WO2011045258A1 - Condensed azine - derivatives for the treatment of diseases related to the acetylcholine receptor - Google Patents

Condensed azine - derivatives for the treatment of diseases related to the acetylcholine receptor Download PDF

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Publication number
WO2011045258A1
WO2011045258A1 PCT/EP2010/065160 EP2010065160W WO2011045258A1 WO 2011045258 A1 WO2011045258 A1 WO 2011045258A1 EP 2010065160 W EP2010065160 W EP 2010065160W WO 2011045258 A1 WO2011045258 A1 WO 2011045258A1
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Prior art keywords
methyl
esi
alkyl
mmol
optionally substituted
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PCT/EP2010/065160
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French (fr)
Inventor
Paul David Ratcliffe
Thomas Russell Clarkson
Fiona Jeremiah
John Kinnaird Ferguson Maclean
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N.V. Organon
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Priority to JP2012533593A priority Critical patent/JP2013507417A/en
Priority to BR112012008518A priority patent/BR112012008518A2/en
Priority to IN2968DEN2012 priority patent/IN2012DN02968A/en
Priority to CN2010800465507A priority patent/CN102666540A/en
Priority to CA2776835A priority patent/CA2776835A1/en
Priority to AU2010305825A priority patent/AU2010305825A1/en
Priority to MX2012004289A priority patent/MX2012004289A/en
Priority to EP10771062.6A priority patent/EP2488520B1/en
Priority to RU2012119488/04A priority patent/RU2012119488A/en
Priority to US13/501,587 priority patent/US8841289B2/en
Publication of WO2011045258A1 publication Critical patent/WO2011045258A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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

Abstract

The present invention relates to a heterocyclic derivative of formula (I) wherein the variables are as defined in the specification or to a pharmaceutically acceptable salt or solvate thereof. The present invention further relates to pharmaceutical compositions comprising said heterocyclic derivatives and to their use in therapy, for instance in the treatment or prevention of disorders mediated by nicotinic acetylcholine receptors, such as schizophrenia and Alzheimer's disease.

Description

CONDENSED AZINE - DERIVATIVES FOR THE TREATMENT OF DISEASES RELATED
TO THE ACETYLCHOLINE RECEPTOR
The present invention relates to heterocyclic derivatives, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular, to their use in the 5 treatment or prevention of diseases or disorders mediated by nicotinic acetylcholine receptors such as schizophrenia or Alzheimer's disease.
Acetylcholine receptors (AChRs) can be divided into two distinct protein families: the metabotrophic muscarinic acetylcholine receptors (mAChRs) and the ionotrophic nicotinic0 acetylcholine receptors (nAChRs). Both receptors are activated by the endogenous neurotransmitter acetylcholine (ACh). Muscarinic acetylcholine receptors (MAChRs) are G-protein coupled proteins. Nicotinic acetylcholine receptors (nAChRs) are members of the ligand-gated ion channel family. When activated, the conductance of ions across the nicotinic ion channel increases. The nicotinic alpha 7 receptor channel is a homomeric5 pentamer and is expressed both in the periphery and central nervous system (CNS). The nicotinic alpha 7 receptor channel is expressed in various brain regions and is therefore involved in many important biological processes in the CNS, including learning and memory. Compounds which bind to nicotinic acetylcholine receptors are therefore useful for the treatment of a range of disorders involving reduced cholinergic function such as0 Alzheimer's disease, cognitive or attention disorders, anxiety, neuroprotection, schizophrenia, analgesia, Tourette's syndrome, Parkinson's disease and immune disorders. For recent reviews on nicotinic acetylcholine receptors and their therapeutic use see D'hoedt and Bertrand in Expert Opin. Ther. Targets (2009), 13(4), 395-41 1 ; Cincotta, S.L. et al. in Current Opin. Invest. Drugs (2008), 9, 47-56 and Hashimoto et al. in5 Current Med. Chem., (2005), 5(3), 171 -184.
Nicotinic acetylcholine receptor ligands comprising bridged multicyclic amines are known in the art. For example, WO 01/60821 relates to biarylcarboxamides indicated to be useful in the treatment of a range of disorders involving reduced cholinergic function, such0 as psychotic and intellectual impairment disorders. WO2004/022556 relates to aza- bicycloalkyl ethers indicated to be oc7 nicotinic acetylcholine receptor agonists and useful in the treatment of psychotic disorders, neurodegenerative disorders and other intellectual impairment disorders. 5 WO 03/062235 relates to thio-bridged aryl compounds capable of modulating acetylcholine receptors and their use in the treatment of nervous system disorders. WO 2008/033764 relates to quinazolinone and isoquinolinone acetamide derivatives indicated to be useful for the treatment of disorders or diseases influenced by modulation of the activity of the HPA axis, such as depression and stress related disorders. WO2009/107236 relates to pyridopyrimidin-4-one derivatives indicated to be vasopressin V1b antagonists and their use in therapy.
In a first aspect, the present inv cyclic derivative of formula I
Figure imgf000003_0001
formula I
wherein
R1 is H, Ci-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8cycloalkylCi-2alkyl, Z-Ci-2alkyl or a 4-8 membered heterocyclyl comprising one or more heteroatomic moiety independently selected from O, S, SO and S02 wherein Z is a 5-6 membered heteroaryl comprising one or more heteroatom independently selected from O, N, and S, said Ci-8alkyl, C3-8cycloalkyl, C3-8cycloalkylCi-2alkyl, 5-6 membered heteroaryl and 4- 8 membered heterocyclyl being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, Ci-6alkoxyl, CONR3R4, S02NR5R6 and C02Ci-6alkyl;
R2 is H, Ci-8alkyl, C3-8cycloalkyl or C3-8cycloalkylCi-2alkyl, said Ci-8alkyl, C3-8cycloalkyl and C3-8cycloalkylCi-2alkyl being optionally substituted with one or more substituent independently selected from halogen, hydroxyl and methoxy or
R2 is C6-ioaryl optionally substituted with one or more substituent independently selected from halogen, hydroxy, cyano, Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3- 6cycloalkyloxy, said Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3-6cycloalkyloxy being optionally substituted with one or more halogens or
R2 is a 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S and optionally substituted with methyl, Ci-6alkyloxy, halogen or cyano; R3 and R4 are independently H or Ci-6alkyl or R3 and R4 together with the N to which they are bonded form a 4-7 membered heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S, SO and S02, said Ci-6alkyl and 4-7 membered heterocyclic ring being optionally substituted with one or more halogens; R5 and R6 are independently H or Ci-6alkyl or R5 and R6 together with the N to which they are bonded form a 4-7 membered heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S, SO and S02, said Ci-6alkyl and 4-7 membered heterocyclic ring being optionally substituted with one or more halogens;
X1 is CO or S02;
X2 is N or CH;
Figure imgf000004_0001
is a substituted arylene or heteroarylene fused to the pyrimidinone at ad acent carbon atoms and is selected from:
Figure imgf000004_0002
R7 is (Y)mR8, wherein
Y is O, NR9 or CR10R11 ;
m is 0 or 1 ;
R8 is a 6-10 membered bridged or fused multicyclic saturated or partially unsaturated ring system comprising a N(R12)n moiety and optionally comprising a N(R13)P moiety, said bridged or fused multicyclic ring system being optionally substituted with methyl or hydroxyl;
R9 is H or Ci-6alkyl;
R10 and R11 are independently H or Ci-6alkyl;
R12 and R13 are independently H, Ci-6alkyl or oxo;
R14 is a further optional substituent selected from methyl, halogen and cyano; n is 0 or 1 and
p is 0 or 1
with the proviso that when R7 is 1 ,4-diazabicyclo[3.2.2]non-4-yl or octahydropyrrolo[1 ,2- a]pyrazin-2-yl, one or both of R3 and R4 cannot be H.
or a pharmaceutically acceptable salt or solvate thereof.
The term Ci-8alkyl, as used herein, represents a branched or unbranched alkyl group having 1-8 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tertiary butyl and n-heptyl. Similarly the term Ci-6alkyl, as used herein, represents a branched or unbranched alkyl group having 1-6 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tertiary butyl and n-pentyl.
The term C2-8alkenyl, as used herein, represents a branched or unbranched alkenyl group having 2-8 carbon atoms and at least one double bond. Examples of such groups are ethenyl, isopropenyl and 2-methylbuten-2-yl.
The term C2-8alkynyl, as used herein, represents a branched or unbranched alkynyl group having 2-8 carbon atoms and at least one triple bond. Examples of such groups are ethynyl, propynyl and 3-methylbuten-1-yl.
The term C3-8cycloalkyl, as used herein, represents a branched or unbranched cyclic alkyl group having 3-8 carbon atoms. Examples of such groups are cyclopropyl, cyclopentyl and 2-methylcyclohexyl. The term C3-8cycloalkylCi-2alkyl, as used herein, represents a Ci-2alkyl group which is substituted with a C3-8cycloalkyl group. Examples of such groups are cyclopropylmethyl, and 2-cyclobutylethyl.
The term Ci-6alkyloxy, as used herein, represents a branched or unbranched alkyloxy group having 1-6 carbon atoms. Examples of such groups are C02CH3 and CO2C2H5.
The term C02Ci-6alkyl, as used herein, represents a carboxylic acid ester formed from an alcohol having 1-6 carbon atoms. Examples of such groups are methoxymethyl, and ethoxyethyl. The term C6-ioaryl, as used herein, represents an aromatic group having 6-10 carbon atoms and comprising one ring or two rings fused together, at least one of which must be aromatic. Examples of such groups include phenyl and naphthyl. The term halogen, as used herein, represents a fluorine, chlorine, bromine or iodine.
The term solvate, as used herein, refers to a complex of variable stoichiometry formed by a solvent and a solute (in this invention, a compound of formula I). Such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include water, ethanol and acetic acid.
Examples of 4-8 membered heterocyclyl comprising one or more moiety independently selected from O, S, SO and S02 include tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl and tetrahydrothiopyranyl.
Examples of 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S include furanyl, pyrrolyl, thienyl, imidazolyl, pyrrazolyl, thiazolyl, pyridinyl pyrimidinyl, indolyl, benzthienyl and quinazolinyl. Likewise, examples of 5-6 membered heteroaryl comprising one or more heteroatom independently selected from O, N and S include furanyl, pyrrolyl, thienyl, imidazolyl, pyrrazolyl, thiazolyl, pyridinyl and pyrimidinyl.
Examples of 4-7 membered heterocyclic rings formed by R3 and R4 together with the N to which they are bonded optionally comprising a further heteroatomic moiety selected from O, S, SO and S02 include azetidine, piperidine, pyrrolidine and morpholine.
Similarly, examples of 4-7 membered heterocyclic rings formed by R5 and R6 together with the N to which they are bonded optionally comprising a further heteroatomic moiety selected from O, S, SO and S02 include azetidine, piperidine, pyrrolidine and morpholine. A 6-10 membered bridged multicyclic ring system comprising a N(R12)n moiety and optionally comprising a N(R13)P moiety, as used herein, represents a multicyclic ring system, wherein atoms in one ring having at least one atom between them, are joined together with further atoms to form an additional ring thereby bridging over the first ring. Examples of 6-10 membered bridged multicyclic saturated ring systems comprising a N(R12)n moiety and optionally comprising a N(R13)P moiety include:
Figure imgf000007_0001
Examples of 6-10 membered bridged multicyclic, partially unsaturated, ring systems comprising a N(R12)n moiety and optionally comprising a N(R13)P moiety include:
Figure imgf000007_0002
A 6-10 membered fused multicyclic ring system comprising a N(R12)n moiety and optionally comprising a N(R13)P moiety, as used herein, represents a multicyclic ring system, wherein adjacent atoms in one ring are joined together with further atoms to form an additional ring.
Examples of 6-10 membered fused multicyclic saturated ring systems comprising a N(R12 moiety and optionally comprising a N(R13)P moiety include:
Figure imgf000007_0003
Examples of 6-10 membered fused multicyclic partially unsaturated ring systems comprising a N(R12 moiety and optionally comprising a N(R13)P moiety include:
Figure imgf000007_0004
The skilled person will a , the
compound of formula I is,
Figure imgf000007_0005
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
In one embodiment of the present invention R1 is H or Ci-8alkyl optionally substituted with halogen, hydroxyl, Ci-6alkoxyl, CONR3R4 or S02NR5R6, wherein R3-R6 have the previously defined meanings. In another embodiment, R1 is H or Ci-4alkyl optionally substituted with halogen, hydroxyl, Ci-6alkoxyl, CONR3R4 or S02NR5R6, wherein R3-R6 have the previously defined meanings. In a further embodiment, R1 is H, methyl, ethyl, propyl or isopropyl, optionally substituted with halogen, hydroxyl, Ci-6alkoxyl, CONR3R4 or S02NR5R6, wherein R3-R6 have the previously defined meanings. In a further embodiment, R1 is H, methyl, ethyl, propyl or isopropyl, optionally substituted with halogen, methoxyl, hydroxyl, C02CH3 or CON(CH3)2. In a further embodiment, R1 is H, methyl, ethyl, propyl or isopropyl, optionally substituted with methoxyl or hydroxyl. In a still further embodiment, R1 is H or methyl. In another embodiment of the present invention R1 is C3-8cycloalkyl or C3-8cycloalkylCi. 2alkyl, said C3-8cycloalkyl and C3-8cycloalkylCi-2alkyl being optionally substituted with halogen, hydroxyl, Ci-6alkoxyl, CONR3R4 or S02NR5R6, wherein R3-R6 have the previously defined meanings. In another embodiment, R1 is C3-8cycloalkyl or C3-8cycloalkylCi-2alkyl, said C3-8cycloalkyl and C3-8cycloalkylCi-2alkyl being optionally substituted with hydroxyl or methoxyl. In another embodiment, R1 is cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl, said cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl being optionally substituted with hydroxyl or methoxyl. In a further embodiment, R1 is cyclopropyl or cyclobutyl, optionally substituted with hydroxyl or methoxyl. In a further embodiment of the present invention, R1 is a 4-8 membered heterocyclyl comprising one or more heteroatomic moiety independently selected from O, S, SO and S02, said 4-8 membered heterocyclyl being optionally substituted with halogen, hydroxyl, Ci-6alkyl or Ci-6alkoxyl. In a further embodiment, R1 is a 4-6 membered heterocyclyl comprising one or more heteroatomic moiety independently selected from O, S, SO and S02, said 4-6 membered heterocyclyl being optionally substituted with halogen, hydroxyl, Ci-6alkyl or Ci-6alkoxyl. In a further embodiment, R1 is a 4-6 membered heterocyclyl comprising O, S, SO or S02, said 4-8 membered heterocyclyl being optionally substituted with hydroxyl or methyl. In a further embodiment of the present invention, R1 is Z-Ci-2alkyl, wherein Z is a 5-6 membered heteroaryl comprising one or more heteroatom independently selected from O, S and N said 5-6 membered heteroaryl being optionally substituted with halogen, hydroxyl, Ci-6alkyl or Ci-6alkoxyl. In a further embodiment, R1 is Z-CH2, wherein Z is a 5-6 membered heteroaryl comprising one or more heteroatom independently selected from O, S and N said 5-6 membered heteroaryl being optionally substituted with halogen, methyl or methoxyl.
In one embodiment of the present invention R2 is H, Ci-8alkyl, C3-8cycloalkyl or C3- 8cycloalkylCi-2alkyl, said Ci-8alkyl, C3-8cycloalkyl and C3-8cycloalkylCi-2alkyl being optionally substituted with one or more halogen. In a further embodiment, R2 is H, d. 4alkyl or C3-6cycloalkyl. In a further embodiment, R2 is H, methyl, ethyl, isopropyl or t- butyl. In a still further embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment of the present invention, R2 is C6-ioaryl optionally substituted with one or more substituent independently selected from halogen, hydroxy, cyano, Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3-6cycloalkyloxy, said Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3-6cycloalkyloxy being optionally substituted with one or more halogens. In a further embodiment, R2 is phenyl optionally substituted with one or more substituent independently selected from halogen, hydroxy, cyano, Ci-8alkyl, C3-8cycloalkyl, Ci_ 6alkyloxy and C3-6cycloalkyloxy, said Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3- 6cycloalkyloxy being optionally substituted with one or more halogens. In a still further embodiment, R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano. In another embodiment of the present invention, R2 is a 5-10 membered heteroaryl system comprising a heteroatom selected from N, O and S and optionally substituted with methyl, Ci-6alkyloxy or halogen. In a further embodiment, R2 is a heteroaryl selected from pyridyl, thienyl, pyrrolyl, furanyl, imidazolyl, thiazolyl and pyrazolyl, said heteroaryl being optionally substituted with methyl, Ci-6alkyloxy or halogen. In a still further embodiment, R2 is pyridyl, thiazolyl or furanyl, said pyridyl, thiazolyl and furanyl being optionally substituted with methyl or halogen.
In one embodiment of the present invention,
Figure imgf000010_0001
In a further embodiment of the present invention,
Figure imgf000010_0002
In a further embodiment of the present invention,
Figure imgf000010_0003
In one embodiment of the present invention R7 is
Figure imgf000010_0004
wherein a, b and c are independently 1 or 2.
