WO2025231227A1 - New compounds for medical use - Google Patents

Abstract

The present disclosure relates to compounds of the formulae herein (e.g, Formula (II)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, which are inhibitors of a GTPase (e.g., cell division control protein 42 homolog (Cdc42)). The present disclosure also provides pharmaceutical compositions comprising the compounds, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating diseases (e.g., malignant neoplastic diseases, diseases associated with aging) by administering to a subject in need thereof the compounds, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof.

Description

  New Compounds for Medical Use Cross-Reference to Related Applications [0001] The present application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application No.63/642,553, filed May 3, 2024, United States Provisional Patent Application No. 63/653,114, filed May 29, 2024, and United States Provisional Patent Application No. 63/753,160, filed February 3, 2025, the contents of each of which are incorporated herein by reference in their entireties. Technical Field [0002] The present disclosure relates to an improved class of inhibitors of a GTPase. Background [0003] Cell division control protein 42 homolog (Cdc42) is a small GTPase of the Rho family. It regulates signaling pathways that control diverse cellular functions including cell morphology, cell migration, endocytosis and cell cycle progression. Inhibitors of Cdc42 may have utility for the treatment of malignant neoplastic diseases (see, e.g.: Xing-Hua Xiao et al., Molecules 23, 787 (2018); Nguyen P. et al., Frontiers in Oncology 9 (2019)), e.g., colon carcinoma or tumors of the pancreas (see, e.g., WO 2021/011800A1). [0004] Additionally, elevated activity of Cdc42 is a hallmark of aging. Aging results in disorder in both hematopoietic stem cells (HSCs) and human T cells (see, e.g., Grigoryan, A., et al., Genome Biol 19, 189 (2018); Kared H, et al., Nat Commun. 11(1), 821 (2020)), and results in more myeloid and less lymphoid cells, leading to reduced immune function. Cdc42 treatment (repolarization) may have utility for the restoration of proper levels of lymphoid cells and function, which could lead to effects such as improved vaccination response. [0005] An exemplary inhibitor of Cdc42 is a molecule named CASIN (Cdc42 Activity Specific Inhibitor; Liu, W. et al., Blood, 112, 68). Formula I: CASIN [0006] In an in vitro binding assay CASIN was reported to bind to Cdc42 with an affinity of 332nM (Kd) (Liu, W. et al, Leukemia, 33, 749-761), and prophylactic CASIN administered in

M1671.70000WO00 1/68 #13885233v1   in vivo animal models at 30 mg/kg has been reported to cause anti-tumor immunity (WO 2021/011800 A1). CASIN has also been reported to prevent tumor growth by inducing Treg instability in vivo, and attenuation of Cdc42 by CASIN enhances antitumor T-cell immunity in a human cancer colon model in a humanized mouse (Kalim KW, et al. J Immunother Cancer 2022; 10:e004806). CareASIN has also been reported to extend the lifespan of mice due to ameliorating disorder associated with aging (see, e.g., Montserrat-Vazquez S, et al., NPJ Regen Med. 2022 Dec 29;7(1):78). Summary of the Invention [0007] The present disclosure provides compounds with Cdc42-inhibitory activity and their use in the treatment of malignant neoplastic diseases (e.g., colon cancer (e.g., colon carcinoma) or pancreatic cancer (e.g., tumors of the pancreas)), in the modulation of the immune system, and in the treatment of diseases associated with aging. [0008] Accordingly, in one aspect, the present disclosure provides compounds of Formula (II): Formula (II): wherein n is 1 or 2; wherein R¹ is H or optionally substituted C1-C3-alkyl; wherein R² is H, optionally substituted C1-C3-alkyl, or optionally substituted phenyl; wherein R³ is phenyl optionally substituted with optionally substituted C₁-C₃-alkyl, optionally substituted benzyl, halogen, optionally substituted 2-methoxyethyl, optionally substituted 2-methoxyethyloxy, optionally substituted methoxy, optionally substituted phenyloxy, optionally substituted methoxycarbonyl, optionally substituted ethoxycarbonyl, optionally substituted hydroxycarbonyl, or optionally substituted 4-tetrahydropyranyl, or R³ is phenyl fused with optionally substituted 5-6 membered heterocyclyl; wherein R⁴ is H, optionally substituted C1-C3-alkyl, optionally substituted phenyl, halogen, cyano, trifluoromethyl, optionally substituted methoxy, or trifluoromethoxy; wherein R⁵ is H, optionally substituted C1-C3-alkyl, optionally substituted benzyl, optionally substituted C1-C6-alkylcarbonyl, optionally substituted benzoyl, optionally

M1671.70000WO00 2/68 #13885233v1   substituted benzylcarbonyl, optionally substituted C1-C6-alkylaminocarbonyl, optionally substituted C1-C6-dialkylaminocarbonyl, optionally substituted C1-C6-alkyloxycarbonyl, optionally substituted benzyloxycarbonyl, or optionally substituted phenyloxycarbonyl; wherein R⁶ is H or optionally substituted C1-C3-alkyl; and wherein R⁷ is H or optionally substituted C1-C3-alkyl, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, provided that the compound of Formula (II) is not of formula: , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient. [0010] In another aspect, the present disclosure provides a kit comprising: a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof; and instructions for its use. [0011] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament. [0012] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof, for use in the treatment of a disease. [0013] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (II), or a pharmaceutically

M1671.70000WO00 3/68 #13885233v1   acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. [0014] In another aspect, the present disclosure provides a method of inhibiting a GTPase in a subject in need thereof or in a cell, tissue, or biological sample, the method comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. [0015] In another aspect, the present disclosure provides a method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the cell, tissue, or organ comprises a hematopoietic stem cell (HPC). [0016] In another aspect, the present disclosure provides a method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. [0017] In another aspect, the present disclosure provides a method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of the compound of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. [0018] In another aspect, the present disclosure provides a method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. Brief Description of the Drawings [0019] FIG.1 shows the polarity of murine hematopoietic stem cells (HSCs). When HSCs are old, polarity in the HSC is lost compared to a young state (left panel). CASIN is able to repolarize the HSC dose dependently, showing the best effect at a concentration of 10 µM

M1671.70000WO00 4/68 #13885233v1   (right panel). Both molecules MO-072 (Product of Example 9), and MO-075 (Product of Example 11) are able to achieve the same level of repolarization as with CASIN, but with a lower concentration of 3.3 µM (middle panel). Definitions [0020] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7^th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. [0021] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0022] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹F with ¹⁸F,

M1671.70000WO00 5/68 #13885233v1   or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. [0023] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C_1-6 alkyl” encompasses, C₁, C₂, C₃, C₄, C₅, C₆, C_1–6, C_1–5, C_1–4, C_1–3, C_1–2, C_2–6, C_2–5, C_2–4, C_2–3, C_3–6, C_3–5, C_3–4, C_4–6, C_4–5, and C_5–6 alkyl. [0024] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C_1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C_1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2-6 alkyl”). Examples of C_1–6 alkyl groups include methyl (C₁), ethyl (C₂), propyl (C₃) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C₆) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈), n-dodecyl (C₁₂), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12 alkyl (such as unsubstituted C1–6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C_1–6 alkyl, e.g., –CH₂F, –CHF₂, –CF₃, –CH₂CH₂F, –CH₂CHF₂, –CH₂CF₃, or benzyl (Bn)).

M1671.70000WO00 6/68 #13885233v1   [0025] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and, in some embodiments, is saturated or contains one or more carbon-carbon double or triple bonds. In some embodiments, heterocyclyl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7- membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. [0026] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2

M1671.70000WO00 7/68 #13885233v1   ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. [0027] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6- 14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl. [0028] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

M1671.70000WO00 8/68 #13885233v1   [0029] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). [0030] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents. [0031] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0032] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in

M1671.70000WO00 9/68 #13885233v1   detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0033] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. [0034] The term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an

M1671.70000WO00 10/68 #13885233v1   integral part of the crystal lattice, in which they interact strongly with the compound and each other. The removal of the solvent molecules will cause instability of the crystal network, which subsequently collapses into an amorphous phase or recrystallizes as a new crystalline form with reduced solvent content. [0035] The term “non-stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure. The amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non-stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound. During drying of a non-stoichiometric solvate, a portion of the solvent may be removed without significantly disturbing the crystal network, and the resulting solvate can subsequently be resolvated to give the initial crystalline form. Unlike stoichiometric solvates, the desolvation and resolvation of non- stoichiometric solvates is not accompanied by a phase transition, and all solvation states represent the same crystal form. [0036] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R^x H₂O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R^0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R^2 H2O) and hexahydrates (R^6 H2O)). [0037] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. [0038] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in

M1671.70000WO00 11/68 #13885233v1   space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. [0039] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0040] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks. [0041] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2θ of, e.g., between 20 and 70°, inclusive, using CuKα radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2θ of between 20 and 70°, inclusive, is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures. [0042] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a

M1671.70000WO00 12/68 #13885233v1   compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein. [0043] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. [0044] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-C8 alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters of the compounds described herein may be preferred. [0045] The terms “composition” and “formulation” are used interchangeably. [0046] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In

M1671.70000WO00 13/68 #13885233v1   certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease. [0047] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. [0048] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. [0049] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [0050] The terms “condition,” “disease,” and “disorder” are used interchangeably. [0051] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required

M1671.70000WO00 14/68 #13885233v1   frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). [0052] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting a GTPase (e.g., Cdc42). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease (e.g., a malignant neoplastic disease). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting a GTPase (e.g., Cdc42) and treating a disease (e.g., a malignant neoplastic disease). [0053] As used herein the term “inhibit” or “inhibition” in the context of enzymes, for example, in the context of a GTPase (e.g., Cdc42), refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., GTPase (e.g., Cdc42) activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., GTPase (e.g., Cdc42) activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.

