From 459,000 Recorded Ring Systems to 3,902 Candidate Ring Systems: Selection Patterns of Clinically Relevant Ring Systems

Introduction

Ring systems can influence the conformational constraints, three-dimensional shape, local electronic distribution, and spatial organization of substituents in drug molecules. Once a ring scaffold is incorporated into a complete molecule, its atomic composition, connectivity topology, and substitution positions can further affect hydrogen-bonding characteristics, ionization behavior, lipophilicity, metabolic stability, and geometric complementarity with target protein binding sites.

Using compounds in Phase I–III clinical trials as of January 2020 and drugs listed in the U.S. Food and Drug Administration (FDA) Orange Book during the same period as their data sources, Shearer et al. systematically fragmented ring systems and analyzed their connectivity patterns. They also obtained 458,748 distinct ring systems (approximately 459,000) from approximately 2.24 billion molecules collected from public databases, the literature, patents, and commercial sources. Clinical-trial compounds involved 450 unique ring systems, accounting for only approximately 0.1% of this ring-system set; 67% of clinical-trial molecules were composed entirely of ring systems that had already appeared in marketed drugs.[1]

These data reveal pronounced structural concentration: a large number of clinically relevant molecules repeatedly reuse existing drug ring systems, while new structures expand primarily through local structural modifications around existing ring systems, changes in attachment sites, and new combinations of ring systems.

1 Ring Systems, Molecular Frameworks, and Growth Vectors

1.1 Structural Definitions of Ring Systems and Molecular Frameworks

Bemis–Murcko (BM) scaffolds are generated by removing terminal non-ring portions of a molecule while retaining the ring systems and the chains connecting them, thereby describing the principal scaffold structure of a molecule.[4]

Shearer et al. further decomposed complete molecules using a previously established recursive fragmentation method. The algorithm progressively generates ring systems and molecular frameworks, retains exocyclic double bonds, and records the growth vectors of each ring system from the original framework, namely the sites at which the ring system is connected to the remainder of the structure. The drug, clinical-trial, and RINGO datasets in the study were all constructed on the basis of this structural definition.[1]

The fragmentation of chlorthalidone illustrates three distinct structural levels: “individual ring–ring system–molecular framework.”

Figure 1. Example of the decomposition of chlorthalidone into rings, ring systems, and molecular frameworks. The complete chlorthalidone structure is shown at the top; the lower part shows three individual rings, two ring systems, and three recursive molecular frameworks. In this fragmentation process, the original study retained exocyclic double bonds and recorded the growth vectors of each ring system from the molecular frameworks.[1]

Image source: Shearer J, Castro JL, Lawson ADG, MacCoss M, Taylor RD. Rings in Clinical Trials and Drugs: Present and Future. Journal of Medicinal Chemistry, 2022, 65(13): 8699–8712, Figure 2. DOI: 10.1021/acs.jmedchem.2c00473. © 2022 The Authors. Published by American Chemical Society. Licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0).

Different types of structural information serve different purposes:

Structural Information	What It Represents	Significance for Scaffold Analysis
Ring	A single closed cycle	Basic structural unit that constitutes a ring system
Ring system	A single ring, or a multiring structure formed through fused, bridged, spiro, or related connections	Describes the core ring topology and atomic composition
Molecular framework	Ring systems together with the structures connecting different ring systems	Describes the principal scaffold organization of the complete molecule
Growth vector	The site at which a ring system is connected to a side chain, linker, or another ring system	Describes how the ring system is connected within the complete molecule

2 High-Frequency Reuse of Established Drug Ring Systems and Expansion into New Rings

Among the 1,034 clinical-trial compounds analyzed by Shearer et al., 696 were Class 1 compounds, accounting for 67%, meaning that all ring systems in these molecules had already appeared in marketed drugs. Another 253 compounds were Class 2 compounds, accounting for 24%, meaning that an existing drug ring system was combined with one new ring system that had not previously been used in a marketed drug.[1]

Statistical Category	Number	Proportion
Clinical-trial compounds	1,034	—
Class 1 molecules containing only existing drug ring systems	696	67%
Class 2 molecules containing existing drug ring system(s) + 1 new ring system	253	24%
Unique ring systems in clinical trials	450	—
Existing drug ring systems among them	170	38%
New ring systems not previously used in marketed drugs	280	62%

