<sup2 / >? <sub2 / >?2b?5-htserotonin receptor antagonists, pharmaceutical compositions thereof, and methods of use thereof

Abstract

Disclosed are compounds of formulas (I) and (II), a salt thereof, or an optical isomer thereof, wherein R1-R3, X, and Y are as defined herein, which are 5-HT2B serotonin receptor selective antagonists, pharmaceutical compositions comprising such compounds, and methods of treating various diseases and conditions in an animal including fibrosis of the lung, skin, coronary, and liver, pulmonary arterial hypertension, valvular heart disease, pain, and cancer by the use of these compounds.

Description

5-HT2BSEROTONIN RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USE THEREOFCROSS-REFERENCE TO A RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 527,244, filed July 17, 2023.STATEMENT REGARDINGFEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0092] This invention was made with Government support under Grant Number ZIADK03117 awarded by the National Institute of Diabetes & Digestive & Kidney Diseases, Division of Intramural Research. The Government has certain rights in this invention.BACKGROUND OF THE INVENTION

[0003] Serotonin (or 5 -hydroxy tryptamine, 5-HT) is a neurotransmitter of the peripheral and central nervous systems (PNS and CNS). 5-HT is associated with mood disorders such as depression and schizophrenia as well as in controlling food intake, gastrointestinal function, cardiovascular function, cell development, drug seeking behavior, and pain.

[0004] The serotonin receptor 2 (5-HTz) subfamily consists of three subtypes: 5-HTZA, 5-HT2B, and 5-HT2C. The 5-HT2B receptor is found in both the peripheral and central nervous system. The 5-HT2B receptor binds the neurotransmitter serotonin and mediates many of the central and peripheral physiologic functions of serotonin. 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA. Some of the effects of serotonin on the CNS include presynaptic inhibition, neuronal sensitization to tactile stimuli, mediation of some of the effects of hallucinogenic substituted amphetamines, and behavioral modifications. It has been contemplated that 5-HTZB receptor antagonists would be useful in cardioprotection, liver protection, and central nervous system activity.

[0005] There is an unmet need for compounds and compositions for treating various disease conditions, including fibrosis of the lung, liver, skin, and coronary, pulmonary arterialhypertension, valvular heart disease, pain, cancer, autoimmune diseases, and neuropathic pain of diverse states by selectively antagonizing 5-HT2B receptors relative to 5-HT2C receptors.BRIEF SUMMARY OF THE INVENTION

[0006] The invention provides compounds and compositions for treating various disease conditions, including fibrosis of the lung, liver, skin, and coronary, pulmonary arterial hypertension, valvular heart disease, pain, cancer, autoimmune diseases, and neuropathic pain of diverse states by selectively antagonizing 5-HT2B receptors relative to 5-HT2C receptors. In an aspect, the compounds of the invention, advantageously, do not reduce body core temperature. The invention also provides methods of treating such diseases by the use of these compounds and compositions.

[0007] Thus, the present invention provides a compound of formula (I) or formula (II), a salt thereof, or an optical isomer thereof.wherein, in the compound of formula (I),R1is selected from the group consisting of ary l, arylalkyl, cycloalky l, cycloalkyl alky l, di-cycloalkylalkyl, di-bicycloalkyl, tricycloalkyl, alky l, (cycloalkyl)(alkyl)alkylenyl, and H, wherein the aryl, alkyl, and cycloalkyl moieties can be optionally substituted with one or more of alkyd, halo, and cyano groups;R2is selected from the group consisting of H, halo, alky Ithio, arylalky Ithio, heteroaryl, tetrahydropyrrolyl, cyano, and thienylalkyny 1, wherein each of said moieties, other than H and halo, can be optionally substituted with one or more of alkyl, halo, and cyano groups; andR3is selected from the group consisting of optionally substituted 5 -membered aromatic heterocyclyl, 3-alky 1-1,2, 4-oxadiazol-5-yl, triazoly lalky l, cyano,alkylaminocarbonyl, alkylaminothiocarbonyl, alkyloxycarbonyl, alkyloxythiocarbonyl, hydroxyalkyl, monohaloalkyl, dihaloalkyl, cyanoalkyl, and cyanothioalkyl; and Y = N or CH; and in the compound of formula (II), R1is cycloalkyl or di-cycloalkylalkyl; R2is halo; X is NH, O, S, Se or CH2, and R3is COXR4or CSXR4, and R4is H, alkyl, or alkyloxy; and Y = N or CH; and with the provisos: (i) in formula (II), when R3is CH2OH and R1is H, alkyl, di-cycloalkyl alkyl, or (cycloalkyl)(alkyl)alkylenyl, then R2is not chloro or H; (ii) in formula (I), when R3is alkylaminocarbonyl and R1is di-cycloalkyl alkyl, or (chloro substituted aryl) alkyl, then R2is not chloro; and (iii) in formula (I), when R3is alkylaminocarbonyl and R1is (chloro substituted aryl) alkyl, then R2is not (halo substituted thienyl)alkynyl. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figures 1A-1B depict reaction schemes to produce compounds in accordance with an aspect of the invention. Figures 2A-2J depict calcium efflux values for certain compounds in accordance with an aspect of the invention. Figure 3 depicts preferred substituents for providing affinity to 5-HT2B receptors in accordance with an aspect of the invention. Figure 4 depicts a reaction scheme to prepare compounds 47, 48, 94, and 95 in accordance with an aspect of the invention. Figure 5 depicts a reaction scheme to prepare compounds 49 and 50 in accordance with an aspect of the invention. Figure 6A depicts a reaction scheme to prepare compounds 51 and 54 in accordance with an aspect of the invention. Figure 6B depicts a reaction scheme to prepare compounds 87 and 103 in accordance with an aspect of the invention.

[0015] Figure 7 depicts a reaction scheme to prepare compound 40. which is a compound of formula (I) and depicted as MRS 8209.

[0016] Figure 8 depicts a reaction scheme for the synthesis of 4’-cyano and difluoromethyl (N)-methanocarba adenosine derivatives in accordance with an aspect of the invention.

[0017] Figure 9 depicts a reaction scheme for the synthesis of 4’-aryl modified (N)- methanocarba adenosine derivatives in accordance with an aspect of the invention.

[0018] Figure 10A depicts that compound 40 (MRS8209) in accordance with an aspect of the invention advantageously does not reduce core body temperature or locomotor activity in wild type male mice at a dose of 1 mg / kg ip. Figure 10B depicts that compound 40 (MRS 8209) in accordance with an aspect of the invention advantageously failed to reduce core body temperature or locomotor activity in wild type male mice at a dose of 3 mg / kg ip.

[0019] Figure 11, in parts A-D, respectively, depicts the binding affinities of compounds 18, 29, 32, and 27 relative to SB 206553 as a function of concentration.

[0020] Figure 12 depicts a scheme for molecular interactions of an antagonist of the invention with the 5-hydroxytryptamine receptor 2A.DETAILED DESCRIPTION OF THE INVENTION

[0021] In an aspect, the present invention provides a compound of formula (I) or formula (II), a salt thereof, or an optical isomer thereof,wherein, in the compound of formula (I),R1is selected from the group consisting of aryl, arylalkyd, cycloalky 1, cycloalkyl alkyl, di-cycloalkylalkyl, di-bicycloalkyl, tricycloalkyl, alkyl, (cycloalkyl)(alkyl)alkylenyl,and H, wherein the aryl, alkyl, and cycloalkyl moieties can be optionally substituted with one or more of alkyl, halo, and cyano groups;R2is selected from the group consisting of H, halo, alkylthio, arylalkylthio, heteroaryl, tetrahydropyrrolyl, cyano, and thienylalkynyl, wherein each of said moieties, other than H and halo, can be optionally substituted with one or more of alkyl, halo, and cyano groups; andR3is selected from the group consisting of optionally substituted 5 -membered aromatic heterocyclyl, 3-alkyl-l,2,4-oxadiazol-5-yl, triazolylalkyl, cyano, alkydaminocarbonyl, alkylaminothiocarbonyl, alkydoxy carbonyl, alkydoxythiocarbonyl, hydroxyalkyl, monohaloalkyl, dihaloalkyd, cyanoalkyl, and cyanothioalkyl; andY = N or CH; and in the compound of formula (II), R1is cycloalkyl or di-cycloalkylalkyl;R2is halo;X is NH, O, S, Se or CH2, andR3is COXR4or CSXR4, and R4is H, alkyl, or alkyloxy; andY = N or CH; and with the provisos:(i) in formula (II), when R3is CH2OH and R1is H, alkyl, di-cycloalkyl alkyl, or (cycloalkyl)(alkyl)alkylenyl, then R2is not chloro or H;(ii) in formula (I), when R3is alkylaminocarbonyl and R1is di-cycloalkyl alkyl, or (chloro substituted aryl)alkyl, then R2is not chloro; and(iii) in formula (I), when R3is alkylaminocarbonyl and R1is (chloro substituted aryl) alkyl, then R2is not (halo substituted thienyl)alkynyl.

[0022] In an aspect, the invention provides a compound, a salt, or an optical isomer according to formula (I), wherein the aryl moiety of aryl and arylalkyl in R1is phenyl, biphenyl, naphthyl, anthracenyl, or pyrenyl. In a particular aspect, R1is phenyl optionally substituted with one or more of alkyd, halo, and cyano groups. In an additional aspect, the invention provides a compound, salt, or optical isomer according to formula (I) as described above, wherein R3is an optionally substituted 5-membered aromatic heterocyclyl. In an aspect, R3is selected from the group consisting of thienyl, furyl, oxadiazolyl, diazolyl, thiazolyl, triazolyl, pyrazolyl, and pyrrolyl, each of which is optionally substituted with halo,6C1-C6 alkyl, C1-C6 alkylthio, aryl, or aryl C1-C6 alkylthio. For example, R3can be 3-alkyl- l,2,4-oxadiazol-5-yl or triazolylalkyl.

[0023] In an aspect, the invention provides a compound, a salt, or an optical isomer according to formula (I), wherein R1is selected from the group consisting of phenyl, phenylalkyl, halophenyl, dihalophenyl, halobenzyl, C3-C8 cycloalkyl, di-C3-C8 cycloalkyl C3- C8 alkyl, and C3-C8 alkyl; R2is selected from the group consisting of chloro, bromo, iodo, C1- C8 alkylthio, aryl C1-C8 alkylthio, heteroaryl, thienylalkynyl, pyrrolidinyl, and halothienylalkynyl; and R3is selected from the group consisting of 3-methyl-l,2,4-oxadiazol- 5-yl, cyano, hydroxy C1-C8 alkyl, cyano C1-C8 alkyl, and cyanothio C1-C8 alky l.

[0024] In aspect, the invention provides a compound, salt, or optical isomer according to formula (I), wherein R1is selected from the group consisting of di-cyclopropylmethyl, di- bicyclobutylmethyl, di-bicyclopentylmethyl, di-bicyclohexylmethyl, (isopropyl)(cyclopropyl)methyl, (cyclopropyl)(cyclobutyl)methyl, and dicyclopentylmethyl.

[0025] In any of the above aspects, R2is selected from the group consisting of methylthio, chloro, and iodo.10026] In any of the above aspects, the invention provides a compound, salt, or optical isomer according to formula (I), wherein R3is selected from the group consisting of 3- methyl-l,2,4-oxadiazol-5-yl, cyano, dihalomethyl, hydroxymethyl, cyanomethyl, methylaminocarbonyl, trizolylmethyl, and cyanothiomethyl.[00271 In accordance with any one of the above aspects of compound, salt, or optical isomer of formula (I), wherein the compound is:NH2HN HNN N N. _ NHO N N' NO <zNX N fuiOH OH OH OH OH OH

[0028] In an aspect, the invention provides compounds of formula (I) with the following structures:and pharmaceutically acceptable salts thereof or optical isomers thereof.[0029| In particular, the invention provides a compound, salt, or optical isomer wherein:R1is , R2is Cl, and R3is CH2OH;R1is , R2is H. and R3is CH2OH;R1is di(cyclopropyl)methyL R2is Cl, and R3is CHF2;R1is isopropyl(cyclopropyl)methyl (R), R2is Cl, and R3is CHF2;R1is (cyclopropyl)(cyclobuty l)methyl (R), R2is I, and R3is CHF2;R1is (cyclopropyl)(cyclobutyl)methyl (5), R2is I, and R3is CHF2;R1is m-chlorobenzyl, R2is I. and R3is CHF2;R1is H, R2is Cl, and R3is CN;R1is methyl, R2is I, and R3is CN;R1is n-propyl, R2is I, and R3is CN;R1is isopropyl(cyclopropyl)methyl (R), R2is Cl, and R3is CN;R1is isopropyl(cyclopropyl)methyl (R), R2is I, and R3is CN;35: R1is (cyclobutyl)(cyclopropyl)methyl (R). R2is I. and R3is CN;R1is (cyclobutyl)(cyclopropyl)methyl (R), R2is I, and R3is CH2SCN;R1is (cyclobutyl)(cyclopropyl)methyl (<S), R2is I, and R3is CN;R1is (cyclobutyl)(cyclopropyl)methyl (R), R2is I, and R3is CH2CN;R1is (cyclopropyl)(cyclobutyl)methyl (S), R2is I, and R3is CH2CN;R1is cyclopentyl, R2is I, and R3is CN;R1is cyclopentyl, R2is I, and R3is CH2CN;R1is 3-difluorocyclopentyl (R), R2is I, and R3is CN;R1is 3-difluorocyclopentyl (R), R2is I, and R3is CH2CN;R1is 3-difluorocyclopentyl (S), R2is I, and R3is CN;R1is 3-difluorocyclopentyl (5), R2is I, and R3is CH2CN;R1is , R2is I, and R3is CN;R1is bicyclo [1.1.2] butyl, R2is I, and R3is CH2CN;R1is m-chlorobenzyl, R2is I, and R3is CN;R1is m-chlorobenzyl, R2is I, and R3is CH2CN;R1is Me, R2is 5-Cl-thien-2-yl, and R3is CN;R1is nPr, R2is 5-Cl-thien-2-yl, and R3is CN;R1is Me. R2is 5-Cl-thien-2-yl -ethynyl, and R3is CN;R1is H, R2is S-CH2Ph, and R3is CH2OH;R1is Me, R2is S-CH2PI1, and R3is CH2OH;R1is Me, R2is S-CH2PI1, and R3is CH2CN;R1is (cyclopropyl)(cyclobutyl)methyl, R2is Cl, and R3is COOCH2CH3;R1is H. R2is 1. and R3is CONHCH3;R1is Me, R2is I, and R3is CONHCH3;R1is phenylethyl, R2is I, and R3is CONHCH3;R1is Me, R2is 5-Cl-thien-2-yl, and R3is CONHCH3;R1is nPr, R2is 5-Cl-thien-2-yl, and R3is CONHCH3;R1is Me. R2is 5-Cl-thien-2-yl-ethynyl, and R3is CONHCH3;R1is nPr, R2is 4-pyridyl, and R3is CONHCH3;R1is Me, R2is I, and R3is COOCH2CH3; orR1is (cyclopropyl)(isopropyl)methyl, R2is 5-Cl-thien-2-yl-ethynyl, and R3isCONHCH3; orR1is Me. R2is H (Z=C-1). and R3is COOCH2CH3.

[0030] In accordance with a further aspect, the invention provides a compound, salt, or optical isomer according to formula (I), wherein:R1is Me, R2is Cl-thienyl-ethynyl, and R3is CH2CN;R1is c-Bu, R2is I; and R3is CH2OH;R1is c-Bu, R2is I, and R3is CN;R1is c-Hex, R2is I, and R3is CH2OH;R1is c-Hex, R2is I. and R3is CN;R1is (CH2)2cPr, R2is I, and R3is CH2OH;R1is (CH2)2cPr, R2is I, and R3is CN;R1is (CH2)2cPr, R2is I, and R3is CH2CN;R1is (CH2)2cPr, R2is I, and R3is CH2CI;R1is (CH2)2cPr, R2is I, and R3is CChEt;R1is (CH2)2cPr, R2is I, and R3is CONHCH3;R1is (CH2)2cPr, R2is I, and R3is CH2SH;R1is Ph, R2is I, and R3is CH2OH;R1is Ph, R2is I, and R3is CN;R1is Ph, R2is I, and R3is CH2CN;R1is Ph, R2is I, and R3is CChEt;R1is Ph, R2is Cl-thienyl-ethynyl, and R3is CONHCH3;R1is (cyclobutyl)(cyclopropyl)methyl, R2is Cl-thienyl-ethynyl, and R3is CH2OH;R1is (CH2)sPh. R2is Cl-thienyl-ethynyl. and R3is CChEtR1is (3-F-Ph), R2is I, and R3is CH2OH;R1is (3-F-Ph), R2is I, and R3is CN;R1is (3,5-diCl-Ph), R2is I, and R3is CH2OH;R1is (3,5-F-Ph), R2is I, and R3is CN;R1is NH-(3,4-diCl-Ph), R2is I, and R3is CH2OH;R1is (3,4-diCl-Ph), R2is I. and R3is CN;R1is (3-Cl-Bn), R2is I, and R3is CN;R1is (3-Cl-Bn), R2is I, and R3is CChEt;R1is (3-Cl-Bn), R2is Cl-thienyl-ethynyl, and R3is CH2CN;R1is pyrrolyl, R2is I, and R3is CH2OH;R1tetrahydropyrrolyl,R1is tetrahydropyrrolyl, R2is 2-H, Z=C-CN, and R3is CH2OH;R1is tetrahydropyrrolyl, R2is 2-H, Z=C-CN, and R3is CN;0-N Ux X. R1is H, R2is I, and R3is N ;0-N yCkR1is tetrahydropyrrolyl, R2is I, and R3is N ;OrR1is (cyclopropyl)(cyclobutyl) (R), R2is I, and R3is

[0031] The present invention also provides a compound, salt, or optical isomer according to formula (II), wherein R1is selected from the group consisting of cycloalkyd or di-cycloalkylalkyl; R2is halo; and R3is CH2OH or COOR4, wherein R4is alkyl, more particularly, a compound of formula The compound, salt, or optical isomer according to formula (II), wherein R1is cyclopropyl, cyclobuty l, cyclopentyl, or cyclohexyl; R2is chloro, iodo, or methylthio; and R3is COOR4, or CONHR4, wherein R4is C1-C3 alkyd.