M1671.70000WO00 15/68 #13885233v1   Detailed Description of the Invention Disclosed herein are compounds of Formula (II): Formula (II): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, wherein: n is 1 or 2; R¹ is H or optionally substituted C1-C3-alkyl; R² is H, optionally substituted C1-C3-alkyl, or optionally substituted phenyl; R³ is phenyl optionally substituted with optionally substituted C₁-C₃-alkyl, optionally substituted benzyl, halogen, optionally substituted 2-methoxyethyl, optionally substituted 2- methoxyethyloxy, optionally substituted methoxy, optionally substituted phenyloxy, optionally substituted methoxycarbonyl, optionally substituted ethoxycarbonyl, optionally substituted hydroxycarbonyl, or optionally substituted 4-tetrahydropyranyl, or R³ is phenyl fused with optionally substituted 5-6 membered heterocyclyl; R⁴ is H, optionally substituted C1-C3-alkyl, optionally substituted phenyl, halogen, cyano, trifluoromethyl, optionally substituted methoxy, or trifluoromethoxy; R⁵ is H, optionally substituted C1-C3-alkyl, optionally substituted benzyl, optionally substituted C1-C6-alkylcarbonyl, optionally substituted benzoyl, optionally substituted benzylcarbonyl, optionally substituted C₁-C₆-alkylaminocarbonyl, optionally substituted C₁- C₆-dialkylaminocarbonyl, optionally substituted C₁-C₆-alkyloxycarbonyl, optionally substituted benzyloxycarbonyl, or optionally substituted phenyloxycarbonyl; R⁶ is H or optionally substituted C₁-C₃-alkyl; and R⁷ is H or optionally substituted C₁-C₃-alkyl; provided that the compound of Formula (II) is not of formula: ,

M1671.70000WO00 16/68 #13885233v1   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0054] In some embodiments, n is 1. In some embodiments, n is 2. [0055] In some embodiments, R¹ is H or C1-C3-alkyl. In some embodiments, R¹ is H or methyl. In some embodiments, R¹ is H. In some embodiments, R¹ is methyl. [0056] In some embodiments, R² is H, C₁-C₃-alkyl, or phenyl. In some embodiments, R² is H, methyl or phenyl. In some embodiments, R² is H. In some embodiments, R² is methyl. In some embodiments, R² is phenyl. [0057] In some embodiments, R³ is phenyl optionally substituted with C₁-C₃-alkyl, benzyl, halogen, 2-methoxyethyl, 2-methoxyethyloxy, methoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, or 4-tetrahydropyranyl, or R³ is phenyl fused with 5-6 membered heterocyclyl. In some embodiments, R³ is phenyl optionally substituted with methyl, ethyl, benzyl, fluorine, chlorine, 2-methoxyethyl, 2-methoxyethyloxy, methoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, or 4-tetrahydropyranyl. In some embodiments, R³ is phenyl. In some embodiments, R³ is phenyl optionally substituted with optionally substituted methyl or optionally substituted ethyl. In some embodiments, R³ is phenyl optionally substituted with methyl or ethyl. [0058] In some embodiments, R⁴ is H, C1-C3-alkyl, phenyl, halogen, cyano, trifluoromethyl, methoxy, or trifluoromethoxy. In some embodiments, R⁴ is H, methyl, ethyl, propyl, phenyl, chlorine, bromine, cyano, trifluoromethyl, methoxy, or trifluoromethoxy. In some embodiments, R⁴ is H, methyl or chlorine. In some embodiments, R⁴ is H. In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is chlorine. [0059] In some embodiments, R⁵ is H, C₁-C₃-alkyl, benzyl, C₁-C₆-alkylcarbonyl, benzoyl, benzylcarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-dialkylaminocarbonyl, C1-C6- alkyloxycarbonyl, benzyloxycarbonyl, or phenyloxycarbonyl. In some embodiments, R⁵ is H. [0060] In some embodiments, R⁶ is H or C₁-C₃-alkyl. In some embodiments, R⁶ is H. [0061] In some embodiments, R⁷ is H or C1-C3-alkyl. In some embodiments, R⁷ is H. [0062] In some embodiments of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof: n is 1 or 2; R¹ is H or C₁-C₃-alkyl; R² is H, C₁-C₃-alkyl, or phenyl;

M1671.70000WO00 17/68 #13885233v1   R³ is phenyl optionally substituted with methyl, ethyl, benzyl, fluorine, chlorine, 2- methoxyethyl, 2-methoxyethyloxy, methoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, or 4-tetrahydropyranyl; R⁴ is H or methyl, ethyl, propyl, phenyl, chlorine, bromine, cyano, trifluoromethyl, methoxy, or trifluoromethoxy; R⁵ is H, C₁-C₃-alkyl, benzyl, C₁-C₆-alkylcarbonyl, benzoyl, benzylcarbonyl, C₁-C₆- alkylaminocarbonyl, C₁-C₆-dialkylaminocarbonyl, C₁-C₆-alkyloxycarbonyl, benzyloxycarbonyl, or phenyloxycarbonyl; R⁶ is H or C₁-C₃-alkyl; and R⁷ is H or C₁-C₃-alkyl. [0063] In some embodiments of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof: R¹ is H or methyl; R² is H, methyl or phenyl; R³ is phenyl; and R⁴ is H, methyl or chlorine. [0064] In some embodiments of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof: n is 1; R¹ is H or methyl; R² is H, methyl or phenyl; R³ is phenyl; and R⁴ is H, methyl or chlorine. [0065] In some embodiments, the compound of Formula (II) is of Formulae (II-a) or (II-b): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

M1671.70000WO00 18/68 #13885233v1   [0066] In some embodiments, the compound of Formula (II) is of Formulae (II-c) to (II-f): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.  [0067] In some embodiments, the compound of Formula (II) is of Formulae (II-g) to (II-j): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0068] In some embodiments, the compound of Formula (II) is of Formulae (II-g-1) to (II-g-

M1671.70000WO00 19/68 #13885233v1   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0069] In some embodiments, the compound of Formula (II) is of Formulae (II-k) to (II-n): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0070] In some embodiments, the compound of Formula (II) is of Formulae (II-o) to (II-r):

M1671.70000WO00 20/68 #13885233v1   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0071] In some embodiments, the compound of Formula (II) is of Formulae (II-s) or (II-t): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0072] In some embodiments, the compound of Formula (II) is of Formulae (II-s-1) to (II-s- 4) or (II-t-1) to (II-t-4): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0073] Pharmaceutically acceptable salts of the compounds of formula (II) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non- toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate,

M1671.70000WO00 21/68 #13885233v1   bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, male- ate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. [0074] In some embodiments, the compound of Formula (II) is selected from the group consisting of: 2-{[6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol; 2-{[6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol; 1-{[6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; 1-{[6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; 1-{[6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; 1-{[6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; 1-{[7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 1-{[7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 2-{[8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; 2-{[8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; 1-{[5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 1-{[5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 2-[(8-chloro-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]ethan-1-ol; 1-{[5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 1-{[5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 1-phenyl-2-((6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethan-1-ol; and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [0075] In some embodiments, the compound of Formula (II) is selected from the group consisting of: (2S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol; (2R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol;

M1671.70000WO00 22/68 #13885233v1   (2S)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2S)-1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2R)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2R)-1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2S)-1-{[(3R)-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; (2S)-1-{[(3S)-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 2-{[(1R)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; 2-{[(1S)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; (2S)-1-{[(3R)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; (2S)-1-{[(3S)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; 2-[(8-chloro-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]ethan-1-ol; (2S)-1-{[(3S)-5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; (2S)-1-{[(3R)-5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; (1R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [0076] In some embodiments, the compound is selected from the group consisting of: (2S)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2S)-1-{[(3R)-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 2-{[(1R)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; 2-{[(1S)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; (2S)-1-{[(3R)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; and (2S)-1-{[(3S)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol;

M1671.70000WO00 23/68 #13885233v1   and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [0077] In some embodiments, the compound is selected from the group consisting of: (1R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. [0078] In some embodiments, the compound of Formula (II) is not of formula: , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0079] In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, or stereoisomer thereof. In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula (II).

M1671.70000WO00 24/68 #13885233v1   [0080] The compounds according to the present disclosure can be obtained as set forth in the following reaction scheme: [0081] Reaction conditions: a) NaNO₂ / hydrochloric acid / 0°C / 1 hour b) 2-formyl-cyclohexanone or 2-formyl-cyclopentanone / methanol / 1.5 hours c) hydrochloric acid / acetic acid (1:2) / 125°C / 2 hours d) R³-boronic acid (1.4 eq) / Pd(PPh₃)₄ (10 mol%) / K₂CO₃ (2.4 eq) / dioxane/water (5:1) / 80°C / 16 hours e) H2N-CHR¹-CHR²-O-R⁵ (30 eq) / toluene / toluenesulfonic acid (pTsOH * H2O) (0.1 eq) / reflux / 3 hours f) sodium-borohydride (1.5 eq) / THF/methanol (3:10) / 0°C / 4 hours. g) The resulting products are mixtures of stereoisomers that can be separated e.g. by means of chiral chromatography. Medical Use [0082] The compounds of the present disclosure may be used for the treatment of malignant neoplastic diseases, e.g., colon carcinoma (e.g., non-neoplastic polyps, adenomas, familial syndromes, colorectal carcinogenesis, colorectal carcinoma, carcinoid tumors) or tumors of

M1671.70000WO00 25/68 #13885233v1   the pancreas (e.g., tumors of the exocrine gland and endocrine gland, adenocarcinomas, acinar cell carcinomas, intraductal papillary-muemous neoplasm, mucinous cystic neoplasm with an invasive adenocarcinoma, gastrinomas, glucaganomas, insulinomas, somatostatinoma, VTPoma (vasoactive intestinal peptide), nonfunctional islet cell tumor, squamous tumors, pancreatic progenitor tumors, immunogenic tumors) (see, e.g.: Xing-Hua Xiao et al., Molecules 23, 787 (2018); Natasha P. Murphy et al., Biochemical Society Transactions 491425–1442 (2021); Nguyen P. et al., Frontiers in Oncology 9 (2019); Zhang Z. et al., Biochemical Society Transactions 2021). The compounds of the present disclosure may also be used for modulating the immune system, and for the treatment of diseases associated with aging. [0083] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0084] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in the treatment of a disease. [0085] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in the manufacture of a medicament for the treatment of a disease. [0086] In some embodiments, the disease is associated with a GTPase. In some embodiments, the GTPase is cell division control protein 42 homolog (Cdc42). In some embodiments, the disease is a cancer. In some embodiments, the disease is a malignant neoplastic disease. In some embodiments, the disease is colon cancer (e.g., colon carcinoma) or pancreatic cancer (e.g., tumors of the pancreas). In some embodiments, the disease is a hematologic cancer. [0087] In some embodiments, the disease is a colon cancer. In some embodiments, the disease is a colon carcinoma. In some embodiments, the disease is selected from non- neoplastic polyps, adenomas, familial syndromes, colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors.