In another embodiment of the present invention, R7 is selected from:
Figure imgf000011_0001
another embodiment of the present invention, R7
Figure imgf000011_0002
wherein d, e and f are independently 1 or 2.
In another embodiment of the present invention, R7 is:
Figure imgf000011_0003
wherein R13 has the previously defined meanings.
In another embodiment of the present invention R7 is
Figure imgf000011_0004
wherein Y is O, CH or N and g, h and i are independently 1 or 2.
In another embodiment of the present invention, Y is O and m is 1 ;
In another embodiment of the present invention, Y is NH and m is 1 ; another embodiment of the present invention, R7 is selected from
Figure imgf000012_0001
In another embodiment of the present invention R7 is
Figure imgf000012_0002
wherein j, and k are independently 1 or 2 and wherein R13 has the previously defined meanings.
In another embodiment of the prese
Figure imgf000012_0003
wherein R13 has the previously defined meanings. In another embodiment of the pre
Figure imgf000012_0004
wherein I, and o are independently 1 or 2 and wherein R12 has the previously defined meanings.
In another embodime :
Figure imgf000012_0005
wherein R12 has the previously defined meanings. In another embodiment of the present invention, R7 is
Figure imgf000013_0001
wherein w, x, y and z are independently 1 or 2.
In another embodiment of the resent invention, R7 is selected from:
Figure imgf000013_0002
In a further embodiment, R is a 6-10 membered saturated bridged tricyclic ring system comprising a N(CH3)n moiety and optionally comprising a further N(CH3)P moiety, wherein n and p are independently 0 or 1 and wherein said saturated bridged bicyclic ring system is optionally substituted with methyl or hydroxyl.
In a further embodiment, R8 is a 6-10 membered saturated fused bicyclic ring system comprising a N(CH3)n moiety and optionally comprising a further N(CH3)n moiety, wherein n and p are independently 0 or 1 and wherein said saturated bridged bicyclic ring system is optionally substituted with methyl or hydroxyl.
In a further embodiment of the present invention is a heterocyclic derivative of formula II
Formula II
wherein R1, R2 and R7 have the previously defined meanings.
In a further embodiment of the present invention is a heterocyclic derivative of formula III
Figure imgf000014_0001
Formula III
wherein,
R1 is H, methyl, ethyl, propyl or isopropyl, optionally substituted with hydroxyl or methoxyl; R2 is H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano or
R2 is pyridyl, thiazolyl or furanyl, said pyridyl, thiazolyl and furanyl being optionally substituted with methyl or halogen and
R7 is
Figure imgf000014_0002
wherein a, b and c are independently 1 or 2
or a pharmaceutically acceptable salt or solvate thereof.
In a still further embodiment of the present invention is a heterocyclic derivative of formula IV
Figure imgf000014_0003
Formula IV
wherein,
R1 is H, methyl, ethyl, propyl or isopropyl, optionally substituted with hydroxyl or methoxyl; R2 is H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano or
R2 is pyridyl, thiazolyl or furanyl, said pyridyl, thiazolyl and furanyl being optionally substituted with methyl or halogen and
R7 is
Figure imgf000015_0001
or a pharmaceutically acceptable salt or solvate thereof.
In a still further embodiment of the present invention is a heterocyclic derivative of formula V
Figure imgf000015_0002
Formula V
wherein,
R1 is H or methyl;
R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano or
R2 is pyridyl, thiazolyl or furanyl, said pyridyl, thiazolyl and furanyl being optionally substituted with methyl or halogen and
R7 is
Figure imgf000015_0003
or a pharmaceutically acceptable salt or solvate thereof.
In a still further embodiment of the present invention is a heterocyclic derivative of formula VI
Figure imgf000016_0001
Formula VI
wherein,
R1 is H or methyl;
R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano or
R2 is pyridyl, thiazolyl or furanyl, said pyridyl, thiazolyl and furanyl being optionally substituted with methyl or halogen and
R7 is
Figure imgf000016_0002
or a pharmaceutically acceptable salt or solvate thereof.
In a still further embodiment of the present invention is a heterocyclic derivative of formula VII
Figure imgf000016_0003
Formula VII
wherein,
R1 is H or methyl;
R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano or
R2 is pyridyl, thiazolyl or furanyl, said pyridyl, thiazolyl and furanyl being optionally substituted with methyl or halogen and
R7 is
Figure imgf000017_0001
or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment of the present invention is a heterocyclic derivative selected from:
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
or a pharmaceutically acceptable salt or solvate thereof.
The heterocyclic derivatives of the present invention are prepared by methods well known in the art of organic chemistry. See, for example, J. March, 'Advanced Organic Chemistry' 4th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts 'Protective Groups in Organic Synthesis' 2nd Edition, John Wiley and Sons, 1991 . The protective groups are optionally removed at a convenient subsequent stage using methods
Figure imgf000024_0002
formula I
In particular, heterocyclic derivatives of formula I may also be prepared according to the general synthetic sequences presented in WO2008033764 pages 14-20. The skilled person will appreciate that the methods shown can be adapted for the synthesis of analogous derivatives wherein the heteroaryl ring A is a fused thienyl or a fused pyridyl or wherein X1 is a S02 or wherein X2 is a CH.
The present invention also includes within its scope all stereoisomeric forms of heterocyclic derivatives according to the present invention resulting, for example, because of configurational or geometrical isomerism. Such stereoisomeric forms are enantiomers, diastereoisomers, c/'s and trans isomers etc. In the case of the individual stereoisomers of heterocyclic derivatives of formula I or salts or solvates thereof, the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1 % of the other stereoisomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention. For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g., synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art.
The heterocyclic derivatives of the present invention, in the form of a free base, are isolated from reaction mixtures as pharmaceutically acceptable salts. These salts are also obtained by treatment of said free base with an organic or inorganic acid, for example, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.
The heterocyclic derivatives of the present invention may also exist as amorphous forms. Multiple crystalline forms are also possible. All these physical forms are included within the scope of the present invention. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601 -61 1 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS P armSciTec ., 5(1 ), article 12 (2004); and A. L. Bingham et al, C em. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
The present invention also embraces isotopically labelled compounds of the heterocyclic derivatives described and claimed herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively.
Certain isotopically labelled compounds of Formula I (e.g., those labelled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. Prodrugs of the heterocyclic derivatives of the invention are also contemplated within the scope of the invention. A prodrug is a compound which acts as a drug precursor which, upon administration to a subject, undergoes conversion by metabolic or other chemical processes to yield a tetracyclic heterocyclic derivative of formula I or a solvate or salt thereof. A discussion of prodrugs and their use is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 1_4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987.
In a further aspect, the heterocyclic derivatives of the present invention and their pharmaceutically acceptable salts and solvates are useful in therapy. As such the heterocyclic derivatives of the present invention are useful for the manufacture of a medicament for the treatment or prevention of disorders mediated by nicotinic acetylcholine receptors, such as Alzheimer's disease, cognitive or attention disorders, anxiety, neuroprotection, schizophrenia, pain, Tourette's syndrome, Parkinson's disease and immune disorders.
The present invention further includes a heterocyclic derivative for use in the treatment of any of the aforementioned diseases or disorders. The present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from any of the aforementioned diseases or disorders, which comprises administering an effective amount of a heterocyclic derivative according to the present invention or a pharmaceutically acceptable salt or solvate thereof. By effective amount or therapeutically effective amount is meant an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The amount of a heterocyclic derivative of the present invention or a pharmaceutically acceptable salt or solvate thereof, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient and the particular disorder or disease being treated. A suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day. The desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day. Whilst it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The present invention therefore also provides a pharmaceutical composition comprising a heterocyclic derivative according to the present invention in admixture with one or more pharmaceutically acceptable excipient, 5 such as the ones described in Gennaro et. al., Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing. Suitable excipients are also described e.g., in the Handbook of Pharmaceutical Excipients, 2nd Edition; Editors A. Wade and P. J. Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 10 1994. Compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous, intravenous and intramuscular) or rectal administration.
The mixtures of a heterocyclic derivative according to the present invention and one or 15 more pharmaceutically acceptable excipient or excipients may be compressed into solid dosage units, such as tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g., a nasal or buccal spray. For making dosage units e.g., tablets, the use of conventional additives 20 such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive can be used. The heterocyclic derivatives of the invention are also suitable for use in an implant, a patch, a gel or any other preparation for immediate and/or sustained release.
25 Suitable fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as
30 propylene glycol or butylene glycol.
The present invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as 35 hereinbefore described. The invention is further illustrated by the following examples which are not intended to limit the scope thereof.
Methods
General Chemical Procedures: All reagents were either purchased from common commercial sources or synthesised according to literature procedures beginning from commercial reagents. Commercial reagents were used without further purification. Unless otherwise indicated, percent is percent by weight given the component and the total weight of the composition, temperature is in °C or is at ambient temperature and pressure is at or near atmospheric. Ion exchange chromatography was performed using Isolute Flash SCX-II (acidic) resin cartridges. Flash column chromatography was performed using pre-packed silica cartridges (RediSep or Biotage) on a Combiflash™ Retrieve™ system or similar. Microwave reactions were performed using an Emrys Optimizer™ (Personal Chemistry). Semi-preparative high pressure liquid chromatography (semi-prep. HPLC) was performed using the methods outlined below:
Method (i): Phenomenex Gemini (C18, 5 μηι) 30 mm ID x 100 mm; 10-95% acetonitrile- water over a 30 minute gradient; 30 ml/min; 0.1 % trifluoroacetic acid buffer; detection by UV at 254 nm.
Method (ii): Waters XBridge (C18, 5 μηι) 19 mm x 50 mm; 5-20% acetonitrile-water over a 3 minute gradient then 20- 95% acetonitrile-water over a 2 minute gradient; 20 ml/min; 0.1 % trifluoroacetic acid buffer; detection by UV at 254 nm.
Method (iii): Waters XBridge (C18, 5 μηη) 19 mm x 50 mm; 5-95% acetonitrile-water over a 8 minute gradient; 20 ml/min; 0.1 % trifluoroacetic acid buffer; detection by UV at 254 nm.
Mass spectra were recorded on a Shimadzu LC-8A (HPLC) PE Sciex API 150EX LC/MS or on an Agilent 1200 UPLC with Agilent 6140 LC/MS.
Abbreviations
dimethylformamide (DMF), dichloromethane (DCM), diethylamime (DEA), ethyl acetate (EtOAc), ethanol (EtOH), high pressure liquid chromatography (HPLC), hour (hr), liquid chromatography / mass spectroscopy (LC/MS), methanol (MeOH), mass spectroscopy (MS), preparative (prep), racemic (rac), strong cation exchange (SCX), tetrahydrofuran (THF), acid base wash (ABW).
Procedure 1 Intermediate 1A: 5-Fluoro-2-nitrobenzoyl chloride
Figure imgf000030_0001
5-Fluoro-2-nitrobenzoic acid (15.0 g, 81 .0 mmol) was refluxed in thionyl chloride (67.5 g, 5 567 mmol) for 2.5 hours. The reaction mixture was allowed to cool to room temperature and the excess thionyl chloride removed under reduced pressure, to afford 5-fluoro-2- nitrobenzoyl chloride (16.5 g, 81 .0 mmol).
Procedure 2
0 Intermediate 2A: 5-Fluoro-/V-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide
Figure imgf000030_0002
A solution of 2-amino-/V-isopropylacetamide (1 1 .3 g, 97.0 mmol) and N,N- diisopropylethylamine (20.1 g, 162 mmol) in dichloromethane (200 mL) was cooled using an ice water bath. A solution of 5-fluoro-2-nitrobenzoyl chloride (16.5 g, 81.0 mmol) in5 dichloromethane (200 mL) was added dropwise over 15 minutes. The resulting solution was stirred overnight. The reaction mixture was washed with 2N HCI solution (2 x 250 mL), brine (250 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-/V-(2-(isopropylamino)-2- oxoethyl)-2-nitrobenzamide (18.5 g, 65.0 mmol).
0 MS (ESI) m/z 284.0 [M+H]+
Similarly prepared were:
Intermediate 2B: 5-Fluoro-2-nitrobenzamide
Figure imgf000030_0003
5 Intermediate 2C: 5-Fluoro-/V-((1 -(hvdroxymethyl)cvclobutyl)methyl)-2-nitrobenzamide Intermediate 2D:
Intermediate 2E:
Figure imgf000031_0001
Intermediate 2F: 5-Fluoro-/V-(3-hvdroxy-2,2-dimethylpropyl)-2-nitrobenzamide
Figure imgf000031_0002
Procedure 3
Intermediate 3A: 5-Fluoro-/V-methyl-2-nitrobenzamide
Figure imgf000031_0003
A solution of 5-fluoro-2-nitrobenzoic acid (0.5 g, 2.7 mmol) in dichloromethane (10 mL) was cooled with an ice water bath before the addition of Λ/,/V-diisopropylethylamine (1.13 g, 8.1 mmol). To this solution 2M methylamine in tetrahydrofuran (1.6 g, 3.24 mmol) was added dropwise over 5 minutes. 1 -Propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (2.56 mL, 4.05 mmol) was added dropwise. The ice bath was then removed and stirring continued overnight. The mixture was purified on a 2g ABW column to afford 5-fluoro-/V-methyl-2-nitrobenzamide (0.26 g, 1.31 mmol).
Similarly prepared were:
Intermediate 3B: 5-Fluoro-/V-ethyl-2-nitrobenzamide
Figure imgf000031_0004
Intermediate 3C: 5-Fluoro-/V-propyl-2-nitrobenzamide
Figure imgf000032_0001
Intermediate 3D: 5-Fluoro-/V-isobutyl-2-nitrobenzamide
Figure imgf000032_0002
Intermediate 3E: 5-Fluoro-/V-((tetrahvdro-2/-/-pyran-4-yl)methyl)-2-nitrobenzamide
Figure imgf000032_0003
Intermediate 3F: 5-Fluoro-/V-(3-hvdroxy-3-methylbutyl)-2-nitrobenzamide
Figure imgf000032_0004
Intermediate 3G: 5-Fluoro-/V-(propan-3-ol)-2-nitrobenzamide
Figure imgf000032_0005
Intermediate 3H: 5-Fluoro-/V-(cvclopropylmethyl)-2-nitrobenzamide
Figure imgf000032_0006
Intermediate 3I: 5-Fluoro-/V-(isopropyl)-2-nitrobenzamide
Figure imgf000032_0007
Intermediate 3J: 5-Fluoro-/V-((tetrahvdro-2H-thiopyran-4-yl 1 ,1 -dioxide)methyl)-2- nitrobenzamide Intermediate 3K:
Figure imgf000033_0001
Intermediate 3L: 4-Fluoro-/V-methyl-2-nitrobenzamide
Figure imgf000033_0002
Intermediate 3M: 5-Fluoro-/V-(2-methoxyethyl)-2-nitrobenzamide
Figure imgf000033_0003
Procedure 4
Intermediate 4A: 5-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-(2-(isopropylamino)-2- oxoethyl)-2-nitrobenzamide
Figure imgf000033_0004
To a solution of 5-fluoro-/V-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (Intermediate 2A) (7.39 g, 26.1 mmol) in acetonitrile (240 mL) was added potassium carbonate (14.6 g, 104 mmol) followed by 1 ,4-diazabicyclo[3.2.2]nonane dihydrochloride (5.45 g, 27.4 mmol). The resulting suspension was heated to reflux at 96°C overnight. The reaction mixture was filtered and concentrated. Sample was diluted in methanol (100 mL) and split between two 20g SCX cartridges. Purification by SCX and evaporation to dryness afforded 5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-(2-(isopropylamino)-2-oxoethyl)- 2-nitrobenzamide (7.0 g, 18.0 mmol). MS (ESI) m/z 390.0 [M+H]+
Similarly prepared were:
Intermediate 4B: te/f-Butyl 2-(5-(1 ,4-diazabicvclor3.2.21nonan-4-yl)-2- nitrobenzamido)acetate (from Intermediate 3K
Figure imgf000034_0001
Intermediate 4C: /V-(2-(lsopropylamino)-2-oxoethyl)-5-(8-methyl-8- azabicvclor3.2.1 loctan-3-ylamino)-2-nitrobenzamide (from Intermediate 2A)
Figure imgf000034_0002
Intermediate 4D: 5-(1 ,4-Diazabicyclor3.2.21nonan-4-yl)-2-nitrobenzamide (from
Intermediate 2B)
Figure imgf000034_0003
Intermediate 4E: 5-( 1 ,4-Diazabicvclor3.2.21nonan-4-yl)-/\/-methyl-2-nitrobenzamide (from Intermediate 3A)
Figure imgf000034_0004
Intermediate 4F: 5-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-/\/-ethyl-2-nitrobenzamide (from
Intermediate 3B)
Figure imgf000034_0005
Intermediate 4G: 5-(1 ,4-Diazabicvclo[3.2.21nonan-4-yl)-2-nitro-/V-propylbenzamide (from Intermediate 3C)
Figure imgf000035_0001
Intermediate 4H: 5-( 1 ,4-Diazabicvclor3.2.21nonan-4-yl)-A/-isobutyl-2-nitrobenzamide (from Intermediate 3D)
Figure imgf000035_0002
Intermediate 4I: 5-(1 ,4-Diazabicyclor3.2.21nonan-4-yl)-/V-(cvclopropylmethyl)-2- nitrobenzamide (from Intermediate 3H
Figure imgf000035_0003
Intermediate 4J: 5-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-/V-isopropyl-2-nitrobenzamide (from Intermediate 3I)
Figure imgf000035_0004
Intermediate 4K: 5-(114-Diazabicvclor3.2.2lnonan-4-yl)-A/-cvclopropyl-2-nitrobenzamide (from Intermediate 2D)
Figure imgf000035_0005
Intermediate 4L: 5-( 1 ,4-Diazabicvclor3.2.21nonan-4-yl)-/V-cvclobutyl-2- nitrobenzamide (from Intermediate 2E)
Figure imgf000035_0006
Intermediate 4M: 5-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-2-nitro-/V-(tetrahvdro-2H-pyran-4- vDbenzamide (from Intermediate 2E
Figure imgf000036_0001
Intermediate 4N: 5-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-(3-hvdroxy-3-methylbutyl)-2- nitrobenzamide (from Intermediate 3F
Figure imgf000036_0002
Intermediate 40: 5-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-(3-hvdroxypropyl)-2- nitrobenzamide (from Intermediate 3G)
Figure imgf000036_0003
Intermediate 4P: 5-(1 ,4-Diazabicyclo[3.2.2lnonan-4-yl)-/V-(tetrahvdro-2/-/-thiopyran-4-yl 1 ,1 -dioxide)methyl)-2-nitrobenzamide from Intermediate 3J)
Figure imgf000036_0004
Intermediate 4Q: 5-( 1 ,4-Diazabicyclor3.2.2lnonan-4-yl)-/V-((1 - (hvdroxymethyl)cvclobutyl)meth l)-2-nitrobenzamide (from Intermediate 2C)
Figure imgf000036_0005
Intermediate 4R: 5-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-(3-hvdroxy-2,2-dimethylpropyl)-
2-nitrobenzamide (from Intermediate 2F)
Figure imgf000037_0001
Intermediate 4S: 5-( 1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-(2-methoxyethyl)-2- nitrobenzamide (from Intermediate 3M
Figure imgf000037_0002
Procedure 5
Intermediate 5A: (1 S,4S)-te/f-Butyl 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4- nitrophenyl)-2,5-diazabicvclo[2.2.1lheptane-2-carboxylate
Figure imgf000037_0003
To a solution of 5-fluoro-/V-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (1.0 g, 3.53 mmol) (Intermediate 2A) in acetonitrile (20 mL) was added potassium carbonate (1 .46 g, 10.9 mmol) followed by (1 S,4S)-ie f-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.70 g, 3.53 mmol). The resulting suspension was heated to reflux at 90°C for 6 hours. The reaction mixture was allowed to cool to room temperature, then filtered and concentrated. The resultant crude material was purified by a 25g silica column in neat ethylacetate (Biotage Snap cartridge). Fractions of the product were combined and reduced to dryness under reduced pressure to afford {1 S,4S)-tert-buty\ 5-(3-(2- (isopropylamino)-2-oxoethylcarbamoyl)-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (1 .5 g, 3.25 mmol).
