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Bioisosteres of Common Functional Groups N N O OH N O OH N Cl Cl Hydroxyzine Ian Perry MacMillan Group Meeting May 16 th , 2019
Transcript of Bioisosteres of Common Functional Groupschemlabs.princeton.edu/.../6/...2019-PDF-Unlayered.pdf ·...
Bioisosteres of Common Functional Groups
N
NO
OHN
OOH
N
ClCl
Hydroxyzine
Ian PerryMacMillan Group Meeting
May 16th, 2019
Introduction to Isosterism
Irving Langmuir
JACS 1919: “The Arrangement of Electrons in Atoms and Molecules”
JACS 1919: “Isomorphism, Isosterism and Covalence
1932 Nobel Prize in Chemistry for Discoveries in Surface Chemistry
OC
ON
N
OO
CN
N
NN
HH
CO
HH
Langmuir, I. J. Am. Chem. Soc., 1919, 41, 1543
NN
HH
CO
HH
Introduction to Bioisosterism
Friedman, H. L. NASNRS., 1951, 206, 358
1951: H. L. Friedman coins “Bioisostere” - Molecules or groups “which fit the broadest definition of isosteres and have the same type of biological activity.”
1932: Erlenmeyer Demonstrates Bioisosterism of some of Langmuir’s Isosteres - Antibodies were found to not discriminate in the binding of several artificial antigens
O
NH
peptide
HN
NH
peptide
H2C
NH
peptide
Erlenmeyer, H., Berger, E., Biochem Z. 1932, 252, 22
Talk Outline
examples of bioisostereism are abundant in medicinal chemistry, this talk is not comprehensive. For a more detailed review, see:
Meanwell, N. A. J. Med. Chem. 2011, 54, 2529
Part 2 - Nonclassical Bioisosteres
Common examples of Nonclassical Bioisosteres
Strained (hetero)cycles as Bioisosteres
Bioisosteres of Aromatic Rings
Part 1 - Classical Bioisosteres
3 case studies of isosteric atom substitution:
Procaine vs. Procainamide
Haloperidol vs. Silahaloperidol
The importance of Celebrex-CH3
examples of bioisosterism are abundant in medicinal chemistry, this talk is not comprehensive. For a more detailed review, see:
Meanwell, N. A. J. Med. Chem. 2011, 54, 2529
Case Study in Classical Bioisosteres: Procaine vs. Procainamide
Imming, P., Sinning, C., Meyer, A. Nat. Rev. Drug Discov. 2006, 6, 126
H2N
O
ONEt2
procaine
H2N
O
NH
NEt2
procainamide
substitution ofa divalent atom
Nav channel blocker
Analgesic
Metabolsim viaester hydrolysis
(pseudocholinesterase)
H2N
O
OH
Nav channel blocker
Analgesic
Metabolsim viaAcylation or oxidation
(P450)
NH
O
NH
NEt2
Me
O
OH
Case Study in Classical Bioisosteres: Haloperidol vs. Sila-haloperidol
Tacke, R. et al. ChemMedChem 2008, 3, 152
haloperidolAntipsychotic
N
HOO
F
Cl3
Janssen, P. A. J., J. Med. Chem. 1958, 1, 105
Developed for the treatment of neuropsychiatric disorders
Alleviates allucinations and delusions associated with chizophrenia
Irreversible side effects associated with long-term use
NO
F
3
Cl
aromatizationN
O
F
3
Cl
neurotoxin associated with dyskinesia
HPP+
Alleviates hallucinations and delusions associated with schizophrenia
Case Study in Classical Bioisosteres: Haloperidol vs. Sila-haloperidol
Tacke, R. et al. ChemMedChem 2008, 3, 152
haloperidolAntipsychotic
N
HOO
F
Cl3
Janssen, P. A. J., J. Med. Chem. 1958, 1, 105
SiN
O
F
3
Cl
no detected neurotoxic metabolites
SiN
HOO
F
Cl3
Silahaloperidol
substitution of carbon for silicon has limited effecton pharmacokinetic properties
strong Si-OH bond and weak Si=C bond disfavorselimination compared to carbon analogue