M1671.70000WO00 26/68 #13885233v1   [0088] In some embodiments, the disease is pancreatic cancer. In some embodiments, the disease is a tumor of the pancreas. In some embodiments, the disease is selected from tumors of the exocrine gland and endocrine gland, adenocarcinomas, acinar cell carcinomas, intraductal papillary-muemous neoplasm, mucinous cystic neoplasm with an invasive adenocarcinoma, gastrinomas, glucaganomas, insulinomas, somatostatinoma, VTPoma (vasoactive intestinal peptide), nonfunctional islet cell tumor, squamous tumors, pancreatic progenitor tumors, and immunogenic tumors. [0089] In some embodiments, the disease is a myeloproliferative neoplasm. In some embodiments, the disease is selected from polycythemia vera, essential thrombocytopenia, and myelofibrosis. [0090] In some embodiments, the disease is multiple myeloma. In some embodiments, the multiple myeloma is melphalan-resistant and/or bortezomib-resistant multiple myeloma. [0091] In some embodiments, the disease is acute lymphoid leukemia. In some embodiments, the disease is relapsed acute lymphoid leukemia or refractory acute lymphoid leukemia. In some embodiments, the subject in need thereof is adminstered quinacrine, cytarabine, or a combination thereof. In some embodiments, the subject in need thereof has been adminstered quinacrine, cytarabine, or a combination thereof. [0092] In some embodiments, the disease is alopecia. In some embodiments, the disease is selected from male alopecia and female alopecia. In some embodiments, the method further comprises increasing hair regrowth. In some embodiments, the method further comprises inducing anagen onset. [0093] In another aspect, the present disclosure provides a method of enhancing immune response to a vaccine in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and administering to the subject in need thereof the vaccine. In some embodiments, the vaccine is DNA-based. In some embodiments, the vaccine is mRNA-based. [0094] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in enhancing immune response to a vaccine. In some embodiments, the vaccine is DNA-based. In some embodiments, the vaccine is mRNA-based.

M1671.70000WO00 27/68 #13885233v1   [0095] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in the manufacture of a medicament for enhancing immune response to a vaccine. In some embodiments, the vaccine is DNA-based. In some embodiments, the vaccine is mRNA-based. [0096] In another aspect, the present disclosure provides a method of promoting hematopoietic stem cell (HSC) engraftment in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, the subject in need thereof has Fanconi anemia. In some embodiments, the method does not comprise myeloablation in the subject in need thereof. In some embodiments, the HSC is a CD34⁺ UCB cell. [0097] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in promoting hematopoietic stem cell (HSC) engraftment. In some embodiments, the HSC is a CD34⁺ UCB cell. [0098] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in the manufacture of a medicament for promoting hematopoietic stem cell (HSC) engraftment. In some embodiments, the HSC is a CD34⁺ UCB cell. [0099] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient. [0100] In another aspect, the present disclosure provides a kit comprising: a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof; and instructions for its use. [0101] The compounds of the disclosure can be given parenterally, orally, rectally or as a dermal application.

M1671.70000WO00 28/68 #13885233v1   [0102] The compound can be administered in a pharmaceutically acceptable carrier. Compositions intended for oral use can be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. [0103] Oral dosage forms may contain the compound according to the disclosure in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets or capsules, such as hard gelatine capsules. Examples of such excpients are inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated. In soft gelatine capsules the active ingredient may be mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. [0104] The oral dosage form may also be a suspension containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In case of aqueous suspensions such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [0105] In case of non-aqueous liquid formulations, e.g., oily suspensions compound of the disclosure may be suspended in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents

M1671.70000WO00 29/68 #13885233v1   such as those set forth above, and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. [0106] The compounds of the disclosure can also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols. Determination of the Biological Activity, Measurement of the Potency [0107] Control of cell migration has been reported as one of the cellular functions of Cdc42 (see, e.g.,: Y. Harada et al, Blood, (2012), 119 (19), 4451-4461, Natasha P. Murphy et al., Biochemical Society Transactions (2021) 491443–1456). Therefore, an assay was established that measures the migration of cells evoked by chemotaxis. In this assay CASIN was shown to reduce the number of cells that migrate within a certain time period in a concentration dependent manner. The percent inhibition of cell migration at a certain compound concentration is therefore a surrogate parameter for the Cdc42 inhibitory potency of that compound (see detailed description of the assay protocol in Example 20). Additional Methods [0108] In another aspect, the present disclosure provides a method of inhibiting a GTPase in a subject in need thereof or in a cell, tissue, or biological sample, the method comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. [0109] In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, for use in the inhibition of a GTPase. [0110] In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,

M1671.70000WO00 30/68 #13885233v1   stereoisomer, isotopically labeled compound, or prodrug thereof, for use in the manufacture of a medicament for the inhibition of a GTPase. [0111] In some embodiments, the GTPase is cell division control protein 42 homolog (Cdc42). [0112] In some embodiments, Cdc42 inhibition is determined by measuring the migration of cells evoked by chemotaxis. In some embodiments, Cdc42 inhibition is determined by measuring a reduction in the number of cells that migrate within a certain time period in a concentration dependent manner. In some embodiments, % inhibition of Cdc42 is the % decrease of cell migration after treatment with the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, compared to the migration of an untreated cell. [0113] Given the programmed nature of cellular and organismal aging, it is possible to evaluate the “biological age” of a cell or organism by means of phenotypic characteristics that are correlated with aging. For example, biological age can be deduced from patterns of gene expression, resistance to stress (e.g., oxidative or genotoxic stress), rate of cellular proliferation, and the metabolic characteristics of cells (e.g., rates of protein synthesis and turnover, mitochondrial function, ubiquinone biosynthesis, cholesterol biosynthesis, ATP levels within the cell, levels of a Krebs cycle intermediate in the cell, glucose metabolism, nucleic acid (e.g., engineered nucleic acid) metabolism, ribosomal translation rates, etc.). As used herein, “biological age” is a measure of the age of a cell or organism based upon the molecular characteristics of the cell or organism. Biological age is distinct from “temporal age,” which refers to the age of a cell or organism as measured by days, months, and years, and “apparent chronological age,” which refers to the age that a cell, organ, or tissue matches based on biomarkers or other metrics from individuals of such chronological age. [0114] In another aspect, the present disclosure provides a method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the cell, tissue, or organ is within a subject. In some embodiments, the cell, tissue, or organ comprises a hematopoietic stem cell (HSC). In some embodiments, the cell, tissue, or organ is in vitro. In some embodiments, the cell, tissue, or organ is in vivo.

M1671.70000WO00 31/68 #13885233v1   [0115] In another aspect, the present disclosure provides a method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the cell, tissue, or organ is within a subject. In some embodiments, the cell, tissue, or organ comprises a hematopoietic stem cell (HSC). In some embodiments, the cell, tissue, or organ is in vitro. In some embodiments, the cell, tissue, or organ is in vivo. [0116] In another aspect, the present disclosure provides a method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of the compound of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the cell, tissue, or organ is within a subject. In some embodiments, the cell, tissue, or organ comprises a hematopoietic stem cell (HSC). In some embodiments, the cell, tissue, or organ is in vitro. In some embodiments, the cell, tissue, or organ is in vivo. [0117] In another aspect, the present disclosure provides a method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the cell, tissue, or organ is within a subject. In some embodiments, the cell, tissue, or organ comprises a hematopoietic stem cell (HSC). In some embodiments, the cell, tissue, or organ is in vitro. In some embodiments, the cell, tissue, or organ is in vivo. Examples [0118] List of abbreviations: AcOH acetic acid CC column chromatography DCM dichloromethane DIPEA Diisopropylethylamine EtOAc ethylacetate EtOH ethanol HATU O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium- hexafluorophosphate HCl hydrocloric acid

M1671.70000WO00 32/68 #13885233v1   HPLC High Performance Liquid Chromatography IPA: isopropylamine KOAc potassium acetate K₂CO₃ potassium carbonate MeOH methanol MTBE methyl-tert.butyl-ether NaBH₄ sodium borohydride NaHCO3 sodium hydrogencarbonate Na2SO4 sodium sulfate Pd(dppf)Cl2 [1,1′-Bis-(diphenylphosphino)-ferrocen]-dichloro-palladium(II) Pd(PPh3)4 tetrakis(triphenylphosphino)palladium(0) PE petrol ether pTsOH p-toluene sulfonic acid rm: reaction mixture rt: room temperature THF tetrahydrofuran Example 1: -6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan- 1-ol. Example 1a: 1-Oxo-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol (C₁₈H₁₅NO) [0119] A mixture of 1-oxo-6-bromo-2,3,4,9-tetrahydro-1H-carbazol (1.0 g, 3.79 mmol), dioxane (30 mL), water (6 mL), phenylboronic acid (0.65 g, 5.30 mmol), potassium carbonate (1.26 g, 9.10 mmol), and tetrakis-triphenylphosphino-palladium (0.40 g, 0.38 mmol) was stirred under argon in a pressure tube for 16 h at 80 °C. Then the reaction mixture was cooled to rt and filtered through celite. The celite was rinsed with EtOAc (2 × 25 mL) and the filtrate was evaporated. The crude product was dissolved in DCM (50 mL), washed with water (30 mL) and brine (40 mL), and dried over anhydrous Na2SO4. After evaporation the crude product thus obtained was purified by CC on silica gel, (EtOAc: MeOH, 10:1) (Rf ≈ 0.80). Recovery from EtOH gave 1-oxo-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol as a yellowish solid (0.59 g, 60%)

M1671.70000WO00 33/68 #13885233v1   [0120] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 2.12–2.21 (m, 2H), 2.54–2.60 (m, 2H), 2.97–3.04 (m, 2H), 7.29–7.35 (m, 1H), 7.41–7.51 (m, 3H), 7.60–7.66 (m, 1H), 7.66–7.72 (m, 2H), 7.92–7.96 (m, 1H), 11.67 (s, 1H) ppm. [0121] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.9, 24.7, 38.1, 113.2, 119.0, 125.7, 125.8, 126.6, 126.7, 128.4, 128.8, 131.9, 132.1, 137.5, 141.1, 190.4 ppm. Example 1b: (S)-2-[(2,3,4,9-Tetrahydro-6-phenyl-1H-carbazol-1-yl)amino]propanol (C21H24N2O) [0122] To a solution of 1-oxo-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol (Example 1a) (400 mg, 1.53 mmol) in toluene (S)-2-amino-1-propanol (1.2 mL, 15.3 mmol) and pTsOH x H2O (29 mg, 0.15 mmol) were added under an argon atmosphere. The rm was refluxed for 4 hours using a Dean-Stark trap, then evaporated to dryness. The crude product was dissolved in MeOH (20 mL) and THF (4 mL), cooled to 0°C, and then NaBH4 (87 mg, 2.3 mmol) was added. After stirring at rt for 4 hours water (4 mL) was added and the mixture was evaporated to dryness. The product was dissolved in DCM (40 mL), washed with saturated NaHCO₃ (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and evaporated. Purification by CC on silica gel (DCM : MeOH, 4:1) gave (S)-2-[(2,3,4,9-tetrahydro-6-phenyl-1H-carbazol-1- yl)amino]propanol as a mixture of diastereomers. Example 1c: Separation of the diastereomeric mixture of Example 1b [0123] The diastereomers of Example 1b were separated by chromatography on a chiralpak IG column (Eluent: 99% DCM, 1% IPA, 90% DCM, 0.1% aminoethanol). [0124] The first fraction was identified as (2S)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}propan-1-ol, the second fraction was identified as (2S)-2-{[(1S)-6- phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol. (C₂₁H₂₄N₂O) [0125] ¹H NMR spectrum: (400 MHz, CDCl₃, δ): 1.18 (d, 3H, J=6.5 Hz), 1.60–1.70 (m, 1H), 1.77–1.90 (m, 2H), 2.01–2.12 (m, 2H), 2.26–2.36 (m, 1H), 2.68–2.82 (m, 2H), 3.09–3.18 (m,