MS (ESI) m/z 484.0 [M+Na]+
Similarly prepared were:
Intermediate 5B: te f-Butyl 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4- nitrophenyl)hexahydropyrrolo[3,4-clpyrrole-2(1 /-/)-carboxylate (from Intermediate 2A)
Figure imgf000038_0001
Intermediate 5C: te/f-Butyl 5-(3-(methylcarbamoyl)-4-nitrophenyl)hexahvdropyrrolo[3,4- clpyrrole-2(1 HVcarboxylate (from Intermediate 3A)
Figure imgf000038_0002
Intermediate 5D: (1 S,4S)-te/f-Butyl 5-(3-(methylcarbamoyl)-4-nitrophenyl)-2,5- diazabicyclo[2.2.1 lheptane-2-carboxylate (from Intermediate 3A)
Figure imgf000038_0003
Procedure 6
Intermediate 6A: /V-Methyl-2-nitr -5-(quinuclidin-3-ylamino)benzamide
Figure imgf000038_0004
To a mixture of quinuclidin-3-amine hydrochloride (1.06 g, 5.30 mmol) and polymer supported dimethylperhydro-1 ,3,2-diazaphosphorine (7.0 g, 15.4 mmol) in DMSO (50 mL) was added 5-fluoro-/V-methyl-2-nitrobenzamide (Intermediate 3A) (1 g, 5.05 mmol) and reaction heated at 60 °C for 72 hours. The resin was removed by filtration and washed thoroughly with methanol and dichloromethane. The filtrate was purified using a 20g SCX cartridge followed by trituration with dichloromethane/methanol/diethyl ether to afford /V-methyl-2-nitro-5-(quinuclidin-3-ylamino)benzamide ( 0.41 g, 1.36 mmol).
MS (ESI) m/z 305.2 [M+H]+
Procedure 7 Intermediate 7A: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-(2-(isopropylamino)-2- oxoethvDbenzamide
Figure imgf000039_0001
5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzam (Intermediate 4A) (7.0 g, 18.0 mmol) was dissolved in methanol (120 mL) and palladium on carbon (0.7 g) added. The resulting solution was hydrogenated at room temperature under 4 bar pressure of hydrogen overnight. The reaction mixture was filtered through a celite pad, washed with methanol and dichloromethane, and concentrated to afford 2- amino-5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-(2-(isopropylamino)-2-oxoethyl)benzamide (6.4 g, 17.8 mmol).
MS (ESI) m/z 360.2 [M+H]+
Similarly prepared were:
Intermediate 7B: te/f-Butyl 2-(2-amino-5-( 1 ,4-diazabicyclo[3.2.21nonan-4- yl)benzamido)acetate (from Intermediate 4B
Figure imgf000039_0002
Intermediate 7C: 2-Amino-/V-(2-(isopropylamino)-2-oxoethyl)-5-(8-methyl-8- azabicyclo[3.2.1 loctan-3-ylamino)benzamide (from Intermediate 4C)
Figure imgf000039_0003
Intermediate 7D: tef-Butyl 5-(4-amino-3-(2-(isopropylamino)-2- oxoethylcarbamoyl)phenyl)hexahydropyrrolo[3,4-clpyrrole-2(1 /-/)-carboxylate (from Intermediate 5B)
Figure imgf000040_0001
Intermediate 7E: 2-Amino-5-((1 S,4S)- 2,5-diazabicvclor2.2.1lheptan-2-yl)-/V-(2- (isopropylamino)-2-oxoethyl)benz mide (from Intermediate 10A)
Figure imgf000040_0002
Intermediate 7F: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-methylbenzamide (from Intermediate 4E)
Figure imgf000040_0003
Intermediate 7G: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-ethylbenzamide (from Intermediate 4F)
Figure imgf000040_0004
Intermediate 7H: 2-Amino-5-(1 ,4-diazabicyclo[3.2.21nonan-4-yl)-/V-propylbenzamide (from Intermediate 4G)
Figure imgf000040_0005
Intermediate 7I: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-isobutylbenzamide (from Intermediate 4H)
Figure imgf000041_0001
Intermediate 7J: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V- (cyclopropylmethyl)benzamide from Intermediate 4I)
Figure imgf000041_0002
Intermediate 7K: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-isopropylbenzamide (from Intermediate 4J)
Figure imgf000041_0003
Intermediate 7L: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-cvclopropylbenzamide (from Intermediate 4K)
Figure imgf000041_0004
Intermediate 7M: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-cvclobutylbenzamide (from Intermediate 4L)
Figure imgf000041_0005
Intermediate 7N: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-((tetrahvdro-2H-pyran- 4-yl)methyl)benzamide (from Intermediate 4M)
Figure imgf000041_0006
Intermediate 70: 2-Amino-5-( 1 ,4-diazabicvclo[3.2.21nonan-4-yl)-/V-(3-hvdroxy-3- methylbutvDbenzamide (from Intermediate 4N)
Figure imgf000042_0001
Intermediate 7P: 2-Amino-5-( 1 ,4-diazabicyclo[3.2.21nonan-4-yl)-/V-(3- hvdroxypropyQbenzamide (from Intermediate 40)
Figure imgf000042_0002
Intermediate 7Q: 2-Amino-5-(1 ,4-Diazabicvclo[3.2.2lnonan-4-yl)-/V-(tetrahvdro-2/-/- thiopyran-4-yl 1 , 1 -dioxide)methyl)benzamide from Intermediate 4P)
Figure imgf000042_0003
Procedure 8
Intermediate 8A: 2-Amino-/V-methyl-5-(5-methylhexahvdropyrrolo[3,4-clpyrrole-2(1 /-/)- vDbenzamide
Figure imgf000042_0004
/V-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 /-/)-yl)-2-nitrobenzamide
(Intermediate 13A) (900 mg, 2.96 mmol) was dissolved in ethanol (140 mL). The resulting solution was hydrogenated using the H-cube at 40 °C under 30 bar pressure of hydrogen, with a flow rate of 1 mL per minute through a 10% palladium on charcoal cartridge. The reaction mixture was concentrated to afford 2-amino-/V-methyl-5-(5- methylhexahydropyrrolo[3,4-c]pyrrole-2(1 /-/)-yl)benzamide, (824 mg, 3.01 mmol).
MS (ESI) m/z 275.2 [M+H]+
Similarly prepared were:
Intermediate 8B: 2-Amino-/V-methyl-5-((1 S,4S)-5-methyl-2,5-diazabicvclor2.2.1 lheptan-2- vDbenzamide (from Intermediate 13B)
Figure imgf000043_0001
Intermediate 8C: 2-Amino-/V-methyl-5-(quinuclidin-3-ylamino)benzamide (from Intermediate 6A)
Figure imgf000043_0002
Intermediate 8D: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)benzamide (from Intermediate 4D)
Figure imgf000043_0003
Intermediate 8E: 2-Amino-5-( 1 ,4-diazabicyclo[3.2.2lnonan-4-yl)-/V-((1 - (hydroxymethvDcvclobutvDmethvDbenzamide from Intermediate 4Q)
Figure imgf000043_0004
Intermediate 8F: 2-Amino-5-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-/V-(3-hvdroxy-2,2- dimethylpropyDbenzamide (from Intermediate 4R)
Figure imgf000043_0005
Intermediate 8G: 2-Amino-5-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-/V-( 2- methoxyethvDbenzamide (from Intermediate 4S)
Figure imgf000043_0006
Intermediate 8H: 2-Amino-4-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-/V-methylbenzamide
(from Intermediate 15A)
Figure imgf000044_0001
Procedure 9
Intermediate 9A: 2-(2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)benzamido)acetic acid
Figure imgf000044_0002
2,2,2-Trifluoroacetic acid (3.26 g, 28.0 mmol) was added to a solution of ie f-butyl 2-(2- amino-5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetate (Intermediate 7B) (1 .0 g, 2.67 mmol) in dichloromethane (20 mL) and methanol (2 mL). The resulting solution was stirred for 7 hours before leaving to stand over the weekend. The resultant crude material purified using a 5g SCX cartridge to afford methyl 2-(2-amino-5-(1 ,4- diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetate. This was dissolved in tetrahydrofuran (20 mL) and 1 M lithium hydroxide solution (5.34 mL, 5.34 mmol) and water (2 mL) was added and the solution stirred overnight. The reaction mixture was then acidified and purified using a 5g SCX cartridge to afford 2-(2-amino-5-(1 ,4-diazabicyclo[3.2.2]nonan-4- yl)benzamido)acetic acid (849 mg, 2.67 mmol).
MS (ESI) m/z 319.2 [M+H]+
Procedure 10
Intermediate 10A: 5-((1 S.4S)-2.5-Diazabicvclor2.2.1 lheptan-2-yl)-/V-(2-(isopropylamino)- 2-oxoethyl)-2-nitrobenzamide
Figure imgf000044_0003
2,2,2-Trifluoroacetic acid (4.6 g, 39.5 mmol) was added to a solution of {1S,4S)-tert-buty\ 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4-nitrophenyl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (Intermediate 5A) (1 .5 g, 3.25 mmol) in dichloromethane (15ml_). The resulting solution was stirred overnight. The resultant crude material was purified using a 20g SCX cartridge to afford 5-((1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)-/V-(2- (isopropylamino)-2-oxoethyl)-2-nitrobenzamide (984 mg, 2.72 mmol).
MS (ESI) m/z 362.4 [M+H]+
Similarly prepared were:
Intermediate 10B: 5-(Hexahvdropyrrolor3,4-clpyrrol-2( 1 /-/)-yl)-/V-methyl-2- nitrobenzamide (from Intermediate 5C
Figure imgf000045_0001
Intermediate 10C: 5-((1 S.4S)-2.5-Diazabicvclor2.2.1lheptan-2-yl)-/V-methyl-2- nitrobenzamide (from Intermediate 5D
Figure imgf000045_0002
Procedure 11
Intermediate 11 A: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-4- oxoquinazolin-3(4/-/)-yl)acetic acid
Figure imgf000045_0003
2-(2-Amino-5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (85.3 mg, 0.27 mmol) (Intermediate 9A) was dissolved in ethanol (3 mL). 3-Chlorobenzaldehyde (56.5 mg, 0.046 mL, 0.40 mmol) was added followed by 2 drops of acetic acid. The reaction mixture was refluxed at 85 °C overnight. The reaction mixture was diluted with methanol and purified directly using a 1 g SCX cartridge. The crude material was concentrated to dryness before re-dissolving in dichloromethane and manganese dioxide (18.8 mg, 0.32 mmol) added. The solution was then stirred overnight before filtering and concentrated under reduced pressure to give 2-(6-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(3- chlorophenyl)-4-oxoquinazolin-3(4/-/)-yl)acetic acid (54 mg, 0.12 mmol).
MS (ESI) m/z 439.0 [M+H]+
Procedure 12
Intermediate 12A: te/f-Butyl 5-(3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-2-phenyl-3,4- dihvdroquiazolin-6-yl)hexahydropyrrolo[3,4-clpyrrole-2(1 /-/)-carboxylate
Figure imgf000046_0001
te/f-Butyl 5-(4-amino-3-(2-(isopropylamino)-2-oxoethylcarbamoyl)phenyl)hexahydro pyrrolo[3,4-c]pyrrole-2(1 /-/)-carboxylate (Intermediate 7D) (286 mg, 0.64 mmol) was dissolved in ethanol (2 mL) before addition of benzaldehyde (82 mg, 0.77 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a Reactivial ® and heated at 95 °C for 24 hours. Reaction mixture was then cooled to room temperature and diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX, and the solvent removed under reduced pressure. The resultant product was re-dissolved in dichloromethane (2 mL) and manganese dioxide (66 mg, 0.75 mmol) added. The solution was stirred overnight. The reaction mixture was filtered and concentrated. The resultant crude material was purified using a 20g SCX cartridge to afford ie f-butyl 5-(3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-2-phenyl-3,4-dihydroquiazolin- 6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1 /-/)-carboxylate (129 mg, 0.24 mmol), and 2-(6- (hexahydropyrrolo[3,4-c]pyrrol-2(1 /-/)-yl)-4-oxo-2-phenylquinazolin-3(4/-/)-yl-/V- isopropylacetamide (59 mg, 0.14 mmol).