The 170 existing drug ring systems recur across many different clinical molecules, whereas the 280 new ring systems are generally used at lower frequencies. Clinical-trial structures therefore show the coexistence of high-frequency reuse of a relatively small number of established ring systems and low-frequency expansion into a larger number of new ring systems.[1]

This distribution is consistent with earlier data on marketed drugs. Taylor et al. analyzed FDA Orange Book drugs available before 2013 and identified 351 ring systems. Historically, approximately six new ring systems entered drug structural space each year, and approximately 28% of new drugs contained a ring system that had not previously been used in a drug.[2]

3 Local Structural Relationships between Existing Drug Ring Systems and New Clinical-Trial Ring Systems

3.1 47% of the Analyzed New Clinical-Trial Ring Systems Differ from Existing Drug Ring Systems by Only 1–2 Local Modifications

Shearer et al. observed that many ring systems newly appearing in clinical trials are structurally close to existing drug ring systems. The authors restricted the analysis to ring systems containing fewer than six rings and compared the structural differences between 276 new clinical-trial ring systems and existing drug ring systems.[1]

Two types of local structural modifications were used for enumeration:

① Single-atom substitution, for example C→N in an aromatic ring;

② Addition or removal of one exocyclic double bond.

The generated structures were then subjected to valence plausibility checks and substructure-based stability filtering before being matched against ring systems newly appearing in clinical trials.[1]

Structural Relationship to Existing Drug Ring Systems	Number of New Clinical-Trial Ring Systems	Proportion
Differing by one local structural modification	98/276	36%
Differing by no more than two local structural modifications	130/276	47%

Among the 276 new clinical-trial ring systems, 36% differed from existing drug ring systems by only one local modification, while 47% differed by no more than two local modifications.[1] On this basis, the original paper noted that approximately half of the new clinical-trial ring systems lie within a structurally local region around existing drug ring systems.

3.2 Local Modifications Can Preserve the Main Ring Topology while Altering Local Chemical Properties

Single-atom substitution can adjust electronic structure while causing relatively little change to ring connectivity. Consider, for example, replacement of a ring C–H site by N in a six-membered aromatic ring:

When the ring carbon atom is replaced by a pyridine-type nitrogen atom, the connectivity topology of the six-membered ring is largely retained, while a nitrogen atom bearing a lone pair is introduced into the ring. This can alter local electron density, electrostatic potential, dipole characteristics, and the distribution of hydrogen-bond acceptors. Once incorporated into a complete molecule, it may also affect lipophilicity, solubility, metabolic stability, and interactions with target and off-target proteins.

In a nitrogen-scanning study of a Raf/MEK inhibitor series, Aoki et al. found that replacing aromatic C–H positions with N at different sites produced different effects on solubility, metabolic stability, target activity, and interactions with cytochrome P450 enzymes and the hERG channel.[5]

The other type of local modification defined in the original study was the addition or removal of an exocyclic double bond.[1] Such changes can alter the hybridization states of adjacent atoms and the π-electron system, thereby further affecting the extent of conjugation, conformational restriction, planarity, and local electronic distribution.

The two types of modifications share a common structural feature:

The principal ring scaffold retains a closely related topology while the local atomic composition or bond order changes.

This relationship explains why numerous new ring systems that are structurally similar yet chemically distinct can arise around existing drug ring systems. The specific property changes still depend on the site of modification, the atom type, and the structure of the complete molecule.

3.3 Local Structural Proximity Provides the Basis for Candidate Ring-System Selection

This local structural proximity provided the basis for the subsequent selection of candidate ring systems. The authors then applied the same local modification rules to both existing drug ring systems and clinical-trial ring systems to generate new candidate ring structures. These were cross-matched with RINGO ring systems that had actually been reported or synthesized, followed by further selection based on occurrence frequency and heteroatom composition.