[0032] Referring now to terminology' used generically herein, the term “alkyl” means a straight-chain or branched alkyd substituent containing from, for example, 1 to about 6 carbon atoms, preferably from 1 to about 4 carbon atoms, more preferably from 1 to 2 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-buty l, pentyd, isoamyl, hexyl, and the like.[00331 The term “cycloalkyl,” as used herein, means a cyclic alkyd substituent containing from, for example, about 3 to about 8 carbon atoms, preferably from about 4 to about 7 carbon atoms, and more preferably from about 4 to about 6 carbon atoms. Examplesof such substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The cyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.

[0034] The term “alkylcarbonyl,” as used herein, refers to an alkyl group linked to a carbonyl group and further linked to a molecule via the carbonyl group, e.g., alky l C(=O) . The term “alkoxycarbonyl,” as used herein, refers to an alkoxy group linked to a carbonyl group and further linked to a molecule via the carbonyl group, e.g., alkyl O C(=O) .

[0035] The term “halo” or “halogen,” as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.

[0036] Whenever a range of the number of atoms in a structure is indicated (e.g., a C1-C12. Ci-Cs, Ci-C6, C1-C4. or C2-C12, C2-C8. C2-C6, C2-C4 alkyl, alkenyl, or alkynyl). it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1- 8 carbon atoms (e.g., Ci-Cs), 1-6 carbon atoms (e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and / or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms. 1-12 carbon atoms. 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3- 6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms. 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms, and / or 4- 12 carbon atoms, etc., as appropriate). Similarly, the recitation of a range of 6-10 carbon atoms (e.g., C6-C10) as used with respect to any chemical group (e.g., aryl) referenced herein encompasses and specifically describes 6, 7, 8, 9, and / or 10 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 6-10 carbon atoms, 6-9 carbon atoms, 6-8 carbon atoms, 6-7 carbon atoms, 7-10 carbon atoms, 7-9 carbon atoms, 7-8 carbon atoms, 8-10 carbon atoms, and / or 8-9 carbon atoms, etc., as appropriate).j 00371 In any of the above aspects, the compound or salt of formula (I) or formula (II) can have at least one asymmetric carbon atom. When the compound or salt has at least one asymmetric carbon atom, the compound or salt can exist in the racemic form, in the form of its pure optical isomers, or in the form of a mixture wherein one isomer is enriched relative to the other. In particular, in accordance with the present invention, when the inventive compounds have a single asymmetric carbon atom, the inventive compounds may exist as racemates, i.e., as mixtures of equal amounts of optical isomers, i.e., equal amounts of two enantiomers, or in the form of a single enantiomer. As used herein, "single enantiomer" is intended to include a compound that comprises more than 50% of a single enantiomer (i.e., enantiomeric excess more than 60%, more than 70%, more than 80%, more than 90%, or up to 100% pure enantiomer).

[0638] When the compound or salt has more than one chiral center, the compound or salt can therefore exist as a mixture of diastereomers or in the form of a single diastereomer. As used herein, "single diastereomer” is intended to mean a compound that comprises more than 50% of a single diastereomer (i.e., diastereomeric excess more than 60%, more than 70%, more than 80%, more than 90%, or up to 100% pure diastereomer).

[0039] In a particular aspect, the optical isomers of the compounds of the invention, in particular those of formula (I), have optical isomerism at the N6group, not the entire molecule. Thus, 7? and S' in this disclosure refer to the optical isomerism at the N6group.

[0040] The phrase “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Berge, S. M., at al., Journal of Pharmaceutical Science, 66, 1-19 (1977).[00411 Suitable bases include inorganic bases such as alkali and alkaline earth metal bases, e.g., those containing metallic cations such as sodium, potassium, magnesium, calcium and the like. Non-limiting examples of suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Suitable acids include inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzene sulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acids, long chain fatty acids, and the like. Preferred pharmaceutically acceptable salts of inventive compounds having an acidic moiety include sodium and potassium salts. Preferred pharmaceutically acceptable salts of inventive compounds having a basic moiety (e.g., a dimethylaminoalkyl group) include hydrochloride and hydrobromide salts. The compounds of the present invention containing an acidic or basic moiety are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof.10042] It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. j00431 It is further understood that the above compounds and salts may form solvates, or exist in a substantially uncomplexed form, such as the anhydrous form. As used herein, the term “solvate” refers to a molecular complex wherein the solvent molecule, such as the cry stallizing solvent, is incorporated into the crystal lattice. When the solvent incorporated in the solvate is water, the molecular complex is called a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms.100441 The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or (II), salt, or optical isomer thereof, as described above and a pharmaceutically acceptable carrier. The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount, e.g., a therapeutically effective amount, including a prophylactically effective amount, of one or more of the aforesaid compounds, or salts thereof, of the present invention.

[0045] The pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceuticalcompositions; the compounds of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.S0046] The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.[0047 j The choice of carrier will be determined in part by the particular active agent, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary' and are in no w ay limiting.[0048 j Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) pow ders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary' hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.j 0049] The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

[0050] Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxy methylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0051] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and poly oxy ethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary7ammonium salts, and (3) mixtures thereof.[00521 The parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity7of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.10053 j The compounds of the present invention may be made into injectable formulations. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy’ Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), wdASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

[0054] Topical formulations, including those that are useful for transdermal drug release, are w ell-know n to those of skill in the art and are suitable in the context of the invention for application to skin. Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels. Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa. In some aspects, the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant. The carrier can be a liquid, solid or semi-solid. In aspects, the composition is an aqueous solution. Alternatively, the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components. In one aspect, the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral. The liquid vehicle can include other materials, such as buffers, alcohols, glycerin,and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH. consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site. In aspects of the invention, the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.|0055] Additionally, the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0056] The dose administered to a mammal, particularly, a human, in accordance with the present invention should be sufficient to effect the desired response. Such responses include reversal or prevention of the adverse effects of the disease for which treatment is desired or to elicit the desired benefit. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the age, condition, and body weight of the human, as well as the source, particular type of the disease, and extent of the disease in the human. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.10057] Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The present inventive method typically will involve the administration of about 0. 1 to about 300 mg of one or more of the compounds described above per kg body weight of the animal or mammal.j 00581 The therapeutically effective amount of the compound or compounds administered can vary depending upon the desired effects and the factors noted above. Typically, dosages will be between 0.01 mg / kg and 250 mg / kg of the subject’s body weight, and more typically between about 0.05 mg / kg and 100 mg / kg, such as from about 0.2 to about 80 mg / kg, from about 5 to about 40 mg / kg or from about 10 to about 30 mg / kg of the subject’s body weight. Thus, unit dosage forms can be formulated based upon the suitable ranges recited above and the subject’s body weight. The term “unit dosage form” as used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated.|0059] Alternatively, dosages are calculated based on body surface area and from about 1 mg / m2to about 200 mg / m2, such as from about 5 mg / m2to about 100 mg / m2will be administered to the subject per day. In particular aspects, administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg / m2to about 50 mg / m2, such as from about 10 mg / m2to about 40 mg / m2per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day. Thus, unit dosage forms also can be calculated using a subject’s body surface area based on the suitable ranges recited above and the desired dosing schedule.[00601 The present invention provides a method of antagonizing a 5-HT2B serotonin receptor in an animal in need thereof comprising administering a compound, salt, or isomer or a pharmaceutical composition as described above.[00611 The present invention further provides a method of treating fibrosis of the lung, skin, coronary and or liver fibrosis, pulmonary arterial hypertension, valvular heart disease, pain, or cancer in an animal in need thereof, comprising administering a compound, salt, or isomer or a pharmaceutical composition as described above.[0062 [ The present invention discloses use of a compound of formula (I) or (II), salt, or optical isomer as described above, or a pharmaceutical composition thereof, for antagonizing a 5-HT2B serotonin receptor in an animal in need thereof, in particular, for treating fibrosis of the lung, skin, coronary and or liver fibrosis, pulmonary arterial hypertension, valvular heart disease, pain, or cancer in an animal in need thereof.j 00631 The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.EXAMPLE 1

[0064] This example illustrates a method of synthesis of certain compounds of the present invention, as illustrated in FIG. 1. The protected 6-chloro nucleoside precursors 57 and 58 were synthesized by a Mitsunobu reaction from methanocarba sugar 56. Amination of the nucleobase 6 position with either ammonia or various dicycloalkyl-methylamines in the presence of DIPEA in isopropanol provided 2-C1 and 2-1 intermediates 59 - 64. Silyl deprotection at the 5'-position of the nucleoside precursor with TBAF gave the isopropylidene-protected intermediates 65 - 68. The 5 '-hydroxymethyl group was modified with different functional groups to give chloro derivatives (72, 73, using thionyl chloride), fluoro derivative (75, using DAST) or mesylated compounds 69 - 71 (using mesyl chloride). 5 '-Chi oro-5 '-deoxy nucleosides (72, 73) were further transformed to various thioalkyl derivatives by a SN2 reaction with the appropriate sodium alkylthioate in DMF. In the direct fluorination reaction by DAST, some unwanted impurities often contaminated the desired product. In order to avoid this problem, an indirect method was used where the mesylated compounds (69 - 71) were converted to 4'-fluoromethyl derivatives 74, 76 in the presence of tetrabutylammonium fluoride (TBAF) in THF under reflux condition. The silyl and isopropylidene group together (59 - 62) or only isopropylidene group (72 - 87) was hydrolyzed in the presence of DOWEX50 in aqueous methanol or with aqueous TFA in MeOH to afford the final compounds (9b, 11, 12, 15, 16, 19, 23, 24, and 26 - 36). A 3-deaza methanocarba nucleoside 25 w as prepared by a similar route. The N6amination of compound 88 to obtain 89 with dicylopentylmethylamine was performed at 140 °C under microwave condition for 25 h to give 89 in only moderate yield (22%), which upon subsequent acid hydrolysis afforded compound 25.

[0065] Reagents and Conditions: (i) 6-Cl-purine derivative, Ph?P. DIAD, THF, rt; (ii) NH3 / 2-propanol, 80°C; (iii) R1NH2, DIPEA, 2-propanol, rt; (iv) TBAF. THF, rt; (v) MsCl. pyridine, rt; (vi) SOCk, pyridine, CH3CN, -5 °C to rt; (vii) TBAF, THF, reflux, (viii) DAST, CH2CI2, rt; (ix) R4SNa, DMF, rt; (x) 10% TFA, MeOH, 70°C; (xi) DOWEX50, MeOH-H2O, rt.