MS (ESI) m/z 532 [M+H]+
Similarly prepared were:
Intermediate 12B: te/f-Butyl 5-(3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-3,4- dihvdroquinazolin-6-yl)hexahydropyrrolo[3,4-clpyrrole-2(1 /-/)-carboxylate (from
Intermediate 7D)
Figure imgf000047_0001
Intermediate 12C: te/f-Butyl 5-(2-cvclopropyl-3-(2-(isopropylamino)-2-oxoethyl)-4-oxo- 3,4-dihvdroquinazolin-6-yl)hexahydropyrrolo[3,4-clpyrrole-2(1 /-/)-carboxylate (fro m
Intermediate 7D)
Figure imgf000047_0002
Intermediate 12D: 2-(6-((1 S,4S)-2,5-Diazabicvclor2.2.1 lheptan-2-yl)-2-cvclopropyl-4- oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide (from Intermediate 7E)
Figure imgf000047_0003
Procedure 13
Intermediate 13A: /V-Methyl-5-(5-methylhexahvdropyrrolor3,4-clpyrrol-2( 1 H)-y\)-2- nitrobenzamide
Figure imgf000047_0004
5-(hexahydropyrrolo[3,4-c]pyrrol-2(1 /-/)-yl)-/V-methyl-2-nitrobenzamide (1 .78 g, 6.13 mmol) (Intermediate 10B) was dissolved in acetonitrile (45 mL) before addition of formaldehyde (0.6 g, 7.36 mmol) and MP-cyanoborohydride (3.6 g, 9.25 mmol) followed by 6 drops of acetic acid. The resulting mixture was split into 3 microwave vials and heated at 130 °C for 20 minutes. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 50g silica column in 100% dichloromethane, 20% methanol in dichloromethane, 100% methanol (Biotage Snap cartridge). Fractions of the product were combined and reduced to dryness under reduced pressure to afford /V-methyl-5-(5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1 /-/)-yl)-2-nitrobenzamide (900 mg, 2.96 mmol). MS (ESI) m/z 305.0 [M+H]+ Similarly prepared were:
Intermediate 13B: /V-Methyl-5-((1 S,4S)-5-methyl-2,5-diazabicvclor2.2.1 lheptan-2-yl)-2- nitrobenzamide (from Intermediate 10C
Figure imgf000048_0001
Procedure 14
Intermediate 14A: 2-(6-(1 ,4-Diazabicvclo[3.2.21nonan-4-yl)-2-ethyl-4-oxoquinazolin- 3(4/-/)-yl)acetic acid
Figure imgf000048_0002
2-(2-Amino-5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (85.3 mg, 0.27 mmol) (Intermediate 9A) (100 mg, 0.36 mmol) was dissolved in triethoxypropane (1 mL), and heated in the microwave at 160 °C for 10 minutes. Reaction allowed to cool to room temperature and lithium hydroxide solution added (0.5 mL, 1 M in methanol) and reaction stirred overnight. Organic layer purified using a 1 g SCX cartridge, followed by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-2-ethyl-4-oxoquinazolin-3(4/-/)-yl)acetic acid (76 mg, 0.21 mmol).
MS (ESI) m/z 357.2 [M+H]+
Procedure 15
Intermediate 15A: 4-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-methyl-2-nitrobenzamide
Figure imgf000048_0003
To a solution of 4-fluoro-/V-methyl-2-nitrobenzamide (Intermediate 3L) (0.65 g, 3.3 mmol) in dimethylsulfoxide (50 mL) was added 1 ,4-diazabicyclo[3.2.2]nonane (0.62 g, 4.9 mmol) and potassium carbonate (1 .36g, 9.8 mmol). The resulting suspension was heated at 90 °C for 4 days. The mixture was filtered and the filtrate purified using a 20g SCX cartridge to afford 4-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-methyl-2-nitrobenzamide (0.8 g, 2.7 mmol).
1H NMR (400 MHz, CDCI3): 7.35 (1 H, d J=16.8Hz), 7.1 (1 H, d J=2.8Hz), 6.85 (1 H, dd J=8.8, 2.8 Hz) 5.68-5.76 (1 H, bs), 4.03-4.09 (1 H, bs), 3.58-3.61 (2H, m), 3.06-3.18 (4H, m), 2.95-3.03 (2H, m), 3.0 (3H, d J=4.8Hz), 2.06-2.13 (2H, m), 1 .71 -1.81 (2H, m)
Procedure 16
Intermediate 16A: 5-Fluoro-/V-methyl-2-nitrobenzenesulfonamide
Figure imgf000049_0001
A solution of 5-fluoro-2-nitrobenzene-1 -sulfonyl chloride (2.0 g, 8.35 mmol) in dichloromethane (50 mL) was cooled using an ice water bath. 2M methylamine in tetrahydofuran (5.0 mL, 10.0 mmol) was added. The resulting solution was stirred for 2 hours. The reaction mixture was washed with 2N HCI solution (2 x 100 mL), brine (100 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-/V-methyl-2- nitrobenzenesulfonamide (1 .79 g, 7.64 mmol).
1H NMR; δ (ppm)(CHCI3-d): 7.99-7.95 (1 H, m), 7.87 (1 H, dd, J = 7.53, 2.5 Hz), 7.43-7.38 (1 H, m), 5.33 (1 H, bs), 2.83 (3 H,s,).
Similarly prepared were:
Intermediate 16B: 5-Fluoro-2-nitrobenzenesulfonamide
Figure imgf000049_0002
Procedure 17
Intermediate 17A: 5-( 1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-methyl-2- nitrobenzenesulfonamide
Figure imgf000050_0001
To a solution of 5-fluoro-/V-methyl-2-nitrobenzenesulfonamide (Intermediate 16A) (1.0 g, 4.27 mmol) in acetonitrile (10 mL) was added potassium carbonate (1.77 g, 12.81 mmol) followed by 1 ,4-diazabicyclo[3.2.2]nonane 2,2,2-trifluoroacetate (1 .17 g, 4.27 mmol). The resulting suspension was heated to reflux at 96°C overnight. The reaction mixture was diluted in water (50 mL) and split between two 20g SCX cartridges. Purification by SCX and evaporation to dryness afforded 5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-methyl-2- nitrobenzenesulfonamide (1 .17 g, 3.44 mmol).
MS (ESI) m/z 341 .2 [M+H]+
Similarly prepared were:
Intermediate 17B: 5-(1 ,4-Diazabicyclo[3.2.2lnonan-4-yl)-2-nitrobenzenesulfonamide
(from Intermediate 16B)
Figure imgf000050_0002
Procedure 18
Intermediate 18A: 2-Amino-5-( 1 ,4-diazabicyclo[3.2.21nonan-4-yl)-/V- methylbenzenesulfonamide
Figure imgf000050_0003
5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-methyl-2-nitrobenzenesulfonamide (Intermediate 17A) (1 .0 g, 2.94 mmol) was dissolved in 2M ammonia in methanol (1 10 mL). The resulting solution was hydrogenated using the H-cube at 40 °C under 30 bar pressure of hydrogen, with a flow rate of 1 mL per minute through a 10% palladium on charcoal cartridge. The reaction mixture was purified by SCX and evaporated to afford 2-amino-5- (1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-methylbenzenesulfonamide, (868 mg, 2.8 mmol). 1H NMR; δ (ppm)(CHCI3-d): 7.17 (1 H, d, J = 3.01 Hz), 6.88 (1 H, dd, J = 9.04, 3.01 Hz), 6.72 (1 H, d, J = 9.04 Hz), 4.82 (1 H, bs), 4.31 (2H, bs), 3.88-3.87 (1 H, m), 3.42-3.39 (2H, m), 3.13-2.97 (6H, m), 2.57 (3H, d, J = 3.51 Hz), 2.1 1 -2.04 (2H, m),1 .76-1.68 (2H, m). Similarly prepared were:
Intermediate 18B: 2-Amino-5-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)benzenesulfonamide (from Intermediate 17B)
Figure imgf000051_0001
Procedure 19
Intermediate 19A: 6-Bromo-3-methylquinazolin-4(3/-/)-one
Figure imgf000051_0002
To a suspension of 6-bromoquinazolni-4(3/-/)-one (0.5 g, 2.22 mmol) in THF (12 mL) under nitrogen, was added sodium hydride (0.13 g, 3.33 mmol) and reaction stirred for 30 minutes. The reaction was then cooled using an ice bath and methyl 4- nitrobenzenesulfonate (0.48 g, 2.22 mmol) was added. Reaction allowed to warm to room temperature and stirred overnight. Diluted with water and extracted with ethylacetate. Organic layer washed with brine, dried (MgS04) and concentrated under reduced pressure. The resultant crude material was purified by a 25g silica column in 0-10% methanol in DCM (Biotage Snap cartridge) followed by preparative-HPLC and 10 g SCX cartridge to afford 6-bromo-3-methylquinazolin-4(3/-/)-one (0.22 g, 0.90 mmol).
MS (ESI) m/z 240.0 [M+H]+ Similarly prepared were:
Intermediate 19B: 7-Bromo-2-methylisoquinolin-1 (2/-/)-one
Figure imgf000051_0003
Procedure 20
Intermediate 20A: te/f-Butyl 5-(3-methyl-4-oxo-3,4-dihvdroquinazolin-6- yl)hexahvdropyrrolo[3,4-clpyrrole -2(1 HVcarboxylate
Figure imgf000052_0001
A mixture of 6-bromo-3-methylquinazolin-4(3/-/)-one (Intermediate 19A) (0.46 g, 1.92 mmol), ie f-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1 /-/) carboxylate (0.49 g, 2.31 mmol), potassium phosphate, tribasic (1 .33g g, 5.77 mmol), 2-dicyclohexylphosphino-2',6'-di-i- propoxy-1 ,1 -biphenyl (26.9 mg, 0.06 mmol) and tris(dibenzyllideneacetone)dipalladium (0) (17.6 mg, 0.02 mmol) in dioxane (10 mL) was heated at 90 °C for 20h. The mixture was diluted with water and the product extracted into dichloromethane. The organic layer was evaporated to dryness, re-dissolved in methanol and purified using a 5g SCX column. The mixture was then further purified on silica (25g SNAP column on SP4). Eluting with dichloromethane to 60/40 dichloromethane/(2M NH3 in methanol) to afford tert-butyl 5-(3- methyl-4-oxo-3,4-dihydroquinazolin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1 /-/)-carboxylate (270 mg, 0.73 mmol).
MS (ESI) m/z 371 .2 [M+H]+ Similarly prepared were:
Intermediate 20B: te/f-Butyl 5-(2-methyl-1 -oxo-1 ,2-dihydroisoquinolin-7- yl)hexahydropyrrolo[3,4-clpyrrole-2(1 /-/)-carboxylate (from Intermediate 19B)
Figure imgf000052_0002
Procedure 21
Intermediate 21 A: 6-(Hexahvdropyrrolo[3,4-clpyrrol-2(1 /-/)-yl)-3-methylquinazolin-4(3/-/)- one
Figure imgf000053_0001
To a solution of ie f-butyl 5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1 /-/)-carboxylate (Intermediate 20A) (80 mg, 0.22 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and the reaction allowed to stand overnight. The reaction was diluted with methanol and passed through a sex cartridge (500 mg) to afford 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1 /-/)-yl)-3- methylquinazolin-4(3/-/)-one (58 mg, 0.21 mmol).
MS (ESI) m/z 271 .2 [M+H]+ Procedure 22
Intermediate 22A: 5-Bromo-/V,2-dimethylbenzamide
Figure imgf000053_0002
To a solution of 5-bromo-2-methylbenzoic acid (2.325 mmol, 0.5 g) in dichloromethane (25 mL) under nitrogen was added Λ/,/V-diisopropylethylamine (0.75 g, 5.8 mmol). Reaction then cooled in an ice bath to 2°C and the yellow solution treated with 2M methylamine in tetrahydrofuran (3.49 mL, 6.98 mmol) over 5 minutes, followed by 1 - propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (2.08 mL, 3.49 mmol) added dropwise. The ice bath was then removed and stirring continued overnight. The mixture was purified on silica (15g column on Isolera 4) eluting with 0-5% methanol in dichloromethane to afford 5-Bromo-/V,2-dimethylbenzamide (0.5 g, 2.2 mmol). MS (ESI) m/z 228, 230 [M+H]+
Procedure 23
Intermediate 23A: 7-Bromo-3-(3-chlorophenyl)isoquinolin-1 (2/-/)-one
Figure imgf000053_0003
To a solution of 2M lithium diisopropylamide (19.73 ml_, 39.5 mmol) in tetrahydrofuran (30 mL) at -78°C was added dropwise a solution of 5-bromo-/V,2-dimethylbenzamide (Intermediate 22A) (3.0 g, 13.15 mmol) in THF (14 mL) followed by a solution of 3- chlorobenzonitrile (1.809 g, 13.15 mmol) in THF (14 mL) and the mixture was stirred at - 78°C for 2.5 hours. Reaction allowed to warm to room temperature and saturated NH4CI (aq) was added. The THF was removed under reduced pressure and the resulting mixture extracted into ethyl acetate and washed with brine (precipitate was observed in both layers). Organics were evaporated to dryness, washed with methanol and dried in a vacuum oven to afford 7-bromo-3-(3-chlorophenyl)isoquinolin-1 (2/-/)-one (0.9 g, 2.69 mmol).
MS (ESI) m/z 333.8, 336.8 [M+H]+
Procedure 24
Intermediate 24A: 7-Bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1 (2/-/)-one
Figure imgf000054_0001
7-Bromo-3-(3-chlorophenyl)isoquinolin-1 (2/-/)-one (Intermediate 23A) (0.1 g, 0.299 mmol) was dissolved in THF (4 mL), under an atmosphere of nitrogen. Sodium hydride (0.018 g, 0.448 mmol) was added and reaction stirred for 30 minutes. The reaction was then cooled using an ice bath and methyl 4-nitrobenzenesulfonate (0.065 g, 0.299 mmol) was added. The reaction was allowed to warm to room temperature and left to stir overnight. Water was added to the reaction mixture and extracted with EtOAC (x2). The organics were combined and washed with brine, dried (MgS04) filtered and concentrated under reduced pressure. The mixture was purified on silica (25g column on Isolera 4) eluting with 0- 10% methanol in dichloromethane to afford 7-bromo-3-(3-chlorophenyl)-2- methylisoquinolin-1 (2/-/)-one (51 mg, 0.15 mmol).
1H NMR; δ (ppm)(CHCI3-d): 8.59 (1 H, d, J = 2.0 Hz), 7.74-7.71 (1 H, dd, J = 8.4, 2.0 Hz), 7.46-7.30 (5H, m), 6.40 (1 H, s), 3.42 (3H, s).
Procedure 25
Intermediate 25A: 2-Chloro-5-nitroisonicotinic acid
Figure imgf000055_0001
2-chloro-4-methyl-5-nitropyridine (1 .0 g, 5.8 mmol) was cooled using an ice water bath. Sodium dichromate dihydrate (3.45 g, 1 1 .6 mmol) dissolved in sulphuric acid (50 mL) was added dropwise, ensuring reaction temperature does not exceed 15°C. After complete addition, reaction allowed to warm to room temperature and stirred overnight. Quenched with ice, extracted into ethylacetate and concentrated under reduced pressure to afford 2- chloro-5-nitroisonicotinic acid (1.3 g, 6.4 mmol).
Procedure 26
Intermediate 26A: Methyl 2-chloro-5-nitroisonicotinate
Figure imgf000055_0002
To a solution of 2-chloro-5-nitroisonicotinic acid (Intermediate 25A) (0.64 g, 3.17 mmol) in DMF (15 mL) under nitrogen was added sodium carbonate (1.0 g, 9.51 mmol). Reaction cooled in an ice bath and methyliodide (1 .35 g, 9.51 mmol) was added dropwise. After complete addition, reaction allowed to warm to room temperature and stirred overnight under nitrogen. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 20g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-chloro-5-nitroisonicotinate (0.62 g, 2.86 mmol). Procedure 27
Intermediate 27A: Methyl 2-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-5-nitroisonicotinate
Figure imgf000055_0003
To a solution of methyl 2-chloro-5-nitroisonicotinate (Intermediate 26A) (0.1 g, 0.46 mmol) in methanol (3 mL) under nitrogen was added 1 ,4-diazabicyclo[3.2.2]nonane (0.18 g, 0.55 mmol) and triethylamine (7 mg, 0.69 mmol), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 10g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-5- nitroisonicotinate. Similarly prepared were:
Intermediate 27B: Methyl 5-((1 S,4S)-5-methyl-2,5-diazabicvclor2.2.1 lheptan-2-yl)-2- nitrobenzoate (from methyl 5-bromo-2-nitrobenzoate)
Figure imgf000056_0001
Procedure 28
Intermediate 28A: 2-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-methyl-5-nitroisonicotinamide
Figure imgf000056_0002
Methyl 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)5-nitroisonicotinate (Intermediate 27A) (0.1 g, 0.46 mmol) and 2M methylamine in methanol (5 mL) were sealed in a tube and heated at 90°C overnight. The reaction mixture was concentrated and purified by a 10g silica column eluting with 0-10% methanol in DCM to afford 2-(1 ,4-diazabicyclo[3.2.2]nonan-4- yl)-/V-methyl-5-nitroisonicotinamide (96 mg, 0.31 mmol).
Similarly prepared were:
Intermediate 28B: 2-(1 ,4-Diazabicvclo[3.2.2lnonan-4-yl)-5-nitroisonicotinamide (from Intermediate 27A)
Figure imgf000056_0003
Procedure 29
Intermediate 29A: 2-(1 ,4-Diazabicvclo[3.2.21nonan-4-yl)-5-nitroisonicotinic acid
Figure imgf000056_0004
To a solution of methyl 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)5-nitroisonicotinate (Intermediate 27A) (6.0 g, 19.6 mmol) in tetrahydrofuran (15 mL) under nitrogen was added lithium hydroxide (2.47 g, 58.8 mmol), methanol (10 mL) and water (15 mL), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 50g silica column eluting with 10-40% methanol in DCM to afford 2-(1 ,4- diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (3.2 g, 10.9 mmol).