4 From 458,748 Recorded Ring Systems to 3,902 Candidate Ring Systems

Shearer et al. further used the local structural relationships described above to identify candidate scaffolds with structural features close to those of drug and clinical-trial ring systems from a large collection of recorded ring systems.[1]

4.1 458,748 RINGO Ring Systems Define the Recorded Ring Space

The researchers compiled approximately 2.24 billion unique molecules from commercial databases, the literature, patents, and academic resources and recursively fragmented them into ring systems using a unified set of rules. This process yielded 458,748 distinct ring systems, forming the RINGO database.[1]

RINGO was derived primarily from molecules that had been commercialized, synthesized, or reported and did not include purely virtual enumeration databases such as GDB. The occurrence frequency of each ring system in RINGO was also recorded to reflect its existing chemical use and synthetic precedent.[1]

This database therefore provided a range of ring systems that had actually been recorded, rather than an unrestricted theoretical space of potentially possible ring structures.

4.2 3,902 Candidate Ring Systems Were Selected Jointly on the Basis of Local Structural Relationships and RINGO Records

Candidate structures were first generated from existing drug ring systems and clinical-trial ring systems. The authors applied no more than two local structural modifications to these rings, including single-atom substitutions and the addition or removal of exocyclic double bonds, followed by checks for valence plausibility and structural stability.[1]

The generated ring systems were then matched against the RINGO database and further restricted to those that:

① already existed in actual molecules included in RINGO;

② occurred more than 100 times in the RINGO dataset;

③ contained numbers of nitrogen, oxygen, and sulfur atoms within the ranges defined by the authors on the basis of the composition of drug ring systems.[1]

After these filters were applied, 3,902 candidate ring systems were obtained from the 458,748 RINGO ring systems, corresponding to approximately 0.85% of the database.[1]

These 3,902 structures correspond to what the original study termed “future clinical trial ring systems.” The authors predicted that this set could cover approximately 50% of future new clinical-trial ring systems.[1]

4.3 Approximately 1% of Recorded Ring Systems Are Predicted to Be Sufficient for Constructing 85% of New Drugs

The original study combined three categories of ring systems:

378 existing drug ring systems + 280 new clinical-trial ring systems + 3,902 candidate ring systems = 4,560 ring systems

The 4,560 ring systems represent approximately 0.99% of the 458,748 RINGO ring systems.[1]

Earlier data on marketed drugs indicated that approximately 70% of new drugs are composed entirely of existing drug ring systems, whereas the remaining approximately 30% contain at least one new ring system. Combining this with the observation that approximately half of new clinical-trial ring systems lie within the local structural neighborhood of existing clinically relevant ring systems, the authors obtained:

70% + 30% × 50% ≈ 85%

Accordingly, the authors predicted that approximately 85% of new drugs would be constructed from combinations of ring systems within the above set of 4,560 structures; this set accounts for approximately 1% of the ring systems recorded in RINGO.[1]

The 85% value is a prediction of structural coverage for new drugs based on historical distributions of drug and clinical ring systems. The 3,902 candidate ring systems represent a prioritized structural selection space and do not indicate that these rings have already entered clinical trials.

Figure 2. Relationship among drug ring systems, clinical-trial ring systems, recorded ring space, and predicted candidate ring systems. The RINGO database contains 458,748 ring systems, including 378 that have already been used in marketed drugs, 280 that newly appeared in clinical trials, and an additional 3,902 candidate ring systems selected on the basis of local structural relationships, occurrence frequency in RINGO, and heteroatom composition. The 3,902 candidate ring systems are predicted to cover approximately 50% of future new clinical-trial ring systems.[1]

Image source: Shearer J, Castro JL, Lawson ADG, MacCoss M, Taylor RD. Rings in Clinical Trials and Drugs: Present and Future. Journal of Medicinal Chemistry, 2022, 65(13): 8699–8712, Figure 4. DOI: 10.1021/acs.jmedchem.2c00473. © 2022 The Authors. Published by American Chemical Society. Licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0).

5 Growth Vectors Introduce Connectivity Differences Beyond Ring-System Identity

5.1 The Same Ring System Can Use Different Attachment Sites

When generating molecular frameworks, Shearer et al. recorded the growth-vector combinations for each ring system and retained the corresponding enantiomeric forms.[1]

The clinical-trial set contained 450 unique ring systems, of which 170 were existing drug ring systems, giving an overlap of 38% at the ring-system level.