[0066] Materials and instrumentation: Dimethyl sulfoxide (DMSO), and other reagents were obtained from Sigma- Aldrich (St. Louis, MO). 'H NMR spectra were obtained with aBruker 400 spectrometer using CDCl3, CD3OD and DMSO as solvents. Chemical shifts are expressed in δ values (ppm) with tetramethylsilane (δ 0.00) for CDCl3and water (δ 3.30) for CD3OD. NMR spectra were collected with a Bruker AV spectrometer equipped with a z- gradient [1H,13C,15N]-cryoprobe. TLC analysis was carried out on glass sheets precoated with silica gel F254 (0.2 mm) from Sigma- Aldrich. The purity of final nucleoside derivatives was checked using a Hewlett−Packard 1100 HPLC equipped with a Zorbax SB- Aq 5 μm analytical column (50 × 4.6 mm; Agilent Technologies Inc., Palo Alto, CA, USA). Mobile phase: linear gradient solvent system, 5 mM TBAP (tetrabutylammonium dihydrogen phosphate): CH3CN from 80:20 to 0:100 in 13 min; the flow rate was 0.5 mL / min. Peaks were detected by UV absorption with a diode array detector at 230, 254, and 280 nm. All derivatives tested for biological activity showed >95% purity by HPLC analysis (detection at 254 nm). Low-resolution mass spectrometry was performed with a JEOL SX102 spectrometer with 6-kV Xe atoms following desorption from a glycerol matrix or on an Agilent LC / MS 1100 MSD, with a Waters (Milford, MA, USA) Atlantis C18 column. High resolution mass spectroscopic (HRMS) measurements were performed on a proteomics optimized Q-TOF-2 (Micromass-Waters) using external calibration with polyalanine, unless noted. Observed mass accuracies are those expected based on known performance of the instrument as well as trends in masses of standard compounds observed at intervals during the series of measurements. Reported masses are observed masses uncorrected for this time- dependent drift in mass accuracy. (1R,2R,3S,4R,5S)-4-(6-((Dicyclopropylmethyl)amino)-2-iodo-9H-purin-9- yl)-1- (hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (11): DOWEX 50 (50 mg) was added to a solution of compound 68 (99 mg, 0.18 mmol) in MeOH (3 mL) and water (2 mL), and the mixture was stirred for 6 h at room temperature. After completion of staring material, the reaction mixture was filtered, and the filtrate was evaporated under vacuum. The crude mixture was purified on flash silica gel column chromatography (CH2Cl2:MeOH = 20:1) to give compound 11 (78 mg, 86%) as a colorless powder.1H NMR (CD3OD, 400 MHz) δ 8.38 (s, 1H), 4.81 (s, 1H), 4.78 (d, J = 6.0 Hz, 1H), 4.28 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 6.8 Hz, 1H), 3.39 (br s, 1H), 3.37 (d, J = 11.6 Hz, 1H), 1.61-1.58 (m, 1H), 1.54 (d, J = 4.8 Hz, 1H), 1.16-1.07 (m, 2H), 0.78-0.74 (m, 1H), 0.59-0.54 (m, 2H), 0.47-0.37 (m, 6H). HRMS calculated for C19H25N5O3I (M + H)+: 498.1002; found 498.1007.(1S,2R,3S,4R,5S) 4 (2 Chloro 6 ((dicyclopropylmethyl)amino) 9H purin 9 yl)-1- (fluoromethyl)bicyclo[3.1.0]hexane-2,3-diol (12). Compound 12 (83%) was prepared from compound 74 following the same method as for compound 11.1H NMR (CD3OD, 400 MHz) δ 8.13 (s, 1H), 5.09 (dd, J1 = 10.0 Hz, J2 = 50.2 Hz, 1H), 4.84 (s, 1H), 4.74 (d, J = 6.8 Hz, 1H), 4.38 (dd, J1 = 10.0 Hz, J2 = 50.2 Hz, 1H), 3.90 (d, J = 6.4 Hz, 1H), 3.46 (br s, 1H),1.83-1.80 (m, 1H), 1.73-1.69 (m, 1H), 1.18-1.10 (m, 2H), 0.90-0.87(m, 1H), 0.60-0.55 (m,2H), 0.47-0.39 (m, 6H). HRMS calculated for C19H24N5O2FCl (M+H) +:408.1603; found408.1609. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopropylmethyl)amino)-9H-purin-9- yl)-1- ((methylthio)methyl)bicyclo[3.1.0]hexane-2,3-diol (15): Compound 15 (84%) wasprepared from compound 85 following the same method as forcompound 11. 1H NMR(CD3OD, 400 MHz) δ 8.34 (s, 1H), 4.80 (d, J = 6.8 Hz, 1H), 4.76 (s,1H), 3.98 (d, J = 6.8Hz, 1H), 3.46 (br s, 1H), 3.25 (d, J = 13.6 Hz, 1H), 2.76 (d, J = 13.6 Hz, 1H), 2.21 (s, 3H), 1.65-1.62 (m, 1H), 1.57 (t, J = 4.8 Hz, 1H), 1.18-1.10 (m, 2H), 0.84-0.81 (m, 1H), 0.60-0.55 (m, 2H), 0.47-0.40 (m, 6H). HRMS calculated for C20H27N5O2SCl (M + H)+: 436.1574; found 436.1580. (1S,2R,3S,4R,5S)-4-(6-((Dicyclopropylmethyl)amino)-2-iodo-9H-purin-9- yl)-1- ((methylthio)methyl)bicyclo[3.1.0]hexane-2,3-diol (16). Compound 16 (84%) wasprepared from compound 86 following the same method as forcompound 11. 1H NMR(CD3OD, 400 MHz) δ 8.24 (s, 1H), 4.82 (d, J = 7.2 Hz, 1H), 4.76 (s,1H), 3.97 (d, J = 6.8Hz, 1H), 3.48 (br s, 1H), 3.24 (d, J = 11.6 Hz, 1H), 2.82 (d, J = 11.6 Hz, 1H), 2.20 (s, 3H), 1.61-1.58 (m, 1H), 1.53 (d, J = 4.8 Hz, 1H), 1.17-1.08 (m, 2H), 0.84-0.81 (m, 1H), 0.61-0.54 (m, 2H), 0.47-0.37 (m, 6H). HRMS calculated for C20H27N5O2SI (M + H)+: 528.0930; found 528.0929. (1R,2R,3S,4R,5S)-4-(6-((Dicyclobutylmethyl)amino)-2-iodo-9H-purin-9-yl)- 1- (hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (19). Compound 19 (90%) was preparedfrom compound 62 following the same method as forcompound 9b. 1H NMR (CD3OD, 400MHz) δ 8.38 (s, 1H), 4.81 (s, 1H), 4.79 (d, J = 6.0 Hz,1H), 4.35-4.31 (m, 1H), 4.28 (d, J =11.6 Hz, 1H), 3.89 (d, J = 6.8 Hz, 1H), 3.38 (d, J = 11.6 Hz, 1H), 2.51-2.47 (m, 2H), 1.99- 1.83 (m, 10H), 1.79-1.76 (m, 2H), 1.62-1.59 (m, 1H), 1.55 (t, J = 4.8 Hz, 1H), 0.78-0.74 (m, 1H). HRMS calculated for C21H29N5O3I (M + H)+: 526.1315; found 526.1321.(1R,2R,3S,4R,5S) 4 (2 Chloro 6 ((dicyclopentylmethyl)amino) 9H purin 9 yl)-1- (hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (24). Compound 24 (91%) wasprepared from compound 63 following the same method as forcompound 9b. 1H NMR(CD3OD, 400 MHz) δ 8.44 (s, 1H), 4.81 (s, 1H), 4.79 (d, J = 6.4 Hz,1H), 4.40 (t, J = 6.8 Hz,1H), 4.29 (d, J = 11.6 Hz, 1H), 4.14-4.08 (m, 1H), 3.91 (d, J = 6.8 Hz, 1H), 2.22-2.14 (m,2H), 1.81-1.71 (m, 5H), 1.62-1.54 (m, 7H), 1.30-1.23 (m, 5H), 1.13-1.05 (m,1H), 0.76-0.75(m, 1H). HRMS calculated for C23H33N5O3Cl (M + H)+: 462.2272; found462.2274.(1R,2R,3S,4R,5S)-4-(6-Chloro-4-((dicyclopentylmethyl)amino)-1H- imidazo[4,5-c]pyridin-1- yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (25). Compound 25 (90%) was prepared from compound 89 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.53 (s, 1H), 6.88 (s, 1H), 4.68 (d, J = 6.4 Hz, 1H), 4.59 (s, 1H), 4.36 (br s, 1H), 4.30 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 5.6 Hz, 1H), 2.20- 2.14 (m, 2H), 1.76-1.71 (m, 5H), 1.60-1.53 (m, 9H), 1.45-1.31 (m, 4H), 0.80-0.77 (m, 1H).HRMScalculated for C24H34N4O3Cl (M + H)+: 461.2319; found 461.2316.(1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H-purin-9- yl)-1- (fluoromethyl)bicyclo[3.1.0]hexane-2,3-diol (26). Compound 26 (89%) was prepared from compound 75 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz)δ8.16 (s, 1H), 5.08 (dd, J1 = 10.0 Hz; J2 = 50.2 Hz, 1H), 4.85 (s, 1H), 4.74 (d, J = 6.4 Hz, 1H), 4.41-4.27 (m, 2H), 3.93 (d, J = 6.8 Hz, 1H), 2.28-2.15 (m, 2H), 1.83-1.69 (m, 4H), 1.62-1.55 (m, 9H), 1.44-1.25 (m, 5H), 0.93-0.88 (m, 1H). HRMS calculated for C23H32N5O2ClF (M + H) +: 464.2229; found 464.2220. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H-purin-9- yl)-1- (chloromethyl)bicyclo[3.1.0]hexane-2,3-diol (27). Compound 27 (88%) was prepared from compound 72 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz)δ8.29 (s, 1H), 4.82-4.79 (m, 2H), 4.40 (t, J = 6.8 Hz, 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.00 (d, J = 6.8 Hz, 1H), 3.69 (d, J = 11.6 Hz, 1H), 2.25-2.14 (m, 2H), 1.83-1.73 (m, 5H), 1.65-1.52 (m, 8H), 1.44-1.28 (m, 5H), 0.98-0.95 (m, 1H). HRMS calculated for C23H32N5O2Cl2 (M + H)+: 480.1933; found 480.1937. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H-purin-9- yl)-1- ((methylthio)methyl)bicyclo[3.1.0]hexane-2,3-diol (28). Compound 28 (90%) was prepared from compound 77 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.35 (s, 1H), 4.80-4.76 (m, 2H), 4.40 (t, J = 6.8 Hz, 1H), 4.00 (d, J =6.4 Hz, 1H), 3.24 (d, J 13.6 Hz, 1H), 2.77 (d, J 13.6 Hz, 1H), 2.242.14 (m, 5H), 1.84 1.71 (m, 4H), 1.65-1.50 (m, 9H), 1.44-1.28 (m, 5H), 0.84-0.81 (m, 1H). HRMS calculated for C24H35N5O2ClS (M+H)+: 492.2200; found 492.2203. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H-purin-9- yl)-1-((ethylthio)methyl)bicyclo[3.1.0]hexane-2,3-diol (29). Compound 29 (93%) was prepared from compound 78 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.33 (s, 1H), 4.80-4.77 (m, 2H), 4.40 (t, J = 6.8 Hz, 1H), 3.99 (d, J = 6.4 Hz, 1H), 3.30 (d, J = 13.6 Hz, 1H), 2.73 (d, J = 13.6 Hz, 1H), 2.68-2.65 (m, 2H), 2.25- 2.14 (m, 2H), 1.81-1.76 (m, 5H), 1.65-1.55 (m, 9H), 1.44-1.25 (m, 7H), 0.84-0.81 (m, 1H). HRMS calculated for C25H37N5O2ClS (M + H)+: 506.2357; found 506.2354. (1S,2R,3S,4R,5S)-1-((Butylthio)methyl)-4-(2-chloro-6- ((dicyclopentylmethyl)amino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol (30). Compound 30 (90%) was prepared from compound 79 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.40 (s, 1H), 4.83 (d, J = 7.2 Hz, 1H), 4.77 (s, 1H), 4.40 (t, J = 6.8 Hz, 1H), 4.01 (d, J = 6.4 Hz, 1H), 3.29 (d, J = 13.6 Hz, 1H), 2.75 (d, J = 13.6 Hz, 1H), 2.62-2.58 (m, 2H), 2.25-2.15 (m, 2H), 1.81-1.78 (m, 5H), 1.63-1.51 (m, 9H), 1.45-1.27 (m, 8H), 0.92 (t, J = 7.2 Hz, 3H), 0.83-0.80. HRMS calculated for C27H41N5O2ClS (M + H)+: 534.2670; found 534.2665. (1S,2R,3S,4R,5S)-4-(6-((Dicyclopentylmethyl)amino)-2-(methylthio)-9H-purin-9-yl)-1-((methylthio)methyl)bicyclo[3.1.0]hexane-2,3-diol (31).CH3SNa (27 mg,0.38 mmol) was added to a solution of compound 28 (19 mg, 0.03 mmol) indry DMF (1 mL)and heated at 90oC under microwave condition for 1 h. Solvent was evaporated under vacuum, and the residue was purified on flash silica gel column chromatography (hexane: ethylacetate = 1:1) to give compound 31 (11 mg, 57%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.24 (s, 1H), 4.81-4.78 (m, 2H), 4.50 (t, J = 6.8 Hz, 1H), 4.01 (d, J = 6.8 Hz, 1H), 3.23 (d, J = 13.6 Hz, 1H), 2.73 (d, J = 13.6 Hz, 1H), 2.56 (s, 3H), 2.22-2.16 (m, 5H), 1.77-1.75 (m, 5H), 1.64-1.52 (m, 9H), 1.45-1.31 (m, 4H), 0.82-0.79 (m, 1H). HRMS calculated for C25H38N5O2S2 (M + H)+: 504.2467; found 504.2458. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H-purin-9- yl)-1-(((2- fluorophenyl)thio)methyl)bicyclo[3.1.0]hexane-2,3-diol (32). Compound 32(88%) was prepared from compound 81 following the same method as forcompound 9b. 1HNMR (CD3OD, 400 MHz) δ 8.13 (s, 1H), 7.49-7.45 (m, 1H), 7.20-7.14 (m,1H), 7.07-7.01(m, 2H), 4.84 (d, J 6.8 Hz, 1H), 4.71 (s, 1H), 4.40 (t, J 6.8 Hz, 1H), 4.05 (d, J 6.4 Hz, 1H), 3.69 (d, J = 14.0 Hz, 1H), 3.82 (d, J = 14.0 Hz, 1H), 2.25-2.15 (m, 2H), 1.85-1.72 (m, 4H), 1.62-1.55 (m, 9H), 1.45-1.27 (m, 5H), 0.91-0.89 (m, 1H). HRMS calculated for C29H36N5O2ClSF (M + H)+: 572.2262; found 572.2273. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H-purin-9- yl)-1-(((3,4-dimethoxyphenyl)thio)methyl)bicyclo[3.1.0]hexane-2,3-diol (33). Compound 33 (87%) was prepared from compound 84 following the same method as for compound 9b. 1H NMR (CD3OD, 400 MHz) δ 8.11 (s, 1H), 7.06 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.79 (d, J = 6.0 Hz, 1H), 4.70 (s, 1H), 4.40 (d, J = 6.8 Hz, 1H), 4.00 (d, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.67 (d, J = 14.4 Hz, 1H), 3.21 (d, J = 14.4 Hz, 1H), 2.23- 2.15 (m, 2H), 1.87-1.71 (m, 4H), 1.61-1.56 (m, 9H), 1.40-1.29 (m, 5H), 0.91-0.87 (m, 1H). HRMS calculated for C31H41N5O4ClS (M + H) +: 614.2568; found 614.2565. (1R,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclohexylmethyl)amino)-9H-purin-9- yl)-1-(hydroxymethyl) bicyclo[3.1.0]hexane-2,3-diol (34). Compound 34 (88%) was prepared from compound 64 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.45 (s, 1H), 4.81-4.78 (m, 2H), 4.29 (d, J = 11.6 Hz, 1H), 4.17 (t, J = 6.4 Hz, 1H), 3.90 (d, J = 6.8 Hz, 1H), 3.36 (d, J = 11.6 Hz, 1H), 1.77-1.62 (m, 15H), 1.54 (t, J = 4.8 Hz, 1H), 1.37-1.05 (m, 8H), 0.78-0.75 (m, 1H). HRMS calculated for C25H37N5O3Cl (M + H) +: 490.2585; found 490.2579. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclohexylmethyl)amino)-9H-purin-9- yl)-1-(fluoromethyl)bicyclo[3.1.0]hexane-2,3-diol (35). Compound 35 (91%) was prepared from compound 76 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H), 5.08 (dd, J1 = 11.2 Hz, J2 = 49.8 Hz, 1H), 4.84 (s, 1H), 4.74 (d, J = 6.8 Hz, 1H), 4.38 (dd, J1 = 11.2 Hz, J2 = 49.8 Hz, 1H), 4.17 (t, J = 6.4 Hz, 1H), 3.92 (d, J = 6.4 Hz, 1H), 1.83-1.65 (m, 15H), 1.33-1.04 (m, 9H), 0.91-0.87 (m, 1H). HRMS calculated for C25H36N5O2F (M + H) +: 492.2542; found 492.2543. (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclohexylmethyl)amino)-9H-purin-9-yl)- 1-(chloromethyl)bicyclo[3.1.0]hexane-2,3-diol (36). Compound 36 (89%) was prepared from compound 73 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 8.29 (s, 1H), 4.83-4.79 (m, 2H), 4.31 (d, J = 11.6 Hz, 1H), 4.17 (t, J = 6.4 Hz, 1H), 4.00 (d, J = 6.8 Hz, 1H), 3.69 (d, J = 11.6 Hz, 1H), 1.84-1.65 (m, 15H), 1.36-1.04 (m, 9H), 0.98-0.95 (m, 1H). HRMS calculated for C25H36N5O2Cl2 (M + H) +: 508.2246; found 508.2244.(1R,2R,3S,4R,5S) 4 (6 (((R) Cyclobutyl(cyclopropyl)methyl)amino) 2 iodo 9H-purin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (43). A solution of compound 90 (108 mg, 0.13 mmol) in methanol (2 mL) and 10% TFA was heated at 70 oC overnight. Solvent was evaporated under reduced pressure and the residue was purified on flash silica gel column chromatography (CH2Cl2:MeOH = 15:1) to provide compound 43 (56 mg, 81%) as colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 4.81 (s, 1H), 4.78 (d, J = 6.8 Hz, 1H), 4.28 (d, J = 10.6 Hz, 1H), 3.88 (d, J = 6.4 Hz, 1H), 3.79 (br s, 1H), 3.38 (d, J = 10.6 Hz, 1H), 2.70-2.66 (m, 1H), 2.18-2.09 (m, 1H), 2.02-1.87 (m, 4H), 1.82-1.80 (m, 1H), 1.60-1.58 (m, 1H), 1.55-1.53 (m, 1H), 0.94-0.90 (m, 1H), 0.78-0.75 (m, 1H), 0.55 (t, J = 8.0 Hz, 1H), 0.41-0.39 (m, 3H). HRMS calculated for C20H27N5O3I (M + H) +: 512.1159; found 512.1165. (1R,2R,3S,4R,5S)-4-(6-(((S)-Cyclobutyl(cyclopropyl)methyl)amino)-2-iodo- 9H-purin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (45). Compound 45 (85%) was prepared from compound 91 following the same method for compound 43.1H NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 4.81 (s, 1H), 4.78 (d, J = 6.8 Hz, 1H), 4.28 (d, J = 10.6 Hz, 1H), 3.88 (d, J = 6.4 Hz, 1H), 3.78 (br s, 1H), 3.38 (d, J = 10.6 Hz, 1H), 2.69-2.65 (m, 1H), 2.18-2.07 (m, 1H), 1.97-1.86 (m, 4H), 1.82-1.80 (m, 1H), 1.60-1.58 (m, 1H), 1.55- 1.52 (m, 1H), 0.93-0.91 (m, 1H), 0.77-0.74 (m, 1H), 0.54 (t, J = 8.0 Hz, 1H), 0.42-0.38 (m, 3H). HRMS calculated for C20H27N5O3I (M + H)+: 512.1159; found 512.1166. Ethyl (1S,2R,3S,4R,5S)-4-(2-Chloro-6-((dicyclopentylmethyl)amino)-9H- purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carboxylate (47). Compound 47 (91%) was prepared from compound 94 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 7.98 (s, 1H), 5.24 (d, J = 6.8 Hz, 1H), 4.77 (s, 1H), 4.39 (t, J = 6.8 Hz, 1H), 4.28-4.23 (m, 2H), 4.12 (d, J = 6.4 Hz, 1H), 2.24-2.14 (m, 3H), 1.88-1.86 (m, 1H), 1.81- 1.76 (m, 4H), 1.63-1.50 (m, 9H), 1.44-1.34 (m, 2H), 1.33-1.28 (m, 5H). HRMS calculated for C25H35N5O4Cl (M + H)+: 504.2378; found 504.2381. Ethyl (1S,2R,3S,4R,5S)-4-(2-Chloro-6-(((S)- cyclobutyl(cyclopropyl)methyl)amino)-9H- purin-9-yl)-2,3- dihydroxybicyclo[3.1.0]hexane-1-carboxylate (48). Compound 48 (88%) was prepared from compound 95 following the same method as for compound 9b.1H NMR (CD3OD, 400 MHz) δ 7.89 (s, 1H), 5.24 (d, J = 6.4 Hz, 1H), 4.76 (s, 1H), 4.30-4.25 (m, 2H), 4.11 (d, J = 6.4 Hz, 1H), 3.78 (br s, 1H), 2.69-2.63 (m, 1H), 2.17-2.14 (m, 1H), 2.11-2.06 (m, 1H), 2.02-1.89 (m, 4H), 1.861.79 (m, 1H), 1.621.59 (m, 1H), 1.351.31 (m, 4H), 0.94 0.90 (m, 1H), 0.54 (t, J = 8.0 Hz, 1H), 0.37 (br s, 3H). HRMS calculated for C22H29N5O4I (M + H) +: 554.1264; found 554.1263. (1S,2R,3S,4R,5S)-4-(6-Amino-2-chloro-9H-purin-9-yl)-2,3-dihydroxy-N,N- bis(2- methoxyethyl)bicyclo[3.1.0]hexane-1-carboxamide (49) and (1S,2R,3S,4R,5S)-4- (2-Chloro-6-((dicyclopropylmethyl)amino)-9H-purin-9-yl)-2,3- dihydroxy-N,N-bis(2- methoxyethyl)bicyclo[3.1.0]hexane-1-carboxamide (50). Dowex50 (75 mg) was added to a solution of compound 99 (55 mg, 0.10 mmol) in MeOH (1 mL) - water (1 mL) and the mixture was stirred overnight at room temperature. After completion of staring material, the reaction mixture was filtered, and evaporated under vacuum. The crude mixture was purified on flash silica gel column chromatography (CH2Cl2: MeOH = 20:1) to give the desired compound 50 (28 mg, 56%) as a colorless syrup. Further elution with (CH2Cl2:MeOH = 15:1) gave a N6truncated derivative 49 (11 mg, 26%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.93 (s, 1H), 4.82 (s, 1H), 4.66 (d, J = 6.4 Hz, 1H), 4.25-4.21 (m, 1H), 3.94 (d, J = 6.4 Hz, 1H), 3.66-3.48 (m, 8H), 3.38 (s, 3H), 3.36 (s, 3H), 2.02-1.96 (m, 2H), 1.39-1.37 (m, 1H), 1.16-1.10 (m, 2H), 0.60-0.56 (m, 2H), 0.48-0.40 (m, 6H). HRMS calculated for C25H36N6O5Cl (M + H) +: 535.2436; found 535.2438. (1S,2R,3S,4R,5S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2,3-dihydroxy-N,N- bis(2-methoxyethyl)bicyclo[3.1.0]hexane-1-carboxamide (49):1H NMR (CD3OD, 400 MHz) δ 8.98 (s, 1H), 4.83 (s, 1H), 4.66 (d, J = 6.4 Hz, 1H), 4.25-4.21 (m, 1H), 3.97 (d, J = 6.6 Hz, 1H), 3.86-3.59 (m, 8H), 3.38 (s, 3H), 3.36 (s, 3H), 2.01-1.96 (m, 2H), 1.39-1.36 (m, 1H). HRMS calculated for C18H26N6O5Cl (M + H) +: 441.1653; found 441.1648. (2R,3R,4S,5R)-2-(6-(((S)-Cyclobutyl(cyclopropyl)methyl)amino)-2-iodo-9H- purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (51) and (S)-N- (Cyclobutyl(cyclopropyl)methyl)-2-iodo-9H-purin-6-amine (54). A solution of compound 101 (20 mg, 0.03 mmol) in methanol (2 mL) and 10% TFA (2 mL) was heated at 70 oC for 2 h. After completion of starting material, solvent was evaporated under reduced pressure and the residue was purified on flash silica gel column chromatography (CH2Cl2:MeOH = 40:1) to give a compound 54 (2.4 mg, 18%) as colorless syrup, which was found to be fragmented base moiety. Further elution with (CH2Cl2: MeOH = 20:1) gave the desired compound 51 (10 mg, 52%) as syrup. Data for compound 54: 1H NMR (CD3OD, 400 MHz) δ 7.96 (s, 1H), 3.79 (br s, 1H), 2.72-2.64 (m, 1H), 2.15-2.05 (m, 1H), 2.02-1.84 (m, 4H), 1.84-1.79 (m, 1H),0.970.88 (m, 1H), 0.570.53 (m, 1H), 0.39 0.37 (m, 3H). HRMS calculated for C13H17N5I (M + H) +: 370.0529; found 370.0526. Data for compound 51: 1H NMR (CD3OD, 400 MHz) δ 8.16 (s, 1H), 5.91 (d, J = 5.2 Hz, 1H), 4.68 (d, J = 9.2 Hz, 1H), 4.32-4.31 (m, 1H), 4.16 (s, 1H), 3.91-3.74 (m, 3H), 2.70-2.66 (m, 1H), 2.10-2.09 (m, 1H), 2.03-1.89 (m, 4H), 1.86-1.76 (m, 1H), 0.94-0.92 (m, 1H), 0.55-0.53 (m, 1H), 0.37 ( br s, 3H). HRMS calculated for C18H25N5O4I (M + H)+: 502.0951; found 502.0951. (S)-N-(Cyclobutyl(cyclopropyl)methyl)-2-iodo-9H-purin-6-amine (55). Compound 55 (84%) was prepared from compound 102 following the same method as for compound 61.1H NMR (CD3OD, 400 MHz) δ 7.23 (s, 1H), 2.62 (br s, 2H), 0.37-0.35 (m, 1H), 0.21-0.23 (m, 2H), 0.44-0.46 (m, 2H). HRMS calculated for C9H11N5Cl (M + H) +: 224.0703; found 224.0702. 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2,6-dichloro-9H- purine (57). Compound 57 was synthesized as reported (compound 54 in Tosh et al.9). 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-6-chloro-2-iodo- 9H- purine (58). Compound 58 was synthesized as reported (compound 11 in Tosh et al.40). 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-iodo-N- (dicyclopropylmethyl)-9H-purin-6-amine (61). Compound 61 (83%) was prepared from compound 58 following the same method as for compound 62; see below.1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H), 7.66-7.62 (m, 4H), 7.43-7.27 (m, 6H), 5.30 (d, J =6.8 Hz, 1H), 4.90 (s, 1H), 4.71(d, J = 6.8 Hz, 1H), 4.23 (d, J = 10.4 Hz, 1H), 3.88 (d, J = 10.4 Hz, 1H), 3.42 (br s, 1H), 1.58-1.52 (m, 4H), 1.32-1.25 (m, 4H), 1.17-1.11 (m, 2H), 1.07 (s, 9H), 1.01-0.98 (m, 1H), 0.60-0.54 (m, 2H), 0.49-0.39 (m, 6H). HRMS calculated for C38H47N5O3SiI (M + H) +: 776.2490; found 776.2493. 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydro cyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N- (dicyclobutylmethyl)-2-iodo-9H-purin-6-amine (62). Dicyclobutylmethanamine hydrochloride (99 mg, 0.71 mmol) and DIPEA (0.24 mL, 1.42 mmol) was added to a solution of compound 58 (100 mg, 0.14 mmol) in isopropanol (1.5 mL) stirred at room temperature overnight. Solvent was evaporated under vacuum, and the residue was purified on flash silicagel column chromatography (hexane: ethyl acetate 2:1) to give compound 62 (94 mg, 82%) as colorless foamy solid.1H NMR (CD3OD, 400 MHz) δ 7.89 (s, 1H), 7.65-7.62 (m, 4H), 7.43-7.29 (m, 6H), 5.64 (d, J = 6.8 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 4.95 (s, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.30 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 2.46- 2.41 (m, 2H), 1.97-1.79 (m, 12H), 1.56-1.54 (m, 4H), 1.25 (s, 3H), 1.08 (s, 9H), 1.01-1.00 (m, 1H). HRMS calculated for C40H51N5O3SiI (M + H)+: 804.2806; found 804.2814. 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydro cyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-chloro-N- (dicyclopentylmethyl)-9H- purin-6-amine (63). Compound 63 (79%) was prepared from compound 57 following the same method as for compound 61.1H NMR (CD3OD, 400 MHz) δ 8.26 (s, 1H), 7.66-7.43 (m, 4H), 7.43-7.30 (m, 6H), 5.35 (d, J = 7.2 Hz, 1H), 4.95 (s, 1 H), 4.72 (d, J = 6.8 Hz, 1H), 4.42 (t, J = 7.2 Hz, 1H), 4.24 (d, J = 10.8 Hz, 1H), 3.75 (d, J = 10.8 Hz, 1H), 2.20-2.14 (m, 2H), 1.81-1.77 (m, 4H), 1.64-1.53 (m, 9H), 1.52 (s, 3H), 1.45-1.33 (m, 4H), 1.25 (s, 3H), 1.14-1.12 (m, 1H), 1.08 (s, 9H), 0.98-0.92 (m, 1H). HRMS calculated for C42H55N5O3SiCl (M + H)+: 740.3763; found 740.3753. 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydro cyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-chloro-N- (dicyclohexylmethyl)-9H-purin-6-amine (64). Compound 64 (84%) was prepared from compound 57 following the same method as for compound 61.1H NMR (CD3OD, 400 MHz) δ 8.28 (s, 1H), 7.66-7.64 (m, 4H), 7.43-7.31 (m, 6H), 5.35 (d, J = 7.2 Hz, 1H), 4.96 (s, 1H), 4.73 (d, J = 6.8 Hz, 1H), 4.29-4.15 (m, 2H), 3.75 (d, J = 6.8 Hz, 1H), 1.77-1.69 (m, 12H), 1.65-1.61 (m, 7H), 1.52 (s, 3H), 1.38-1.22 (m, 5H), 1.14-1.l2 (m, 3H), 1.07 (s, 9H), 0.99-0.95 (m, 1H). HRMS calculated for C44H59N5O3SiCl (M + H)+: 768.4076; found 768.4087. ((3aR,3bR,4aS,5R,5aS)-5-(2-chloro-6-((dicyclopentylmethyl)amino)-9H- purin-9-yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol- 3b(3aH)-yl)methanol (66). TBAF (0.6 mL, 1M solution in THF) was added to a solution of compound 62 (296 mg, 0.4 mmol) in dry THF (5 mL) and stirred for 1 h until completion of starting material. Solvent was evaporated under vacuum and the residue was purified on flash silica gel column chromatography (hexane: ethylacetate = 1:2) to give the alcohol 66 (182 mg, 91%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.22 (s, 1H), 5.39 (d, J = 6.8 Hz, 1H), 4.95 (s, 1H), 4.71 (d, J = 7.2 Hz, 1H), 4.39 (t, J = 6.8 Hz, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.62 (d, J = 11.6 Hz, 1H), 2.24-2.14 (m, 2H), 1.81-1.69 (m, 5H), 1.63-1.54 (m, 7H), 1.52(s, 3H), 1.431.30 (m, 5H), 1.28 (s, 3H), 1.14 (d, J 5.2 Hz, 1H), 0.990.95 (m, 1H). HRMS calculated for C26H37N5O3Cl (M + H) +: 502.2585; found 502.2587. ((3aR,3bR,4aS,5R,5aS)-5-(2-Chloro-6-((dicyclohexylmethyl)amino)-9H- purin-9-yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol- 3b(3aH)-yl)methanol (67). Compound 67 (90%) was prepared from compound 64 following the same method as for compound 66.1H NMR (CD3OD, 400 MHz) δ 8.22 (s, 1H), 5.39 (d, J = 7.2 Hz, 1H), 4.95 (s, 1H), 4.71 (d, J = 7.2 Hz, 1H), 4.17 (t, J = 6.4 Hz, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.62 (d, J = 11.6 Hz, 1H), 1.77-1.66 (m, 16H), 1.52 (s, 3H), 1.33-1.24 (m, 5H), 1.21-1.02 (m, 6H), 0.99-0.96 (m, 1H). HRMS calculated for C28H41N5O3Cl (M + H) +: 530.2898; found 530.2900. ((3aR,3bR,4aS,5R,5aS)-5-(6-((Dicyclopropylmethyl)amino)-2-iodo-9H- purin-9-yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol- 3b(3aH)-yl)methanol (68). Compound 68 (91%) was prepared from compound 61 following the same method as for compound 66.1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H), 5.35 (d, J = 7.2 Hz, 1H), 4.93 (s, 1H), 4.71 (d, J = 6.4 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.4 (br s, 1H), 1.66-1.62 (m, 1H), 1.52 (s, 3H), 1.26 (s, 3H), 1.16- 1.07 (m, 3H), 0.99-0.96 (m, 1H), 0.59-0.54 (m, 2H), 0.47-0.37 (m, 6H). HRMS calculated for C22H29N5O3I (M + H) +: 538.1315; found 538.1314. ((3aR,3bR,4aS,5R,5aS)-5-(2-Chloro-6-((dicyclopropylmethyl)amino)-9H- purin-9-yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol- 3b(3aH)-yl)methyl methanesulfonate (69). Methanesulfonyl chloride (30 µL, 0.37 mmol) was added to a solution of compound 65 (84 mg, 0.18 mmol) in dry pyridine (1 mL) and the mixture was stirred for 30 min at room temperature. Saturated NaHCO3solution was added to quench the reaction, and the aqueous layer was extracted with CH2Cl2 (3 times), dried (Na2SO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 1:2) to give the mesylated derivative 69 (64 mg, 65%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.09 (s, 1H), 5.40 (d, J = 7.2 Hz, 1H), 4.97 (s, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 6.8 Hz, 1H), 3.50 (br s, 1H), 3.16 (s, 3H), 1.85-1.80 (m, 1H), 1.72-1.66 (m, 1H), 1.54 (s, 3H), 1.32-1.30 (m, 1H), 1.27 (s, 3H), 1.21-1.12 (m, 2H), 0.60-0.55 (m, 2H), 0.46-0.39 (m, 6H). HRMS calculated for C23H31N5O5ClS (M + H) +: 524.1734; found 524.1734.((3aR,3bR,4aS,5R,5aS) 5 (2 Chloro 6 ((dicyclohexylmethyl)amino) 9H purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol- 3b(3aH)-yl)methyl methanesulfonate (71). Compound 71 (70%) was prepared from compound 67 following the same method as for compound 69.1H NMR (CD3OD, 400 MHz) δ 8.11 (s, 1H), 5.44 (d, J = 6.8 Hz, 1H), 4.97 (s, 1H), 4.87 (d, J = 11.2 Hz, 1H), 4.81 (d, J = 7.2 Hz, 1H), 4.27 (d, J = 11.2 Hz, 1H), 4.17 (t, J = 6.4 Hz, 1H), 3.17 (s, 3H), 1.85-1.82 (m, 1H), 1.77-1.66 (m, 14H), 1.33-1.30 (m, 2H), 1.27 (s, 3H), 1.21-1.04 (m, 8H). HRMS calculated for C29H43N5O5ClS (M + H)+: 608.2673; found 608.2684. 2-Chloro-9-((3aR,3bS,4aS,5R,5aS)-3b-(chloromethyl)-2,2- dimethylhexahydrocyclopropa [3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N- (dicyclopentylmethyl)-9H-purin-6-amine (72). SOCl2 (57 µL, 0.78 mmol) was added dropwise to a solution of compound 66 (131 mg, 0.26 mmol) in dry CH3CN (4 mL) followed by pyridine (42 µL, 0.52 mmol) at -5oC, and the resulting mixture was stirred for 30 min under the same conditions. After 30 min the reaction mixture was brought to room temperature and stirred for 6 hrs. The reaction mixture was quenched with water and neutralized with 1M NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3 times), dried over Na2SO4, filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 2:1) to afford the chloro derivative 72 (101 mg, 75%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.22 (s, 1H), 5.37 (d, J = 7.2 Hz, 1H), 4.94 (s, 1H), 4.78 (d, J = 7.2 Hz, 1H), 4.39 (t, J = 6.8 Hz, 1H), 4.16 (d, J = 11.6 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 2.22-2.14 (m, 2H), 1.82-1.74 (m, 5H), 1.62-1.56 (m, 7H), 1.53 (s, 3H), 1.43- 1.28 (m, 6H), 1.26 (s, 3H), 1.13-1.09 (m, 1H). HRMS calculated for C26H35N5O2Cl2(M + H)+: 520.2246; found 520.2244. 2-Chloro-9-((3aR,3bS,4aS,5R,5aS)-3b-(chloromethyl)-2,2- dimethylhexahydrocyclopropa [3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N- (dicyclohexylmethyl)-9H-purin-6-amine (73). Compound 73 (73%) was prepared from compound 67 following the same method as for compound 72.1H NMR (CD3OD, 400 MHz) δ 8.15 (s, 1H), 5.37 (d, J = 6.8 Hz, 1H), 4.94 (s, 1H), 4.78 (d, J = 7.2 Hz, 1H), 4.16-4.13 (m, 2H), 3.78 (d, J = 11.6 Hz, 1H), 1.83-1.65 (m, 16H), 1.53 (s, 3H), 1.33-1.21 (m, 5H), 1.21- 1.04 (m, 7H). HRMS calculated for C28H40N5O2Cl2 (M + H)+: 548.2559; found 548.2552. 2-Chloro-N-(dicyclopropylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-3b- (fluoromethyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl) 9H purin 6 amine (74). TBAF (0.12 mL, 1M solution in THF) was added to a solution of compound 69 (21 mg, 0.04 mmol) in dry THF and the mixture heated at 70oC for two h. Solvent was evaporated, and the residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 1:1) to provide the fluoro derivative 74 (15 mg, 83%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.07 (s, 1H), 5.38 (d, J = 6.8 Hz, 1H), 4.98 (d, J = 2.0 Hz, 1H), 4.76-4.72 (m, 1H), 4.58 (dd, J1 = 10.0 Hz, J2 = 48.2 Hz, 1H), 3.46 (br s, 1H), 3.27-3.23 (m, 1H), 1.80-1.77 (m, 1H), 1.72-1.64 (m, 1H), 1.53 (s, 3H), 1.48- 1.39 (m, 1H), 1.27 (s, 3H), 1.16-1.08 (m, 2H), 0.60-0.55 (m, 2H), 0.46-0.39 (m, 6H). HRMS calculated for C22H28N5O2ClF (M + H) +: 448.1916; found 448.1924. 2-Chloro-N-(dicyclopentylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-3b- (fluoromethyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5- yl)-9H-purin-6-amine (75). DAST (17 µL, 0.13 mmol) was added dropwise to a solution of compound 66 (44 mg, 0.08 mmol) in dry CH2Cl2 (1 mL) at 0oC and stirred for 30 min at the same condition. After completion of the starting material solvent was evaporated under vacuum, and the residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 2:1) to give fluoro derivative 75 (24 mg, 55%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.16 (s, 1H), 5.39 (d, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.81-4.74 (m, 2H), 4.76 (d, J = 7.2 Hz, 1H), 4.37 (t, J = 6.8 Hz, 1H), 2.22-2.16 (m, 2H), 1.86-1.71 (m, 5H), 1.63- 1.61 (m, 9H), 1.53 (s, 3H), 1.38-1.31 (m, 4H), 1.27 (s, 3H), 1.12-1.06 (m, 1H). HRMS calculated for C26H36N5O2ClF (M + H)+: 504.2542; found 504.2545. 2-Chloro-N-(dicyclohexylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-3b- (fluoromethyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5- yl)-9H-purin-6-amine (76). Compound 76 (85%) was prepared from compound 71 following the same method as for compound 74.1H NMR (CD3OD, 400 MHz) δ 8.09 (s, 1H), 5.38 (d, J = 6.8 Hz, 1H), 4.97 (s, 1H), 4.86-4.74 (m, 2H), 4.57 (dd, J1 = 10 Hz, J2 = 48.6 Hz, 1H), 1.17 (t, J = 6.4 Hz, 1H), 1.76-1.65 (m, 15H), 1.53 (s, 3H), 1.33-1.24 (m, 5H), 1.20-1.04 (m, 8H). HRMS calculated for C28H40N5O2ClF (M + H) +: 532.2855; found 532.2857. 2-Chloro-N-(dicyclopentylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl- 3b- ((methylthio)methyl)hexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)- 9H-purin- 6-amine (77). Compound 77 (65%) was prepared from compound 72 following the same method as for compound 87, as described later herein.1H NMR (CD3OD, 400 MHz) δ 8.15 (s, 1H), 5.33 (d, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.77 (d, J = 7.2 Hz, 1H), 4.40 (t, J6.8 Hz, 1H), 3.24 (d, J 13.6 Hz, 1H), 2.75 (d, J 13.6 Hz, 1H), 2.222.14 (m, 5H), 1.81 1.74 (m, 4H), 1.66-1.54 (m, 9H), 1.53 (s, 3H), 1.44-1.28 (m, 4H), 1.26 (s, 3H), 1.19 (t, J = 4.8 Hz, 1H), 1.00-0.97 (m, 1H). HRMS calculated for C27H39N5O2ClS (M + H) +: 532.2513; found 532.2513. 2-Chloro-N-(dicyclopentylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-3b- ((ethylthio)methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol- 5-yl)-9H-purin-6-amine (78). Compound 78 (70%) was prepared from compound 72 following the same method as for compound 87.1H NMR (CD3OD, 400 MHz) δ 8.17 (s, 1H), 5.33 (d, J = 6.8 Hz, 1H), 4.90 (s, 1H), 4.77 (d, J = 7.2 Hz, 1H), 4.40 (t, J = 6.8 Hz, 1H), 3.22 (d, J = 13.4 Hz, 1H), 2.85 (d, J = 13.4 Hz, 1H), 2.64-2.59 (m, 2H), 2.24-2.14 (m, 2H), 1.81- 1.63 (m, 4H), 1.63-1.54 (m, 9H), 1.52 (s, 3H), 1.44-1.22 (m, 10H), 1.17 (t, J = 4.8 Hz, 1H), 1.00-0.96 (m, 1H). HRMS calculated for C28H41N5O2ClS (M + H) +: 546.2670; found 546.2667. 9-((3aR,3bS,4aS,5R,5aS)-3b-((butylthio)methyl)-2,2- dimethylhexahydrocyclopropa[3,4] cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-chloro-N- (dicyclopentylmethyl)-9H-purin-6-amine (79). Compound 79 (73%) was prepared from compound 72 following the same method as for compound 87.1H NMR (CD3OD, 400 MHz) δ 8.16 (s, 1H), 5.33 (d, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.79 (d, J = 7.2 Hz, 1H), 4.40 (t, J = 6.8 Hz, 1H), 3.19 (d, J = 13.2 Hz, 1H), 2.87 (d, J = 13.2 Hz, 1H), 2.56 (t, J = 7.2 Hz, 2H), 2.22- 2.14 (m, 2H), 1.78-1.74 (m, 5H), 1.65-1.55 (m, 8H), 1.52 (s, 3H), 1.41-1.29 (m, 8H), 1.27 (s, 3H), 1.15 (t, J = 4.8 Hz, 1H), 1.00-0.94 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H). HRMS calculated for C30H45N5O2ClS (M + H)+: 574.2983; found 574.2988. 