DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-24 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/09/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 3 and 24 are objected to because of the following informalities:
Claims 1 and 3 include “benzine” which should be spelled “benzene”;
Claim 24 includes a compound structure that is too blurry to interpret. For purpose of examination, the corresponding structure from claim 24 of the parent claim set of PCT/US2022/021720 has been examined.
Appropriate correction is required.
Claim Interpretation
Claim 3 is directed toward a method for treating a Markush group of diseases and/or disorders including “a T- and B-cell malignancy” comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt thereof from instant Formula I. The language “a T- and B-cell malignancy” is interpreted as claiming utility for the treatment of a malignant cancer that simultaneously involves aberrant pathophysiology of both T-cells and B-cells, otherwise known as “composite lymphoma”. See, for example, Kuppers_2014 (Kuppers, et al.; The Lancet, v15, pages e435-e446; 2014). Kuppers_2014 provides a review of composite lymphomas, wherein two distinct lymphomas concurrently occur in a patient (Abstract, page e435). Kuppers teaches that, in addition to composite lymphomas that combine a non-Hodgkin lymphoma with a Hodgkin lymphoma, composite lymphomas can consist of two distinct types of non-Hodgkin lymphoma can occur, such as combinations of chronic lymphocytic leukemia (a B-cell lymphoma) with anaplastic large-cell lymphoma (a T-cell lymphoma) or with a peripheral T-cell lymphoma (pages e-436-e437, bridging paragraph).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2 and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is drawn to a method comprising administering to a subject in need of, or has been recognized as being in need of, treatment with a MALT1 inhibitor, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, from instant Formula I. The claim is indefinite because a person of ordinary skill in the art cannot reasonably determine the metes and bounds of the patient population that is meant by the term “in need of, or has been recognized as being in need of, treatment with a MALT1 inhibitor”. The claim does not provide further information on how to identify a subject is in need of treatment with a MALT1 inhibitor, and the instant Specification also does not elucidate the patient population. The Specification does indicate that there are neoplastic and inflammatory diseases associated with deregulated MALT1 signaling (page 1, lines 26-28) but does not name which diseases these are. On page 8, lines 35-37, the Specification indicates that the inhibitors disclosed therein may1 be efficacious and wide ranging in terms of therapeutic applications for MALT1 driven malignancies and overactive inflammatory diseases, but again does not name any particular disease or disorder. On page 24, lines 28-32 and page 25, lines 1-5, the Specification does provide a list of “illustrative” T- and B-cell malignancies, carcinomas and autoimmune and inflammatory diseases. As these are “illustrative” examples, the lists are not understood to be limiting.
The field of art in MALT1 inhibition also does not provide any clear limitation on the population of patients who are “in need of treatment with a MALT1 inhibitor”, as shown by Jaworski_2016 (Jaworski, M. and Thome, M.; Cellular and Molecular Life Sciences, v73, pp.459-473; 2016) and Hamp_2021 (Hamp, et al.; Expert Opinion on Therapeutic Patents, v31, pp.1079-1096; 2021). Jaworski_2016 provides a review on the biological function and potential for therapeutic inhibition of the paracaspase enzyme MALT1. Regarding the biological function of MALT1, Jaworski_2016 teaches the following aspects of uncertainty with regard to the scope of diseases/conditions for which MALT1 inhibition may have relevance:
Jaworski_2016 teaches that the protease activity of MALT1 is thought to promote NF-kB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) activation through the cleavage of the deubiquitinating enzyme A20 and of the NF-kB subunit RelB, however Jaworski also teaches that “how exactly A20 cleavage affects NF-kB activation remains unclear,” (page 464);
Jaworski_2016 teaches that the “exact consequences of MALT1 autoprocessing remain unclear, but include an effect on NF-kB target gene expression downstream of nuclear NF-kB accumulation” (page 464);
Jaworski_2016 teaches that “In addition to its roles in transcription and transcript stabilization, MALT1 has been suggested to have a role in promoting T-cell adhesion through cleavage of its binding partner BCL10, by mechanisms that are not yet understood” (page 464);
Jaworski_2016 teaches that “While MALT1 activity has not yet been assessed in other lymphoma types, it seems likely that additional types of B- or T-cell lymphomas with constitutive antigen receptor signaling are sensitive to MALT1 inhibition” (page 467);
Jaworski_2016 teaches that “results hold promise that MALT1 inhibition might be beneficial in tissue transplantation, especially for the transplantation of less immunogenic tissues. However, since MALT1 protease inhibition is less efficient in preventing T cell activation than complete CARMA1-deficiency, the benefit will have to be determined experimentally” (page 467);
Jaworski_2016 teaches that “An important perspective for future research on MALT1 will be to further explore its molecular function and to identify the full spectrum of its substrates, which may open additional windows for therapeutic applications. Another major challenge will be to better understand MALT1’s physiological function in non-immune cells, and its relevance not only for immune but also for non-immune pathologies.”