M1671.70000WO00 34/68 #13885233v1   1H), 3.39 (dd, 1H, J = 10.6, 5.4 Hz), 3.73 (dd, 1H, J = 10.6, 4.0 Hz), 3.96–4.03 (m, 1H), 7.27–7.32 (m, 1H), 7.35–7.46 (m, 4H), 7.63–7.69 (m, 3H), 8.52 (s, 1H) ppm [0126] ¹³C NMR spectrum: (100 MHz, CDCl₃, δ): 19.5, 21.1, 21.8, 31.9, 51.4, 52.4, 65.4, 111.2, 111.7, 117.1, 121.6, 126.3, 127.5, 128.1, 128.7, 132.9, 135.6, 137.1, 143.0 ppm Example 2: -6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan- 1-ol Example 2a: (R)-2-[(2,3,4,9-Tetrahydro-6-phenyl-1H-carbazol-1-yl)amino]propanol [0127] Following the procedure of Example 1b, 1-oxo-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol (Example 1) was reacted with (R)-amino-1-propanol to obtain the diastereomeric mixture of (2R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol and (2R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol. (Yield: 92% over two steps). Example 2b: Separation of the diastereomeric mixture of Example 2a [0128] The diasteromers of the product of Example 2a were separated by chromatography on a chiralpak IG column (Eluent: 99% DCM, 1% IPA, 90% DCM, 0.1% aminoethanol). [0129] The second fraction is (2R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1- yl]amino}propan-1-ol (C₂₁H₂₄N₂O) [0130] spectrum: (400 MHz, CDCl₃, δ): 1.18 (d, 3H, J=6.5 Hz), 1.60–1.70 (m, 1H), , 2.01–2.12 (m, 2H), 2.26–2.34 (m, 1H), 2.68–2.82 (m, 2H), 3.09–3.18 (m,

M1671.70000WO00 35/68 #13885233v1   1H), 3.39 (dd, 1H, J = 10.6, 5.4 Hz), 3.74 (dd, 1H, J = 10.6, 4.0 Hz), 3.96–4.03 (m, 1H), 7.27–7.33 (m, 1H), 7.35–7.46 (m, 4H), 7.63–7.69 (m, 3H), 8.63 (s, 1H) ppm. [0131] ¹³C NMR spectrum: (100 MHz, CDCl₃, δ): 19.5, 21.1, 21.8, 31.9, 51.4, 52.4, 65.4, 111.2, 111.7, 117.1, 121.6, 126.3, 127.5, 128.1, 128.7, 132.9, 135.6, 137.1, 143.0 ppm. Example 3: -6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan- 2-ol Example 3a: (S)-2-[(2,3,4,9-Tetrahydro-6-phenyl-1H-carbazol-1-yl)amino]-1-methyl-ethanol [0132] Using the procedure as described in Example 1b, 1-oxo-6-phenyl-2,3,4,9-tetrahydro- 1H-carbazol (Example 1a) was reacted with (S)-1-amino-propan-2-ol followed by reduction with NaBH₄ to yield a mixture of (2S)-1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1- yl]amino}propan-2-ol and (2S)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1- yl]amino}propan-2-ol (Yield: 77% over two steps). Example 3b: Separation of the diastereomeric mixture of Example 2a. [0133] The mixture of Example 2a was dissolved in boiling ethanol, then slowly cooled to rt. A solid precipitated, was filtered off and recovered from ethanol to give (2S)-1-{[(1R)-6- phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol (C₂₁H₂₄N₂O) [0134] ¹H NMR spectrum: (400 MHz, DMSO-d₆, δ): 1.08 (d, 3H, J=6.2 Hz), 1.63–1.77 (m, 2H), 1.88–2.06 (m, 3H), 2.42–2.49 (m, 1H), 2.62–2.70 (m, 3H), 3.61–3.71 (m, 1H), 3.81– 3.89 (m, 1H), 4.48 (d, 1H, J=3.6 Hz), 7.24–7.30 (m, 1H), 7.31–7.45 (m, 4H), 7.61–7.67 (m, 3H), 10.78 (s, 1H) ppm.

M1671.70000WO00 36/68 #13885233v1   [0135] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.7, 20.8, 21.4, 29.8, 51.9, 54.4, 66.1, 109.6, 111.3, 115.9, 119.8, 126.0, 126.6, 127.5, 128.7, 130.6, 135.5, 137.9, 142.1 ppm. Example 4: -1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan- 2-ol [0136] From the mother liquor of Example 3b that still contained both isomers, the title compound was isolated and purified by repeated column chromatography on silica gel (Biotage SNAP cartrige, KP-Sil) using a DCM-MeOH gradient (0% to 30% MeOH in 25 min) [0137] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.21 (d, 3H, J=6.2 Hz), 1.25–1.28 (m, 1H), 1.58–1.70 (m, 1H), 1.72–1.84 (m, 1H), 1.88–2.00 (m, 1H), 2.09–2.19 (m, 1H), 2.59 (dd, 1H, J=12.2, 9.2 Hz), 2.64–2.86 (m, 4H), 3.89–3.97 (m, 1H), 3.98–4.05 (m, 1H), 7.27–7.33 (m, 1H), 7.36–7.46 (m, 4H), 7.63–7.69 (m, 3H), 8.75 (s, 1H) ppm. [0138] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.8, 21.1, 21.3, 29.8, 51.7, 52.9, 65.9, 111.3, 112.4, 117.1, 121.8, 126.3, 127.5, 127.9, 128.7, 133.0, 135.6, 135.7, 142.9 ppm. Example 5: -6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan- 2-ol Example 5a: (R)-2-[(2,3,4,9-Tetrahydro-6-phenyl-1H-carbazol-1-yl)amino]-1-methyl-ethanol [0139] Using the procedure as described in Example 1b, 1-oxo-6-phenyl-2,3,4,9-tetrahydro- 1H-carbazol (Example 1a) was reacted with (R)-1-amino-propan-2-ol followed by reduction with NaBH4 to yield a mixture of (R)-2-[(2,3,4,9-tetrahydro-6-phenyl-1H-carbazol-(R)-1-

M1671.70000WO00 37/68 #13885233v1   yl)amino]-1-methyl-ethanol and (R)-2-[(2,3,4,9-tetrahydro-6-phenyl-1H-carbazol-(S)-1- yl)amino]-1-methyl-ethanol (Yield: 76% over two steps). Example 5b: Separation of the diastereomeric mixture of Example 5a [0140] Following the same procedure as described in Example 1c the mixture of the product of Example 5a was separated and purified to give (2R)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro- 1H-carbazol-1-yl]amino}propan-2-ol (C₂₁H₂₄N₂O) [0141] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.09 (d, 3H, J=6.2 Hz), 1.67–1.86 (m, 2H), 1.94–2.12 (m, 3H), 2.57–2.73 (m, 4H), 3.71–3.87 (m, 1H), 4.00–4.12 (m, 1H), 4.56– 4.80 (m, 1H), 7.24–7.31 (m, 1H), 7.32–7.47 (m, 4H), 7.61–7.70 (m, 3H), 10.88 (s, 1H) ppm. [0142] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.5, 20.7, 21.4, 28.5, 51.1, 53.2, 64.9, 111.5, 116.0, 120.2, 126.0, 126.6, 127.3, 128.7, 130.7, 135.5, 142.0 ppm. Example 6: -6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan- 2-ol [0143] The second fraction of the separation of the diastereomeric mixture of Example 5a is (2R)-1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol (C₂₁H₂₄N₂O). [0144] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.08 (d, 3H, J=6.2 Hz), 1.63–1.78 (m, 2H), 1.90–2.08 (m, 3H), 2.42–2.49 (m, 1H), 2.62–2.70 (m, 3H), 3.61–3.71 (m, 1H), 3.81– 3.89 (m, 1H), 4.49 (d, 1H, J=3.2 Hz), 7.24–7.30 (m, 1H), 7.31–7.45 (m, 4H), 7.61–7.67 (m, 3H), 10.79 (s, 1H) ppm [0145] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.7, 20.8, 21.4, 29.8, 51.9, 54.4, 66.1, 109.6, 111.3, 115.9, 119.8, 126.0, 126.6, 127.5, 128.7, 130.6, 135.5, 137.8, 142.1 ppm

M1671.70000WO00 38/68 #13885233v1   Example 7: -7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl] Example 7a: 2-[2-(4-bromophenyl)hydrazin-1-yl]cyclopentan-1-one (C₁₁H₁₁BrN₂O) [0146] A solution of 4-bromoaniline (7.36 g) in 20 mL concentrated HCl was diluted with 20 mL of water. It was then cooled to 0°C and a solution of NaNO₂ (3.54 g) in 10 mL of water was slowly added. The rm was stirred at 0°C for one hour and then slowly added to a cold solution (0°C) of 2-formylcyclopentanone and sodium acetate (7.0 g) in methanol (40 mL). After one hour the precipitate was collected by filtration, washed with water and recovered from ethanol to give the title product as a yellow solid (6.0 g, 52%). [0147] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.99 (p, 2H, J = 7.7 Hz), 2.33 (t, 2H, J = 7.7 Hz), 2.64 (t, 2H, J = 7.4 Hz), 7.18–7.23 (m, 2H), 7.41–7.46 (m, 2H), 10.01 (s, 1H) ppm [0148] ¹³C NMR spectrum: (100 MHz, DMSO-d₆, δ): 17.0, 26.1, 37.5, 112.5, 115.9, 131.8, 142.8, 143.7, 202.5 ppm Example 7b: 7-Bromo-1,4-dihydrocyclpenta[b]indol-3(2H)-one (C₁₁H₈BrNO) [0149] 2-Oxo-cyclopentane-(4-bromophenyl)-hydrazone (Example 7a, 5.80 g) was dissolved in a mixture of AcOH (30 mL) and HCl ( 20 mL) and refluxed for two hours. The rm was then cooled to rt and poured into ice water (50 mL). The precipitate was collected by filtration and purified by CC on silica gel (EtOAc : PE 1:2), then recovered from EtOH to obtain the title product as a yellowish solid (2.0 g; 37%). [0150] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 2.85–2.92 (m, 2H), 2.97–3.04 (m, 2H), 7.37–7.47 (m, 2H), 7.93–7.96 (m, 1H), 11.85 (s, 1H) ppm