Case Study in Classical Bioisosteres: Haloperidol vs. Sila-haloperidol
Tacke, R. et al. ChemMedChem 2008, 3, 152
Haloperidol
N
HOO
F
Cl3
Janssen, P. A. J., J. Med. Chem. 1958, 1, 105
SiN
HOO
F
Cl3
Silahaloperidol
HN
O Br
Cl
Mg0
NH
HO
Cl
Cl
OCl
F
ClO
PhF
short and convergent synthesis from readily available feedstock materials
Case Study in Classical Bioisosteres: Haloperidol vs. Sila-haloperidol
Tacke, R. et al. ChemMedChem 2008, 3, 152Janssen, P. A. J., J. Med. Chem. 1958, 1, 105
SiN
HOO
F
Cl3
Silahaloperidol
SiMeO OMe
OMeMeO H2NOO
F
12 steps, 7% overall yield
SiOPG
II
Cl
F
NH2OO
F
NOO
SiOPG
Cl
key silacycle formation
incorporation of non-native functionality as bioisosteres often involves lengthy syntheses
Case Study in Classical Bioisosteres: Celecoxib
Penning, T. D., J. Med. Chem. 1997, 40, 1347
NSAID developed by Pfizer
Selective COX-2 inhibitor
Marketed for the treatment of Arthritis
SNH2
O O
NN
F3C
H
SNH2
O O
NN
F3C
F
SNH2
O O
NN
F3C
CF3
SNH2
O O
NN
F3C
OMe
µM level IC50 for COX-2 in all cases
high specificity for COX-2 vs. COX-1
SNH2
O O
NN
F3C
CF3
SNH2
O O
NN
F3C
Cy
SNH2
O O
NN
F3C
CF2H
SNH2
O O
NN
F3C
CF3
SNH
O O
NN
F3C
Me
n-pentylSNH2
O O
NN
F3CBr
SNH2
O O
NN
F3C
CD3
SNH2
O O
NN
F3C
CO2H
FF
SNH2
O O
NN
F3C
CO2Me
NHBoc
SNH2
O O
NN
F3C
N NPh
SNH2
O O
NN
F3C
O
SNH2
O O
NN
F3C
Me
Case Study in Classical Bioisosteres: Celecoxib
Penning, T. D., J. Med. Chem. 1997, 40, 1347
SNH2
O O
NN
F3C
H
HH
SNH2
O O
NN
F3C
F
FF
fluorine atom substitution
Increased metabolic stability?
SNH2
O O
NN
F3C
H
SNH2
O O
NN
F3C
F
SNH2
O O
NN
F3C
CF3
SNH2
O O
NN
F3C
OMe
undesirably long half life (>200 hours!)
For an excellent review on rational incorporation of fluorine as a hydrogen isostere, see:Meanwell, N. A. J. Med. Chem. 2018, 61, 5822
isosteric substitution that removes benzylic metabolic handle results in undesirable pharmacokinetic properties
Part 2 - Nonclassical Bioisosteres
Common examples of Nonclassical Bioisosteres
Strained (hetero)cycles as Bioisosteres
Bioisosteres of Aromatic Rings
Talk Outline
examples of bioisostereism are abundant in medicinal chemistry, this talk is not comprehensive. For a more detailed review, see:
Meanwell, N. A. J. Med. Chem. 2011, 54, 2529
Part 1 - Classical Bioisosteres
3 case studies of isosteric atom substitution:
Procaine vs. Procainamide
Haloperidol vs. Silahaloperidol
The importance of Celebrex-CH3
examples of bioisosterism are abundant in medicinal chemistry, this talk is not comprehensive. For a more detailed review, see:
Meanwell, N. A. J. Med. Chem. 2011, 54, 2529
O
OH
Introduction to Nonclassical Bioisosteres
Ballatore, C., Huryn, D. M. & Smith, A. B. ChemMedChem 2013, 8, 385
Unlike their classical counterparts, nonclassical bioisosteres do not conform to Langmuir’s broad definition of “isostere.”
Nonclassical bioisosteres are groups capable of emulating the steric or electronic profile of the original functional group
N
NBu
Cl
OH
IC50 [µM] dose [mg/kg]
NH
NNN
losartan scaffoldhigh blood pressure
0.23
0.019
3
0.8
pKa
4.2
4.5
Introduction to Nonclassical Bioisosteres
Am. J. Med., 1976, 10, 1107
Unlike their classical counterparts, nonclassical bioisosteres do not conform to Langmuir’s broad definition of “isostere.”