Hamp_2021 summarizes the literature on MALT1 patents and applications, and discusses the potential therapeutic uses for MALT1 inhibitors based on patents and scientific literature (Abstract, page 1079). Hamp_2021 teaches that while “the critical function for MALT1 scaffolding in NF-kB activation and transcriptional reprogramming of activated lymphocytes is well defined, the biological relevance of the cleavage of individual substrates in these processes has so far remained elusive”, and also that, while MALT1 was suggested to promote growth and survival of certain tumors, including glioblastoma, breast cancer, or melanoma “clear evidence on the pathophysiological role and the potential therapeutic benefits of MALT1 protease inhibitors in these solid cancers are still lacking” (page 1080).
Thus, neither claim 1, nor the instant Specification, nor the field of art provides clarity on the scope of the patient population that is “in need of treatment with a MALT1 inhibitor”.
Claim 2 is indefinite because it depends from claim 1 and dose not result the indefiniteness of patient population described by the term “in need of, or has been recognized as being in need of, treatment with a MALT1 inhibitor”.
Claim 10 further limits the method of claim 3 to wherein the
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group of Formula I is
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wherein R5 and R6 are each independently -CH2-, -O- or N. Claim 10 is ambiguous, and therefore indefinite, because nitrogen is not strictly a bivalent atom and claim 10 does not specify whether the nitrogen atom is anionic (no charge symbol shown) or includes any hydrogen, alkyl, or other substituent(s).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-23 are rejected under 35 U.S.C. 101 because the disclosed invention is inoperative and therefore lacks utility. Claims 1, 3, 10, 22 and 23 include uninterpretable structural drawings that render the claims ambiguous as to the scope of the genera of compounds being claimed:
Claims 1, 3, 22 and 23 include the structural moiety “a”, shown below:
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The structure of moiety “a” shows a cyclohexatriene ring wherein two of the pi bonds form an allene with an sp-hybridized carbon that somehow maintains the hexagonal angularity of the cyclohexyl ring, a third pi bond in conjugation to the allene, and a single sp3 carbon. This structure is inoperable, because it is known in the art that sp-hybridized carbons adopt a linear geometry: see, for example, Carey_1977 (Carey, F.A., and Sundberg, R.J.; Advanced Organic Chemistry, Part A: Structure and Mechanisms, page 5; Plenum Press, New York; 1977).
Claim 10 includes the structural moiety shown below, that includes a cyclohexatetra-ene (at right):
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The ring on the right hand side of the structure shown above from claim 10 includes a double-allene with at least one sp-hybridized carbon (located ortho to the R5 position and meta to the R6 position) that somehow maintains the hexagonal angularity of the cyclohexyl ring contrary to known carbon bonding geometry, as discussed above. Additionally, the carbon at the R5-position displays 5 bonds, whereas the known valency of carbon is a maximum of 4 bonds.
Claim 2 depends from claim 1 and does not resolve the inoperability of the chemical structure of the genus of claimed compounds. Claims 4-21 depend from claim 3 directly or indirectly and do not resolve the inoperability of the structure of the genus of claimed compounds.
For purpose of examination, the claims are interpreted in this action as claiming structures wherein the aberrant rings shown above are treated as benzene rings.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Invention in General
The disclosed invention regards a methods of treatment comprising the administration of a compound from a genus of compounds expected to inhibit MALT1 (mucosa associated lymphoid tissue lymphoma translocation protein-I), a protease enzyme.
The Claimed Invention
Claims 1-21 are drawn to methods of treatment comprising administering a compound of instant Formula I, shown below:
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Formula I, as claimed in claims 1-8, allows for a wide breadth of groups (or their absence) at positions X and R1-R8, including alkyl (substituted or unsubstituted), carbonyl, sulfonyl, amide and alkoxy groups. The genus could amount to hundreds of distinct compounds across its full breadth given the independent variability across the X and R groups. Claims 9-21 further limit the scope of Formula I, each to a slightly narrower genus by more narrowly defining one or a few of the nine variable groups.