When attachment-site combinations were also included in the comparison, the clinical set contained 1,003 distinct “ring system–growth vector” combinations, of which 239 were identical to combinations present in drugs, corresponding to 24%.[1]

Level of Comparison	Number in Clinical-Trial Set	Overlap with Drug Set
Ring system	450	170, 38%
Ring system + growth-vector combination	1,003	239, 24%

When the comparison was refined from ring identity alone to include attachment sites, the overlap decreased from 38% to 24%, a difference of approximately 14 percentage points. Existing drug ring systems can therefore enter different complete molecular frameworks through new substitution positions and connection patterns.

Such novelty does not require changes in ring atomic composition. For example, when the same six-membered ring uses different 1,2-, 1,3-, or 1,4-connection patterns, the ring structure itself remains unchanged, but the two molecular fragments attached to the ring adopt different relative spatial relationships.

5.2 Attachment Positions Influence the Spatial Exit Directions of Substituents

In the study by Shearer et al., growth vectors were used primarily to record attachment points and combinations of attachment points. The three-dimensional geometric relationships of growth vectors can be further described through exit-vector analysis.

Grygorenko et al. defined four geometric parameters for bifunctionalized ring scaffolds:

① the distance r between the two attachment points;

② the planar angles φ₁ and φ₂ of the two exit vectors relative to the line connecting the attachment points;

③ the relative dihedral angle θ between the two exit vectors.[7]

These parameters respectively describe scaffold dimensions and the relative directions in which the two substituents extend into three-dimensional space. Changes in ring size, substitution position, and cis/trans stereochemical relationship can alter r, φ₁, φ₂, and θ, thereby changing the relative spatial positions of two functional fragments.[7]

This geometric relationship is directly relevant to structure-based drug design. Attachment sites need to orient functional groups in appropriate directions toward a protein binding site, while also being constrained by scaffold conformation and stereochemistry.

5.3 Growth Vectors and Synthetic Accessibility Jointly Constrain Structural Expansion

The attachment direction required for a target structure does not necessarily correspond to the position that is easiest to modify chemically.

Grainger et al. noted in fragment-based drug discovery research that the growth vectors required by structure-based design often lie at sp² or sp³ ring carbons, which may lack directly usable synthetic handles. The researchers used direct C–H functionalization and reactivity mapping to address synthetic access to specific growth directions.[6]

Shearer et al. further analyzed the numbers of growth vectors actually used by ring systems in drugs and clinical trials. Monocyclic ring systems used an average of approximately 2.5 growth vectors. For bicyclic and higher ring systems, the average was close to one growth vector per ring; for example, bicyclic systems typically used approximately two vectors, while tricyclic systems used approximately three.[1]

The structural information of a ring building block is therefore determined jointly by three factors:

Ring-system identity + accessible attachment sites + spatial directions of attachment sites

In practical molecular building-block design, whether a specific site can be selectively functionalized, whether the corresponding precursor can be prepared in a stable form, and whether stereochemistry can be reliably controlled all directly affect whether a theoretical growth vector can be converted into a usable synthetic route.

6 Ring-System Combination Relationships in Clinical-Trial Molecules

When a molecule contains multiple ring systems, the manner in which different ring systems are combined constitutes important structural information for the complete molecular scaffold, in addition to the structures and attachment sites of the individual rings.

Earlier enumeration of the combinatorial space of ring systems from FDA-approved drugs also showed that the potential combination space among drug ring systems is far larger than the actual coverage provided by commercial compound libraries.[3]

Shearer et al. used network analysis to compare ring-system combinations in clinical-trial molecules with those in marketed drugs. Each ring system was treated as a node. When two different ring systems occurred within the same molecule, a connection was established between the two nodes. Here, a connection represents co-occurrence of two ring systems within the same molecule and does not require the two ring systems to be directly connected by a chemical bond.[1]

Network Parameter	Clinical-Trial Set	Marketed-Drug Set
Number of ring-system nodes	450	377
Number of ring-system co-occurrence connections	1,184	590
Proportion of isolated nodes	0.14	0.26
Network density ×10⁻²	1.17	0.83

The clinical-trial set contained 1,184 ring-system co-occurrence connections and had a network density of 1.17 × 10⁻², compared with 590 connections and a density of 0.83 × 10⁻² in the marketed-drug set. The proportion of isolated nodes was also lower in the clinical-trial set, at 0.14 compared with 0.26 in the marketed-drug set.[1] These results indicate that ring systems in clinical trials, on average, co-occur with a larger variety of other ring systems within complete molecules, resulting in richer combination relationships than those observed in the marketed-drug set.