M1671.70000WO00 39/68 #13885233v1   [0151] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 19.6, 40.5, 112.3, 115.7, 123.7, 124.5, 128.9, 140.0, 142.2, 144.2, 193.8 ppm [0152] Mass spectrum: M/Z: 251.94 [M+H]⁺ Example 7c: 7-Phenyl-1,4-dihydrocyclpenta[b]indol-3 -one (C17H13NO) [0153] To a solution of 7-Bromo-1,4-dihydrocyclpenta[b]indol-3(2H)-one (Example 7b, 1.0 g) in a 5:1 mixture of dioxane/water (48 mL) in a pressure tube phenylboronic acid (680 mg), K2CO3 (1.33 g) and Pd(PPh3)4 (0.42 g) were added. The rm was stirred under argon atmosphere at 80°C for 40 hours. The rm was then filtered through celite and evaporated to dryness. The crude product was dissolved in DCM (50 mL), the solution washed with water (30 mL) and brine (40 mL), dried over anhydrous Na2SO4 and evaporated. The product thus obtained was the purified by CC on silica gel (EtOAc : PE 1:2) and recovered from EtOH to give the title compound as a brownish solid (Yield: 65%). [0154] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 2.89–2.94 (m, 2H), 3.05–3.10 (m, 2H), 7.30–7.36 (m, 1H), 7.42–7.55 (m, 3H), 7.65–7.73 (m, 3H), 7.98–8.01 (m, 1H), 11.72 (s, 1H) ppm [0155] ¹³C NMR spectrum: (100 MHz, DMSO-d₆, δ): 19.7, 40.6, 114.1, 119.2, 123.5, 125.9, 126.7, 128.9, 132.4, 139.7, 140.9, 143.3, 145.6, 193.6 ppm [0156] Mass spectrum: M/Z: 248.1 [M+H]⁺ Example 7d: (2S)-1-[(7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)amino]propan-2-ol (C20H22N2O) [0157] Using the procedure as described in Example 1b, 7-phenyl-1,4- dihydrocyclpenta[b]indol-3(2H)-onewas reacted with (S)-1-amino-propan-2-ol followed by reduction with NaBH₄ to yield the title compound as a mixture of diastereomers (yellowish solid, Yield: 54% over two steps).

M1671.70000WO00 40/68 #13885233v1   [0158] ¹H NMR spectrum of the mixture of diastereomers: (400 MHz, DMSO-d6, δ): 1.06 (s, 3H), 1.08 (s, 3H), 1.90–1.98 (m, 2H), 2.12–2.23 (m, 2H), 2.54–2.78 (m, 6H), 2.80–2.90 (m, 2H), 3.62–3.72 (m, 2H), 4.24–4.31 (m, 2H), 4.44–4.48 (m, 2H), 7.24–7.45 (m, 10H), 7.60– 7.68 (m, 6H), 10.92 (s, 1H), 10.93 (s, 1H) [0159] ¹³C NMR spectrum of the mixture of diastereomers: (100 MHz, DMSO-d6, δ): 21.6, 21.7, 22.6, 36.6, 36.8, 54.5, 54.7, 56.9, 57.0, 65.8, 65.9, 112.3, 116.5, 118.4, 119.5, 124.3, 126.0, 126.6, 128.7, 131.0, 140.6, 142.0, 146.6, 146.7 ppm [0160] Mass spectrum: M/Z : 307.2 [M+H]⁺ Example 7e: Separation of the diastereomeric mixture of Example 7d. [0161] The diasteromers of the product of Example 7d were separated by chromatography on a chiralpak IG column (Eluent: 99% DCM, 1% IPA, 90% DCM, 0.1% 2-aminoethanol) as described in Example 1c to give (2S)-1-{[(3R)-7-phenyl-1,2,3,4- tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol Example 8: -7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl] [0162] The title compound was isolated from the product of Example 7d using the same procedure as described in Example 1c. [0163] ¹H NMR spectrum: (600 MHz, DMSO-d6, δ): 1.07 (d, 3H, J=6.2 Hz), 2.20-2.27 (m, 1H), 2.50-2.53 (m, 1H), 2.63-2.71 (m, 2H), 2.72-2.90 (m, 2H), 3.68-3.76 (m, 1H), 4.33-4.40 (m, 1H), 4.62 (br s, 1H), 7.25-7.30 (m, 1H), 7.32-7.36 (m, 1H), 7.37-7.45 (m, 3H), 7.61-7.67 (m, 3H), 11.05 (s, 1H) ppm. [0164] ¹³C NMR spectrum: (150 MHz, DMSO-d6, δ): 21.6, 22.5, 36.0, 53.9, 56.7, 65.3, 112.4, 116.6, 119.2, 119.7, 124.2, 126.1, 126.6, 128.7, 131.0, 140.7, 141.9, 145.3 ppm [0165] Mass spectrum: M/Z : 307.20 [M+H]⁺

M1671.70000WO00 41/68 #13885233v1   Example 9: 2-{[(1R)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1- yl]amino}ethan-1-ol (MO-072) Example 9a: 2-[2-(4-bromo-2-methylphenyl)hydrazinylidene]cyclohexan-1-one [0166] Using the procedure described in Example 7a the title compound was prepared from 2-formylcyclohexanone and 4-bromo-2-methyl-aniline. The yield of the product was 74%. [0167] Mass spectrum: M/Z: 295.2/297.2 [M+H]⁺ Example 9b: 6-bromo-8-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one [0168] Using the same method as described in Example 7b the title compound was obtained as a yellowish solid (Yield:35%). [0169] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 2.13 (p, 2H, J = 6.1 Hz), 2.47 (s, 3H), 2.54–2.59 (m, 2H), 2.91 (t, 2H, J = 6.1 Hz), 7.21–7.23 (m, 1H), 7.68–7.71 (m, 1H), 11.72 (s, 1H) ppm [0170] ¹³C NMR spectrum: (100 MHz, DMSO-d₆, δ): 16.7, 20.8, 24.5, 38.3, 112.1, 120.7, 125.2, 126.6, 127.8, 128.5, 132.1, 136.3, 190.5 ppm [0171] Mass spectrum: M/Z: 278.1/280.1 [M+H]⁺

M1671.70000WO00 42/68 #13885233v1   Example 9c: 8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-one [0172] The title compound was synthesized following the procedure as described in Example 1a. After recovery from ethanol the reaction product was isolated as a yellowish solid (Yield: 53%) [0173] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ):2.16 (p, 2H, J = 6.1 Hz), 2.55 (s, 3H), 2.56–2.61 (m, 2H), 3.00 (t, 2H, J = 6.1 Hz), 7.28–7.34 (m, 1H), 7.41–7.47 (m, 3H), 7.67–7.71 (m, 2H), 7.74–7.77 (m, 1H), 11.58 (s, 1H) ppm [0174] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 17.1, 21.0, 24.7, 38.3, 116.4, 122.9, 125.9, 126.0, 126.5, 126.7, 128.8, 129.0, 131.9, 132.4, 137.3, 141.1, 190.3 ppm [0175] Mass spectrum: M/Z: 276.3 [M+H]⁺   Example 9d: 2-[(8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]ethan-1-ol [0176] Using the procedure as described in Example 1b the racemic title compound was obtained in two reaction steps as a white solid (Yield 59%). [0177] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.66–1.81 (m, 2H), 1.92–2.02 (m, 2H), 2.52 (s, 3H), 2.61–2.81 (m, 4H), 3.46–3.58 (m, 2H), 3.87–3.93 (m, 1H), 4.47–4.60 (m, 1H), 7.14–7.17 (m, 1H), 7.23–7.29 (m, 1H), 7.38–7.44 (m, 2H), 7.45–7.47 (m, 1H), 7.62–7.67 (m, 2H), 10.60 (s, 1H) ppm [0178] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 17.1, 20.3, 21.0, 29.2, 48.6, 51.1, 61.0, 110.3, 113.6, 120.4, 120.6, 125.9, 126.6, 127.1, 128.7, 130.8, 135.0, 137.5, 142.2 ppm [0179] Mass spectrum: M/Z : 321.1 [M+H]⁺

M1671.70000WO00 43/68 #13885233v1   Example 9e: 2-{[(1R)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan- 1-ol [0180] The enantiomers of Example 9d were separated by chromatography on a chiralpak IG column (Eluent: 99% DCM, 1% IPA, 90% DCM, 0.1% aminoethanol). The title compound is fraction A (white solid). [0181] ¹H NMR spectrum: (600 MHz, DMSO-d₆, δ): 1.66-1.80 (m, 2H), 1.92-2.01 (m, 2H), 2.01-2.12 (m,1H), 2.51 (s, 3H), 2.58-2.80 (m, 4H), 3.46-3.56 (m, 2H), 3.86-3.93 (m, 1H), 4.49-4.56 (m, 1H), 7.15 (s, 1H), 7.23-7.28 (m, 1H), 7.38-7.43 (m, 2H), 7.45 (s, 1H), 7.61- 7.66 (m, 2H), 10.60 (s, 1H) ppm [0182] ¹³C NMR spectrum: (150 MHz, DMSO-d₆, δ): 17.1, 20.3, 20.9, 29.2, 48.6, 51.1, 61.0, 110.3, 113.6, 120.3, 120.6, 125.9, 126.5, 127.1, 128.7, 130.8, 134.9, 137.5, 142.2 ppm [0183] Mass spectrum: M/Z : 321.23 [M+H]⁺ Example 10: 2-{[(1S)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1- yl] [0184] The title compound was obtained as fraction B of the chromatograhic separation of the enantiomers of Example 9d (white solid). [0185] ¹H NMR spectrum: (600 MHz, DMSO-d₆, δ): 1.66-1.80 (m, 2H), 1.92-2.01 (m, 2H), 2.01-2.12 (m,1H), 2.51 (s, 3H), 2.58-2.80 (m, 4H), 3.46-3.56 (m, 2H), 3.86-3.93 (m, 1H), 4.49-4.56 (m, 1H), 7.15 (s, 1H), 7.23-7.28 (m, 1H), 7.38-7.43 (m, 2H), 7.45 (s, 1H), 7.61- 7.66 (m, 2H), 10.60 (s, 1H) ppm [0186] ¹³C NMR spectrum: (150 MHz, DMSO-d6, δ): 17.1, 20.3, 20.9, 29.2, 48.6, 51.1, 61.0, 110.3, 113.6, 120.3, 120.6, 125.9, 126.5, 127.1, 128.7, 130.8, 134.9, 137.5, 142.2 ppm [0187] Mass spectrum: M/Z : 321.23 [M+H]⁺