Nonclassical bioisosteres are groups capable of emulating the steric or electronic profile of the original functional group
HO
Me
H
H H
OH
estrogenprimary female sex hormone
OH
HO
Me
Me
diethyl stilbestrol“synthetic estrogen”
Prescribed to pregnant women1940-1970
Thought to prevent miscarriagesin pregnant women with low estrogen
Use discontinued after DES linked todevelopment of clear cell carcinoma
by women exposed in utero
Bioisosteres of Common Functional Groups
OH
O
NH
NNN NO
OH
OO
OH
O
SO O
NH2
OMe Me
O
NH
H H
FF
O
NH
CF3
NH
F
NH
O
Me
Me
CF3 SF5
HN
NH
HN
O
HN
…and many more
HN
HN
HN
HN
Escaping Flatland
Lovering, F., Bikker, J. & Humblet, C., J. Med. Chem. 2009, 52, 6752
Incorporating highly saturated fragments in drug discovery correlates with clinical success
Greater three-dimensionality imparts higher specificity in binding
N
& enantiomers
Aside from synthetic accessibility, is there a caveat to increased sp3 character?
Escaping Flatland
Bolleddula, J. et al. Drug Metab. Rev. 2014, 46, 379
NHN
easily synthetically accessed
high likelihood ofclinical success
HNO
H2N O
NO
more pathwaysavailable for
oxidative metabolism
HNH
H
NN N
NFe
MeMeR
RMe MeO
cytochrome P450 amine oxidase
Escaping Flatland
Bolleddula, J. et al. Drug Metab. Rev. 2014, 46, 379Vitaku, E., Smith, D. T., Njardarson, J. T. J. Med. Chem. 2014, 57, 10257
Despite metabolic instability, saturated heterocycles remain some of the most utilized functionality in medicinal chemistry
Most frequiently used saturated nitrogen heterocycles in FDA approved pharmaceuticals
NH N
H
HN
NH HN O
HN
NH
HN
N
HN
72 59 37 13 12 11 10
number of approved drugs containing each saturated heterocyclic core
expanding the scope of saturated heterocycles toward molecules of increased metabolic stability could greatly impact the rate of success in drug development
expanding the scope of accessible functionality toward saturated heterocycles of increased metabolic stability could greatly impact the rate of success in drug development
Spirocyclic Azetidines as Bioisosteres of Nitrogen Heterocycles
O
HN
O
HN
HN
HN
HN
NH
HN
NH
HN
2, 3 & 4-substituted piperidine analogues
2 & 3 substituted morpholine analogues
2 & 3 substituted piperazine analogues
X
HN
2-azaspiro[3.3]heptanecore
6-oxa-2-azabicyclo[3.3]heptane in an MCHr1 Antagonist
Johansson, A. et al. J. Med. Chem. 2016, 59, 2497
High throughput screening at AstraZeneca generated compound 1 for lead optimization
Melanin concentrating hormone receptor 1 (MCHr1)has been linked to regulation of appetite.