Procedure 30
Intermediate 30A: 2-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-/V-(3-hvdroxy-2,2- dimethylpropyl)-5-nitroisonicotinamide
Figure imgf000057_0001
To a solution of 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (Intermediate 29A) (2.0 g, 6.8 mmol) in DMF (25 mL) was added 3-amino-2,2-dimethylpropan-1 -ol (0.85 g, 8.2 mmol), triethylamine (1 g, 10.3 mmol) and HATU (3.16, 10.3 mmol) under nitrogen, reaction then stirred overnight. The reaction mixture was concentrated and purified by HPLC to afford 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-(3-hydroxy-2,2-dimethylpropyl)-5- nitroisonicotinamide.
Procedure 31
Intermediate 31A: 5-Amino-2-( 1 ,4-diazabicyclo[3.2.21nonan-4-yl)-/V- methylisonicotinamide
Figure imgf000057_0002
To a solution of 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-methyl-5-nitroisonicotinamide (Intermediate 28A) (50 mg, 0.16 mmol) in methanol (0.3 mL) under nitrogen was added palladium on carbon (25 mg). Reaction subjected to a hydrogen atmosphere and stirred overnight. The reaction mixture was filtered and concentrated to afford 5-amino-2-(1 ,4- diazabicyclo[3.2.2]nonan-4-yl)-/V-methylisonicotinamide.
Similarly prepared were: Intermediate 31 B: 5-Amino-2-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)isonicotinamide (from Intermediate 28B)
Figure imgf000058_0001
Intermediate 31 C: 5-Amino-2-(1 ,4-diazabicvclor3.2.2lnonan-4-yl)-/V-(3-hvdroxy-2,2- dimethylpropyQisonicotinamide (from Intermediate 30A)
Figure imgf000058_0002
Intermediate 31 D: 2-Amino-5-((1 S,4S)-5-methyl-2,5-diazabicvclor2.2.1 lheptan-2- vDbenzamide (from Intermediate 27B
Figure imgf000058_0003
Procedure 32
Intermediate 32A: 2-Amino-5-hvdroxy-/V-methylbenzamide
Figure imgf000058_0004
A solution of 6-hydroxy-1 H-benzo[d][1 ,3]oxazine-2,4-dione (500 mg, 2.79 mmol) in ethanol (20 mL) was cooled to 0 °C and methylamine solution (33% in ethanol, 2.92 mL, 27.9 mmol) added and the reaction stirred for 3 days. The solvent was removed under reduced pressure and the product purified by silica chromatography, eluent 5% methanol in dichloromethane to yield 2-amino-5-hydroxy-/V-methylbenzamide (280 mg, 1.68 mmol).
Similarly prepared was: Intermediate 32B: 2-Amino-5-hvdroxy-/V-ethylbenzamide
Figure imgf000059_0001
Procedure 33
Intermediate 33A: 2-(3-Chlorophenyl)-6-hvdroxy-3-methylquinazolin-4(3/-/)-one
Figure imgf000059_0002
To a solution of 2-amino-5-hydroxy-/V-methylbenzamide (Intermediate 32A) (280 mg, 1 .68 mmol) and 3-chlorobenzaldehyde (0.23 mL, 2.02 mmol) in ethanol (10 mL) was added a catalytic amount of acetic acid (0.07 mL) and the mixture heated under reflux for 23 h. The reaction was cooled before manganese (iv) oxide (225 mg, 1.68 mmol) was added and the reaction heated under reflux until complete by lc/ms. On cooling the reaction was filtered and the filtrate evaporated to dryness to afford 2-(3-chlorophenyl)-6-hydroxy-3- methylquinazolin-4(3/-/)-one (450 mg, 1.57 mmol).
MS (ESI) m/z 287 [M+H]+
Similarly prepared were:
Intermediate 33B: 3-Methyl-6-hvdroxyquinazolin-4(3/-/)-one (from Intermediate 32A)
Figure imgf000059_0003
Intermediate 33C: 3-Ethyl-6-hvdroxy-2-phenylquinazolin-4(3/-/)-one (from Intermediate
32B)
Figure imgf000059_0004
Synthesis of Examples According to the Invention
EXAMPLE 1A: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-quinazolin-4(3H)-one
Figure imgf000060_0001
A mixture of 6-bromoquinazolin-4(3/-/)-one (0.50 g, 2.22 mmol), 1 ,4- diazabicyclo[3.2.2]nonane hydrochloride (0.44 g, 2.22 mmol), triethylamine (0.45 g, 4.44 mmol), potassium tert-butoxide (0.25 g, 2.22 mmol), dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (1.06 2.22 mmol) and tris(dibenzyllideneacetone)dipalladium (0) (0.41 g, 0.44 mmol) in Tetrahydrofuran (15 mL) was heated in the microwave at 120 °C for 30mins. The solvent was evaporated off and to the residue was added methanol and the mixture acidified with acetic acid then loaded on to a 5g SCX column. The mixture was purified on silica (25g SNAP column on SP4) eluting with dichloromethane to 60/40 dichloromethane/(2M ammonia in methanol) to afford 6-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-quinazolin-4(3/-/)-one (18.5 mg, 0.07 mmol). MS (ESI) m/z 271 .2 [M+H]+ Similarly prepared were:
EXAMPLE 1 B: 7-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)2-methylisoquinolin-1 (2H)-one (from Intermediate 19B)
Figure imgf000060_0002
MS (ESI) m/z 284 [M+H]+
EXAMPLE 1 C: (R)-6-(1 ,4-Diazabicvclor3.2.1 loctan-4-yl)-3-methylquinazolin-4(3H)-one (from Intermediate 19A)
Figure imgf000060_0003
MS (ESI) m/z 271 .2 [M+H]+ EXAMPLE 1 D: (S)-6-(1 ,4-Diazabicvclor3.2.1 loctan-4-yl)-3-methylquinazolin-4(3H)-one (from Intermediate 19A)
Figure imgf000061_0001
MS (ESI) m/z 271 .2 [M+H]+
EXAMPLE 2A: 2-(6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4- oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide
Figure imgf000061_0002
2-Amino-5-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-(2-(isopropylamino)-2- oxoethyl)benzamide (Intermediate 7A) (70 mg, 0.20 mmol) was dissolved in ethanol (2 mL) before addition of 3-chloro-5-fluorobenzaldehyde (46.3 mg, 0.29 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a Reactivial ® and heated at 95 °C for 24 hours. Reaction mixture was then cooled to room temperature and diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX and concentrated under reduced pressure. The resultant product was re- dissolved in dichloromethane (2 mL), manganese dioxide (33.8 mg, 0.39 mmol) was added and reaction stirred overnight. The sample was then washed with water (5 mL) and extracted into dichloromethane. The organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1 ,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5- fluorophenyl)-4-oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide (9.0 mg, 0.018 mmol) 9% yield.
MS (ESI) m/z 498.0 [M+H]+
Similarly prepared were:
EXAMPLE 2B: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-4-oxo-2-p-tolylquinazolin-3(4H)- yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000062_0001
MS (ESI) m/z 460.2 [M+H]+
EXAMPLE 2C: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-4-oxo-2-phenylquinazolin-3(4H)- yl)-/V-isopropylacetamide (from Intermediate 7A
Figure imgf000062_0002
MS (ESI) m/z 446.2 [M+H]+
EXAMPLE 2D: 2-(6-(1 .4-Diazabicvclor3.2.21nonan-4-ylV2-(2-fluorophenvn-4- oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000062_0003
MS (ESI) m/z 464.2 [M+H]+
EXAMPLE 2E: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-vn-2-(4-fluorophenvn-4- oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000062_0004
MS (ESI) m/z 464.2 [M+H]+ EXAMPLE 2F: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-4-oxo-2-m-tolylquinazolin-3(4H)- yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000063_0001
MS (ESI) m/z 460.2 [M+H]+
EXAMPLE 2G: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-cvanophenyl)-4- oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000063_0002
MS (ESI) m/z 471 .2 [M+H]+
EXAMPLE 2H: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-4-oxo-2-(3- (trifluoromethyl)phenyl)quinazolin-3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000063_0003
MS (ESI) m/z 514.2 [M+H]+
EXAMPLE 2I: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-4-oxo-2-(3- (trifluoromethoxy)phenyl)quinazolin-3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000064_0001
MS (ESI) m/z 530.2 [M+H]+
EXAMPLE 2J: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-ethoxyphenvn-4- oxoquinazolin-3(4 -/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000064_0002
MS (ESI) m/z 490.2 [M+H]+
EXAMPLE 2K: 2-(6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-fluorophenvn-4- oxoquinazolin-3(4H)-yl)-A/-isopropylacetamide from Intermediate 7A)
Figure imgf000064_0003
MS (ESI) m/z 464.2 [M+H]+
EXAMPLE 2L: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(3,5-difluorophenvn-4- oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000064_0004
MS (ESI) m/z 482.2 [M+H]+
EXAMPLE 2M: 2-(6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(2,5-difluorophenvn-4- oxoquinazolin-3(4/-/)-yl)-A/-isopropylacetamide from Intermediate 7A)
Figure imgf000065_0001
MS (ESI) m/z 482.2 [M+H]+
EXAMPLE 2N: 2-(6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(2.3-difluorophenvn-4- oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000065_0002
MS (ESI) m/z 482.2 [M+H]+
EXAMPLE 20: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chloro-2-fluorophenyl)-4- oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000065_0003
MS (ESI) m/z 498.2 [M+H]+ EXAMPLE 2P: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chloro-2-chlorophenyl)-4- oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000066_0001
MS (ESI) m/z 514 [M+H]+
EXAMPLE 2Q: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3,4-difluorophenvn-4- oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000066_0002
MS (ESI) m/z 482.2 [M+H]+
EXAMPLE 2R: 2-(6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(5-chloro-2-fluorophenyl)-4- oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000066_0003
MS (ESI) m/z 498 [M+H]+
EXAMPLE 2S: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-vn-4-oxoquinazolin-3(4H)-yl)-A - isopropylacetamide (from Intermediate 7A)
Figure imgf000067_0001
MS (ESI) m/z 370.2 [M+H]+
EXAMPLE 2T: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-methyl-4-oxoquinazolin-3(4H)- yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000067_0002
MS (ESI) m/z 385.2 [M+H]+
EXAMPLE 2U: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-isopropyl-4-oxoquinazolin- 3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000067_0003
MS (ESI) m/z 412.2 [M+H]+
EXAMPLE 2V: 2-(6-( 1 ,4-Diazabicvclo[3.2.21nonan-4-yl)-2-cvclopropyl-4-oxoquinazolin- 3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000067_0004
MS (ESI) m/z 410.2 [M+H]+
EXAMPLE 2W: 2-(6-( 1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopentyl-4-oxoquinazolin- 3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 7A)
Figure imgf000068_0001
MS (ESI) m/z 438.2 [M+H]+
EXAMPLE 2X: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-4-oxo-2-(3,3,3- trifluoropropyl)quinazolin-3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000068_0002
MS (ESI) m/z 467.2 [M+H]+
EXAMPLE 2Y: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-sec-butyl-4-oxoquinazolin- 3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000068_0003
MS (ESI) m/z 427.2 [M+H]+
EXAMPLE 2Z: 2-(6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-isobutyl-4-oxoquinazolin-3(4H)- yl)-/V-isopropylacetamide (from Intermediate 7A
Figure imgf000068_0004
MS (ESI) m/z 426.2 [M+H]+ EXAMPLE 2AA: 2-(6-(1.4-Diazabicvclof3.2.21nonan-4-yl)-2-ethyl-4-oxoquinazolin-3(4H)- yl)-A/-isopropylacetamide (from Intermediate 7A
Figure imgf000069_0001
MS (ESI) m/z 398.2 [M+H]+
EXAMPLE 2AB: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-tert-butyl-4-oxoquinazolin- 3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000069_0002
MS (ESI) m/z 426.2 [M+H]+
EXAMPLE 2 AC: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-vn-2-cvclohexyl-4-oxoquinazolin- 3(4/-/)-yl)-/V-isopropylacetamide from Intermediate 7A)
Figure imgf000069_0003
MS (ESI) m/z 453.2 [M+H]+
EXAMPLE 2 AD: 2-(2-(3-Chlorophenyl)-6-(8-methyl-8-azabicvclor3.2.1 loctan-3-ylamino)- 4-oxoquinazolin-3(4H)-yl)-/V-isopropylacetamide (from Intermediate 7C)
Figure imgf000070_0001
MS (ESI) m/z 494.2 [M+H]+
EXAMPLE 2AE: 2-(2-Fluorophenyl)-3-methyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrole- 2(1 -/)-yl)quinazolin-4(3H)-one from Intermediate 8A)
Figure imgf000070_0002
MS (ESI) m/z 380.2 [M+H]+
EXAMPLE 2AF: 2-(3-Chlorophenyl)-3-methyl-6-(5-methylhexahvdropyrrolor3.4-clpyrrol- 2(1 H)-yl)quinazolin-4(3/-/)-one from Intermediate 8A)
Figure imgf000070_0003
MS (ESI) m/z 395 [M+H]+
EXAMPLE 2 AG: 3-(3-Methyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)-yl)-4-oxo- 3,4-dihydroquinazolin-2-yl)benzonitrile (from Intermediate 8A)
Figure imgf000071_0001
MS (ESI) m/z 386.2 [M+H]+
EXAMPLE 2 AH: 2-Cvclopropyl-3-methyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)- yl)quinazolin-4(3/-/)-one (from Intermediate 8A
Figure imgf000071_0002
MS (ESI) m/z 325.2 [M+H]+
EXAMPLE 2AI: 2-(2-Fluorophenyl-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate
Figure imgf000071_0003
MS (ESI) m/z 366.0 [M+H]+
EXAMPLE 2AJ: 2-(3-Chlorophenyl)-6-(1 ,4-diazabicvclor3.2.21nonan-4-yl)-quinazolin- 4(3/-/)-one (from Intermediate 8D)
Figure imgf000071_0004
MS (ESI) m/z 381 .5 [M+H]+ EXAMPLE 2AK: 6-(1 .4-Diazabicvclor3.2.21nonan-4-ylV2-(3-chlorophenvn-3-(2- methoxyethyl) quinazolin-4(3/-/)-one (from Intermediate 8G
Figure imgf000072_0001
MS (ESI) m/z 439.0 [M+H]+
EXAMPLE 2AL: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-ylV2-(3-chlorophenyl 3- methylquinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000072_0002
MS (ESI) m/z 395.0 [M+H]+
EXAMPLE 2AM: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- ethylquinazolin-4(3/-/)-one (from Intermediate 7G
Figure imgf000072_0003
MS (ESI) m/z 409.2 [M+H]+
EXAMPLE 2AN: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- propylquinazolin-4(3/-/)-one (from Intermediate 7H)
Figure imgf000072_0004
MS (ESI) m/z 423.2 [M+H]+
EXAMPLE 2AO: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-propylquinazolin-4(3H)- one (from Intermediate 7H)
Figure imgf000073_0001
MS (ESI) m/z 341 .2 [M+H]+
EXAMPLE 2AP: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- isobutylquinazolin-4(3H)-one (from Intermediate 7\)
Figure imgf000073_0002
MS (ESI) m/z 437.2 [M+H]+
EXAMPLE 2AQ: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3-(3-hvdroxy-3- methylbutyl)-quinazolin-4(3/-/)-one (from Intermediate 70
Figure imgf000073_0003
MS (ESI) m/z 467.2 [M+H]+
EXAMPLE 2AR: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3-((tetrahvdro- 2H-pyran-4-yl)methyl)-quinazolin-4(3/-/)-one (from Intermediate 7N)
Figure imgf000074_0001
MS (ESI) m/z 479.2 [M+H]+
EXAMPLE 2 AS: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3-(propan-3-ol)- quinazolin-4(3/-/)-one (from Intermediate 7P)
Figure imgf000074_0002
MS (ESI) m/z 439.0 [M+H]+
EXAMPLE 2 AT: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-((tetrahvdro-2H-pyran-4- yl)methyl)-quinazolin-4(3/-/)-one (from Intermediate 7N)
Figure imgf000074_0003
MS (ESI) m/z 397.2 [M+H]+
EXAMPLE 2AU: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- (cvclopropylmethyl)-quinazolin-4(3/-/)-one (from Intermediate 7J)
Figure imgf000074_0004
MS (ESI) m/z 435.2 [M+H]+ EXAMPLE 2AV: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-(cvclopropylmethyl)- quinazolin-4(3/-/)-one (from Intermediate 7J
Figure imgf000075_0001
MS (ESI) m/z 353.2 [M+H]+
EXAMPLE 2 AW: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3- (cvclopropylmethyl)-quinazolin-4(3/-/)-one from Intermediate 7J)