Structural variation in clinical candidates does not depend entirely on introducing new ring systems. Recombining existing ring systems with different ring systems can likewise generate new complete molecular frameworks.

At the ring-system level, the expansion of clinically relevant structures can therefore be described by three types of change:

Local structural modifications of the ring itself → changes in attachment sites on the same ring → recombination of different ring systems.

These correspond to three distinct levels—ring structure, attachment position, and scaffold composition—and together form a continuous progression from individual ring systems to complete molecular structures.

7 Scope of Applicability of Statistical Patterns in Ring Systems

7.1 Data Scope and Structural Selection Criteria

Shearer et al. used a January 2020 data snapshot. The clinical-trial dataset included compounds in Phase I, II, and III trials at that time, while the marketed-drug data were taken from the FDA Orange Book from the same period.[1]

The structures included in the analysis were also subjected to unified filtering criteria, including:

① molecular weight below 1,000;

② absence of metals;

③ fewer than 10 bonds in any individual ring.[1]

Data from different clinical phases were also deduplicated, such that compounds that had already progressed to a higher clinical phase or entered the marketed-drug set were no longer retained in lower-phase datasets.[1]

In addition, the authors noted that the structures of compounds in Phase I clinical programs are not all publicly disclosed; the relevant structures are often released only at Phase II or later stages. Consequently, statistics on Phase I ring systems may also be affected by structural data availability.[1]

The 67%, 47%, 458,748 RINGO ring systems, 3,902 candidate ring systems, and other results discussed in this article all correspond to this specific data scope and structural-processing scheme. They do not represent all small molecules, all clinical programs, or the entire theoretical ring-system space.

7.2 Ring-System Distributions Reflect Patterns of Structural Use but Do Not Constitute a Developability Assessment

The original study analyzed which ring systems were used, how frequently they were used, their structural distance from existing drug ring systems, and the connection patterns that were adopted. These data can identify structurally concentrated regions in historical drugs and clinical trials and can be used to prioritize candidate ring systems and compound libraries.[1]

The occurrence frequency of a ring system does not itself correspond to the probability of clinical success. The original study did not establish a complete control analysis of failed clinical compounds that would allow failure to be chemically attributed, because clinical failure may involve efficacy, safety, pharmacokinetics, trial design, and other factors, and databases do not always provide explicit reasons for failure.[1]

A high occurrence frequency in RINGO indicates that a ring system has repeatedly appeared in public, patent, or commercial molecules and can therefore provide indirect information about existing synthetic precedent. Conversely, a low occurrence frequency does not demonstrate that a ring system is difficult to synthesize.[1]

The 3,902 candidate ring systems and the associated predictions of new-drug coverage are both based on historical distributions of ring systems in drugs and clinical trials.[1] These results are intended to identify structural regions worthy of research prioritization and do not indicate that an individual ring system necessarily has higher target activity, superior pharmacokinetic properties, or a greater probability of clinical success.

The actual performance of a complete candidate molecule still depends on the combined effects of its ring systems, substitution positions, overall molecular conformation, target interactions, physicochemical properties, and pharmacokinetic properties. The original study provides structural selection patterns at the ring-system level rather than a developability criterion that can be applied to a ring system independently of the complete molecule.

8 Representative Chemicals for Research on Local Structural Editing, Growth Vectors, and Three-Dimensional Scaffolds in the Structural Selection of Clinically Relevant Ring Systems