The Supporting Disclosure
The instant Specification discloses a group of 45 specific drawn compounds (pages 17-23) without providing any numerical designation or name thereof, nor any synthesis or prior reference for any of the compounds. The first 2 of these compounds match to the structures of instant compounds M1i-124 and M1i-124d1 disclosed in instant Figures 2B and 2G, respectively. The instant Specification provides exemplary data relevant to the potency of compounds M1i-124 and M1i-124d1 for the inhibition of binding between MALT1 and its binding partner BCL10, with IC50 values of 89 mm and 8.45 mm, respectively (pages 5-6, bridging paragraph). The Specification also discloses cellular assays wherein administration of M1i-124 or M1i-124d1 inhibits induction of MALT1 proteolytic cleavage of RelB and N4BP1 target proteins in Jurkat T cells and disrupts the phosphorylation of the IKK complex (inhibitor of Kappa B kinase), indicating the disruption of MALT1 scaffolding that recruits the signaling proteins that effect such phosphorylation (Figure 3 and page 6, lines 4-27). The Specification further discloses additional in vitro and in vivo experiments evidencing the utility of compounds M1i-124 and M1i-124d1 in inhibiting MALT1-associated biological function (Figures 4-6 and pages 6-7). No other compounds within the broad genus of Formula I have been evaluated for any in vitro or in vivo MALT1-associated biological activity. Applicant discloses “in silico screening” to predict small molecules targeting the predicted BCL10-binding groove within MALT1 (Figure 2 and page 5, lines 16-21), from which the only compound of Formula I that was identified is M1i-124. Thus, the expected utility of instant Formula I is based on the evaluation of just two compounds from this broad genus, which differ from each other only in the structure at two of the available variables of the genus, R3 and R4.
The State of the Art
The level of skill and knowledge in the art is best exemplified in the review of MALT1 inhibitors provided by Hamp_2021 (Hamp, et al.; Expert Opinion on Therapeutic Patents, v31, pp.1079-1096; 2021). Hamp_2021 details the breadth of known MALT1 inhibitors, particularly allosteric inhibitors, from early-generation phenothiazine-based inhibitors reported in 2013, through heteroaryl-urea and heteroaryl-carboxamide based later-generations reported from 2015-2018 (pages 1082-1089). Hamp_2021 teaches that the earliest allosteric inhibitors reported for MALT1 are phenothiazines including mepazine, promazine and thoridazine inhibitors shown below, which exhibited inhibition constants in the micromolar range:
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(page 1086).
A subsequent generation of phenothiazine inhibitors showed somewhat better inhibition with a pendant chain including a hydrazine carboxamide linkage:
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930
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(page 1086).
A core amide-family functional group persists across subsequent generations of allosteric MALT1 inhibitors, which have evolved to include a heteroaryl-urea motif, with variation across the heteroaryl ring types and peripheral substituents:
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(page 1088).
Additional later-generation allosteric MALT1 inhibitors include heteroaryl-carboxamide and heterocycloalkyl-amide compounds:
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(page 1089);
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776
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(page 1090).
Thus, the state of art is a field of study based on structure-activity-relationship (SAR) investigations of heteroaryl-urea, heteroaryl-carboxamide and heterocyclyl-carboxamide cores, with variable peripheral rings and substituents. Within this common family of motifs, the field of art would appear to be somewhat predictable; however, Applicant’s genus appears to be a departure from the state of the art in structural motif, and done without any disclosed SAR methodology to support the distinction and the brevity of experimental results with just two compounds from the instantly claimed genus and in silico study showing anticipated activity for just one compound from the instant genus. Applicant has not disclosed any molecular modeling or other rationale to support the breadth of structure of instant Formula I as likely to function as inhibitors of MALT1.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 10 further limits the method of claim 3 to wherein the
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group of Formula I is
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wherein R5 and R6 are each independently -CH2-, -O- or N. Claim 10 does not include all the limitations of claim 3, because claim 3 does not allow nitrogen as X or as any other substituent at the phenyl rings attached to X.
Applicant may cancel the claim, amend the claim(s) to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 23 is anticipated by PubChem.
Claim 23 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by PubChem (PubChem CID 7111, “Benzidine”, Creation date: 03/26/2005)2.
Claim 23 is drawn to a genus of compounds and pharmaceutical salts thereof, defined by instant Formula I, being a family of biphenyl, benzophenone, diphenylsulphone, fluorene and related bicyclic core moieties, bounded by amine groups on each side and optional alkyl or functional group spacers and terminal phenyl rings:
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PubChem teaches the structure and properties of benzidine3, that falls within the scope of instant Formula 1 as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
PubChem
23
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wherein:
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Thus, claim 23 is anticipated by the teaching of PubChem.
Claim 23 is anticipated by Ito
Claim 23 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ito (Ito, et al.; Chemistry Letters, v45, pp1379-1381; 2016).