M1671.70000WO00 44/68 #13885233v1   Example 11: -5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl] 075) Example 11a: 2-[2-(4-bromo-2-methylphenyl)hydrazinylidene]cyclopentan-1-one [0188] Using the method as described in Example 7a the title hydrazone derivative was obtained after recovery from ethanol as an orange solid in a yield of 38%. [0189] Mass spectrum: M/Z: 283.05, 282.32 [M+H]⁺ Example 11b: 7-bromo-5-methyl-1,4- 3(2H)-one [0190] Following the procedure as described in Example 7b the title ketone was obtained as a yellowish solid in a yield of 39%. [0191] ¹H NMR spectrum: (600 MHz, DMSO-d6, δ): 2.46 (s, 3H), 2.87–2.91 (m, 2H), 2.98– 3.01 (m, 2H), 7.28 (s, 1H), 7.76 (s, 1H), 11.81 (s, 1H) ppm [0192] ¹³C NMR spectrum: (150 MHz, DMSO-d₆, δ): 16.5, 19.6, 40.5, 112.3, 121.0, 124.1, 125.9, 128.7, 139.8, 142.0, 144.7, 193.8 ppm Example 11c: 5-methyl-7-phenyl-1,4-dihydrocyclopenta[b]indol-3(2H)-one

M1671.70000WO00 45/68 #13885233v1   [0193] The C-C-coupling reaction as described in Example 1a gave the title compound in a yield of 47% after recovery from ethanol as a yellowish solid. [0194] ¹H NMR spectrum: (600 MHz, DMSO-d₆, δ): 2.54 (s, 3H), 2.91–2.93 (m, 2H), 3.06- 3.08 (m, 2H), 7.31–7.33 (m, 1H), 7.43–7.46 (m, 2H), 7.48-7.49 (m, 1H), 7.69–7.71 (m, 1H), 7.81-7.83 (m, 1H), 11.67 (s, 1H) ppm [0195] ¹³C NMR spectrum: (150 MHz, DMSO-d₆, δ): 17.0, 19.7, 40.6, 116.6, 123.3, 123.6, 126.1, 126.6, 126.7, 128.8, 132.5, 139.5, 141.0, 143.0, 146.1, 193.7 ppm Example 11d: (2S)-1-[(5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)amino]propan-2-ol [0196] Following the procedure as described in Example 1b the product of Example 11c was reacted with (S)-1-amino-2-hydroxypropane. In a second step the resulting imino compound was reduced with NaBH₄ in a mixture of methanol and THF. The title compound was obtained as a light brown solid (Yield: 46% over two steps). [0197] ¹H NMR spectrum for the mixture of diastereomers: (600 MHz, CDCl3, δ): 1.18-1.21 (m, 3H), 2.20-2.33 (m, 1H), 2.52 and 2.54 (s, 3H), 2.72–3.0 (m, 6H), 3.76-3.81 and 3.91-3.96 (m, 1H), 4.43–4.47 (m, 1H), 7.22–7.23 (m, 1H), 7.28-7.31 (m, 1H), 7.41-7.43 (m, 1H), 7.54- 7.55 (m, 1H), 7.63-7.65 (m, 2H), 8.49 and 8.65 (s, 1H) ppm [0198] ¹³C NMR spectrum for the mixture of diastereomers: (150 MHz, CDCl₃, δ): 17.0, 17.1, 20.9, 23.0, 23.2, 36.7, 36.8, 53.7, 53.8, 57.5, 58.0, 66.0, 66.6, 113.6, 121.3, 121.7, 121.8, 122.3, 124.3, 126.3, 127.5, 128.7, 133.5, 133.6, 140.4, 142.9, 143.7 ppm Example 11e: (2S)-1- -5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-

M1671.70000WO00 46/68 #13885233v1   [0199] The diastereomers of the product of Example 11d were separated according to the procedure described in Example 1c. The title compound is fraction A of the column chromatography (white solid). [0200] ¹H NMR spectrum: (600 MHz, CDCl3, δ): 1.21 (d, 3H, J=6.2 Hz), 2.17-2.24 (m, 1H), 2.51 (s, 3H), 2.55-2.60 (m, 1H), 2.72-2.89 (m, 4H), 3.90-3.96 (m, 1H), 4.39-4.44 (m, 1H), 7.21-7.23 (m, 1H), 7.27-7.31 (m, 1H), 7.40-7.45 (m, 2H), 7.52-7.55 (m, 1H), 7.62-7.66 (m, 2H), 8.58 (s, 1H) ppm [0201] ¹³C NMR spectrum: (150 MHz, CDCl3, δ): 17.0, 20.9, 22.9, 37.1, 54.0, 57.5, 66.3, 115.6, 121.2, 121.5, 122.2, 124.4, 126.3, 127.5, 128.7, 133.5, 140.4, 142.9, 144.2 ppm [0202] Mass spectrum: M/Z : 321.23 [M+H]⁺ Example 12: methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl] [0203] Fraction B of the separation of the product of Example 11d is (2S)-1-{[(3S)-5-methyl- 7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol (white solid). [0204] ¹H NMR spectrum: (600 MHz, CDCl₃, δ): 1.20 (d, 3H, J=6.2 Hz), 2.25-2.33 (m, 1H), 2.46-2.52 (m, 1H), 2.54 (s, 3H), 2.76-2.98 (m, 4H), 3.75-3.81 (m, 1H), 4.42-4.47 (m, 1H), 7.22-7.24 (m, 1H), 7.27-7.32 (m, 1H), 7.40-7.44 (m, 2H), 7.54-7.56 (m, 1H), 7.62-7.66 (m, 2H), 8.42 (s, 1H) ppm. [0205] ¹³C NMR spectrum: (150 MHz, CDCl3, δ): 17.1, 21.0, 23.2, 37.1, 53.9, 58.1, 66.8, 115.6, 121.2, 121.6, 122.2, 124.4, 126.3, 127.5, 128.7, 133.6, 140.4, 142.9, 144.2 ppm [0206] Mass spectrum: M/Z: 321.23 [M+H]⁺ Example 13: 2-[(8-chloro-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]ethan-1- ol

M1671.70000WO00 47/68 #13885233v1   Example 13a: 2-[2-(4-bromo-2-chlorophenyl)hydrazinylidene]cyclohexan-1-one [0207] Following the procedure as described in Example 7a the title compound was prepared from 2-formylcyclohexanone and 4-bromo-2-chloroanoline. The compund was purified by recovery from ethanol. (light brown sold, yield: 54%) [0208] Mass spectrum: M/Z: 315.41 [M+H]⁺ Example 13b: 6-bromo-8-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one [0209] Using the procedure as described in Example 7b this compound was obtained as a brownish solid in a yield of 40%. [0210] ¹H NMR spectrum: (600 MHz, DMSO-d6, δ): 2.13-2.17 (m, 2H), 2.58–2.61 (m, 2H), 2.92-2.96 (m, 2H), 7.56–7.57 (m, 1H), 7.92–7.93 (m, 1H), 12.18 (s, 1H) ppm [0211] ¹³C NMR spectrum: (150 MHz, DMSO-d₆, δ): 21.2, 24.8, 38.8, 111.9, 118.9, 123.1, 127.9, 128.7, 128.8, 155.6, 134.4, 191.0 ppm Example 13c: 8-chloro-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-one [0212] The title compound was prepared following the procedure described in Example 7c and purified by chromatography on silica gel (EtOAc : PE; 1:2) (dark orange solid, yield: 48%). [0213] ¹H NMR spectrum: (600 MHz, DMSO-d₆, δ): 2.17-2.21 (m, 2H), 2.59–2.63 (m, 2H), 3.01-3.05 (m, 2H), 7.35–7.37 (m, 1H), 7.45-7.49 (m, 2H), 7.70-7.72 (m, 1H), 7.73-7.75 (m, 2H), 7.95–7.97 (m, 1H), 12.01 (s, 1H) ppm

M1671.70000WO00 48/68 #13885233v1   [0214] ¹³C NMR spectrum: (150 MHz, DMSO-d6, δ): 21.4, 24.9, 38.9, 118.2, 118.5, 125.2, 127.3, 127.6, 128.2, 129.4, 129.9, 133.3, 133.8, 134.9, 140.1, 190.9 ppm Example 13d: 2-[(8-chloro-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]ethan-1-ol [0215] The title compound was prepared using the procedure as described in Example 1b. [0216] (yellowish solid, yield: 66% over two steps). [0217] ¹H NMR spectrum: (600 MHz, DMSO-d6, δ): 1.66-1.79 (m, 2H), 1.90-2.02 (m, 2H), 2.12-2.21 (m, 1H), 2.59-2.78 (m, 4H), 3.44-3.56 (m, 2H), 3.88-3.95 (m, 1H), 4.55 (br s, 1H), 7.29-7.33 (m, 1H), 7.40 (d, 1H, J=1.6 Hz), 7.41-7.46 (m, 2H), 7.62 (d, 1H, J=1.6 Hz), 7.66- 7.70 (m, 2H), 11.06 (s, 1H) ppm [0218] ¹³C NMR spectrum: (150 MHz, DMSO-d6, δ): 20.1, 20.8, 28.9, 48.5, 50.8, 61.0, 111.3, 115.0, 115.9, 119.1, 126.6, 126.7, 128.8, 129.2, 132.0, 132.1, 139.3, 140.6 ppm [0219] Mass spectrum: M/Z: 341.19 [M+H]⁺ Example 14: chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl] Example 14a: 2-[2-(4-bromo-2-chlorophenyl)hydrazinylidene]cyclopentan-1-one [0220] Following the procedure as described in Example 7a the title compound was prepared from 2-formylcyclopentanone and 4-bromo-2-chloroanoline. The compound was purified by recovery from ethanol (Yield: 53%). [0221] Mass spectrum: M/Z: 301.01, 303.01 [M+H]⁺