Table 1. Aromatic Heterocyclic Cores and Changes in Ring-Atom Composition

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Six-membered monoaza aromatic ring core	110-86-1	P111513	Pyridine	Anhydrous grade, ≥99.8%	A single ring nitrogen replaces a C–H site in a six-membered aromatic ring; used for nitrogen scanning, tuning the electronic properties of heteroaromatic rings, and constructing pyridine scaffolds with different attachment positions.
Six-membered 1,2-diaza aromatic ring core	289-80-5	P137565	Pyridazine	≥98%	Two adjacent ring nitrogen atoms form a 1,2-diaza arrangement; used to compare the effects of nitrogen positions on electron distribution, hydrogen-bond acceptor arrangement, and heteroaromatic properties.
Six-membered 1,3-diaza aromatic ring core	289-95-2	P107070	Pyrimidine	≥99%	A 1,3-diaza aromatic ring used to study increased ring nitrogen content, electron-deficient heteroaromatic scaffolds, and multiposition derivatization.
Six-membered 1,4-diaza aromatic ring core	290-37-9	P109613	Pyrazine	≥99%	The opposite 1,4-diaza arrangement forms a symmetric six-membered heteroaromatic ring; used to compare the effects of different diaza topologies on polarity, electronic structure, and substitution directions.
Five-membered 1,3-diaza aromatic ring core	288-32-4	I432539	Imidazole	Anhydrous grade, ACS, ≥99%	A five-membered diaza aromatic ring with tautomerism and hydrogen-bond recognition characteristics; used for constructing nitrogen-containing five-membered rings, coordination structures, and heterocyclic scaffolds.
Five-membered 1,2-diaza aromatic ring core	288-13-1	P100994	Pyrazole	≥98% (GC)	A five-membered aromatic ring with adjacent nitrogen atoms; used to compare the effects of nitrogen arrangement, tautomerism, and substitution position on heterocyclic properties.
Five-membered triaza aromatic ring core	288-88-0	T100645	1,2,4-Triazole	≥99%	A five-membered aromatic ring with high nitrogen density; used to study the effects of changing ring nitrogen content on polarity, hydrogen bonding, and coordination properties.
Five-membered sulfur-containing aromatic ring core	110-02-1	T108259	Thiophene	≥99%	A sulfur-containing five-membered aromatic ring used for structural replacement between aromatic carbocycles and sulfur-containing heterocycles, comparison of electronic properties, and construction of heteroaromatic scaffolds.
Five-membered N/S heteroaromatic ring core	288-47-1	T122421	Thiazole	≥99%	A five-membered aromatic ring containing two different heteroatoms, N and S; used to tune heteroatom composition, electronic distribution, and hydrogen-bond acceptor positions and to construct nitrogen- and sulfur-containing heterocyclic scaffolds.
Fused nitrogen-containing bicyclic core	120-72-9	I104726	Indole	≥99%	A fused bicyclic scaffold formed by a benzene ring fused to a nitrogen-containing five-membered aromatic ring; used for studies of fused ring systems, increased ring count, and connectivity patterns in aromatic bicyclic systems.
Fused monoaza bicyclic core	91-22-5	Q110656	Quinoline	AR, ≥96%	A bicyclic aromatic scaffold formed by fusion of a benzene ring and a pyridine ring; used to compare how introduction of a ring nitrogen affects electronic structure and attachment positions in benzo-fused heteroaromatic systems.
Fused diaza bicyclic core	253-82-7	Q107983	Quinazoline	≥98%	A fused scaffold composed of a benzene ring and a six-membered diaza aromatic ring; used to study increased nitrogen content in fused heterocycles, modulation of electron deficiency, and multiposition derivatization.

Table 2. Saturated Heterocycles, Small Rings, and Rigid Three-Dimensional Scaffolds