The limitations of claim 23 are discussed in the rejection above and hereby incorporated into the instant rejection.
Ito teaches an enantioselective synthesis of dibenzofuran-based C2-symmetric chiral diamines, including two products, (R,R)-64 and (R,R)-75, that fall within the scope of instant Formula 1 as shown in the table below (page 1380):
Claim Number(s) of Instant Application
Instant Application
Ito
23
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wherein:
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Thus, claim 23 is anticipated by the teaching of Ito.
Claim 23 is anticipated by Schuster.
Claim 23 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schuster (Schuster, et al.; Journal of Medicinal Chemistry, v51, pp4188-4199; 2008).
The limitations of claim 23 are discussed in the rejection above and hereby incorporated into the instant rejection.
Schuster teaches a study on the discovery of small molecule inhibitors of Nonsteroidal 17b-Hydroxysteroid Dehydrogenase 1 (17b-HSD1), and Schuster identifies two compounds that fall within scope of instant Formula I, named as compounds 306 and 347, as shown in the table below (Chart 2, page 4195):
Claim Number(s) of Instant Application
Instant Application
Schuster
23
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wherein:
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Schuster compound 30
23
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wherein:
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Schuster compound 34
Thus, claim 23 is anticipated by the teaching of Schuster.
Claim 23 is anticipated by Kielbasinski.
Claim 23 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kielbasinski (Kielbasinski, et al.; Tetrahedron: Asymmetry, v24, pp.1417-1420; 2013).
The limitations of claim 23 are discussed in the rejection above and hereby incorporated into the instant rejection.
Kielbasinski teaches a study on asymmetric synthesis using polydentate chiral heterorganic ligands/catalysts, and among the ligands that are made and used by Kielbasinski there is a compound 118 that is within scope of instant Formula I, as shown in the table below (Figure 2, page 1418):
Claim Number(s) of Instant Application
Instant Application
Kielbasinski
23
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wherein:
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Kielbasinski compound 11
Thus, claim 23 is anticipated by the teaching of Kielbasinski.
Claim 24 is anticipated by Miyatake.
Claim 24 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Miyatake (WO 2022/065424 A1).
Claim 24 is drawn to a method comprising administering to a subject in need of, or has been recognized as being in need of, treatment with a MALT1 inhibitor, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having a structure within scope of Formula V. While the image of Formula V is too blurry to interpret in claim 24 (see Claim Objections section above), the structure of Formula V from the instant Specification (page 24) indicates a family of N-alkylated tetrahydroquinazoline-diones. Per the instant Specification, a patient who is in need of a MALT1 inhibitor may have a carcinoma (page 24, lines 18-27) and breast cancer is an illustrative carcinoma (page 25, line 2). Miyatake discloses a method for inhibiting cancer and/or carcinogenesis, comprising administering to a subject a compound having mTORC1 inhibitor effect, or a pharmaceutically acceptable salt thereof, and having a structure disclosed therein (paragraph [0022]). Miyatake further discloses a series of anti-cancer agents, including various N-alkylated tetrahydroquinazoline-diones such as Miyatake’s “Compound C”9 shown in the table below and found in Miyatake’s paragraphs [0013] (Chemical Formula 3, compound 1) and [0057] (ligand #3/Compound C), and in Miyatake’s Figure 1 (compound C):
Claim Number(s) of Instant Application
Instant Application
Miyatake
24
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wherein:
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Compound C
Thus, claim 24 is anticipated by the disclosure of Miyatake.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Emphasis provided by Examiner.
2 Accessed on 11/05/2025 via https://pubchem.ncbi.nlm.nih.gov/compound/7111.
3 [1,1'-Biphenyl]-4,4'-diamine
4 (R,R)-4,6-Bis(1-(benzylamino)propyl)dibenzo[b,d]furan
5 (R,R)-4,6-Bis(1-(1-naphthylmethylamino)propyl)dibenzo[b,d]furan
6 N2,N7-diphenyl-9H-fluorene-2,7-disulfonamide
7 N-{4'-benzenesulfonamido-3,3'-dimethyl-[1,1'-biphenyl]-4-yl}benzenesulfonamide
8 [(1R)-1-(naphthalen-2-yl)ethyl]({2-[2-({[(1R)-1-(naphthalen-2-yl)ethyl]amino}methyl)benzenesulfonyl]phenyl}methyl)amine
9 N-[(2H-1,3-benzodioxol-5-yl)methyl]-4-(1-{[(3-chlorophenyl)carbamoyl]methyl}-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)butanamide