2-Chloro-N-(dicyclopentylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-3b-(((2- fluorophenyl)thio) methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2- d][1,3]dioxol-5-yl)-9H-purin-6-amine (81). Compound 81 (74%) was prepared from compound 72 following the same method as for compound 87.1H NMR (CD3OD, 400 MHz) δ 8.06 (s, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.20-7.15 (m, 1H), 7.05-6.98 (m, 2H), 5.35 (d, J = 6.8 Hz, 1H), 4.85 (s, 1H), 4.79 (d, J = 7.2 Hz, 1H), 4.40 (t, J = 6.8 Hz, 1H), 3.65 (d, J = 13.2 Hz, 1H), 3.29 (d, J = 13.2 Hz, 1H), 2.22-2.16 (m, 2H), 1.83-1.73 (m, 4H), 1.68-1.53 (m, 9H), 1.51 (s, 3H), 1.40-1.33 (m, 4H), 1.25 (s, 3H), 1.09 (t, J = 4.8 Hz, 1H), 0.96-0.93 (m, 1H). HRMS calculated for C32H40N5O2ClSF (M + H)+: 612.2575; found 612.2567.2 Chloro N (dicyclopentylmethyl) 9 ((3aR,3bS,4aS,5R,5aS) 3b (((3,4 dimethoxyphenyl) thio)methyl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2- d][1,3]dioxol-5-yl)-9H-purin-6-amine (84). Compound 84 (72%) was prepared from compound 72 following the same method as for compound 87.1H NMR (CD3OD, 400 MHz) δ 8.05 (s, 1H), 7.08-7.04 (m, 2H), 6.84-6.82 (m, 1H), 5.34 (d, J = 6.8 Hz, 1H), 4.88 (s, 1H), 4.76 (d, J = 6.4 Hz, 1H), 4.39 (t, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.60 (d, J = 13.4 Hz, 1H), 3.21(d, J = 13.4 Hz, 1H), 2.24-2.16 (m, 2H), 1.84-1.69 (m, 4H), 1.68-1.56 (m, 8H), 1.54 (s, 3H), 1.45-1.30 (m, 5H), 1.26 (s, 3H), 1.14-1.08 (m, 1H), 0.94-0.87 (m, 1H). HRMS calculated for C34H45N5O4SCl (M + H)+: 654.2881; found 654.2883. 2-Chloro-N-(dicyclopropylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl- 3b-((methylthio) methyl)hexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)- 9H-purin-6-amine (85). Sodium thiomethoxide (17 mg, 0.24 mmol) was added to a solution of compound 69 (25 mg, 0.047 mmol) in dry DMF (1 mL) at 0oC and stirred for 1 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with ethyl acetate (3 times), dried over Na2SO4, filtered, and evaporated. The residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 2:1) to give compound 85 (15 mg, 66%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H), 5.32 (d, J = 6.8 Hz, 1H), 4.90 (s, 1H), 4.75 (d, J = 6.8 Hz, 1H), 3.47 (br s, 1H), 3.21 (d, J = 13.6 Hz, 1H), 2.75 (d, J = 13.6 Hz, 1H), 2.16 (s, 3H), 1.59-1.55 (m, 1H), 1.52 (s, 3H), 1.26 (s, 3H), 1.19- 1.09 (m, 3H), 0.99-0.96 (m, 1H), 0.60-0.55 (m, 2H), 0.47-0.43 (m, 6H). HRMS calculated for C23H31N5O2ClS (M + H)+: 477.0360; found 477.0364. N-(Dicyclopropylmethyl)-9-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b- ((methylthio)methyl) hexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-2- iodo-9H-purin-6-amine (86). Compound 86 (85%) was prepared from compound 70 following the same method as for compound 85.1H NMR (CD3OD, 400 MHz) δ 8.03 (s, 1H), 5.31 (d, J = 6.8 Hz, 1H), 4.91 (s, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.12 (d, J = 13.6 Hz, 1H), 2.71 (d, J = 13.6 Hz, 1H), 2.17 (s, 3H), 1.52-1.50 (m, 4H), 1.26 (s, 3H), 1.17-1.07 (m, 3H), 0.99- 0.95 (m, 1H), 0.60-0.54 (m, 2H), 0.47-0.37 (m, 6H). HRMS calculated for C23H31N5O2IS (M + H)+: 568.1243; found 568.1249. 9-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b- ((methylthio)methyl)hexahydrocyclopropa[3,4] cyclopenta[1,2-d][1,3]dioxol-5-yl)-2- iodo-9H-purin-6-amine (87). Sodium thiomethoxide (29 mg, 0.41 mmol) was added to asolution of compound 104 (38 mg, 0.082 mmol) in dry DMF (1 mL) stirred at room temperature for 1 h. The reaction mixture was evaporated under vacuum and the residue was purified on flash silica gel column chromatography (EtOAc: MeOH = 100:0.5) to give compound 87 (15 mg, 39%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.08 (s, 1H), 5.32 (d, J = 7.2 Hz, 1H), 4.89 (s, 1H), 4.77 (d, J = 7.2 Hz, 1H), 2.72 (d, J = 13.6 Hz, 1H), 2.17-2.14 (m, 4H), 1.53-.151 (m, 4H), 1.27 (s, 3H), 1.17 (d, J = 4.8 Hz, 1H), 1.00-0.96 (m, 1H). HRMS calculated for C16H21N5O2IS (M + H) +: 474.0461; found 474.0461. 1-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydro cyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-4,6-dichloro-1H- imidazo[4,5-c]pyridine (88). Diisopropyl azodicarboxylate (DIAD) (0.22 mL, 1.16 mmol) was added to a solution of triphenylphosphine (306 mg, 1.16 mmol) and 3-deaza-2,6- dichloro-purine (220 mg, 1.16 mmol) in dry THF (5 mL) at 0 °C and stirred at room temperature for 10 min. A solution of compound 56 (256 mg, 0.58 mmol) in THF (2 mL) was added to the reaction mixture and stirred overnight at room temperature. Solvent was evaporated, and the residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 3:1) to give compound 88 (209 mg, 59%) as a colorless foamy solid.1H NMR (CD3OD, 400 MHz) δ 8.88 (s, 1H), 7.72-7.67 (m 5H), 7.46-7.36 (m, 6H), 5.68 (s, 1H), 5.37 (d, J = 6.8 Hz, 1H), 4.79 (d, J = 7.2 Hz, 1H), 4.29 (d, J = 11.2 Hz, 1H), 3.47 (d, J = 11.2 Hz, 1H), 1.94-1.91 (m, 1H), 1.52 (s, 3H), 1.29 (s, 3H), 1.25 (t, J = 4.8 Hz,1H), 1.14 (s, 9H), 0.93- 0.90 (m, 1H). HRMS calculated for C32H36N3O3Cl2Si (M + H) +: 608.1903; found 608.1904. 1-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-6-chloro-N- (dicyclopentylmethyl)-1H-imidazo[4,5-c]pyridin-4-amine (89). Dicyclopentylmethanamine (178 mg, 0.87 mmol) and DIPEA (0.38 mL, 2.18 mmol) was added to a solution of compound 88 (133 mg, 0.21 mmol) in isopropanol (2 mL) and heated at 140oC under microwave condition for 25 h. Solvent was evaporated under vacuum, and the residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 4:1) to give compound 89 (36 mg, 22%) as colorless foamy solid.1H NMR (CD3OD, 400 MHz) δ 8.33 (s, 1H), 7.72-7.65 (m 4H), 7.46-7.35 (m, 6H), 6.73 (s, 1H), 5.36 (d, J = 7.2 Hz, 1H), 4.82 (s, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.38 (br s, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 2.19-2.13 (m, 2H), 1.79-1.73 (m, 5H), 1.60-1.52 (m, 11H), 1.42-1.32 (m,4H), 1.27 (s, 3H), 1.19 (t, J 4.8 Hz, 1H), 1.14 (s, 9H), 0.91 0.87 (m, 1H). HRMS calculated for C43H56N4O3ClSi (M + H) +: 739.3810; found 739.3822. 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydro cyclopropa [3,4]cycloenta[1,2-d][1,3]dioxol-5-yl)-N-((R)- cyclobutyl(cyclopropyl)methyl)-2-iodo-9H-purin-6-amine (90). (R)- cyclobutyl(cyclopropyl)methanamine hydrochloride (115 mg, 0.71 mmol) and DIPEA (0.24 mL, 1.42 mmol) was added to a solution of compound 58 (100 mg, 0.14 mmol) in isopropanol (1.5 mL) stirred at room temperature overnight. Solvent was evaporated under vacuum, and the residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 2:1) to give compound 90 (108 mg, 96%) as colorless foamy solid.1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H), 7.66-7.62 (m, 4H), 7.41-7.27 (m, 6H), 5.30 (d, J = 6.8 Hz, 1H), 4.90 (s, 1H), 4.71 (d, J = 6.8 Hz, 1H), 4.23 (d, J = 10.8 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.80 (br s, 1H), 2.70-2.66 (m, 1H), 2.11-2.09 (m, 1H), 1.98-1.87 (m, 4H), 1.82-1.79 (m, 1H), 1.59-1.52 (m, 4H), 1.25 (s, 3H), 1.11 (s, 9H), 1.01-0.91 (m, 3H), 0.56-0.54 (m, 1H), 0.48-0.37 (m, 3H). HRMS calculated for C39H49N5O3SiI (M + H)+: 790.2649; found 790.2642. 9-((3aR,3bR,4aS,5R,5aS)-3b-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N-((S)- cyclobutyl(cyclopropyl)methyl)-2- iodo-9H-purin-6-amine (91). Compound 91 (89%) was prepared from compound 58 following the same method for compound 90.1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H), 7.67-7.62 (m, 4H), 7.41-7.26 (m, 6H), 5.30 (d, J = 6.8 Hz, 1H), 4.90 (s, 1H), 4.71 (d, J = 6.8 Hz, 1H), 4.23 (d, J = 10.4 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.81 (br s, 1H), 2.72-2.70 (m, 1H), 2.12-2.09 (m, 1H), 2.01-1.89 (m, 4H), 1.85-1.79 (m, 1H), 1.59-1.52 (m, 4H), 1.25 (s, 3H), 1.07 (s, 9H), 1.01-0.92 (m, 3H), 0.57-0.53 (m, 1H), 0.47- 0.37 (m, 3H). HRMS calculated for C39H49N5O3SiI (M + H)+: 790.2649; found 790.2646. Ethyl (3aR,3bS,4aS,5R,5aS)-5-(2-chloro-6-((dicyclopentylmethyl)amino)- 9H-purin-9-yl)- 2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole- 3b(3aH)-carboxylate (94). Compound 94 (84%) was prepared from compound 93a following the same method as for compound 90 (see Fig.4; Reagents and Conditions: (i) R1NH2.HCl, DIPEA, 2-propanol, rt; (ii) 10% TFA, MeOH, 70oC).1H NMR (CD3OD, 400 MHz) δ 8.05 (s, 1H), 5.86 (d, J = 7.2 Hz, 1H), 4.97 (s, 1H), 4.81 (d, J = 6.8 Hz, 1H), 4.38 (d,J 7.2 Hz, 1H), 4.28 4.20 (m, 2H), 2.282.23 (m, 1H), 2.212.13 (m, 2H), 1.841.71 (m, 5H), 1.67-1.52 (m, 9H), 1.51 (s, 3H), 1.43-1.38 (m, 2H), 1.35-1.31 (m, 5H), 1.26 (s, 3H). HRMS calculated for C28H39N5O4Cl (M + H) +: 544.2691; found 544.2689. Ethyl (3aR,3bS,4aS,5R,5aS)-5-(2-iodo-6-(((S)- cyclobutyl(cyclopropyl)methyl)amino)-9H- purin-9-yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate (95). Compound 95 (86%) was prepared from compound 93b following the same method as for compound 90 (Reagents and Conditions: (i) TEMPO, BAIB, CH3CN-H2O, rt; (ii) Deoxo- Fluor, CH2Cl2, rt; (iii) Dowex50, MeOH-H2O).1H NMR (CD3OD, 400 MHz) δ 7.95 (s, 1H), 5.82 (d, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.81 (d, J = 6.8 Hz, 1H), 4.33-4.24 (m, 2H), 3.77 (br s, 1H), 2.71-2.65 (m, 1H), 2.26-2.22 (m, 1H), 2.10-2.06 (m, 1H), 1.99-1.82 (m, 4H), 1.82-1.79 (m, 1H), 1.64-1.60 (m, 1H), 1.53-1.49 (m, 4H), 1.34 (t, J = 7.2 Hz, 3H), 1.28 (s, 3H), 0.93- 0.87 (m, 1H), 0.56 (t, J = 7.2 Hz, 1H), 0.35 (br s, 3H). HRMS calculated for C25H33N5O4I (M + H)+: 594.1577; found 594.1578. (3aR,3bS,4aS,5R,5aS)-5-(2-chloro-6-((dicyclopropylmethyl)amino)-9H- purin-9-yl)-N,N- bis(2-methoxyethyl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxamide (99). Deoxo-Fluor (0.21 mL, 45% solution in THF, 0.32 mmol) was added to a solution of compound 97 (prepared as reported, 975 mg, 0.16 mmol) in dry CH2Cl2and stirred overnight at room temperature (Reagents and Conditions: (i) TEMPO, BAIB, CH3CN-H2O, rt; (ii) Deoxo-Fluor, CH2Cl2, rt; (iii) Dowex50, MeOH-H2O). Solvent was evaporated and the residue was purified on flash silica gel column chromatography (hexane:ethyl acetate = 1:2) to give a product 99 (56 mg, 60%) as colorless syrup instead of desired product 98.1H NMR (CD3OD, 400 MHz) δ 8.48 (s, 1H), 5.30 (d, J = 7.2 Hz, 1H), 5.02 (s, 1H), 4.74 (d, J = 7.2 Hz, 1H), 4.08-4.05 (m, 1H), 3.71-3.48 (m, 14H), 2.26-2.22 (m, 1H), 1.60-1.57 (m, 4H), 1.44-1.40 (m, 1H), 1.27 (s, 3H), 1.18-1.09 (m, 2H), 0.60-0.55 (m, 2H), 0.44-0.42 (m, 6H). HRMS calculated for C28H40N6O5Cl (M + H)+: 575.2745; found 575.2748. ((3aR,4R,6R,6aR)-6-(6-(((S)-cyclobutyl(cyclopropyl)methyl)amino)-2-iodo- 9H-purin-9-yl)- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (101). Compound 101 (82%) was prepared from compound 100 (see Fig.6A; Reagents and Conditions: A. (i) (S)-(c-Bu)(c-Pr)CHNH2.HCl, DIPEA, 2-propanol, rt; (iii) 10% TFA, MeOH, 70oC. B. (i) c-Pr(CH2)NH2, DIPEA, 2-propanol, rt.) following the same method asfor compound 62. H NMR (CD3OD, 400 MHz) δ 8.15 (s, 1H), 6.11 (d, J 7.2 Hz, 1H), 5.25-5.23 (m, 1H), 5.03-5.01 (m, 1H), 4.36-4.33 (m, 1H), 3.82-3.72 (m, 3H), 2.70-2.64 (m, 1H), 2.11-2.06 (m, 1H), 1.99-1.88 (m, 4H), 1.84-1.79 (m, 1H), 1.62 (s, 3H), 1.39 (s, 3H), 0.94-0.89 (m, 1H), 0.55 (t, J = 7.6 Hz, 1H), 0.37 (br s, 3H). HRMS calculated for C21H29N5O4I (M + H) +: 541.1264; found 541.1264. 9-((3aR,3bS,4aS,5R,5aS)-3b-(chloromethyl)-2,2- dimethylhexahydrocyclopropa[3,4] cyclopenta[1,2-d][1,3]dioxol-5-yl)-2-iodo-9H-purin- 6-amine (104). SOCl2(62 µL, 0.78 mmol) was added dropwise to a solution of compound 68 (152 mg, 0.28 mmol) in dry CH3CN (3 mL) followed by pyridine (46 µL, 0.56 mmol) at -5oC, and the resulting mixture was stirred for 30 min under the same conditions (see FIG.6B; Reagents and Conditions: (i) SOCl2, pyridine, CH3CN, -5oC to rt; (iii) 10% TFA, MeOH, 70oC; (iii) CH3SNa, DMF, rt.). After 30 min the reaction mixture was brought to room temperature and stirred overnight. The reaction mixture was quenched with water and neutralized with 1M NaHCO3solution. The aqueous layer was extracted with CH2Cl2(3 times), dried over Na2SO4, filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane: ethyl acetate = 1:2) to afford the chloro derivative 104 (90 mg, 69%) as a colorless syrup.1H NMR (CD3OD, 400 MHz) δ 8.09 (s, 1H), 5.36 (d, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.79 (d, J = 7.2 Hz, 1H), 4.26 (d, J = 11.6 Hz, 1H), 3.73 (d, J = 11.6 Hz, 1H), 1.79-1.75 (m, 1H), 1.53 (s, 3H), 1.30-1.25 (m, 4H), 1.13-1.09 (m, 1H). HRMS calculated for C15H18N5O2ClI (M + H)+: 462.0194; found 462.0200. (3aR,3bR,4aS,5R,5aS)-5-(6-(cyclopentylamino)-2-iodo-9H-purin-9-yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carbonitrile. This compound is an intermediate in the synthesis of MRS8209 (see below). As shown in Fig.7, TEMPO (8.5 mg, 0.05 mmol) and iodine (201 m, 1.68 mmol) were added to a solution of 4'-hydroxymethyl derivative (291 mg, 0.56 mmol) in CH2Cl2(5 mL) and stirred for 2 h at room temperature. After 2 h, iodine (201 m, 1.68 mmol) was again added followed by ammonium hydroxide solution (5 mL) and heated the reaction mixture at 60oC overnight. Saturated solution of Na2S2O3 (10 mL) was added into the reaction mixture to quench the reaction and aqueous layer was extracted with CH2Cl2(3 times), dried (Na2SO4), filtered and evaporated under vacuum. The crude reaction mixture was purified on flash silica gel column chromatography (hexane:ethyl acetate = 1:2) to give the 4'- cyano derivative as a colorless powder (245 mg, 85%).1H NMR (CD3OD, 400 MHz) δ 7.93 (s, 1H), 5.61 (d, J = 7.2 Hz,1H), 4.99 (s, 1H), 4.87 (d, J 7.2 Hz, 1H), 4.51 (br s, 1H), 2.442.40 (m, 1H), 2.122.06 (m, 2H), 1.84-1.80 (m, 2H), 1.77-1.67 (m, 2H), 1.64-1.58 (m, 4H), 1.55 (s, 3H), 1.28 (s, 3H). HRMS calculated for C20H24N6O2I (M + H) +: 507.1005; found 507.1010. (1R,2R,3S,4R,5S)-4-(6-(cyclopentylamino)-2-iodo-9H-purin-9-yl)-2,3- dihydroxybicyclo[3.1.0]hexane-1-carbonitrile (MRS8209) (40). As shown in Fig.7, a solution of 245 mg (0.48 mmol) of the 4'-cyano derivative, as described in the preceding paragraph, in methanol (5 mL) and 10% TFA (aqueous, 5 mL) was heated at 70oC for 3 h. Solvent was evaporated under reduced pressure and the residue was purified on flash silica gel column chromatography (CH2Cl2:MeOH = 20:1) to provide compound MRS8209 (205 mg, 91%) as colorless powder.1H NMR (CD3OD, 400 MHz) δ 7.97 (s, 1H), 5.13 (d, J = 7.2 Hz, 1H), 4.79 (s, 1H), 4.51 (br s, 1H), 4.08 (d, J = 6.8 Hz, 1H), 2.38-2.34 (m, 1H), 2.14-2.06 (m, 2H), 1.94 (t, J = 5.2 Hz, 1H), 1.84-1.80 (m, 2H), 1.77-1.67 (m, 2H), 1.66-1.55 (m, 2H), 1.47-1.43 (m, 1H). HRMS calculated for C17H20N6O2I (M + H)+: 467.0692; found 467.0697. 2-((1S,2R,3S,4R,5S)-4-(6-(cyclopentylamino)-2-iodo-9H-purin-9-yl)-2,3- dihydroxybicyclo [3.1.0]hexan-1-yl)acetonitrile (41). Compound 41 was prepared following the same method as per above method for compound 40.1H NMR (CD3OD, 400 MHz) δ 8.02 (s, 1H), 4.77 (s, 1H), 4.74 (d, J = 6.4 Hz, 1H), 4.50 (br s, 1H), 3.94 (d, J = 6.8 Hz, 1H), 3.19-3.01 (m, 2H), 2.13-2.06 (m, 2H), 1.83-1.77 (m, 2H), 1.71-1.65 (m, 3H), 1.62- 1.55 (m, 3H), 0.92-0.88 (m, 1H). HRMS calculated for C18H22N6O2I (M + H) +: 481.0849; found 481.0850. (1R,2R,3S,4R,5S)-4-(6-(((R)-3,3-difluorocyclopentyl)amino)-2-iodo-9H- purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carbonitrile (42).1H NMR (CD3OD, 400 MHz) δ 8.00 (s, 1H), 5.13 (d, J = 6.8 Hz, 1H), 4.80 (s, 1H), 4.70 (br s, 1H), 4.08 (d, J = 6.4 Hz, 1H), 2.72-2.60 (m, 1H), 2.38-2.29 (m, 3H), 2.20-2.08 (m, 2H), 1.94 (t, J = 4.8 Hz, 1H), 1.91-1.83 (m, 1H), 1.48-1.44 (m, 1H). HRMS calculated for C17H18N6O2IF2(M + H) +: 503.0504; found 503.0509. 2-((1S,2R,3S,4R,5S)-4-(6-(((R)-3,3-difluorocyclopentyl)amino)-2-iodo-9H- purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)acetonitrile (43).1H NMR (CD3OD, 400 MHz) δ 8.02 (s, 1H), 4.78 (s, 1H), 4.74-4.71 (m, 2H), 3.94 (d, J = 6.8 Hz, 1H), 3.19-3.05 (m, 2H), 2.72-2.60 (m, 1H), 2.39-2.29 (m, 2H), 2.23-2.08 (m, 2H), 1.94-1.83 (m, 1H), 1.68- 1.65 (m, 1H), 1.56 (t, J = 5.2 Hz, 1H), 0.92-0.88 (m, 1H). HRMS calculated for C18H20N6O2IF2 (M + H) +: 517.0660; found 517.0659.(1R,2R,3S,4R,5S) 4 (6 (((S) 3,3 difluorocyclopentyl)amino) 2 iodo 9H purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carbonitrile (44).1H NMR (CD3OD, 400 MHz) δ 7.99 (s, 1H), 5.13 (d, J = 6.8 Hz, 1H), 4.80 (s, 1H), 4.70 (br s, 1H), 4.08 (d, J = 6.4 Hz, 1H), 2.72-2.60 (m, 1H), 2.38-2.29 (m, 3H), 2.21-2.08 (m, 2H), 1.94 (t, J = 4.8 Hz, 1H), 1.91-1.84 (m, 1H), 1.48-1.44 (m, 1H). HRMS calculated for C17H18N6O2IF2 (M + H) +: 503.0504; found 503.0509. 2-((1S,2R,3S,4R,5S)-4-(6-(((S)-3,3-difluorocyclopentyl)amino)-2-iodo-9H- purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)acetonitrile (45).1H NMR (CD3OD, 400 MHz) δ 8.01 (s, 1H), 4.78 (s, 1H), 4.74-4.71 (m, 2H), 3.94 (d, J = 6.8 Hz, 1H), 3.19-3.05 (m, 2H), 2.72-2.60 (m, 1H), 2.39-2.29 (m, 2H), 2.23-2.08 (m, 2H), 1.93-1.83 (m, 1H), 1.68- 1.65 (m, 1H), 1.56 (t, J = 5.2 Hz, 1H), 0.92-0.88 (m, 1H). HRMS calculated for C18H20N6O2IF2(M + H) +: 517.0660; found 517.0654. (1R,2R,3S,4R,5S)-4-(6-(bicyclo[1.1.1]pentan-1-ylamino)-2-iodo-9H-purin-9- yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carbonitrile (46).1H NMR (CD3OD, 400 MHz) δ 7.97 (s, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.79 (s, 1H), 4.07 (d, J = 6.4 Hz, 1H), 2.52 (s, 1H), 2.38-2.34 (m, 1H), 2.25 (s, 6H), 1.95 (t, J = 4.8 Hz, 1H), 1.47-1.43 (m, 1H). HRMS calculated for C17H18N6O2I (M + H) +: 465.0536; found 465.0537. 2-((1S,2R,3S,4R,5S)-4-(6-(bicyclo[1.1.1]pentan-1-ylamino)-2-iodo-9H-purin- 9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)acetonitrile (47).1H NMR (CD3OD, 400 MHz) δ 8.00 (s, 1H), 4.77 (s, 1H), 4.74 (d, J = 6.8 Hz, 1H), 3.93 (d, J = 6.4 Hz, 1H), 3.19- 3.04 (m, 2H), 2.52 (s, 1H), 2.48 (s, 6H), 1.68-1.65 (m, 1H), 1.56 (t, J = 5.2 Hz, 1H), 0.91- 0.87 (m, 1H). HRMS calculated for C18H20N6O2I (M + H) +: 479.0692; found 479.0698. (1R,2R,3S,4R,5S)-4-(6-((3-chlorobenzyl)amino)-2-iodo-9H-purin-9-yl)-2,3- dihydroxy bicyclo[3.1.0]hexane-1-carbonitrile (48).1H NMR (CD3OD, 400 MHz) δ 7.99 (s, 1H), 7.43 (s, 1H), 7.34-7.24 (m, 3H), 5.13 (d, J = 6.8 Hz, 1H), 4.79 (s, 1H), 4.72 (br s, 2H), 4.08 (d, J = 6.4 Hz, 1H), 2.39-2.35 (m, 1H), 1.94 (t, J = 5.2 Hz, 1H), 1.47-1.43 (m, 1H). HRMS calculated for C19H17N6O2ICl (M + H) +: 523.0146; found 523.0142. 2-((1S,2R,3S,4R,5S)-4-(6-((3-chlorobenzyl)amino)-2-iodo-9H-purin-9-yl)- 2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)acetonitrile (49).1H NMR (CD3OD, 400 MHz) δ 8.01 (s, 1H), 7.43 (s, 1H), 7.34-7.25 (m, 3H), 4.78 (s, 1H), 4.74-4.73 (m, 3H), 3.94 (d, J = 6.8 Hz, 1H), 3.18-3.05 (m, 2H), 1.69-1.66 (m, 1H), 1.56 (t, J = 5.2 Hz, 1H), 0.91-0.88 (m, 1H). HRMS calculated for C20H20N6O2ICl (M + H) +: 537.0303; found 537.0302.1R,2R,3S,4R,5S) 4 (2 (5 chlorothiophen 2 yl) 6 (methylamino) 9H purin 9 yl)-2,3-dihydroxybicyclo [3.1.0]hexane-1-carbonitrile (50).1H NMR (CD3OD, 400 MHz) δ 8.02 (s, 1H), 7.88 (d, J = 4.0 Hz, 1H), 7.00 (d, J = 4.0 Hz, 1H), 5.41 (d, J = 6.8 Hz, 1H), 4.82 (s, 1H), 4.22 (d, J = 6.8 Hz, 1H), 3.17 (br s, 3H), 2.42-2.38 (m, 1H), 1.91 (t, J = 4.8 Hz, 1H), 1.50-1.47 (m, 1H). HRMS calculated for C17H16N6O2SCl (M + H) +: 403.0744; found 403.0744. (1R,2R,3S,4R,5S)-4-(2-(5-chlorothiophen-2-yl)-6-(propylamino)-9H-purin- 9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carbonitrile (51).1H NMR (CD3OD, 400 MHz) δ 8.03 (s, 1H), 7.87 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 4.0 Hz, 1H), 5.41(d, J = 6.4 Hz, 1H), 4.82 (s, 1H), 4.22 (d, J = 6.8 Hz, 1H), 3.63 (br s, 2H), 2.42-2.38 (m, 1H), 1.91 (t, J = 4.8 Hz, 1H), 1.79-1.73 (m, 2H), 1.50-1.46 (m, 1H), 1.05 (t, J = 7.6 Hz, 3H). HRMS calculated for C19H20N6O2SCl (M + H) +: 431.1057; found 431.1053. (1R,2R,3S,4R,5S)-4-(2-((5-chlorothiophen-2-yl)ethynyl)-6-(methylamino)- 9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carbonitrile (52).1H NMR (CD3OD, 400 MHz) δ 8.21 (s, 1H), 7.36 (d, J = 4.0 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 5.10 (d, J = 6.4 Hz, 1H), 4.85 (s, 1H), 4.08 (d, J = 6.4 Hz, 1H), 3.15 (br s, 3H), 2.47-2.43 (m, 1H), 2.01 (t, J = 5.2 Hz, 1H), 1.51-1.48 (m, 1H). HRMS calculated for C19H16N6O2SCl (M + H)+: 427.0744; found 427.0748. (1R,2R,3S,4R,5S)-4-(2-(benzylthio)-6-(methylamino)-9H-purin-9-yl)-1- (hydroxymethyl) bicyclo[3.1.0]hexane-2,3-diol (54).1H NMR (CD3OD, 400 MHz) δ 8.36 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.31-7.19 (m, 3H), 4.85 (s, 1H), 4.76 (d, J = 6.4 Hz, 1H), 4.52-4.44 (m, 2H), 4.27 (d, J = 12.0 Hz, 1H), 3.88 (d, J = 6.4 Hz, 1H), 3.22 (d, J = 7.2 Hz, 1H), 3.11 (br s, 3H), 1.62-1.59 (m, 1H), 1.55 (d, J = 4.8 Hz, 1H), 0.77-0.74 (m, 1H). HRMS calculated for C20H24N5O3S (M + H)+: 414.1600; found 414.1605. 2-((1S,2R,3S,4R,5S)-4-(2-(benzylthio)-6-(methylamino)-9H-purin-9-yl)-2,3- dihydroxy bicyclo[3.1.0]hexan-1-yl)acetonitrile (55).1H NMR (CD3OD, 400 MHz) δ 8.05 (s, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.30-7.19 (m, 3H), 4.82 (s, 1H), 4.66 (d, J = 6.4 Hz, 1H), 4.52-4.44 (m, 2H), 4.00 (d, J = 6.8 Hz, 1H), 3.13-3.09 (m, 4H), 2.86 (d, J = 17.2 Hz, 1H), 1.75-1.72 (m, 1H), 1.63 (d, J = 5.2 Hz, 1H), 0.90-0.86 (m, 1H). HRMS calculated for C21H23N6O2S (M + H)+: 423.1603; found 423.1609. Figure 8 depicts a reaction scheme to synthesize certain 4′-modified (N)- methanocarba-adenosine derivatives in accordance with an aspect of the invention. Reagentsand Conditions: (i) R1NH2, DIPEA, 2-propanol, rt-70oC; (ii) TBAF, THF, rt; (iii) TEMPO, I2,CH2Cl2, NH4OH, rt-60oC; (iv) (a) TEMPO, BAIB, CH3CN, rt; (b) Deoxofluoro or DAST, CH2Cl2, rt;(v) acetone cyanohydrin, Ph3P, DIAD, THF, rt; (vi) (a) MsCl, pyridine, rt; (b) KSCN, DMF, 80oC;(vii) 2H-1,2,3-triazole, Ph3P, DIAD, THF, rt; (viii) 10% TFA, MeOH, 70oC.Figure 9 depicts a reaction scheme to synthesize certain 4’-aryl derivatives in accordance with another aspect of the invention. Reagents and Conditions: (i) TEMPO, BAIB, CH3CN-H2O rt; (ii) DCC, N'-hydroxyacetimidamide, DMF, 90oC; (iii) 10% TFA, MeOH, 70oC. EXAMPLE 2 This example illustrates the binding affinities of some of the compounds of the invention. The binding affinity at the three human (h) 5-HT2Rs and 2 - 3 subtypes of hARs was determined as reported in Tosh et al.2016. The compounds showed weak binding at the 5-HT2AR. An N6-alkyl, cycloalkyl or dicycloalkylmethyl group was required for binding at 5- HT2Rs, as indicated by the inactivity of 6-NH2 derivatives 9 and 10, which nevertheless displayed AR affinity. In the series of N6-dicycloalkylmethyl 4′-CH2OH analogues with the same (Cl) substitution at the C2 position, with increasing the cycloalkyl ring size from 3 to 5 carbons, there was a progression toward lower 5-HT2BR affinity (Ki, nM): 4 (11) > 18 (136) > 24 (797). However, the progression was opposite when comparing 5-HT2CR affinity of the series of N6-dicycloalkylmethyl 4′-CH2Cl analogues with the same C2-chloro substitution. Upon increasing ring size in that series from 4 to 6, 5-HT2C affinities increased with Ki values of 908, 580 and 73.5 nM, for 21, 27 and 36, respectively. However, in the same series the 5-HT2Baffinity trended lower (Ki, nM): 21 (205), 27 (496), 36 (586). With asymmetric Cα substitution, there was a small stereochemical preference. The 5-HT2BR affinity varied according to asymmetric N6substitution: (R)-cyclobutyl-cyclopropyl) (42, Ki 77 nM) > ((R)- cyclopropyl-prop-2-yl) (37, Ki 163 nM) analogues (both being 2-Cl-4′-CH2OH analogues). When these two compounds were modified with 2-I, the 5-HT2BR affinity improved significantly in both cases (43, 17 nM; 38, 82 nM, respectively). Among 4′-CH2OH N6- (cyclobutyl-cyclopropylmethyl) analogues, there was a roughly two-fold difference in 5- HT2BR affinity with a preference for the N6-(R)- compared to the (S)-diastereomer (42 cf.44; 43 cf.45). However, there was no preference for the N6- (cyclopropyl-prop-2-ylmethyl) analogues (39 cf.41). Upon examining symmetrically N6- substituted 2-iodo derivatives incomparison to the corresponding 2 chloro analogues, the 5 HT2BR affinity improved 2 fold for dicyclobutyl analogue 19 (80 nM) compared to 18 but remained the same for the dicyclopropyl 11 (11.2 nM) analogue compared to 4. The adenine 3-deaza substitution was well tolerated at the 5-HT2BR with retention of moderate affinity in 25 compared to 24. 5′-Hydroxyl substitution with halo (Cl or F) when small rings were present at N6either lowered (e.g., dicyclopropylmethyl 12 cf.4) and or preserved (dicyclobutylmethyl 21 cf.18) the 5-HT2B affinity. However, with the largest (dicyclohexyl) rings, the 5-HT2CR affinity was slightly improved with 5′-deoxy-5′-halo, e.g. compound 36 compared to 34. The corresponding 5′- alkylthio-5′-deoxy analogues 28 and 29 displayed moderate 5-HT2B and 5- HT2CR affinity (Ki ~200 nM), while the latter disappeared with the longer thioalkyl chains. In the dicyclopropyl series, the 4′-CH2F analogue 12 displayed moderate 5- HT2BR but not 5-HT2CR affinity, while the corresponding 4′-CH2SCH3analogue 15 displayed greater 5-HT2BR (23 nM) and 5-HT2CR affinity. However, 2-iodo substitution in 16 significantly reduced the 5-HT2BR affinity (24-fold) compared to 15 without change at the 5- HT2CR. Truncation of the 5′ group combined with 2-iodo substitution greatly reduced affinity in 13 (5-HT2BR Ki 1270 nM) and the corresponding 7-deaza analogue 14. The 2- chloro equivalent of truncated derivative 13 (not shown) 9 displayed Ki values of 675 and 1860 nM at the 5-HT2BR and 5-HT2CR, respectively.5′-Phenyl-thio ethers in the N6- dicyclopentylmethyl series displayed moderate 5-HT2BR affinity, e.g., Ki of 256 nM with 3,4-dimethoxy substitution in 33. In the 5′-ester series, the rank order of 5-HT2BR affinity (Ki, nM) was 5 (dicyclopropyl, 15 nM) > 7 nM (dicyclobutyl, 136 nM) ≥ 47 (dicyclopentyl, 239 nM). The 5-HT2BR affinity of ribosides appeared only in a 5′-CONH2 derivative 52 compared to the inactive 4′-CH2OH analogue 51. A 2-iodo-adenine nucleobase 54 displayed moderate 5-HT2BR affinity (313 nM). At the ARs, affinity generally varied in the order hA1AR > hA3AR > hA2AAR. A2BAR affinity was not determined, because this receptor is consistently the weakest for this series of (N)-methanocarba adenosine derivatives. Compounds 11, 15, 19, 38 and 43 (2-I) had nearly balanced A1AR and 5-HT2BR affinity, and 5-HT2CR affinity was somewhat lower. Compound 43 was 3.7-, 186- and >500-fold fold selective in 5-HT2BR binding compared to A1AR, A2AAR and A3AR. However, ((S)-cyclobutyl-cyclopropyl)-2-iodo 4′-CH2OH analogue 44 had at least an order of magnitude 5-HT2BR selectivity compared to other 5-HT2Rs and ARs. It is also to be noted that the mouse (m) AR affinity can vary greatly compared to the hARs, especially at the A3AR. Substitution of the 5′-hydroxyl with halo (Cl or F) increased A1AR affinity for N6- cyclopropylmethyl analogues (cf.12 and 4; 39 and 37). With larger cycloalkyl rings, the A1AR affinity either remained the same (27) or decreased (20, 21, 26, 35 and 36). The 2-S- alkyl substitution (31) greatly decreased A1AR affinity. A 5′-deoxy-5′-methylthio substitution decreased A1AR, but not A3AR affinity, by roughly 2 – 10-fold (10, 15, 16 and 28). A 2-iodo group substantially decreased the AR affinity compared to 2-chloro. The adenine 3-deaza substitution in 25 greatly reduced A1AR and A3AR affinity. Compound 51 was selective for the A1AR and lacked 5-HT2B / CR affinity. A direct comparison of analogous (N)-methanocarba analogues with the corresponding ribosides (cf.45 and 51; 18 and 53) indicated a major reduction in 5-HT2B / CR affinity of roughly three orders of magnitude with a furanose ring. Thus, the (N)- methanocarba substitution is essential for 5-HT2B / CR binding in the 4′-CH2OH series. However, when a 5′-carbonyl group is present in ribose series, e.g., primary carboxamide 52 (Ki 178 nM), the 5-HT2B affinity was restored. This was consistent with µM affinity of selective A3AR agonists that are ribosides having 5′-methylamides and N6-(3-iodobenzyl) groups. The adenine nucleobase alone 54, with appropriate ((S)-cyclobutyl-cyclopropyl)-2- iodo substitution provided weak 5-HT2Baffinity (only 9-fold weaker than the corresponding (N)-methanocarba derivative 44) that was dependent on optimal 2- and 6-position substitutions (cf.55). Furthermore, the ribose equivalent of 18 was reported to have Ki values of >10,000 and 1450 nM at 5-HT2B / CRs, respectively, i.e., substantially lower affinity. Table 1. Affinity at 5HT2receptors and ARs of N6-, C2-, and 5′-modified (N)-methanocarba-adenosine derivatives. Y = N, unless noted. Affinity is expressed as mean ±SEM (N = 2 – 3, unless noted).ccRadioligands (parental cells) used are: 5-HT2A, [3H]ketanserin (HEKT); 5-HT2B, [3H]LSD (stable HEK); 5-HT2C, [3H]mesulergine (Flp-IN HEK); A1, [3H]R-PIA (HEK); A2A, [3H]CGS21680 (HEK); A3, [125I]I-AB-MECA (HEK), according to published proceduresc. D. K. Tosh (2021), D. K. Tosh et al. (2019); and J. Besnard et al. (2012). When a percent is given, it refers to inhibition at 10 µM (or 1 µM, as noted). For 5-HT2Rs, the pKi value as a mean ± SEM is given in parentheses. For ARs, the Ki value or percent inhibition at the A2AAR is given in parentheses (under A1AR data) as a mean ± SEM.dKi at 5HT1D receptor is 1.99 µM.eData from Jacobson et al., 2005. Synthesis reported in Tosh et al., 2020.gPottie, 2022.hn = 1. NA, not applicable. ND, not determined. EXAMPLE 3 This example illustrates some of the pharmacological properties of compounds in accordance with an aspect of the invention. Three compounds having high affinity, 43, 45 and 48, were examined in functional assays in Flp-In 293 T-Rex cell lines stably-expressing 5-HT2AR, 5-HT2BR and 5-HT2CR measuring Gq protein-mediated calcium flux activity (Figure 2, Table 2). The KB values of all 3 compounds at the 5-HT2BR were in the range of 2 – 3 nM. The ratio of 5-HT2BR and 5-HT2CR functional antagonist affinities ranged from 45 (48) to 113-fold (43). Compound 43 was >500- and 32-fold fold selective in binding compared to 5-HT2AR and 5-HT2CR. Weak antagonism (>10,000 nM) with the 5-HT2AR was detected, consistent with the binding results, and all three compounds proved to be antagonists, with no agonist activity. Furthermore, compounds were tested in 5-HT2B BRET orthologous assays measuring Gq dissociation, β-arrestin1 and β-arrestin2 recruitment assays (Figure 2). Compounds again showed no agonist activity in these assays, thus demonstrating lack of agonism or functional selectivity at this receptor subtype. In fact, some compoundsdisplayed inverse agonist activities in Gq and P-arrestin2 recruitment assays further supporting lack of agonist activity.HH53] Table 2 sets forth antagonist affinity (KB) estimates for selected analogues using 5-HT stimulated 5-HT2 Gq-mediated calcium flux functional responses compared to binding assays3. 5-HT was used as a positive control for each receptor subtype (ECso = 0.24, 0.70 and 0.51 nM for 5-HT2A, 5-HT2B and 5-HT2C, respectively), and clozapine was the reference antagonist. Values represent mean ± SEM performed in three independent experiments.Table 2. Antagonist Affinity' Estimated Values3The corresponding binding pKi values were: at 5-HT2B 43, 7.76; 45, 7.48; 48, 7.48; at 5-HT2c 43, 6.26; 45, 6.22; 48, 6.48.[01541 Fig- 2 depicts functional assays showing antagonism of compounds 43, 45 and 48 in Flp-In 293 T-Rex cell lines stably-expressing 5-HT2BR (A), 5-HT2cR (B) and 5-HT2AR (C) measuring Gq-mediated calcium flux activity. Clozapine was used as a reference antagonist. The absence of agonism in the nucleosides was shown in 5-HT2B BRET orthologous assays measuring Gq dissociation (D), [3-arrestinl (E) and [3-arrestin2 recruitment (F) assays. Serotonin (5-HT) was used as agonist in all assays (at 10 nM in antagonist mode, A-C).