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Four-membered saturated nitrogen-ring core	503-29-7	A123981	Azetidine	≥98%	A small saturated nitrogen-containing ring used to increase ring-scaffold saturation, alter conformational restriction and amine connectivity, and construct azetidine derivatives.
Five-membered saturated nitrogen-ring core	123-75-1	P108562	Pyrrolidine	≥99%	A five-membered saturated monoaza ring used for nitrogen-containing saturated scaffolds, nitrogen substitution, and studies of how five-membered-ring conformation affects molecular spatial organization.
Six-membered saturated nitrogen-ring core	110-89-4	P1506346	Piperidine (regulated precursor chemical)	Biotechnology grade, ≥99.5%	A six-membered saturated monoaza ring used for piperidine scaffold construction, nitrogen substitution, and studies of conformational and basicity modulation in saturated six-membered rings.
Six-membered 1,4-diaza saturated ring core	110-85-0	P755827	Piperazine	Anhydrous grade, UltraBio™, ≥99% (T)	A six-membered saturated ring with nitrogen atoms at the 1,4-positions that can be derivatized at both nitrogen sites; used for dual-attachment-site design and construction of saturated diaza ring scaffolds.
Six-membered saturated N/O ring core	110-91-8	M109058	Morpholine	Distillation grade, ≥99.5%	A six-membered saturated ring containing different N and O heteroatoms; used to introduce both an amine nitrogen and an ether oxygen and to tune scaffold polarity, hydrogen-bonding characteristics, and connectivity.
Three-membered carbocyclic single-attachment building block	1759-53-1	C106979	Cyclopropanecarboxylic acid	≥98%	A highly conformationally constrained building block combining cyclopropane with a carboxyl group. The carboxyl group can be used for amidation and esterification, enabling small-ring scaffolds and expansion from a single growth site.
Four-membered carbocyclic single-attachment building block	3721-95-7	C120879	Cyclobutanecarboxylic acid	≥98%	Cyclobutane provides a saturated four-membered carbocyclic structure, while the carboxyl group serves as a derivatizable attachment site; used to study ring-size changes and the spatial configurations of small rings.
Six-membered carbocyclic single-attachment building block	98-89-5	C110756	Cyclohexanecarboxylic acid	≥99%	A six-membered saturated carbocycle connected to a carboxyl group; used for introducing cyclohexyl scaffolds, comparing aromatic-ring and saturated-ring scaffold replacements, and carboxyl-group derivatization.
Six-membered oxygen-ring site-defined attachment building block	5337-03-1	T161847	Tetrahydropyran-4-carboxylic acid	≥98% (GC)	The tetrahydropyran ring carries a predefined carboxyl attachment point at the 4-position; used for oxygen-containing six-membered rings, fixed attachment positions, and construction of amide- or ester-derived structures.
Rigid bridged single-attachment building block	22287-28-1	B175783	Bicyclo[1.1.1]pentane-1-carboxylic acid	≥97%	A rigid bicyclo[1.1.1]pentane scaffold bearing a carboxyl group at the bridgehead position; used to construct three-dimensional single-attachment scaffolds and study how rigid exit directions affect molecular spatial structure.
Rigid bridged dual-attachment building block	56842-95-6	B176816	Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid	≥97%	Two bridgehead carboxyl groups define clear 1,3-dual attachment sites; used for rigid two-vector scaffolds, opposing spatial connections, and sequential derivatization at both termini.

Table 3. Halogenated Aryl and Heteroaryl Building Blocks with Predefined Attachment Sites

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Ortho dual-attachment aryl building block	583-55-1	B118364	1-Bromo-2-iodobenzene	≥98%, stabilized with copper	The bromo and iodo sites are arranged ortho to one another. Their differing reactivities can be exploited for stepwise functionalization and construction of aryl rings with two ortho growth vectors.
Meta dual-attachment aryl building block	591-18-4	B103587	1-Bromo-3-iodobenzene	≥98% (GC), stabilized with copper	The bromo and iodo sites are arranged meta to one another; used for stepwise cross-coupling and construction of meta dual-attachment aryl rings and for comparison of connectivity topologies with the ortho and para isomers.
Para dual-attachment aryl building block	589-87-7	B107004	1-Bromo-4-iodobenzene	≥98%	The bromo and iodo sites are arranged para to one another; used for stepwise construction of spatially separated dual-attachment aryl rings and comparison of exit directions among different substitution topologies.
Single-attachment-site pyrimidine building block	1722-12-9	C132282	2-Chloropyrimidine	≥99% (GC)	A halogen attachment point is predefined at the 2-position of the pyrimidine ring; it can be used in nucleophilic aromatic substitution and cross-coupling to construct diaza aromatic-ring derivatives substituted at a defined position.
Nonequivalent dual-attachment pyrimidine building block	3934-20-1	D103228	2,4-Dichloropyrimidine	≥98%	Two halogen reactive sites are positioned at the 2- and 4-positions of the pyrimidine ring; under controlled conditions, regioselective and stepwise functionalization can be performed for construction of two-vector heteroaromatic scaffolds.
Symmetric dual-attachment pyrimidine building block	1193-21-1	D106524	4,6-Dichloropyrimidine	≥98%	The 4- and 6-positions of the pyrimidine ring form a symmetric dihalogen attachment pattern; used for dual-site substitution and construction of symmetric or asymmetric heteroaromatic derivatives.
Symmetric dual-attachment pyridine building block	2402-78-0	D105924	2,6-Dichloropyridine	≥97%	The 2- and 6-positions of the pyridine ring form symmetric dual attachment sites; used for functionalization on both sides, construction of two-vector scaffolds, and studies of the influence of the ring nitrogen on reactive sites.
Symmetric dual-attachment pyridine building block	625-92-3	D115760	3,5-Dibromopyridine	≥98%	Symmetric brominated attachment sites are predefined at the 3- and 5-positions of the pyridine ring; used for dual-site cross-coupling and symmetric expansion to construct pyridine scaffolds with well-defined connectivity topology.