Small molecule antagonists of this receptor have been shown to prevent obesity
compound 1 - antagonist of MCHr1
O
NN
O
N N
O Cl
6-oxa-2-azabicyclo[3.3]heptane in an MCHr1 Antagonist
Johansson, A. et al. J. Med. Chem. 2016, 59, 2497
low tolerance for structural modification
basic, benzylic aminecritical for MCHr1 activity
high degree of piperidine lipophilicitylimited degrees of freedom in exploring SAR
O
NN
O
N N
O R
azetidine substitution had limited effect on activity, but allowed for greater freedom in exploring benzylic amine functionality
O
NN
O
N N
O Cl
reduction of HERG activity (off target binding resulting in cardiac arrhythmia) is a priority
6-oxa-2-azabicyclo[3.3]heptane in an MCHr1 Antagonist
Johansson, A. et al. J. Med. Chem. 2016, 59, 2497
low tolerance for structural modification
basic, benzylic aminecritical for MCHr1 activity
high degree of piperidine lipophilicitylimited degrees of freedom in exploring SAR
O
NN
O
N N
O R
azetidine substitution had limited effect on activity, but allowed for greater freedom in exploring benzylic amine functionality
O
NN
O
N N
O Cl
6-oxa-2-azabicyclo[3.3]heptane in an MCHr1 Antagonist
Johansson, A. et al. J. Med. Chem. 2016, 59, 2497
O
NN
O
N N
O OMe
N NMe
MeN N
MeNN
ON
HOlead
reduced metabolic stability
no reduction in hERG interaction
reduced MCHr1 potency
***
* * ** **
low receptor occupancy (efflux)
hydrogen bond donorsor acceptors improve potency
6-oxa-2-azabicyclo[3.3]heptane in an MCHr1 Antagonist
Johansson, A. et al. J. Med. Chem. 2016, 59, 2497
O
NN
O
N N
O OMe
N N N N
lead
Me
OMeO
O
NO
high levels of activity, but no marked improvement in metabolic stability
6-oxa-2-azabicyclo[3.3]heptane in an MCHr1 Antagonist
Golden, M. et al. Org. Proc. Res. Dev. 2016, 20, 675
O
NN
O
N N
O OMe
O
increased metabolic stability - high MCHr1 activity - moved to phase 1
synthetic route to spirocycle:
OHHO
OH OH
HBr
Δ
BrHO
Br Br
NaOH
TBA•HSO4O
BrBrBnNH2
NaOH
then HCl O
NH
Ph
Cl
Li, X.-Q. et al. Drug Metab. Dispos. 2016, 44, 1341
“Spiromorpholine” metabolism
O
N
Bolleddula, J. et al. Drug Metab. Rev. 2014, 46, 379
R
O
N
R
O
N
R
OH
OH
O
N
R
OH
OH
O
HN
O
NH
R
O
OH
O
N
R
O
O
N
R
O
HO
N
R
OHO
O
NOH
O
NO
O
NO R
morpholinemetabolism
metabolism of morpholine dominated by C–H oxidation
Li, X.-Q. et al. Drug Metab. Dispos. 2016, 44, 1341
“Spiromorpholine” metabolism
O
NN
O
N N
O OMe
O
N
HO
OH
N
O R
R
18O
18O
enz
N
R
enz
HO
18O
18O
H218O
N
R
18O
18O
enz
H18O
H16O
enz epoxide hydrolase
Other Analogues of Saturated Heterocycles
X
HN X = CH2X = N, O H
NHN
HN
HN
NH NH
HN
O
HN
NH
HN
HN
NH2NCl
F
N
F
OCO2H
antibacterial drugDaiichi Sankyo
N
O
N
HN
O
CN
antineurodegenerativeRoche
N
HN
O
SO
O
Cl
epoxide hydrolase inhibitorMerck
Other Analogues of Saturated Heterocycles
X
HN fusedbridged
X
HN
HN
X
H HX
HN
NH
XX
X
HN
X
HN
HN
X
H
H
N
HN
HN
O
N N
N
N
NO
O
PI3K inhibitorPfizer
N
N NH
HN
O
N
O
OHH
NF
Me
O
HH
Peptide deformylase inhibitorGSK
spiro, fused, and bridged bicyclic compounds - lower oxidative lability, higher conformational rigidity
Synthesis of Complex Isosteres of Saturated Heterocycles
HN
X
Br
Br
X
Br H2N Ph
HN HO
HO
O
OR
O
RO
BrBr
affords access to N-substituted
spiro-morpholines and spiro-piperazines
modular approachto spiro-piperidine
affords greater substitutional diversityR R R
can a more modular approach to spiroheterocycles afford a broader range of medicinally relevant isosteres?