[0155] The off-target binding affinities at 42 diverse receptors, transporters and channels, in addition to 5-HT2AR, 5-HT2BR and 5-HT2cR affinity, were determined for all of these compounds. Most of the derivatives displayed pM affinity at the ol and / or o2 receptors. Additional interactions were noted at the following receptors or channels (compound, Ki, pM): 5HTID (27, 6.5; 29, 5.2; 35, 5.5); 5HT2A (27, 6.5; 31, 9.2; 35, 7); Hi(43, 2.1); D4(29, 3.6); D5(25, 5.1); a2B (28, 1.7; 31, 1.2; 35, 3.6); a2C (27, 2.5; 29, 2.1); |33 (25, 4.7; 29, 1.5; 33, 2.1); DOR (24, 3.9); KOR (24. 0.11), MOR (24. 3.5; 27, 5.7; 32, 4.9); TSPO (19, 2.1); DAT (25, 3.9; 26, 7.9). Compounds 9, 10 and 48 had no significant off- target interactions at 10 pM (>50% inhibition of radioligand bound). The physicochemical parameters were calculated for compounds 11, 15, 36, 43, 45, 48 and 51 using the StarDrop software. None of the compounds are predicted to cross the BBB, but 15 and 36 are in the predicted human intestinal absorption (H1A) category. Compound 43 had a LogS at pH 7.4 of 1 .144 (predicted aqueous solubility of 14 pg / mL), a LogD of 1.254 and TPSA of 1 16 A2. The calculated ligand efficiency (LE) of 43 was 0.375.|0156] The foregoing shows that 2-iodo modification modestly reduced 5-HT2cR affinity, and at the 5-HT2BR affinity was either the same or slightly increased. In the present set of compounds, a 2-iodo substitution moderately reduced A?AR affinity, but tended to preserve of slightly increase AiAR affinity. The N6group had a major effect on 5- HT2B / CR affinity, with branched substituents at the Ca position favoring affinity: di cyclopropyl, dicyclobulyl. (R)-cyclobutyl-cyclopropyl, (R)-cyclopropyl-prop-2-yl. The highest 5-HT2BR affinities were Ki 10 - 30 nM (N6-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5'-deoxy-5'- methylthio 15 and N6-(R)-cyclobuty-cyclopropyl-methyl-2-iodo 43), followed by 44 and 45.