M1671.70000WO00 49/68 #13885233v1   Example 14b: 7-bromo-5-chloro-1,4-dihydrocyclopenta[b]indol-3(2H)-one [0222] Using the procedure as described in Example 7b this compound was obtained after recovery from silica gel (EtOAc : PE; 2:3) as a yellowish solid (Yield: 19%). [0223] ¹H NMR spectrum: (600 MHz, DMSO-d₆, δ): 2.91–2.93 (m, 2H), 3.01–3.02 (m, 2H), 7.61 (s, 1H), 7.97 (s, 1H), 12.27 (s, 1H) ppm [0224] ¹³C NMR spectrum: (150 MHz, DMSO-d₆, δ): 19.6, 40.6, 111.7, 118.7, 122.9, 125.7, 127.6, 139.3, 140.9, 144.9, 193.8 ppm Example 14c: 5-chloro-7-phenyl-1,4-dihydrocyclopenta[b]indol-3 -one [0225] The title compound was prepared following the procedure described in Example 7c and purified by chromatography on silica gel (methanol : DCM; 1:3) (Yield: 77%). [0226] ¹H NMR spectrum: (600 MHz, DMSO-d₆, δ): 2.93–2.95 (m, 2H), 3.08-3.10 (m, 2H), 7.34–7.37 (m, 1H), 7.45–7.48 (m, 2H), 7.73-7.75 (m, 3H), 8.01-8.02 (m, 1H), 12.12 (s, 1H) ppm [0227] ¹³C NMR spectrum: (150 MHz, DMSO-d₆, δ): 20.2, 41.2, 118.1, 118.2, 124.7, 125.2, 126.8, 127.2, 129.0, Example 14d: (2S)-1-[(5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)amino]propan-2-ol [0228] Under an argon atmosphere the product of Example 14c (1.42 mmol) was dissolved in MeOH/THF (7:1) (32 mL), cooled to 0 °C and NaBH4 (161 mg, 4.26 mmol, 3 equiv.) was added. The reaction mixture was stirred at rt and monitored with TLC. After completion of

M1671.70000WO00 50/68 #13885233v1   reaction (approximately 4 h) water (2 mL) was added and reaction mixture was evopared. DCM (90 mL) was added, the solution washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over anh. Na₂SO₄, filtered, and then evaporated to dryness. The crude product was purified by CC on silica gel, DCM:MeOH (5:1) to give the title compound as a yellow solid 262 mg (54% over 2 steps). [0229] ¹H NMR spectrum for the mixture of diastereomers: (600 MHz, CDCl₃, δ): 1.06-1.08 (m, 3H), 2.19-2.24 (m, 1H), 2.42-2.45 and 2.57-2.60 (m, 1H), 2.52-2.55 (m, 1H), 2.67–2.76 (m, 2H), 2.84-2.89 (m, 1H), 3.65-3.72 (m, 1H), 4.30–4.37 (m, 1H), 4.51-4.58 (m, 1H), 7.30- 7.33 (m, 1H), 7.40-7.41 (m, 1H), 7.42–7.45 (m, 2H), 7.63-7.64 (m, 1H), 7.67-7.69 (m, 2H), 11.24 and 11.27 (s, 1H) ppm [0230] ¹³C NMR spectrum for the mixture of diastereomers: (150 MHz, CDCl3, δ): 21.5, 21.6, 22.6, 22.7, 36.1, 36.3, 53.8, 54.4, 56.4, 56.8, 115.6, 116.3, 118.8, 120.1, 126.0, 126.6, 126.8, 128.8, 132.4, 136.8, 136.9, 140.5, 147.3 ppm Separation of the diastereomeric mixture of Example 14d [0231] Following the same procedure as described in Example 1c the mixture of the product of Example 14d was separated and purified to give (2S)-1-{[(3S)-5-chloro-7-phenyl-1,2,3,4- tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol. [0232] ¹H NMR spectrum: (600 MHz, CDCl₃, δ): 1.23 (d, 3H, J=6.2 Hz), 2.16-2.25 (m, 1H), 2.50-2.65 (m, 1H), 2.61-2.87 (m, 4H), 3.91-3.98 (m, 1H), 4.38-4.43 (m, 1H), 7.30-7.34 (m, 1H), 7.40-7.46 (m, 3H), 7.54-7.56 (m, 1H), 7.59-7.63 (m, 2H), 8.97 (s, 1H) ppm [0233] ¹³C NMR spectrum: (150 MHz, CDCl₃, δ): 20.9, 22.8, 37.0, 54.1, 57.4, 66.4, 116.5, 117.1, 120.6, 122.0, 126.1, 126.9, 127.4, 128.9, 134.3, 137.6, 141.6, 145.6 ppm [0234] Mass spectrum: M/Z: 341.15 [M+H]⁺ Example 15: -5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl] [0235] The second fraction of the separation of the product of Example 14d is (2S)-1-{[(3R)- 5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol.

M1671.70000WO00 51/68 #13885233v1   [0236] ¹H NMR spectrum: (600 MHz, CDCl3, δ): 1.22 (d, 3H, J=6.2 Hz), 2.26-2.33 (m, 1H), 2.48-2.54 (m, 1H), 2.75-2.98 (m, 4H), 3.77-3.83 (m, 1H), 4.43-4.48 (m, 1H), 7.30-7.34 (m, 1H), 7.40-7.46 (m, 3H), 7.57-7.59 (m, 1H), 7.59-7.64 (m, 2H), 8.72 (s, 1H) ppm [0237] ¹³C NMR spectrum: (150 MHz, CDCl3, δ): 20.9, 23.1, 37.1, 54.1, 57.9, 66.9, 116.5, 117.1, 120.6, 122.1, 126.1, 126.9, 127.4, 128.9, 134.4, 137.6, 141.6, 145.3 ppm Example 16: (1R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1- 1- [0238] Using the procedure as described in Example 1b, 1-oxo-6-phenyl-2,3,4,9-tetrahydro- 1H-carbazol (Example 1a) was reacted with (R)-2-amino-1-phenylethan-1-ol followed by reduction with NaBH₄ to yield a mixture of (1R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}-1-phenylethan-1-ol and (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}-1-phenylethan-1-ol as a yellowish solid (Yield: 83% over two steps). [0239] The isomers of this mixture were separated by chiral chromatography (Column: Chiralpak IE, eluent: 5% IPA, 25% Heptane, 70% DCM, 0.1% Et₃N) to obtain the title compound as the first fraction (Fraction A, white solid). [0240] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.65–1.77 (m, 2H), 1.90–2.15 (m, 3H), 2.62–2.68 (m, 2H), 2.71–2.85 (m, 2H), 3.92–3.98 (m, 1H), 4.65–4.71 (m, 1H), 5.24–5.28 (m, 1H), 7.20–7.45 (m, 10H), 7.61–7.67 (m, 3H), 10.76 (s, 1H) ppm [0241] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.7, 20.8, 29.5, 50.8, 54.4, 71.9, 109.9, 111.4, 115.9, 119.9, 125.9, 126.0, 126.6, 126.8, 127.4, 128.0, 128.7, 130.6, 135.5, 137.6, 142.1, 144.4 ppm [0242] Mass spectrum: M/Z : 383.2 [M⁺H]⁺ Example 17: (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1- phenylethan-1-ol [0243] The second fraction (Fraction B) of the chromatographic separation of the diastereomeric mixture (Example 16) is (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}-1-phenylethan-1-ol (white solid):

M1671.70000WO00 52/68 #13885233v1   [0244] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.65–1.76 (m, 2H), 1.90–2.15 (m, 3H), 2.62–2.72 (m, 3H), 2.86–2.93 (m, 1H), 3.86–3.92 (m, 1H), 4.59–4.66 (m, 1H), 5.24–5.28 (m, 1H), 7.21–7.46 (m, 10H), 7.61–7.68 (m, 3H), 10.83 (br, s, 1H) ppm [0245] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.5, 20.7, 29.9, 51.8, 55.2, 72.6, 109.7, 111.3, 115.9, 119.9, 125.9, 126.0, 126.6, 126.8, 127.4, 128.0, 128.7, 130.6, 135.5, 137.7, 142.1, 144.3 ppm [0246] Mass spectrum: M/Z : 383.2 [M⁺H]⁺ Example 18: (1S)-2-{[ 6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1- 1- [0247] Using the procedure as described in Example 1b, 1-oxo-6-phenyl-2,3,4,9-tetrahydro- 1H-carbazol (Example 1a) was reacted with (S)-2-amino-1-phenylethan-1-ol followed by reduction with NaBH₄ to yield a mixture of (1S)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}-1-phenylethan-1-ol and (1S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}-1-phenylethan-1-ol as a yellowish solid (Yield: 92%over two steps). [0248] The isomers of this mixture were separated by chiral chromatography (Column: Chiralpak IE, eluent: 5% IPA, 25% Heptane, 70% DCM, 0.1% Et3N) to obtain the title compound as the first fraction (Fraction A, white solid). [0249] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.65–1.77 (m, 2H), 1.90–2.15 (m, 3H), 2.62–2.68 (m, 2H), 2.71–2.85 (m, 2H), 3.92–3.98 (m, 1H), 4.65–4.71 (m, 1H), 5.24–5.28 (m, 1H), 7.20–7.45 (m, 10H), 7.61–7.67 (m, 3H), 10.76 (br, s, 1H) ppm [0250] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.7, 20.8, 29.5, 50.8, 54.4, 71.9, 109.9, 111.4, 115.9, 119.9, 125.9, 126.0, 126.6, 126.8, 127.4, 128.0, 128.7, 130.6, 135.5, 137.6, 142.1, 144.4 ppm

M1671.70000WO00 53/68 #13885233v1   [0251] Mass spectrum: M/Z : 383.2 [M⁺H]⁺ Example 19: phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1- [0252] The second fraction (Fraction B) of the chromatographic separation of the diastereomeric mixture of Example 18 is (1S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H- carbazol-1-yl]amino}-1-phenylethan-1-ol (white solid). [0253] ¹H NMR spectrum: (400 MHz, DMSO-d6, δ): 1.65–1.76 (m, 2H), 1.90–2.15 (m, 3H), 2.62–2.72 (m, 3H), 2.86–2.93 (m, 1H), 3.86–3.92 (m, 1H), 4.59–4.66 (m, 1H), 5.24–5.28 (m, 1H), 7.21–7.46 (m, 10H), 7.61–7.68 (m, 3H), 10.83 (br, s, 1H) ppm [0254] ¹³C NMR spectrum: (100 MHz, DMSO-d6, δ): 20.5, 20.7, 29.9, 51.8, 55.2, 72.6, 109.7, 111.3, 115.9, 119.9, 125.9, 126.0, 126.6, 126.8, 127.4, 128.0, 128.7, 130.6, 135.5, 137.7, 142.1, 144.3 ppm [0255] Mass spectrum: M/Z : 383.2 [M⁺H]⁺ Example 20: Pharmacological Activity of the Compounds [0256] The Cdc42 inhibitory activities of the compounds were assessed using a trans-well migration assay to determine the activity on the migration of 32D cells (CytoSelect 96-Well Cell Migration Assay) (3µM, Fluorometric Format, Cell Biolabs, Inc., San Diego). The migration was induced by the chemokine SDF-1alpha. The intracellular target was Cdc42 that modifies the actin network and the ability to perform directed/polar migration towards the chemokine. [0257] 32D cells were cultivated in the cell culture medium RPMI 1640, 10% heat- inactivated fetal bovine serum (FBS), 1% Pen/Strep (penicillin/streptomycin mixture of antibiotics) and 20 ng/ml murine interleukin 3 (IL-3). 2x10532D cells in 100 µL medium were transferred into the upper 96 well membrane plate (3 µm pore) in RPMI 1640, 0.5% bovine serum albumine (BSA) and 2 mM CaCl₂ and 2 mM MgCl₂. The test compound was added for 15 min at 37°C prior to transfer of the cells to the membrane plate. The membrane