Synthesis of Complex Isosteres of Saturated Heterocycles
HN NH HN NH
synthetically challenging exit vectors
N
O O
OH
NF
F
HN
Me
Gatifloxacin (BMS)antibiotic
NN
Me
N
Mirtazapine (Organon)antidepressant
OH
HN O
Bn
OHN
N
N
OHN
Me MeMe
Indinavir (Merck)antiretroviral
Synthesis of Complex Isosteres of Saturated Heterocycles
Guérot, C., Tchitchanov, B. H., Knust, H & Carreira, E. M. Org Lett 2011, 13, 780
N
PhPh
O
H2NS
tBu
O
N
PhPh
NSO
tBuSPh2
BF4
N
PhPh
O
KHMDS Ti(OEt)4
LiBF4, toluene
N
PhPh
O
N
PhPh
NSOtBu
R R
RR
R = Me, F
CO2Et
X
N
PhPh
O
N
PhPh
NH2
N
PhPh
OHconditions
N
PhPh
O
OH
O
HNPh
Ph
[ox]
not observedO
Synthesis of Complex Isosteres of Saturated Heterocycles
Kirichok, A. A. et al. Angew. Chem. Int. Ed. 2017, 56, 8865Kirichok, A. A. et al. Chem. Eur. J. 2018, 24, 5444
OHO
O
R
X X
X = H, OMeR = alkyl, aryl
1) SOCl2
2) DIPEA
LiHMDS
reflux
NH
XX
O R
[red]
NH
O
NH
OMeMeO
Me
Me
33% overall
N HN
O Me
MeBu
19% yield
NBu HN
OMe
Me
Bupivacaine
isosteric bupivacaine showed higher protein binding, higher LD50, faster onset, and similar activity to
bupivacaine in vivo (mouse)
5 steps
first demonstration of 1-substituted 2-aza-spiro[3.3]heptane as a 2-piperidine isostere
Mykhailiuk Group has since expanded this platformto [4.3], [5.3], and [6.3] spirocyclic azetidines
Synthesis of Complex Isosteres of Saturated Heterocycles
HN Br
NHR
HN
X
NHRBrBr
X
HN
YZ
spirocycles with exit vectors off of terminal heteroatoms are straightforward to synthesize from feedstock materials
n
n
pathways toward strained spirocycles with exit vectors on carbon and at orthogonal angles are limited, novel developments in this arena are in great demand
For additional examples of spiroheterocycle construction, see: Carreira,E. M. & Fessard, T. C. Chem. Rev. 2014, 114, 8257
Bioisosteres of Benzene Rings
Taylor, R. D., MacCoss, M. & Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845
While many pharmaceutical compounds contain saturated heterocycles, many, many more contain benzene rings (>500 as of 2014)
• 6 exit vectors
• high structural rigidity
• many methods for incorporation and functionalization
2D vectorial space
Bioisosteres of Benzene Rings
Taylor, R. D., MacCoss, M. & Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845
some guidelines for phenyl isosteres
retained structural rigidity
reduced cLogP (lipophilicity) as compared to Ph
increased sp3 incorporation without intoducing metabolic instability
Eaton, ACIE 1992
Stephan, J. Med. Chem. 2012
1,4-disubstituted Benzene Bioisosteres
Nicolau, K. C. et al. ChemMedChem 2016, 11, 31
NH
NN
MeO
NH
Me
N
N
N
Imatinib - ABL1 kinase inhibitor - anticancer
4 aromatic rings, low fraction of sp3–hybridized carbon atoms
nearly insoluble in neutral aqueous media
cLogP = 4.53 (upper end of Lipinski’s rule of 5)
1,4-disubstituted Benzene Bioisosteres
Nicolau, K. C. et al. ChemMedChem 2016, 11, 31
incorporated linkers:
NH
O
NH
Me
N
N
NN
NMe
NH
O
NH
Me
N
N
NN
NMe
1,4-disubstituted Benzene Bioisosteres
Nicolau, K. C. et al. ChemMedChem 2016, 11, 31
fract
ion
sp3
0.2
0.5
0.4
0.3
0.25
0.35
0.45
cLogP
1.5 1.75 2.0 2.25 2.5 2.75 3.0 3.25 3.5 3.75 4.0 4.25 4.5 4.75
(imatinib)
1,4-disubstituted Benzene Bioisosteres
Nicolau, K. C. et al. ChemMedChem 2016, 11, 31
>80-fold increasein solubility
50-fold increasein solubility
10-fold increasein solubility
decrease in binding affinity, potency, and target selectivity across the board
Bioisosteres of Benzene Rings
Stephan, A. F. et al. J. Med. Chem. 2012, 55, 3414
NO
N
F
NS
O
O
Cl
CF3
NH2O
NO
NNS
O
O
Cl
CF3
NH2O
BMS 708,163γ-secretase inhibitor(anti-Alzheimer’s)
n
equipotent to BMS 708,163improved permeability
improved aqueous solubility
fluoro substitution in parent compound not required in bicyclic analogue
Synthesis of Benzene Bioisosteres: [1.1.1]-bicyclopentane
EWG X
BEt3X
EWG
X2
X
X
O
Me Me
O
diacetylhv
R MgBr
Pd, ArI
R
Ar
1)
1)
de Meiere, et al. Eur. J. Org. Chem.