Table 4. Aryl- and Pyridylboronic Acid Connection Building Blocks

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Phenylboronic acid coupling building block	98-80-6	P396095	Phenylboronic acid (PBA) (contains varying amounts of anhydride)	≥99.5%	A commonly used arylboronic acid building block that can form carbon–carbon bonds between aryl groups and aryl or heteroaryl groups through Suzuki–Miyaura cross-coupling; used as a reference for benzene-ring connectivity.
2-Pyridylboronic acid building block	197958-29-5	P123314	Pyridine-2-boronic acid (contains varying amounts of anhydride)	≥95%	A boronic acid attachment point is predefined at the 2-position of the pyridine ring; used to introduce 2-pyridyl fragments and study connectivity topology and heteroaryl coupling adjacent to the ring nitrogen.
3-Pyridylboronic acid building block	1692-25-7	P396303	Pyridine-3-boronic acid (contains varying amounts of anhydride)	≥98%	A boronic acid attachment point is predefined at the 3-position of the pyridine ring; used for constructing carbon–carbon bonds involving 3-pyridyl groups and comparing how different attachment positions affect the spatial direction of heteroaromatic rings.
4-Pyridylboronic acid building block	1692-15-5	P113743	Pyridine-4-boronic acid (contains varying amounts of anhydride)	≥96%	A boronic acid attachment point is predefined at the 4-position of the pyridine ring; used for 4-pyridyl coupling and construction of para-type connectivity topologies and can be compared with the 2- and 3-position isomers as a positional-vector reference.

Note: The products listed above are representative Aladdin products relevant to scientific research. Specific applications should be determined according to the product specification, batch COA, and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin website using the “product name/CAS/catalog number.”

References

[1] Shearer J, Castro JL, Lawson ADG, MacCoss M, Taylor RD. Rings in Clinical Trials and Drugs: Present and Future. Journal of Medicinal Chemistry, 2022, 65(13): 8699–8712. DOI: 10.1021/acs.jmedchem.2c00473.

[2] Taylor RD, MacCoss M, Lawson ADG. Rings in Drugs. Journal of Medicinal Chemistry, 2014, 57(14): 5845–5859. DOI: 10.1021/jm4017625.

[3] Taylor RD, MacCoss M, Lawson ADG. Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug Discovery. Journal of Medicinal Chemistry, 2017, 60(5): 1638–1647. DOI: 10.1021/acs.jmedchem.6b01367.

[4] Bemis GW, Murcko MA. The Properties of Known Drugs. 1. Molecular Frameworks. Journal of Medicinal Chemistry, 1996, 39(15): 2887–2893. DOI: 10.1021/jm9602928.

[5] Aoki T, Hyohdoh I, Furuichi N, et al. Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning. ACS Medicinal Chemistry Letters, 2014, 5(4): 309–314. DOI: 10.1021/ml400379x.

[6] Grainger R, Heightman TD, Ley SV, Lima F, Johnson CN. Enabling Synthesis in Fragment-Based Drug Discovery by Reactivity Mapping: Photoredox-Mediated Cross-Dehydrogenative Heteroarylation of Cyclic Amines. Chemical Science, 2019, 10(8): 2264–2271. DOI: 10.1039/C8SC04789H.

[7] Grygorenko OO, Babenko P, Volochnyuk DM, Raievskyi O, Komarov IV. Following Ramachandran: Exit Vector Plots (EVP) as a Tool to Navigate Chemical Space Covered by 3D Bifunctional Scaffolds. The Case of Cycloalkanes. RSC Advances, 2016, 6: 17595–17605. DOI: 10.1039/C5RA19958A.

For more related articles, see below:

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