M1671.70000WO00 54/68 #13885233v1   plate was set on top of the 96 well migration plate, in which the wells were filled with 150 µL RPMI 1640, 10% FBS and 100 ng/mL SDF-1alpha. [0258] The plate sandwich was then kept 5 h at 37°C, 5% CO₂. Subsequently, the membrane plate was removed, the cells in medium resuspended and 100 µL medium per well transferred to an analysis plate with 33.3 µL 4XLysis Buffer/CyQuant® GR Dye and incubated for 20 min. After that the 485nm/530nm ratio in a fluorescent cell reader was determined. Each datapoint was the mean out of 3 technical repeats (3 wells on one plate). Data per plate was normalized to the number of cells that migrated without any inhibition present on each plate, set to one. Each compound was analyzed with at least 3 biological repeats to result in 3 datapoints or more. [0259] The biological activities of the following compounds were determined as described above. [0260] CASIN is commercially available from a variety of vendors, e.g. Sigma-Aldrich, ABCR, MedChem Express, Aurora Fine Chemicals, BIONET-Key Organics. [0261] Table 1 shows the results of the cell migration assay. The numbers in the table are the % decrease of cell migration after treatment with solutions of the compounds with concentrations of 3.3 µM and 10 µM, compared to the migration of untreated cells. Table 1: Results of Cell Migration Assay of Example 20

M1671.70000WO00 55/68 #13885233v1   [0262] The data show that the compounds of the present disclosure are comparable or better inhibitors of Cdc42 than CASIN at the same concentration as determined by cell migration assay. [0263] Additionally, compounds of the present disclosure demonstrated repolarization of murine hematopoietic stem cells (HSCs) that have lost polarity due to age (FIG.1, left panel). CASIN is able to repolarize the HSCs dose dependently, showing the best effect at a concentration of 10 µM (FIG.1, right panel). Both molecules MO-072 (Product of Example 9), and MO-075 (Product of Example 11) were able to achieve the same level of repolarization as with CASIN, but with a lower concentration of 3.3 µM (FIG.1, middle panel). These data show that compounds of the present disclosure possess improved properties compared to CASIN for repolarizing HSCs. References [0264] Xiao, X.-H. et al., Molecules 23, 787 (2018). [0265] Nguyen, P., et al., Frontiers in Oncology 9 (2019). [0266] Grigoryan, A., et al., Genome Biol 19, 189 (2018). [0267] Kared H, et al., Nat Commun.11(1), 821 (2020). [0268] Liu, W. et al., Blood, 112, 68 (2008). [0269] Liu, W., et al., Leukemia, 33, 749-761 (2019). [0270] Montserrat-Vazquez S, et al., NPJ Regen Med.7(1), 78 (2022). [0271] Leins H, et al., Blood 132(6), 565-576 (2018). [0272] Grockowiak, E., et al., Nat Cancer 4, 1193-1209 (2023). [0273] Wu, L., et al., Nat Commun 12, 6936 (2021). [0274] Tiwari RL, et al., Aging (Albany NY) 13(4), 4778-4793 (2021). [0275] Kalim KW, et al., Journal for ImmunoTherapy of Cancer 10, e004806 (2022). [0276] Du W, et al., Leukemia 32(9), 2041-2046 (2018). [0277] Nguyen P, et al., Front. Oncol.9, 958 (2019).

M1671.70000WO00 56/68 #13885233v1

Claims

  Claims 1. A compound of Formula (II) Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: n is 1 or 2; R¹ is H or optionally substituted C₁-C₃-alkyl; R² is H, optionally substituted C1-C3-alkyl, or optionally substituted phenyl; R³ is phenyl optionally substituted with optionally substituted C1-C3-alkyl, optionally substituted benzyl, halogen, optionally substituted 2-methoxyethyl, optionally substituted 2- methoxyethyloxy, optionally substituted methoxy, optionally substituted phenyloxy, optionally substituted methoxycarbonyl, optionally substituted ethoxycarbonyl, optionally substituted hydroxycarbonyl, or optionally substituted 4-tetrahydropyranyl, or R³ is phenyl fused with optionally substituted 5-6 membered heterocyclyl; R⁴ is H, optionally substituted C1-C3-alkyl, optionally substituted phenyl, halogen, cyano, trifluoromethyl, optionally substituted methoxy, or trifluoromethoxy; R⁵ is H, optionally substituted C₁-C₃-alkyl, optionally substituted benzyl, optionally substituted C1-C6-alkylcarbonyl, optionally substituted benzoyl, optionally substituted benzylcarbonyl, optionally substituted C1-C6-alkylaminocarbonyl, optionally substituted C1- C₆-dialkylaminocarbonyl, optionally substituted C₁-C₆-alkyloxycarbonyl, optionally substituted benzyloxycarbonyl, or optionally substituted phenyloxycarbonyl; R⁶ is H or optionally substituted C1-C3-alkyl; and R⁷ is H or optionally substituted C₁-C₃-alkyl; provided that the compound of Formula (II) is not of formula: ,

M1671.70000WO00 57/68 #13885233v1   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: n is 1 or 2; R¹ is H or C1-C3-alkyl; R² is H, C₁-C₃-alkyl, or phenyl; R³ is phenyl optionally substituted with methyl, ethyl, benzyl, fluorine, chlorine, 2- methoxyethyl, 2-methoxyethyloxy, methoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, or 4-tetrahydropyranyl; R⁴ is H or methyl, ethyl, propyl, phenyl, chlorine, bromine, cyano, trifluoromethyl, methoxy, or trifluoromethoxy; R⁵ is H, C1-C3-alkyl, benzyl, C1-C6-alkylcarbonyl, benzoyl, benzylcarbonyl, C1-C6- alkylaminocarbonyl, C₁-C₆-dialkylaminocarbonyl, C₁-C₆-alkyloxycarbonyl, benzyloxycarbonyl, or phenyloxycarbonyl; R⁶ is H or C1-C3-alkyl; and R⁷ is H or C₁-C₃-alkyl. 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ is H or methyl. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R² is H, methyl or phenyl. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R³ is phenyl.

M1671.70000WO00 58/68 #13885233v1   6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R⁴ is H, methyl or chlorine. 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R⁵ is H. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n is 1. 9. The compound of claim 1 or claim 2, wherein the compound is of Formulae (II-a) or (II-b): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 10. The compound of any one of claims 1, 2, or 9, wherein the compound is of Formulae (II- c) to (II-f): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

M1671.70000WO00 59/68 #13885233v1   11. The compound of any one of claims 1, 2, 9, or 10, wherein the compound is of Formulae (II-g) to (II-j): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 12. The compound of any one of claims 1, 2, or 9-11, wherein the compound is of Formulae

M1671.70000WO00 60/68 #13885233v1   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 13. The compound of claim 1 or claim 2, wherein the compound is of Formulae (II-k) to (II- n): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 14. The compound of any one of claims 1, 2, or 13, wherein the compound is of Formulae (II- o) to (II-r): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

M1671.70000WO00 61/68 #13885233v1   15. The compound of any one of claims 1, 2, 9, or 10, wherein the compound of Formula (II) is of Formulae (II-s) or (II-t): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 16. The compound of any one of claims 1, 2, 9, 10, or 15, wherein the compound of Formula (II) is of Formulae (II-s-1) to (II-s-4) or (II-t-1) to (II-t-4): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

M1671.70000WO00 62/68 #13885233v1   17. The compound of any one of claims 1-7 that is selected from the group consisting of : (2S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol; (2R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-1-ol; (2S)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2S)-1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2R)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2R)-1-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2S)-1-{[(3R)-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; (2S)-1-{[(3S)-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 2-{[(1R)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; 2-{[(1S)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; (2S)-1-{[(3R)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; (2S)-1-{[(3S)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; 2-[(8-chloro-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]ethan-1-ol; (2S)-1-{[(3S)-5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; (2S)-1-{[(3R)-5-chloro-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; (1R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 18. The compound of any one of claims 1-7 that is selected from the group consisting of: (2S)-1-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}propan-2-ol; (2S)-1-{[(3R)-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]amino}propan-2-ol; 2-{[(1R)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; 2-{[(1S)-8-methyl-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}ethan-1-ol; (2S)-1-{[(3R)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol;

M1671.70000WO00 63/68 #13885233v1   (2S)-1-{[(3S)-5-methyl-7-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl]amino}propan-2-ol; or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 19. The compound of any one of claims 1-7 that is selected from the group consisting of: (1R)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1R)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1R)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; (1S)-2-{[(1S)-6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl]amino}-1-phenylethan-1-ol; and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. 20. A pharmaceutical composition comprising the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient. 21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20, for use as a medicament. 22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20, for use in the treatment of a disease. 23. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20.

M1671.70000WO00 64/68 #13885233v1   24. The use or method of any one of claims 21-23, wherein the disease is a malignant neoplastic disease. 25. The use or method of any one of claims 21-24, wherein the disease is colon cancer or pancreatic cancer. 26. The use or method of any one of claims 21-23, wherein the disease is a hematologic cancer. 27. The use or method of any one of claims 21-23 or 26, wherein the disease is a myeloproliferative neoplasm, multiple myeloma, or acute lymphoid leukemia. 28. The use or method of any one of claims 21-23, wherein the disease is alopecia. 29. A method of modulating the immune system in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20. 30. A method of inhibiting a GTPase in a subject in need thereof or in a cell, tissue, or biological sample, the method comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20. 31. The method of claim 30, wherein the GTPase is cell division control protein 42 homolog (Cdc42). 32. A method of enhancing immune response to a vaccine in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled

M1671.70000WO00 65/68 #13885233v1   compound, or prodrug thereof, or the pharmaceutical composition of claim 20; and administering to the subject in need thereof the vaccine. 33. A method of promoting hematopoietic stem cell (HSC) engraftment in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20. 34. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20. 35. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20. 36. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20. 37. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with an effective amount of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20.

M1671.70000WO00 66/68 #13885233v1   38. The method of any one of claims 34-37, wherein the cell, tissue, or organ is within a subject. 39. The method of any one of claims 34-38, wherein the cell, tissue, or organ comprises a hematopoietic stem cell (HSC). 40. A kit comprising: a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 20; and instructions for its use.

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