[0157] The enhancement of AR affinity of adenosine derivatives upon introducing an (N)-methanocarba modification often follows the order A3 > Ai » A2A. However, substantial AiAR selectivity compared to A3AR was still present in many of these compounds, suggestive of dual acting compounds: 5-HT2B antagonist and AiAR agonist. However, the 5-HT2BR-enhancing 2-iodo and 3-deaza substitutions also decreased AiAR affinity. Given its affinity (17 nM) and moderate 5-HT2BR selectivity (32-fold vs. 5-HT2cR, 4-fold vs. AIAR). 2-iodo derivative 43 could potentially be useful for therapy targeting fibrosis. Compound 11 was a balanced mixed 5-HT2BR antagonist (Ki 11 nM) and AiAR agonist (Ki 13 nM). Compound 54 is likely a mixed HT2BR / A3AR antagonist, considering that adenine derivatives lacking a ribose moiety generally bind to ARs as antagonists. Although the Gq-coupled A2AAR is an established anti-inflammatory receptor, the Ai and AsARs also have anti-inflammatory effects in animal models, thus supporting the possible use of compounds with mixed activities. Unexpectedly, 2-chloro-5'-deoxy-5'-chloro-N6- dicyclohexyl-methyl analogue 36 displayed higher affinity at the 5-HT2cR (Ki 73 nM) than at the 5-HT2BR. Only 35 showed moderate 5-HT2AR affinity' (3.6 pM).[0158| Among the three analogues characterized as 5-HT2BR antagonists in functional assays, the selectivity for that subtype varied in the order 43 (426-fold), 45 (>300-fold) > 48 (98.7-fold). The corresponding binding selectivity for the two CH2OH analogues with asymmetric N6groups of opposite chirality was less pronounced with 32-fold for 43 and 18- fold for 45.EXAMPLE 4[01591 This example illustrates affinity' of certain adenosine derivatives at 5-HT2 serotonin and adenosine receptors in accordance with an aspect of the invention, as set forth in Table 3.Table 3. Affinity of adenosine derivatives at 5-HT2 serotonin and adenosine receptorsn = 2-4, unless noted.aData from Tosh et al., 2016 and Tchilibon et al., 2005.bData from Tosh et al., 2023.cRadioligands (parental cells) used are: 5-HT2A, [3H]ketanserin (HEKT); 5-HT2B, [3H]LSD (stable HEK); 5- HT2c, [3H]mesulergine (Flp-IN HEK); Al, [3H]R-PIA (HEK); A2A. [3H]CGS21680 (HEK); A?, [125I]I-AB-MECA (HEK), according to published procedures. Data from D. K. Tosh et al. (2021 ), D. K. Tosh et al. (2019), and J. Besnard et al. (2012). When a percent is given, it refers to inhibition at 10 pM (or 1 pM, as noted).dn = 1.