Figure imgf000075_0002
MS (ESI) m/z 365.2 [M+H]+
EXAMPLE 2 AX: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chloro-4-fluorophenyl)-3- (cvclopropylmethyl)-quinazolin-4(3/-/)-one from Intermediate 7J)
Figure imgf000075_0003
MS (ESI) m/z 453.2 [M+H]+
EXAMPLE 2 AY: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- isopropylquinazolin-4(3/-/)-one from Intermediate 7K)
Figure imgf000075_0004
MS (ESI) m/z 423.2 [M+H]+ EXAMPLE 2AZ: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3- isopropylquinazolin-4(3/-/)-one (from Intermediate 7K
Figure imgf000076_0001
MS (ESI) m/z 353.2 [M+H]+
EXAMPLE 2 AAA: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- ((tetrahvdro-2H-thiopyran-4-yl-1 ,1 -dioxide)methyl)-quinazolin-4(3/-/)-one (from Intermediate 7Q)
Figure imgf000076_0002
MS (ESI) m/z 527.0 [M+H]+
EXAMPLE 2AAB: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-2-(3-chlorophenyl)-3-((1 - (hydroxymethyl) cvclobutyl)methyl)-quinazolin-4(3/-/)-one from Intermediate 8E)
Figure imgf000076_0003
MS (ESI) m/z 479.2 [M+H]+
EXAMPLE 2AAC: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000076_0004
MS (ESI) m/z 325.2 [M+H]+
EXAMPLE 2AAD: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-methylquinazolin- 4(3H)-one (from Intermediate 7F
Figure imgf000077_0001
MS (ESI) m/z 313.2 [M+H]+
EXAMPLE 2AAE: 6-Π .4-Diazabicvclor3.2.21nonan-4-ylV2-(2-fluorophenvn-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000077_0002
MS (ESI) m/z 379.2 [M+H]+
EXAMPLE 2AAF: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-fluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000077_0003
MS (ESI) m/z 379.2 [M+H]+
EXAMPLE 2AAG: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(4-fluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000077_0004
MS (ESI) m/z 379.2 [M+H]+ EXAMPLE 2AAH: 6-(1 .4-Diazabicvclor3.2.21nonan-4-vn-2-(3-chloro-2-fluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000078_0001
MS (ESI) m/z 413.7 [M+H]+
EXAMPLE 2AAI: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2,3-difluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000078_0002
MS (ESI) m/z 397.2 [M+H]+
EXAMPLE 2AAJ: 6-(1 .4-Diazabicvclor3.2.21nonan-4-vn-2-(5-chloro-2-fluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000078_0003
MS (ESI) m/z 413.7 [M+H]+
EXAMPLE 2AAK: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2,5-difluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000079_0001
MS (ESI) m/z 397.2 [M+H]+
EXAMPLE 2AAL: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-m-tolylauinazolin- 4(3H)-one (from Intermediate 7F
Figure imgf000079_0002
MS (ESI) m/z 375.5 [M+H]+
EXAMPLE 2AAM: 3-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-4-oxo-3.4- dihydroquinazolin-2-yl)benzonitrile from Intermediate 7F)
Figure imgf000079_0003
MS (ESI) m/z 386.2 [M+H]+
EXAMPLE 2AAN: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2-fluorophenyl)auinazolin- 4(3H)-one (from Intermediate 8D
Figure imgf000079_0004
MS (ESI) m/z 365.0 [M+H]+
EXAMPLE 2AAO: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-fluorophenyl)quinazolin- 4(3H)-one (from Intermediate 8D)
Figure imgf000080_0001
MS (ESI) m/z 365.2 [M+H]+
EXAMPLE 2AAP: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chloro-2- fluorophenyl)quinazolin-4(3/-/)-one from Intermediate 8D)
Figure imgf000080_0002
MS (ESI) m/z 399.0 [M+H]+
EXAMPLE 2AAQ: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(2.3-difluorophenyl)quinazolin- 4(3H)-one (from Intermediate 8D
Figure imgf000080_0003
MS (ESI) m/z 383.2 [M+H]+
EXAMPLE 2AAR: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-m-tolylquinazolin-4(3H)-one (from Intermediate 8 D)
Figure imgf000080_0004
MS (ESI) m/z 361 .2 [M+H]+
EXAMPLE 2AAS: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-2-(2-fluorophenyl)-3-((1 - (hvdroxymethyl)cvclobutyl)methyl)quinazolin-4(3/-/)-one (from Intermediate 8E)
Figure imgf000081_0001
MS (ESI) m/z 463.2 [M+H]+
EXAMPLE 2AAT: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-2-cvclopropyl-3-((1 - (hvdroxymethyl)cvclobutyl)methyl)quinazolin-4(3/-/)-one (from Intermediate 8E)
Figure imgf000081_0002
MS (ESI) m/z 409.2 [M+H]+
EXAMPLE 2AAU: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-2-phenyl-3-((1 - (hvdroxymethyl)cvclobutyl)methyl)quinazolin-4(3/-/)-one from Intermediate 8E)
Figure imgf000081_0003
MS (ESI) m/z 445.2 [M+H]+
EXAMPLE 2 AAV: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-3-((1 -
(hvdroxymethyl)cvclobutyl)methyl)-2-m-tolylquinazolin-4(3/-/)-one (from Intermediate 8E)
Figure imgf000081_0004
MS (ESI) m/z 459.2 [M+H]+ EXAMPLE 2AAW: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-2-(3-fluorophenyl)-3-((1 - (hvdroxymethyl)cvclobutyl)methyl)quinazolin-4(3/-/)-one (from Intermediate 8E)
Figure imgf000082_0001
MS (ESI) m/z 463.2 [M+H]+
EXAMPLE 2AAX: 3-(6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-3-((1 - (hvdroxymethyl)cvclobutyl)methyl)-4-oxo-3,4-dihvdroquinazolin-2-yl)benzonitrile
Intermediate 8E)
Figure imgf000082_0002
MS (ESI) m/z 470.2 [M+H]+
EXAMPLE 2AAY: 2-(6-((1 S,4S)- 2.5-Diazabicvclor2.2.1 lheptan-2-yl)-4-oxo-2- phenylquinazolin-3(4/-/)-yl)-/V-iso ropylacetamide (from Intermediate 7E)
Figure imgf000082_0003
MS (ESI) m/z 418.2 [M+H]+
EXAMPLE 2AAZ: 2-(2-Fluorophenyl)-3-methyl-6-(quinuclidin-3-ylamino)quinazolin-4(3/-/)- one (from Intermediate 8C)
Figure imgf000082_0004
MS (ESI) m/z 379.2 [M+H]+
EXAMPLE 2AAAA: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(6-methylpyridin-2- yl)quinazolin-4(3/- )-one (from Intermediate 7F)
Figure imgf000083_0001
MS (ESI) m/z 376.2 [M+H]+
EXAMPLE 2AAAB: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-vn-2-(4-fluorophenyl)-3-(3- hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000083_0002
MS (ESI) m/z 451 .2 [M+H]+
EXAMPLE 2AAAC: 6-(1 ,4-Diazabicvclof3.2.21nonan-4-yl)-2-cvclopropyl-3-(3-rivdroxy-2.2- dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000083_0003
MS (ESI) m/z 397.2 [M+H]+
EXAMPLE 2AAAD: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(2-methoxyethyl)-2-(6- methylpyridin-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8G)
Figure imgf000083_0004
MS (ESI) m/z 420.2 [M+H]+
EXAMPLE 2AAAE: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3-(2- methoxyethyl)quinazolin-4(3/-/)-one from Intermediate 8G)
Figure imgf000084_0001
MS (ESI) m/z 369.2 [M+H]+
EXAMPLE 2AAAF: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2-fluorophenyl)-3-(2- methoxyethyl)quinazolin-4(3/-/)-one from Intermediate 8G)
Figure imgf000084_0002
MS (ESI) m/z 423.2 [M+H]+
EXAMPLE 2AAAG: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(2-methoxyethyl)-2-(3- cvanophenyl)quinazolin-4(3/-/)-one from Intermediate 8G)
Figure imgf000084_0003
MS (ESI) m/z 430.2 [M+H]+
EXAMPLE 2AAAH: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(2-methoxyethyl)-2-m- tolylquinazolin-4(3/-/)-one (from Intermediate 8G)
Figure imgf000084_0004
MS (ESI) m/z 419.2 [M+H]+ EXAMPLE 2AAAI: 2-Cvclopropyl-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000085_0001
MS (ESI) m/z 31 1 .2 [M+H]+
EXAMPLE 2AAAJ: 2-(3-Fluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000085_0002
MS (ESI) m/z 365.2 [M+H]+
EXAMPLE 2AAAK: 2-(3-Chlorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000085_0003
MS (ESI) m/z 381.2 [M+H]+
EXAMPLE 2AAAL: 2-(3-Cvanophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000085_0004
MS (ESI) m/z 372.2 [M+H]+
EXAMPLE 2AAAM: 2-(4-Fluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000086_0001
MS (ESI) m/z 365.2 [M+H]+
EXAMPLE 2AAAN: 2-(3-Chloro-2-fluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2.5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000086_0002
MS (ESI) m/z 399.0 [M+H]+
EXAMPLE 2AAAO: 2-(2.3-Difluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2.5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000086_0003
MS (ESI) m/z 383.0 [M+H]+
EXAMPLE 2AAAP: 2-(5-Chloro-2-fluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2.5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000087_0001
MS (ESI) m/z 399.0 [M+H]+
EXAMPLE 2AAAQ: 2-(2,5-Difluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one from Intermediate 8B)
Figure imgf000087_0002
MS (ESI) m/z 383.0 [M+H]+
EXAMPLE 2AAAR: 3-Methyl-6-((1 S,4S)-5-methyl-2.5-diazabicvclor2.2.1 lheptan-2-yl)-2- m-tolylquinazolin-4(3/-/)-one (from Intermediate 8B
Figure imgf000087_0003
MS (ESI) m/z 361 .2 [M+H]+
EXAMPLE 2AAAS: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-3-((1 - (hvdroxymethyl)cvclobutyl)methyl)-2-(6-methylpyridin-2-yl)quinazolin-4(3/-/)-one
Intermediate 8E)
Figure imgf000087_0004
MS (ESI) m/z 460.2 [M+H]+ EXAMPLE 2AAAT: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclopropyl-2-(2- fluorophenyl)quinazolin-4(3/-/)-one from Intermediate 7L)
Figure imgf000088_0001
MS (ESI) m/z 405.2 [M+H]+
EXAMPLE 2AAAU: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-(2- fluorophenyl)quinazolin-4(3/-/)-one from Intermediate 7M)
Figure imgf000088_0002
MS (ESI) m/z 419.2 [M+H]+
EXAMPLE 2AAAV: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-(3- chlorophenyl)quinazolin-4(3/-/)-one from Intermediate 7M)
Figure imgf000088_0003
MS (ESI) m/z 435.2 [M+H]+
EXAMPLE 2AAAW: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2- phenylquinazolin-4(3/-/)-one (from Intermediate 7M
Figure imgf000088_0004
MS (ESI) m/z 401.2 [M+H]+ EXAMPLE 2AAAX: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-(3- methylphenyl)quinazolin-4(3/-/)-one from Intermediate 7M)
Figure imgf000089_0001
MS (ESI) m/z 415.2 [M+H]+
EXAMPLE 2AAAY: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-(3- cvanophenyl)quinazolin-4(3/-/)-one from Intermediate 7M)
Figure imgf000089_0002
MS (ESI) m/z 426.2 [M+H]+
EXAMPLE 2AAAZ: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-(6-methylpyridin- 2-yl)quinazolin-4(3/-/)-one (from Intermediate 7M
Figure imgf000089_0003
MS (ESI) m/z 416.2 [M+H]+
EXAMPLE 2AAAAA: 6-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-3-cvclobutyl-2-(1 -methyl-1 H- pyrazol-4-yl)quinazolin-4(3/-/)-one (from Intermediate 7M)
Figure imgf000090_0001
MS (ESI) m/z 405.2 [M+H]+
EXAMPLE 2 AAAAB: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-(6- methylpyridin-2-yl)quinazolin-4(3H)-one from Intermediate 7M)
Figure imgf000090_0002
MS (ESI) m/z 416.2 [M+H]+
EXAMPLE 2AAAAC: 3-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-4-oxo-3,4- dihydroquinazolin-2-yl)benzonitrile (from Intermediate 7M)
Figure imgf000090_0003
MS (ESI) m/z 426.2 [M+H]+
EXAMPLE 2AAAAD: 7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl 3- methylquinazolin-4(3H)-one (from Intermediate 8H)
Figure imgf000090_0004
MS (ESI) m/z 395.2 [M+H]+
EXAMPLE 2AAAAE: 7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-fluorophenyl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 8H)
Figure imgf000091_0001
MS (ESI) m/z 379.2 [M+H]+
EXAMPLE 2AAAAF: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2-fluorophenyl)-3-(2- hvdroxyethyl)quinazolin-4(3/-/)-one (from Intermediate 7P)
Figure imgf000091_0002
MS (ESI) m/z 409.2 [M+H]+
EXAMPLE 2AAAAG: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3-(2- hydroxyethyl) quinazolin-4(3/-/)-one (from Intermediate 7P)
Figure imgf000091_0003
MS (ESI) m/z 355.2 [M+H]+
EXAMPLE 2AAAAH: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(thiazol-5-yl) quinazolin-4(3/-/)-one (from Intermediate 7F
Figure imgf000091_0004
MS (ESI) m/z 368.2 [M+H]+ EXAMPLE 2AAAAI: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(2-methylthiazol-5- yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000092_0001
MS (ESI) m/z 382.2 [M+H]+
EXAMPLE 2AAAAJ: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(4-methylpyridin-2- yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000092_0002
MS (ESI) m/z 364.2 [M+H]+
EXAMPLE 2AAAAK: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(thiazol-2- yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000092_0003
MS (ESI) m/z 368.0 [M+H]+
EXAMPLE 2AAAAL: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(Dyridin-4- yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000093_0001
MS (ESI) m/z 362.2 [M+H]+
EXAMPLE 2AAAAM: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(4-methylDyridin- 2-yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000093_0002
MS (ESI) m/z 376.2 [M+H]+
EXAMPLE 2AAAAN: 6-(1 ,4-Diazabicvclor3.2.21nonan- -yl)-3-methyl-2-(5-methylDyridin- 3-yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000093_0003
MS (ESI) m/z 376.2 [M+HJ+
EXAMPLE 2AAAAO: 2-(Benzordloxazol-2-yl)-6-(1 ,4-diazabicvclor3.2.21nonan-4-yl)-3- methylquinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000093_0004
MS (ESI) m/z 402.2 [M+H]+
EXAMPLE 2AAAAP: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-(5-methylfuran-2- yl)quinazolin-4(3/-/)-one (from Intermediate 7F)
Figure imgf000094_0001
MS (ESI) m/z 365.2 [M+H]+
EXAMPLE 2AAAAQ: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3-(2- hvdroxyethyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000094_0002
MS (ESI) m/z 397.2 [M+H]+
EXAMPLE 2AAAAR: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2-fluorophenyl)-3-(2- hvdroxyethyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000094_0003
MS (ESI) m/z 451 .2 [M+H]+
EXAMPLE 2AAAAS: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3-(3- hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000095_0001
MS (ESI) m/z 467.2 [M+H]+
EXAMPLE 2AAAAT: 3-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-hvdroxy-2,2- dimethylpropyl)-4-oxo-3,4-dihvdroquinazolin-2-yl)benzonitrile (from Intermediate 8F)
Figure imgf000095_0002
MS (ESI) m/z 458.2 [M+H]+
EXAMPLE 2AAAAU: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(4-fluorophenyl)-3-(3- hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000095_0003
MS (ESI) m/z 451 .2 [M+H]+
EXAMPLE 2AAAAV: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chloro-2-fluorophenyl)-3- (3-hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000096_0001
MS (ESI) m/z 485.2 [M+H]+
EXAMPLE 2AAAAW: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2,3-difluorophenyl)-3-(3- hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000096_0002
MS (ESI) m/z 469.2 [M+H]+
EXAMPLE 2AAAAX: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-(5-chloro-2-fluorophenyl)-3- (3-hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000096_0003
MS (ESI) m/z 485.2 [M+H]+
EXAMPLE 2AAAAY: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2.5-difluorophenyl)-3-(3- hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000097_0001
MS (ESI) m/z 469.2 [M+H]+
EXAMPLE 2AAAAZ: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-hvdroxy-2,2- dimethylpropyl)-2-m-tolylquinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000097_0002
MS (ESI) m/z 447.2 [M+H]+
EXAMPLE 2AAAAAA: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(2-fluorophenyl)-3-(3- hvdroxy-2,2-dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000097_0003
