muscarinic acetylcholine receptor M4
EP3651762B1 (en) Antagonists of the muscarinic acetylcholine receptor m4
US11352344B2 (en) Antagonists of the muscarinic acetylcholine receptor M4
EP3746421B1 (en) Antagonists of the muscarinic acetylcholine receptor m4
US11225484B2 (en) Substituted octahydropyrrolo[3,4-b]pyrroles as antagonists of the muscarinic acetylcholine receptor M4
US11149022B2 (en) Antagonists of the muscarinic acetylcholine receptor M4
US11325896B2 (en) Antagonists of the muscarinic acetylcholine receptor M4
US20240010640A1 (en) Antagonists of the muscarinic acetylcholine receptor m4
US20230322799A1 (en) Antagonists of the muscarinic acetylcholine receptor m4

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18831342

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2018300980

Country of ref document: AU

Date of ref document: 20180712

Kind code of ref document: A

Ref document number: 3068842

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020501337

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20207003737

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2018831342

Country of ref document: EP

Effective date: 20200212