[0160] This example illustrates radioligand binding assays at h5-HT2BR using [3H]LSD, 68. See Fig. 11. Curves for four compounds (A, 18; B, 29; C, 32 and D, 27) are shown (mean, n = 3), compared to reference antagonist 3.5-dihydro-5-meth\ l-.V-3- pyridinylbenzo[l,2-b:4,5-b']dipyrrole-l (2 / / )-carboxamide hydrochloride (SB206553).66Error bars represent SEM.EXAMPLE 5[0161 | This example sets forth in Table 4 the results of functional assays at 5-HT2 receptors of compounds in accordance w ith an aspect of the invention.[01621 Table 4. Results of functional assays at 5-HT2 receptors of compounds of the invention.EXAMPLE 6[01631 The ADMET properties of compound 35 were studied in vitro and in vivo (Tables 5 and 6). Comparable data for a known AsAR-selective (N)-methanocarba nucleoside (reference compound 21) from Tosh et al. 2020 is presented. The oral bioavailability of 35 in the rat was 7.18%F (1.0 mg / kg) and 13. 1 %F (3.0 mg / kg and 10 mg / kg). Its in vivo half-life was 2.2 h at 1.0 mg / kg, 4.3 h at 3.0 mg / kg, and 1.75 h at 10 mg / kg. It was highly stable in the plasma of three species and simulated gastric and intestinal fluids, indicating that the A6- (cyclobutyl-cyclopropyl)-methyl group is not unstable in acid medium, as is the / V’-(di- cyclopropyl)-methyl group (Tosh et al. 2016). In vitro, the inhibition of five human CYP enzymes by 35 was IC50 >20 pM, except for CYP2C9 with an IC50 of 8.64 pM. The lack of hERG inhibition and the microsomal stability are much more favorable than that of the reference compound. The CACO2 cell permeability was moderate with a low efflux ratio. The StarDrop software was used to predict properties of potent antagonists 27, 35, 37, 40, 66 and 67 (Table 5). All of the compounds were predicted to be peripherally selective, with BBB permeability (log([brain]: [blood])) of -0.73 to -1.14. The cLogD ranged from hydrophilic derivatives values 0.611 (66) and 0.829 (40) to more moderately hydrophobic, 2.03 (27). The predicted aqueous solubility at pH 7.4 ranged from 7.7 (27) to 243 (66) pg / mL.[01641 Table 5. In vitro and in vivo ADMET data in male Wistar rats for representative 5-HT2BAR antagonist 21 (Reference Compound) in comparison to a dopamine-containing A3AR agonist 35.The structure of compound 21 is:Mean ± SD, pION method.Species tested for plasma stability were human, rat and mouse; species as indicated for microsomal stability.EXAMPLE 7