MS (ESI) m/z 451.2 [M+H]+
EXAMPLE 2AAAAAB: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclopropyl-2-m- tolylquinazolin-4(3/-/)-one (from Intermediate 7L)
Figure imgf000098_0001
MS (ESI) m/z 401 .2 [M+H]+
EXAMPLE 2AAAAAC: 2-Cvclopropyl-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000098_0002
MS (ESI) m/z 31 1 .2 [M+H]+
EXAMPLE 2AAAAAD: 2-(4-Fluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000098_0003
MS (ESI) m/z 365.2 [M+H]+
EXAMPLE 2AAAAAE: 2-(5-Chloro-2-fluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2.5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000098_0004
MS (ESI) m/z 399.0 [M+H]+
EXAMPLE 2AAAAAF: 2-(2,5-Difluorophenyl)-3-methyl-6-((1 S,4S)-5-methyl-2,5- diazabicvclo[2.2.1 lheptan-2-yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000099_0001
MS (ESI) m/z 383.0 [M+H]+
EXAMPLE 2AAAAAG: 3-(7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-4-oxo-3,4- dihydroquinazolin-2-yl)benzonitrile (from Intermediate 8H)
Figure imgf000099_0002
MS (ESI) m/z 386.2 [M+H]+ EXAMPLE 2AAAAAH: 4-r3-(3-Chloro-phenyl)-2-methyl-1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzo[1 ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18A)
Figure imgf000099_0003
MS (ESI) m/z 431 .0 [M+H]+
EXAMPLE 2AAAAAI: 4-r3-(2-Flouro-phenyl)-2-methyl-1 ,1 -dioxo-1 ,2-dihydro- (6)- benzoH ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18A)
Figure imgf000100_0001
MS (ESI) m/z 415.0 [M+H]+
EXAMPLE 2AAAAAJ: 4-r3-(6-Methyl-pyridin-2-yl)-2-methyl-1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzo[1 ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicvclo[3.2.2lnonane (from Intermediate 18A)
Figure imgf000100_0002
MS (ESI) m/z 412.2 [M+H]+
EXAMPLE 2AAAAAK: 4-(2-Methyl-3-thiazol-2-yl-1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzoH ,2,4lt iadiazin-7-yl)-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18A)
Figure imgf000100_0003
MS (ESI) m/z 404.0 [M+H]+
EXAMPLE 2AAAAAL: 4-r2-Methyl-3-(5-methyl-furan-2-yl)-2-methyl-1 ,1 -dioxo-12- dihydro-1 λ (6)-benzo[1 ,2,4lthiadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from
Intermediate 18A)
Figure imgf000100_0004
MS (ESI) m/z 401 .2 [M+H]+ EXAMPLE 2AAAAAM: 4-(3-Cvclopropyl-2-methyl-1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzo[1 ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18A)
Figure imgf000101_0001
MS (ESI) m/z 361 .4 [M+H]+
EXAMPLE 2AAAAAN: 4-r3-(2-Fluoro-phenyl) -1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzoH ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18B)
Figure imgf000101_0002
MS (ESI) m/z 401 .4 [M+H]+
EXAMPLE 2AAAAAO: 4-r3-(3-Chloro-phenvD- 1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzoH ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18B)
Figure imgf000101_0003
MS (ESI) m/z 417.4 [M+H]+
EXAMPLE 2AAAAAP: 4-r3-(5-Methyl-furan-2-yl)-1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzo[1 ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18B)
Figure imgf000101_0004
MS (ESI) m/z 387.5 [M+H]+ EXAMPLE 2AAAAAQ: 4-(1 ,1 -Dioxo-3-thiazol-2-yl-1 ,2-dihydro- (6)- benzo[1 ,2,4lt iadiazin-7-yl)-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18B)
Figure imgf000102_0001
MS (ESI) m/z 390.4 [M+H]+
EXAMPLE 2AAAAAR: 4-r3-(5-Methyl-thiazol-2-yl)-1 ,1 -dioxo-1 ,2-dihvdro- (6)- benzo[1 ,2,4lt iadiazin-7-yll-1 ,4-diaza-bicyclo[3.2.21nonane (from Intermediate 18B)
Figure imgf000102_0002
MS (ESI) m/z 404.5 [M+H]+
EXAMPLE 2AAAAAS: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-3- methylpyrido[3,4-dlpyrimidin-4(3/-/)-one (from Intermediate 31 A)
Figure imgf000102_0003
MS (ESI) m/z 396.2 [M+H]+
EXAMPLE 2AAAAAT: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3- methylpyrido[3,4-dlpyrimidin-4(3/-/)-one (from Intermediate 31 A)
Figure imgf000102_0004
MS (ESI) m/z 326.2 [M+H]+ EXAMPLE 2AAAAAU: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3- chlorophenyl)pyrido[3,4-dlpyrimidin-4(3/-/)-one (from Intermediate 31 B)
Figure imgf000103_0001
MS (ESI) m/z 381 .9 [M+H]+
EXAMPLE 2AAAAAV: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropylpyridor3,4- dlpyrimidin-4(3/-/)-one (from Intermediate 31 B
Figure imgf000103_0002
MS (ESI) m/z 312.2 [M+H]+
EXAMPLE 2AAAAAW: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3-(3-hvdroxy- 2,2-dimethylpropyl)pyrido[3,4-dlpyrimidin-4(3/-/)-one (from Intermediate 31 C)
Figure imgf000103_0003
MS (ESI) m/z 398.2 [M+H]+
EXAMPLE 2AAAAAX: 7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-cvclopropyl-3- dimethylquinazolin-4(3/-/)-one (from Intermediate 8H)
Figure imgf000103_0004
MS (ESI) m/z 325.2 [M+H]+ EXAMPLE 3A: 3-Methyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrole-2( 1 H)-yl)quinazolin- 4(3H)-one
Figure imgf000104_0001
2-Amino-/V-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1 H)-yl)benzam
(Intermediate 8A) (100 mg, 0.36 mmol) was dissolved in triethoxymethane (1 mL) and sealed in a microwave vial. Heated at 160 °C for 10 minutes. Reaction allowed to cool to room temperature and lithium hydroxide solution added (0.5 mL, 1 M in methanol) and reaction stirred overnight. Organic layer loaded onto a 1 g SCX cartridge. The crude material was purified by SCX, and the solvent removed under reduced pressure. The crude material was then re-dissolved in methanol (1 mL) and purified by preparative- HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 3-methyl-6- (5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1 /-/)-yl)quinazolin-4(3/-/)-one (56 mg, 0.2 mmol).
MS (ESI) m/z 285.2 [M+H]+ Similarly prepared were:
EXAMPLE 3B: 3-Methyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)- \)-2- phenylquinazolin-4(3/-/)-one (from Intermediate 8A
Figure imgf000104_0002
MS (ESI) m/z 361 .2 [M+H]+
EXAMPLE 3C: 2,3-Dimethyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)- yl)quinazolin-4(3/-/)-one (from Intermediate 8A
Figure imgf000104_0003
MS (ESI) m/z 299.2 [M+H]+ EXAMPLE 3D: 2-Ethyl-3-methyl-6-(5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)- yl)quinazolin-4(3/-/)-one (from Intermediate 8A)
Figure imgf000105_0001
MS (ESI) m/z 313.2 [M+H]+
EXAMPLE 3E: 3-Methyl-6-((1 S,4S)-5-methyl-2,5-diazabicvclor2.2.1 lheptan-2- yl)quinazolin-4(3/-/)-one (from Intermediate 8B
Figure imgf000105_0002
MS (ESI) m/z 271 .0 [M+H]+
EXAMPLE 3F: 3-Methyl-6-((1 S,4S)-5-methyl-2.5-diazabicvclor2.2.1 lheptan-2-vn-2- phenylquinazolin-4(3/-/)-one (from Intermediate 8B
Figure imgf000105_0003
MS (ESI) m/z 347.2 [M+H]+
EXAMPLE 3G: 2.3-Dimethyl-6-((1 S,4S)-5-methyl-2,5-diazabicvclor2.2.1 lheptan-2- yl)quinazolin-4(3/- )-one (from Intermediate 8B
Figure imgf000105_0004
MS (ESI) m/z 285.2 [M+H]+
EXAMPLE 3H: 2-Ethyl-3-methyl-6-((1 S.4SV5-methyl-2.5-diazabicvclor2.2.1 lheptan-2- yl)quinazolin-4(3/-/)-one (from Intermediate 8B)
Figure imgf000106_0001
MS (ESI) m/z 299.2 [M+H]+
EXAMPLE 3I: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methylquinazolin-4(3H)-one
Intermediate 7F)
Figure imgf000106_0002
MS (ESI) m/z 285.2 [M+H]+
EXAMPLE 3J: te/f-Butyl 2-(6-(1.4-diazabicvclor3.2.2lnonan-4-yl)-2-ethyl-4-oxoquinazolin- 3(4/-/)-yl)acetate (from Intermediate 7B)
Figure imgf000106_0003
MS (ESI) m/z 413.2 [M+H]+
EXAMPLE 3K: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-phenylquinazolin-4(3H)-one
Intermediate 8D)
Figure imgf000106_0004
MS (ESI) m/z 347.2 [M+H]+
EXAMPLE 3L: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-phenylquinazolin-4(3H)- one (from Intermediate 7F)
Figure imgf000107_0001
MS (ESI) m/z 361 .2 [M+H]+
EXAMPLE 3M: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-methyl-3-methylquinazolin-4(3H)- one (from Intermediate 7F)
Figure imgf000107_0002
MS (ESI) m/z 299.2 [M+H]+
EXAMPLE 3N: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-hvdroxy-2,2- dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000107_0003
EXAMPLE 30: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-(3-hvdroxy-2.2- dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000107_0004
MS (ESI) m/z 357.2 [M+H]+
EXAMPLE 3P: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-3-(2-methoxyethyl)quinazolin-4(3H)- one (from Intermediate 8G)
Figure imgf000108_0001
MS (ESI) m/z 329.2 [M+H]+
EXAMPLE 3Q: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(2-methoxyethyl)-2- methylquinazolin-4(3/-/)-one (from Intermediate 8G
Figure imgf000108_0002
MS (ESI) m/z 343.2 [M+H]+
EXAMPLE 3R: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutylquinazolin-4(3H)-one (from Intermediate 7M)
Figure imgf000108_0003
MS (ESI) m/z 325.2 [M+H]+
EXAMPLE 3S: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-cvclobutyl-2-ethylquinazolin- 4(3/-/)-one (from Intermediate 7M
Figure imgf000108_0004
MS (ESI) m/z 353.2 [M+H]+
EXAMPLE 3T: 7-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2.3dimethylquinazolin-4(3H)-one (from Intermediate 8H)
Figure imgf000108_0005
MS (ESI) m/z 299.2 [M+H]+
EXAMPLE 3U: 7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-methylquinazolin-4(3H)- one (from Intermediate 8H)
Figure imgf000109_0001
MS (ESI) m/z 313.2 [M+H]+
EXAMPLE 3V: 7-(1.4-Diazabicvclor3.2.21nonan-4-yl)-3-methylquinazolin-4(3H)-one Intermediate 8H)
Figure imgf000109_0002
MS (ESI) m/z 285.0 [M+H]+
EXAMPLE 3W: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-hvdroxy-2,2- dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000109_0003
EXAMPLE 3X: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-(3-hvdroxy-2.2- dimethylpropyl)quinazolin-4(3/-/)-one (from Intermediate 8F)
Figure imgf000110_0001
MS (ESI) m/z 385.2 [M+H]+
EXAMPLE 3Y: 4-(3-Ethyl-2-methyl-1 ,1 -dioxo-1 ,2-dihvdro- (6H>enzoM ,2,41thiadiazin-7- yl)-1 ,4-diaza-bicvclor3.2.2lnonane (from Intermediate 18A)
Figure imgf000110_0002
MS (ESI) m/z 349.2 [M+H]+
EXAMPLE 3Z: 4-(2.3-Dimethyl-1 ,1 -dioxo-1 ,2-dihvdro- (6 benzoM .2,41thiadiazin-7-yl)- 1 ,4-diaza-bicvclor3.2.2lnonane (from Intermediate 18A)
Figure imgf000110_0003
MS (ESI) m/z 335.4 [M+H]+
EXAMPLE 3AA: 6-(1 .4-Diazabicvclor3.2.21nonan-4-yl)-3-methylpyridor3.4-dlDyrimidin- 4(3H)-one (from Intermediate 31A)
Figure imgf000110_0004
MS (ESI) m/z 286.2 [M+H]+
EXAMPLE 3AB: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-methylpyridor3.4- dlpyrimidin-4(3H)-one (from Intermediate 31 A)
Figure imgf000111_0001
MS (ESI) m/z 314.2 [M+H]+
EXAMPLE 3 AC: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-methyl-2-phenylDyridor3.4- dlpyrimidin-4(3/-/)-one (from Intermediate 31 A)
Figure imgf000111_0002
MS (ESI) m/z 362.2 [M+H]+
EXAMPLE 3 AD: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-etriylpyridof3,4-d1pyrimidin- 4(3H)-one (from Intermediate 31 B)
Figure imgf000111_0003
MS (ESI) m/z 300.2 [M+H]+
EXAMPLE 3AE: 6-(1.4-Diazabicvclor3.2.21nonan-4-yl)-2-phenylpyridor3,4-dlpyrimidin- 4(3H)-one (from Intermediate 31 B
Figure imgf000111_0004
MS (ESI) m/z 348.2 [M+H]+
EXAMPLE 3AF: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-hvdroxy-2,2- dimethylpropyl)pyridor3,4-dlpyrimidin-4(3H)-one (from Intermediate 31 C)
Figure imgf000112_0001
MS (ESI) m/z 358.2 [M+H]+
EXAMPLE 3 AG: 6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-3-(3-hvdroxy-2,2- dimethylpropyl)pyrido[3,4-dlpyrimidin-4(3/-/)-one (from Intermediate 31 C)
Figure imgf000112_0002
MS (ESI) m/z 386.2 [M+H]+
EXAMPLE 4A: 2-(6-(Hexahvdropyrrolor3,4-clpyrrol-2( 1 /-/)-yl)-4-oxo-2-phenylquinazolin- 3(4/-/)-yl-/V-isopropylacetamide
2,2,2-Trifluoroacetic acid (0.2 g, 1 .72 mmol) was added to a solution of ie f-butyl 5-(3-(2- (isopropylamino)-2-oxoethyl)-4-oxo-2-phenyl-3,4-dihydroquiazolin-6-yl)hexahydropyrrolo [3,4-c]pyrrole-2(1 H)-carboxylate (Intermediate 12A) (129 mg, 0.24 mmol) in dichloromethane (5ml_). The resulting solution was stirred for 2 hours. The resultant crude material was purified using a 1 g SCX cartridge to afford 2-(6-(hexahydropyrrolo[3,4- c]pyrrol-2(1 /-/)-yl)-4-oxo-2-phenylquinazolin-3(4/-/)-yl-/V-isopropylacetamide (65 mg, 0.15 mmol).
MS (ESI) m/z 432.2 [M+H]+ Similarly prepared were:
EXAMPLE 4B: 2-(6-(Hexahydropyrrolor3,4-clpyrrol-2(1 H)-yl)-4-oxoquinazolin-3(4H)-yl)-/V- isopropylacetamide (from Intermediate 12B)
Figure imgf000113_0001
MS (ESI) m/z 396.2 [M+H]+
EXAMPLE 4C: 2-(2-Cvclopropyl-6-(hexahvdropyrrolor3.4-clpyrrol-2(1 H)-yl)-4- oxoquinazolin-3(4/-/)-yl)-/V-isopropylacetamide (from Intermediate 12C)
Figure imgf000113_0002
MS (ESI) m/z 396.2 [M+H]+
EXAMPLE 4D: 7-(Hexahvdropyrrolor3.4-clpyrrol-2(1 H)-yl)-2-methylisoquinolin-1 (2H)-one (from lntermediate20B)
Figure imgf000113_0003
MS (ESI) m/z 270 [M+H]+
EXAMPLE 5A: /V-lsopropyl-2-(6-(5-methylhexahvdropyrrolor3.4-clpyrrol-2(1 H)-yl)-4-oxo- 2-phenylquinazolin-3(4H)-yl)acetamide
Figure imgf000113_0004
2-(6-(hexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)-4-oxo-2-phenylquinazolin-3(4/-/)-yl-/V- isopropylacetamide (EXAMPLE 4A) (100 mg, 0.23 mmol) was dissolved in acetonitrile (2 mL) before addition of formaldehyde (28 mg, 0.35 mmol) and MP-cyanoborohydride (140 mg, 0.36 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a microwave vial and heated at 130 °C for 20 minutes. Reaction mixture was then diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford /V-isopropyl-2-(6-(5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1 /-/)-yl)-4-oxo-2-phenylquinazolin-3(4/-/)-yl)acetamide (38 mg, 0.09 mmol).
MS (ESI) m/z 446.2 [M+H]+
Similarly prepared were:
EXAMPLE 5B: /V-lsopropyl-2-(6-((1 S,4S)- 5-methyl-2,5-diazabicvclor2.2.1 lheptan-2-yl)-4- oxo-2-phenylquinazolin-3(4/-/)- l)acetamide (from EXAMPLE 2AAY)
Figure imgf000114_0001
MS (ESI) m/z 432.2 [M+H]+
EXAMPLE 5C: 2-(2-Cvclopropyl-6-((1 S,4S)-5-methyl-2.5-diazabicvclor2.2.1 lheptan-2-yl)- 4-oxoquinazolin-3(4H)-yl)-/V-iso ropylacetamide (from Intermediate 12D)
Figure imgf000114_0002
MS (ESI) m/z 396.2 [M+H]+
EXAMPLE 5D: 2-Methyl-7-(5-methylhexahvdropyrrolor3,4-clpyrrol-2( 1 H)-ylisoquinolin- 1 (2H)-one (from Example 4D)
Figure imgf000114_0003
MS (ESI) m/z 284 [M+H]+ EXAMPLE 6A: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-(3-chlorophenyl)-4- oxoquinazolin-3(4/-/)-yl)-/V,/\/-climeth lacetamide
Figure imgf000115_0001
2-(6-(1 ,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4 -/)-yl) acetic acid (Intermediate 1 1A) (49 mg, 0.1 1 mmol) and dimethylamine hydrochloride (18.2 mg, 0.22 mmol) were weighed into a round bottomed flask and dichloromethane (1 mL) added to form a suspension. Triethylamine (33.8 mg, 0.33 mmol) was added and the suspension stirred for 5 minutes before dropwise addition of 1 -propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (107 mg, 0.17 mmol) and the resulting reaction mixture stirred for 2 hours. Reaction mixture was washed with sodium bicarbonate solution and the organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. To afford the title compound 2-(6-(1 ,4- diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4/-/)-yl)-/V,/V- dimethylacetamide (5.4 mg, 0.012 mmol).