2000, 1137
Michl & Kaszynski, J. Org. Chem.1988, 53, 4593
Thirumoorthi, N. T., Chem Commun. 2015, 51, 3139
Recent reports: Anderson GroupChem. Sci., 2018, 9, 5259Org. Lett. 2019, 21, 2408
Gianatassio, R. et al. Science, 2016, 351, 241
NR
R
NMgBrR
R
R
X
Ar
X
Ar/R XIr(ppy)3
Nugent, J. et al. ChemRXiv, 2019
[1.1.1]-propellane
Synthesis of Benzene Bioisosteres: cubane
I2
(PhO)2P(O)N3
tBuOH
PhH, hv
Moriarty, R. M. & Khosrowshahi, J. S.JACS 1989, 111, 8944
Eaton, P. E. et alJ. Org. Chem. 1984, 49, 185.
multiple reports
Eaton, P. E. & Maggini, M. J.JACS, 1988, 110, 7230
Toriyama, F et al. JACS, 2016, 138, 11132
Bernhard, S. S. R. et alChem. Eur. J., 2018, 24, 1026
methyl-1,4-cubanedicarboxylate
CO2H
MeO2C
CO2Me
H
PIDA CO2Me
I
NHBoc
MeO2C
2) Ar2ZnFe(acac)3
Ar
MeO2C
1) TCNHPIDCC
2) ArZnClNiCl2•dCO2Mebpy
1) TCNHPIDCC
Ar
MeO2C
Pb(OAc)4Ph
MeO2C
Synthesis of Benzene Bioisosteres: Escaping Straightland?
incorporation of strained sp3-rich scaffolds has a major limitation: nonlinear exit vectors
180°
Synthesis of Benzene Bioisosteres: Escaping Straightland?nonlinear exit vectors from bicyclopentane
Padwa et al. JACS, 1968, 90, 3717
Ohv HO
>280 nmPhH, 60h
~30% yield
Dougherty & Sponsler, JOC 1984, 49, 4978
O3, DCMO
Mazal et al. Org. Lett. 2006, 8, 749
benzvalene
2 steps as reported
for propellane(3 steps)
OHO
HO
O
4 stepsHOOC COOH
COOH
COOH
BrBr
Cl
Cl PhLi, Et2O
Fe(CO)3
Synthesis of Benzene Bioisosteres: Escaping Straightland?nonlinear exit vectors from bicyclopentane
Barborak et al. J. Am. Chem. Soc. 1966, 88, 1328
Bashir-Hashemi, J. Am. Chem. Soc. 1988, 110, 7234
8 stepsO CO2Me
MeO2C
Cl
Cl
Fe(CO)5+
O
O
Br
Br
CANO
OBr
Br 2 stepsHO2C
HO2C
~50% yield fromquinone
CO2Me
MeO2C
N
O
iPr
iPr1) LiTMP/MgBr2
2) CO2
N(iPr)2
O
CO2H
O
(iPr)2NO
(iPr)2N
HO2C
Additional Benzene Bioisosteres: Ortho and Meta
rigidity, increased 3 dimensionality improved physico-chemical properties?
Mykhailiuk, P. K. Org. Biomol. Chem. 2019,17, 2839
OR
O
RO
O LDA
CH2I2 OR
O
RO
O
BrClBr
Cl
Fuchs, J. & Szeimies, G. Chem. Ber. 1992, 125, 2517
MeLi
lower stability than [1.1.1]propellane
3.0 Å
5.1 Å
3.3-3.6 Å
5.0 Å
3.2 Å
Bioisosteres of Common Functional Groups
Bioisosteres are frequently employed in a medicinal chemistry setting to improve or alter physico-chemical properties of lead compounds
The abundance and diversity of bioisosteres is continuously growing as novel chemical methodsfor the installation of complex functionality are developed
While important in elucidating stucture-activity relationships, bioisosteres can often have hard-to-predict effects on the activity and properties of bioactive molecules
Synthetic strategies toward installation of novel exit vectors on spirocyclic, bridged-bicyclic, and polycyclic sp3-rich scaffolds are in high demand in the medicinal chemistry community