MS (ESI) m/z 466.2 [M+H]+
Similarly prepared were:
EXAMPLE 6B: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-4-oxoquinazolin-3(4H)-yl)- Λ/,/V-dimethylacetamide (from Intermediate 14A
Figure imgf000115_0002
MS (ESI) m/z 384.2 [M+H]+
EXAMPLE 6C: 2-(6-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-2-ethyl-4-oxoquinazolin-3(4H)-yl)- /V-isopropyl-ZV-methylacetamide (from Intermediate 14A)
Figure imgf000116_0001
MS (ESI) m/z 412.2 [M+H]+
EXAMPLE 7A: 7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-chlorophenyl)-2- methylisoquinolin-1 (2H)-one
Figure imgf000116_0002
A mixture of 7-bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1 (2/-/)-one (Intermediate 24A) (50 mg, 0.143 mmol), 1 ,4-diazabicyclo[3.2.2]nonane (27.2 mg, 0.215 mmol), sodium t-butoxide (55.1 mg, 0.574 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.13 mg, 0.014 mmol) and (+/-) BINAP (26.8 mg, 0.043 mmol) in degassed dioxane (1 mL) was heated to 85° C under N2 in a sealed vessel overnight. Reaction mixture allowed to cool to room temperature, diluted with water and the product extracted into ethyl acetate. Organics washed several times with water, dried (MgS04), filtered and then evaporated to dryness. The crude product was added to a silica gel column (25g) and was eluted with 0-50% 2M ammonia in methanol in ethylacetate to afford 7-(1 ,4-diazabicyclo[3.2.2]nonan- 4-yl)-3-(3-chlorophenyl)-2-methylisoquinolin-1 (2/-/)-one (19.4 mg, 0.05 mmol).
MS (ESI) m/z 394 [M+H]+
Similarly prepared were:
EXAMPLE 7B: 7-(1 ,4-Diazabicvclor3.2.2lnonan-4-yl)-3-(3-chlorophenyl)isoquinolin-1 (2H)-
(from Intermediate 23A)
Figure imgf000116_0003
MS (ESI) m/z 380 [M+H]+
EXAMPLE 8A: 4-(2-(3-Chlorophenyl)-3-methyl-4-oxo-3,4-dihvdroquinazolin-6-yl)-1 - methyl-4-aza-1 -azoniabicyclo[3.2.2lnonane iodide (from Example 2AL)
Figure imgf000117_0001
To a solution of iodomethane (0.18 g, 1 .3 mmol) in THF (12 mL) was added 6-(1 ,4- diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-3-methylquinazolin-4(3/-/)-one (Example 2AL) (0.5 g, 1.3 mmol) and reaction stirred for two days. The resultant precipitate was collected via filtration, triturated with minimum amount of methanol and dried to afford 4- (2-(3-chlorophenyl)-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-1 -methyl-4-aza-1 - azoniabicyclo[3.2.2]nonane iodide (0.44 g, 0.82 mmol).
MS (ESI) m/z 409.4 [M+H]+
Example 9A: 4-(2-(3-Chlorophenyl)-3-methyl-4-oxo-3,4-dihvdroquinazolin-6-yl)-1 ,4- diazabicyclo[3.2.21nonane 1 -oxide
Figure imgf000117_0002
To a solution of 6-(1 ,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-3- methylquinazolin-4(3/-/)-one (400 mg, 1.013 mmol) (Example 2AL) in dichloromethane ( 12 mL ) was added 3-chloroperbenzoic acid (250 mg, 1 .013 mmol) and the reaction stirred at ambient temperature for 3 h. Sodium carbonate solution was added to neutralise the acid and the aqueous saturated with sodium chloride. The organic layer was separated off and chromatographed on 10g silica, eluting with dichloromethane with 10% ammonia in methanol (1 M). To remove the remaining impurities the mixture was purified by acidic prep hplc, product passed through a carbonate on silica cartridge (2g) to remove the acid to afford 4-(2-(3-chlorophenyl)-3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)-1 ,4-diazabicyclo[3.2.2]nonane 1 -oxide (1 12 mg, 0.273 mmol).
MS (ESI) m/z 41 1.2 [M+H]+ EXAMPLE 10A: 6-((1 S,4S)-5-Methyl-2,5-diazabicvclor2.2.1 lheptan-2-yl)quinazolin-4(3H)- one
Figure imgf000118_0001
To a solution 2-amino-5-((1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)benzamide (Intermediate 31 D) (1 g, 3.83 mmol) in methanol (15 ml) was added trimethyl orthoformate (812 mg, 7.66 mmol) and ammonium acetate (0.60 g, 7.66 mmol). The vessel was sealed and the reaction heated at 120 °C for 4 hours. The methanol was then removed and the product chromatographed on silica elueting with 5% methanol in dichloromethane to afford 6-((1 S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)quinazolin-4(3H)-one (0.60g, 2.33 mmol) as an off-white solid.
MS (ESI) m/z 257.0 [M+H]+
EXAMPLE 11 A: 6-((1 S,4S)-5-Methyl-2,5-diazabicvclor2.2.1 lheptan-2-yl)-3-((5- methylisoxazol-3-yl)methyl)quinazolin-4(3/-/)-one
Figure imgf000118_0002
To a solution of 6-((1 S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)quinazolin-4(3H)- one (Example 10A) (150 mg, 0.583 mmol) in dimethylformamide was cooled to 0 °C added and sodium hydride (21 mg, 0.875 mmol) was added, after 5 minutes 3- bromomethyl-5-methylisoxazole (75 mg, 0.426 mmol) was added and the reaction stirred at room temp for 1 h. The reaction was quenched with ammonium chloride and the dimethylformamide evaporated off. The residue was dissolved in 10% methanol in dichloromethane and dried over sodium sulphate before evaporation to dryness. The product was purified by silica chromatography, elueting with 10% methanol in dichloromethane to afford 6-((1 S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)-3-((5- methylisoxazol-3-yl)methyl)quinazolin-4(3/-/)-one (0.10 g, 0.284 mmol).
MS (ESI) m/z 352.1 [M+H]+
Example 12A: 6-(1 ,4-Diazabicyclo[3.2.2lnonan-4-yl)-3-methylthieno[2,3-dlpyrimidin- 4(3H)-one
Figure imgf000119_0001
A mixture of 6-bromo-3-methylthieno[2,3-d]pyrimidin-4(3/-/)-one (70 mg, 0.28 mmol), copper(l) iodide (13.6 mg, 0.071 mmol), L-proline (16.4 mg, 0.143 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (54.1 mg, 0.428 mmol) and potassium phosphate (132 mg, 5 0.571 mmol) in DMSO (1 mL) was heated at 90 °C in a sealed vessel for 3 days. The reaction was acidified with acetic acid, diluted with methanol and purified on a sex cartridge (1 g), further purified by acid prep HPLC, passed through a sex cartridge (500 mg) and evaporated to dryness to afford 6-(1 ^-DiazabicyclotS^^nonan^-y -S- methylthieno^S-d^yrimidin^S -one (1.8 mg, 0.006 mmol).
10 .MS (ESI) m/z 291.0 [M+H]+
EXAMPLE 13A: 2-(3-Chlorophenyl)-3-methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3/-/)-one
Figure imgf000119_0002
To a solution of 2-(3-chlorophenyl)-6-hydroxy-3-methylquinazolin-4(3/-/)-one (Intermediate 15 33A) (100 mg, 0.35 mmol), 3-quinuclidinol (44 mg, 0.35 mmol) and triphenylphosphine (137 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was added dropwise diisopropyl azodicarboxylate (0.103 mL, 0.52 mmol). The reaction was stirred for 20h. The mixture was purified by sex cartridge (1 g) followed by acidic prep hplc then sex (500 mg) to afford 2-(3-chlorophenyl)-3-methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3/-/)-one (18 mg, 0.045 20 mmol).
MS (ESI) m/z 396.0 [M+H]+
Similarly prepared were:
EXAMPLE 13B: (S)-2-(3-Chlorophenyl)-3-methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3H)- 25 one (from Intermediate 33A)
Figure imgf000120_0001
MS (ESI) m/z 396.0 [M+H]+
EXAMPLE 13C: (R)-2-(3-Chlorophenyl)-3-methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3H)- one (from Intermediate 33A)
Figure imgf000120_0002
MS (ESI) m/z 396.0 [M+H]+
EXAMPLE 13D: (S)-3-Ethyl-2-phenyl-6-(quinuclidin-3-yloxy)quinazolin-4(3/-/)-one (from Intermediate 33C)
Figure imgf000120_0003
MS (ESI) m/z 376.2 [M+H]+
EXAMPLE 13E: (R)-3-Ethyl-2-phenyl-6-(quinuclidin-3-yloxy)quinazolin-4(3/-/)-one (from Intermediate 33C)
Figure imgf000120_0004
MS (ESI) m/z 376.2 [M+H]+
EXAMPLE 13F: (S)-3-Methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3/-/)-one (from Intermediate 33B)
Figure imgf000121_0001
MS (ESI) m/z 286.2 [M+H]+
EXAMPLE 14 Nicotinic Acetylcholine oc7 receptor FLIPR assay.
Test compounds were prepared as a stock solution in 100% dimethylsulfoxide (DMSO) and then further diluted in assay buffer so that the final concentration of DMSO in the assay was 1 %. Each compound was tested for activity over 10 concentrations at half log intervals (ranging 300pM - 10μΜ).
HEK 293 cells stably co-expressing the human nicotinic receptor oc7 subunit with human RIC3 (HEK oc7/RIC3) were grown in MEM + glutamax (Invitrogen Corp., Paisley, UK) supplemented with 10 % FetalClone II (Hyclone, Thermo Scientific, Logan, UT, USA), non-essential amino acids, 1 mg/ml G418 (Invitrogen Corp., Paisley, UK), 0.5mg / ml zeocin (Invitrogen Corp., Carlsbad, CA, USA) at 37°C, 5% C02 and 100% relative humidity. 24 hours prior to the assay, cells were seeded into 384 well black walled plates with clear bottoms, at a density of 5000 cells per well, in growth medium containing no antibiotic selection. Assay plates were pre-treated with Matrigel (BD Biosciences, California, USA).
On the day of the assay, the growth medium was aspirated and replaced with 25μΙ of Fluo3-AM (10μΜ; Invitrogen Molecular Probes, Eugene, Oregon, USA) prepared in oc7 assay buffer (1 X HBSS [Invitrogen Corp., Paisley, UK ], 20mM HEPES; pH 7.4, 200mM probenecid) and incubated for 1 hour at 37°C . The dye was then aspirated and the cells washed with 50μΙ of assay buffer. The cells were transferred to the FLIPR 3 (Molecular Devices Corp., Sunnyvale, CA USA) before being incubated with 25μΙ of the selective oc7 receptor positive allosteric modulator PNU 120596 (commercially available- 7μΜ in assay buffer) for 2 minutes at room temperature. 12.5μΙ of the test compound was added and agonist evoked responses, mediated by nicotinic acetylcholine oc7 receptors, were measured as a function of the change in fluorescence of the Fluo3-AM dye.
Typical EC50 values measured in the in vitro assay described above for the compounds of the invention are 100μΜ or less. For some compounds of the invention the EC50 was found to be below 10μΜ. For many compounds of the invention the EC5o was found to be below 100nM.

Claims

Claims
1. A heterocyclic derivative of formula I
Figure imgf000123_0001
formula I
wherein
R1 is H, Ci-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C3-8cycloalkylCi-2alkyl, Z-Ci-2alkyl or a 4-8 membered heterocyclyl comprising one or more heteroatomic moiety independently selected from O, S, SO and S02, wherein Z is a 5-6 membered heteroaryl comprising one or more heteroatom independently selected from O, N, and S, said Ci-8alkyl, C3-8cycloalkyl, C3-8cycloalkylCi-2alkyl, 5-6 membered heteroaryl and 4- 8 membered heterocyclyl being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, Ci-6alkoxyl, CONR3R4, S02NR5R6 and C02Ci-6alkyl;
R2 is H, Ci-8alkyl, C3-8cycloalkyl or C3-8cycloalkylCi-2alkyl, said Ci-8alkyl, C3-8cycloalkyl and C3-8cycloalkylCi-2alkyl being optionally substituted with one or more substituent independently selected from halogen, hydroxyl and methoxy or
R2 is C6-ioaryl optionally substituted with one or more substituent independently selected from halogen, hydroxy, cyano, Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3- 6cycloalkyloxy, said Ci-8alkyl, C3-8cycloalkyl, Ci-6alkyloxy and C3-6cycloalkyloxy being optionally substituted with one or more halogens or
R2 is a 5-10 membered heteroaryl ring system comprising a heteroatom selected from N, O and S and optionally substituted with methyl, Ci-6alkyloxy, halogen or cyano; R3 and R4 are independently H or Ci-6alkyl or R3 and R4 together with the N to which they are bonded form a 4-7 membered heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S, SO and S02, said Ci-6alkyl and 4-7 membered heterocyclic ring being optionally substituted with one or more halogens;
R5 and R6 are independently H or Ci-6alkyl or R5 and R6 together with the N to which they are bonded form a 4-7 membered heterocyclic ring optionally comprising a further heteroatomic moiety selected from O, S, SO and S02, said Ci-6alkyl and 4-7 membered heterocyclic ring being optionally substituted with one or more halogens;
X1 is CO or S02;
X2 is N or CH;
Figure imgf000124_0001
is a substituted arylene or heteroarylene fused to the pyrimidinone at ad acent carbon atoms and is selected from:
Figure imgf000124_0002
R7 is (Y)mR8, wherein
Y is O, NR9 or CR10R11;
m is 0 or 1 ;
R8 is a 6-10 membered bridged or fused multicyclic saturated or partially unsaturated ring system comprising a N(R12)n moiety and optionally comprising a N(R13)P moiety, said bridged or fused multicyclic ring system being optionally substituted with methyl or hydroxyl;
R9 is H or Ci-6alkyl;
R10 and R11 are independently H or Ci-6alkyl;
R12 and R13 are independently H, Ci-6alkyl or oxo;
R14 is a further optional substituent selected from methyl, halogen and cyano;
n is 0 or 1 and
p is 0 or 1
with the proviso that when R7 is 1 ,4-diazabicyclo[3.2.2]non-4-yl or octahydropyrrolo[1 ,2- a]pyrazin-2-yl, one or both of R3 and R4 cannot be H.
or a pharmaceutically acceptable salt or solvate thereof.
2. The heterocyclic derivative according to claim 1 , wherein R1 is H, methyl, ethyl, propyl or isopropyl, optionally substituted with hydroxyl or methoxyl.
3. The heterocyclic derivative according to claim 1 or claim 2, wherein R1 is H or methyl.
4. The heterocyclic derivative according to any one of claims 1 -3, wherein R2 is H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
5. The heterocyclic derivative according to any one of claims 1 -3, wherein R2 is phenyl optionally substituted with one or two substituents selected from chloro, fluoro, methyl, methoxyl and cyano.
6. The heterocyclic derivative according to any one of claims 1 -3, wherein R2 is pyridyl, thiazolyl or furanyl optionally substituted with methyl or halogen.
7. The heterocyclic derivative according to any one of claims 1 -6, wherein,
Figure imgf000125_0001
and wherein R7 has the previously defined meanings.
9. The heterocyclic derivative according to any one of claims 1 -8, wherein R7 is
Figure imgf000126_0001
wherein a, b and c are independently 1
10. The heterocyclic derivative according to claim 9, wherein a is 2, b is 2 and c is 1 .
1 1. The heterocyclic derivative according to any one of claims 1 -8, wherein R7 is
Figure imgf000126_0002
12. A heterocyclic derivative selected from:
Figure imgf000126_0003
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
or a pharmaceutically acceptable salt or solvate thereof.
13. A pharmaceutical composition comprising a heterocyclic derivative according to any one of claims 1 -12 in admixture with one or more pharmaceutically acceptable excipient.
14. A heterocyclic derivative according to any one of claims 1 -12 for use in therapy.
15. The heterocyclic derivative according to claim 14, for use in the treatment or prevention of schizophrenia or Alzheimer's disease.
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