[0165] This example sets forth the results of in vivo pharmacokinetic parameters of a compound in accordance with an aspect of the invention.

[0166] Table 6. In vivo PK parameters of compound 35EXAMPLE 8

[0167] This example sets forth some of the calculated properties of compounds in accordance with an aspect of the invention.Table 7. Calculated properties of compounds.BBB -0.7314-1.125 -1.125 -1.142 -0.8523 -0.8559 log([brain]:[blood])The stability of the 4 -cyano nucleosides is enabled by the lack of a 4’-oxygen present in native ribosides, and no similar analogues have been reported among ribose derivatives. The nitrile group is present in dozens of approved pharmaceuticals. It has been shown here that a nitrile group at the 4’-position of (N)-methanocarba nucleosides substantially enhances 5-HT2BR affinity and selectivity. It modestly reduces AR affinity. The pharmacokinetic profile of 35 indicates that it is moderately stable in tissues. EXAMPLE 9 This examples illustrates off-target activity of compounds in accordance with an aspect of the invention. The off-target activity was determined according to the published procedures: https: / / pdsp.unc.edu / pdspweb / content / UNC-CH%20Protocol%20Book.pdf. The results obtained are set forth in Table 8. Unless noted in the text, no significant interactions (<50% inhibition at 10 µM) for any of the nucleosides were found at the following sites(human unless noted): 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT2A, 5HT2B, 5HT2C, 5HT3, 5HT5A, 5HT6, 5HT7, α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, β3, BZP rat brain site, D1, D2, D3, D4, D5, GABAA, H1, H2, H3, H4, M1, M2, M5, δ-opioid receptor (DOR), κ-opioid receptor (KOR), μ- opioid receptor (MOR), σ1, σ2, DAT, NET, SERT. Ki values in µM, or % inhibition at 10 µM, are given. Table 8. Off-target activity of the compounds in accordance with an aspect of the invention. Compound numbers and receptor interactions (other than 5-HT2B and 5-HT2C, Ki, µM) are as follows: 9a, none 9b, none 10a, none 10b, none 11, σ18.2, σ25.5 12, σ17.5, σ24.8 13, σ2, α2B14, none 15, σ16.2, σ23.4, β16.2 16, σ10.95, σ21.2 17, none 18, none 19, σ22.0, TSPO 2.1 20, β31.7 21, none 22, none 23, σ15.0, σ22.1 24, σ14.0, σ22.3, DOR 3.9, KOR 0.11, MOR 3.5 25, σ13.1, σ22.5, D55.1, DAT 2.8, β34.7 26, σ11.9, σ21.2, DAT 7.9 27, σ12.0, σ20.79, MOR 5.7, 5HT2A6.5, α2C2.5 28, σ11.8, σ21.5, α2B1.7 29, σ11.8, σ21.0, α2C2.1, β31.5, D43.6, 5HT1D5.2 30, σ20.64 31, σ10.47, σ20.7, 5HT2A9.2, α2B1.2, D51.1 32, σ10.58, σ21.4, MOR 4.9 33, β32.1 34, σ21.0 35, α2B4.6, 5HT1D5.5, 5HT2A7, σ11.8, σ20.76 36, σ20.30 37, none 38, σ23.2 39, none40, α2B8.9 41, none 42, none 43, σ24.9, H12.1 44, none 45, TSPO 3.9 46, none 47, σ16.1, σ23.4, α2A3.2, α2B2.3, D35.2, β33.5 48, TSPO 2.3, σ22.1, α2B1.4 49, none 50, σ24.7, KOR 4.4 51, TSPO 7.6, 5HT5A1.4, D21.5, D30.70, D41.2, β34.6 52, TSPO 1.9 53, none 54, TSPO 7.7, σ21.5 55, none. EXAMPLE 10 This examples illustrates an advantageous property of a compound of formula (I) in accordance with an aspect of the invention. The 4’-cyano derivative MRS8209 (compound 40) was tested in a mouse model of hypothermia, which is a known activity of AR agonists. The mice had implanted sensors to monitor changes in core body temperature and locomotor activity. Agonists of any of the four AR subtypes were previously found to reduce core body temperature and locomotor activity upon i.p. administration in the mouse. However, MRS8209, advantageously, failed to reduce core body temperature or locomotor activity at doses of 1 and 3 mg / kg, i.p.; see, Figure 10A and 10B, respectively. This indicates that the compound has no detectable in vivo AR agonist activity, which justifies use of this nucleoside analogue as a selective 5- HT2B antagonist in vivo. EXAMPLE 11 This examples illustrates advantageous properties of compound 34 as set forth in Table 9. The predicted aqueous solubility at pH 7.4 ranged from 7.7 for compound 27) to 243 for compound 34 µg / mL. Table 9. Calculated properties of selected molecules, using the StarDrop (v.7.3.2) software.EXAMPLE 11 This example provides characterization data of additional compounds in accordance with aspects of the invention: (1R,2R,3S,4R,5S)-4-(6-(cyclobutylamino)-2-iodo-9H-purin-9-yl)-2,3- dihydroxy bicyclo[3.1.0]hexane-1-carbonitrile1H NMR (CD3OD, 400 MHz) δ 8.00 (s, 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.79 (s, 1H), 4.69 (br s, 1H), 4.07 (d, J = 6.4 Hz, 1H), 2.46-2.41 (m, 2H), 2.39-2.35 (m, 1H), 2.13-2.07 (m, 2H), 1.94 (t, J = 4.8 Hz, 1H), 1.85-1.81 (m, 2H), 1.48-1.44 (m, 1H). HRMS calculated for C16H18N6O2I (M + H) +: 453.0536; found 453.0543. (1R,2R,3S,4R,5S)-4-(6-(cyclohexylamino)-2-iodo-9H-purin-9-yl)-1- (hydroxymethyl)bicyclo [3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.38 (s, 1H), 4.81 (s, 1H) 4.77 (d, J = 6.4 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H), 4.10 (br s, 1H), 3.86 (d, J = 6.8 Hz, 1H), 3.37 (d, J = 7.6 Hz, 1H), 2.04-2.03 (m, 2H), 1.84-1.81 (m, 2H), 1.71-1.68 (m, 1H), 1.61-1.58 (m, 1H), 1.54 (t, J = 4.8 Hz, 1H), 1.50-1.47 (m, 1H), 1.44-1.23 (m, 4H), 0.78-0.74 (m, 1H). HRMS calculated for C18H25N5O3I (M + H) +: 486.1002; found 486.0998. (1R,2R,3S,4R,5S)-4-(6-(cyclohexylamino)-2-iodo-9H-purin-9-yl)-2,3- dihydroxybicyclo [3.1.0]hexane-1-carbonitrile1H NMR (CD3OD, 400 MHz) δ 8.08 (s, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.81 (s, 1H), 4.13-4.07 (m, 2H), 2.39-2.36 (m, 1H), 2.05-2.02 (m, 2H), 1.94 (t, J = 5.2 Hz, 1H), 1.84-1.80 (m, 2H), 1.71-1.67 (m, 1H), 1.49-1.42 (m, 3H), 1.39-1.23 (m, 3H). HRMS calculated for C18H22N6O2I (M + H) +: 481.0849; found 481.0844. (1R,2R,3S,4R,5S)-4-(6-((2-cyclopropylethyl)amino)-2-iodo-9H-purin-9-yl)- 1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.38 (s, 1H), 4.81 (s, 1H), 4.78 (d, J = 6.4 Hz, 1H), 4.28 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 6.8 Hz, 1H), 3.63 (br s, 2H), 3.37 (d, J = 11.6 Hz, 1H), 1.61-1.53 (m, 4H), 0.83-0.75 (m, 2H), 0.50-0.46 (m, 2H), 0.13-0.12 (m, 2H). HRMS calculated for C17H23N5O3I (M + H) +: 472.0846; found 472.0840. Ethyl (1S,2R,3S,4R,5S)-4-(6-((2-cyclopropylethyl)amino)-2-iodo-9H-purin- 9-yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carboxylate (14a)1H NMR (CD3OD, 400 MHz) δ 8.01 (s, 1H), 5.24 (d, J = 6.4 Hz, 1H), 4.78 (s, 1H), 4.29-4.24 (m, 2H), 4.13 (d, J = 6.4 Hz, 1H), 3.63 (br s, 2H), 2.18-2.15 (m, 1H), 1.84 (d, J = 5.2 Hz,1H), 1.63-1.54 (m, 3H), 1.33 (t, J = 7.2 Hz, 3H), 0.86-0.75 (m, 1H), 0.50-0.45 (m, 2H), 0.14- 0.10 (m, 2H). HRMS calculated for C19H25N5O4I (M + H) +: 514.0951; found 514.0945. (1S,2R,3S,4R,5S)-4-(6-((2-cyclopropylethyl)amino)-2-iodo-9H-purin-9-yl)-1- (mercaptomethyl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.28 (s, 1H), 4.80 (d, J = 6.8 Hz, 1H), 4.71 (s, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.66 (br s, 2H), 3.23 (d, J = 14.0 Hz, 1H), 2.73 (d, J = 14.0 Hz, 1H), 1.64-1.53 (m, 3H), 0.93-0.87 (m, 2H), 0.83-0.77 (m, 1H), 0.49-0.47 (m, 2H), 0.13-0.12 (m, 2H). HRMS calculated for C17H23N5O2IS (M + H) +: 488.0617; found 488.0610. (1R,2R,3S,4R,5S)-1-(hydroxymethyl)-4-(2-iodo-6-(phenylamino)-9H-purin- 9-yl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.52 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 4.92 (s, 1H), 4.80 (d, J = 5.6 Hz, 1H), 4.30 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 11.6 Hz, 1H), 1.65 (m, 1H), 1.56 (d, J = 4.8 Hz, 1H), 0.80-0.77 (m, 1H). HRMS calculated for C18H19N5O3I (M + H) +: 480.0533; found 480.0533. (1R,2R,3S,4R,5S)-2,3-dihydroxy-4-(2-iodo-6-(phenylamino)-9H-purin-9- yl)bicyclo[3.1.0]hexane-1-carbonitrile1H NMR (CD3OD, 400 MHz) δ 8.11 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 5.17 (d, J = 6.8 Hz, 1H), 4.85 (s, 1H), 4.12 (d, J = 6.8 Hz, 1H), 2.42-2.39 (m, 1H), 1.97 (t, J = 5.2 Hz, 1H), 1.50-1.46 (m, 1H). HRMS calculated for C18H16N6O2I (M + H) +: 475.0379; found 475.0376. 2-((1S,2R,3S,4R,5S)-2,3-dihydroxy-4-(2-iodo-6-(phenylamino)-9H-purin-9- yl)bicyclo[3.1.0]hexan-1-yl)acetonitrile1H NMR (CD3OD, 400 MHz) δ 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 4.83 (s, 1H), 4.77 (d, J = 6.8 Hz, 1H), 3.99 (d, J = 6.4 Hz, 1H), 3.20-3.07 (m, 2H), 1.72-1.69 (m, 1H), 1.58 (t, J = 5.2 Hz, 1H), 0.94-0.90 (m, 1H). HRMS calculated for C19H18N6O2I (M + H) +: 489.0536; found 489.0540. Ethyl (1S,2R,3S,4R,5S)-2,3-dihydroxy-4-(2-iodo-6-(phenylamino)-9H- purin-9-yl)bicyclo [3.1.0]hexane-1-carboxylate1H NMR (CD3OD, 400 MHz) δ 8.04 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 5.27 (d, J = 6.8 Hz, 1H), 4.81 (s, 1H), 4.31-4.26 (m, 2H), 4.16 (d, J = 6.8 Hz, 1H), 2.21-2.17 (m, 1H), 1.86 (t, J = 5.2 Hz, 1H), 1.64-1.60 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H). HRMS calculated for C20H21N5O4I (M + H) +: 522.0638; found 522.0646.(1S,2R,3S,4R,5S)-4-(2-((5-chlorothiophen-2-yl)ethynyl)-6-(phenylamino)- 9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide1H NMR (CD3OD, 400 MHz) δ 8.23 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 4.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 5.08 (d, J = 5.6 Hz, 1H), 4.92 (s, 1H), 4.06 (d, J = 6.4 Hz, 1H), 2.87 (s, 3H), 2.15-2.12 (m, 1H), 1.89 (t, J = 4.8 Hz, 1H), 1.43-1.39 (m, 1H). HRMS calculated for C25H22N6O3SCl (M + H) +: 521.1163; found 521.1154. (1R,2R,3S,4R,5S)-4-(6-((3-fluorophenyl)amino)-2-iodo-9H-purin-9-yl)-1- (hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.52 (s, 1H), 7.87-7.83 (m, 1H), 7.48-7.46 (m 1H), 7.38-7.32 (m, 1H), 6.85-6.80 (m, 1H), 4.88 (s, 1H), 4.79 (d, J = 6.8 Hz, 1H), 4.29 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 6.8 Hz, 1H), 3.40 (d, J = 11.6 Hz, 1H), 1.64-1.62 (m, 1H), 1.56 (t, J = 4.8 Hz, 1H), 0.80-0.76 (m, 1H). HRMS calculated for C18H18N5O3FI (M + H) +: 498.0438; found 498.0443. (1R,2R,3S,4R,5S)-4-(6-((3-fluorophenyl)amino)-2-iodo-9H-purin-9-yl)-2,3- dihydroxybicyclo[3.1.0]hexane-1-carbonitrile1H NMR (DMSO-d6, 400 MHz) δ 10.43 (s, 1H), 8.32 (s, 1H), 7.90-7.86 (m, 1H), 7.71-7.68 (m, 1H), 7.41-7.35 (m, 1H), 6.92-6.87 (m, 1H), 5.61 (d, J = 5.2 Hz, 1H), 5.40 (d, J = 8.4 Hz, 1H), 5.00 (t, J = 7.2 Hz, 1H), 4.76 (s, 1H), 4.04-4.01 (m, 1H), 2.44-2.41 (m, 1H), 1.76 (t, J = 5.2 Hz, 1H), 1.43-1.40 (m, 1H). HRMS calculated for C18H15N6O2FI (M + H) +: 493.0285; found 493.0292. (1R,2R,3S,4R,5S)-4-(6-((3,5-difluorophenyl)amino)-2-iodo-9H-purin-9-yl)- 1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.55 (s, 1H), 7.55-7.49 (m, 2H), 6.67-6.61 (m, 1H), 4.89 (s, 1H), 4.81 (d, J = 6.8 Hz, 1H), 4.30 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 11.6 Hz, 1H), 1.65-1.62 (m, 1H), 1.56 (t, J = 5.2 Hz, 1H), 0.81-0.77 (m, 1H). HRMS calculated for C18H17N5O3FI (M + H) +: 516.0344; found 516.0339. (1R,2R,3S,4R,5S)-4-(6-((3,5-difluorophenyl)amino)-2-iodo-9H-purin-9-yl)- 2,3-dihydroxybicyclo[3.1.0]hexane-1-carbonitrile1H NMR (DMSO-d6, 400 MHz) δ 10.62 (s, 1H), 8.36 (s, 1H), 7.75-7.72 (m, 2H), 6.94-6.88 (m, 1H), 5.61 (d, J = 4.8 Hz, 1H), 5.40 (d, J = 8.0 Hz, 1H), 5.00 (t, J = 6.8 Hz, 1H), 4.77 (s, 1H), 4.03 (t, J = 5.2 Hz, 1H), 2.45-2.41 (m, 1H), 1.76 (t, J = 5.2 Hz, 1H), 1.44-1.41 (m, 1H). HRMS calculated for C18H14N6O2FI (M + H) +: 511.0191; found 511.0195.(1R,2R,3S,4R,5S)-4-(6-((3,4-dichlorophenyl)amino)-2-iodo-9H-purin-9-yl)- 1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.53 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.69-7.66 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 4.88 (s, 1H), 4.81 (d, J = 5.6 Hz, 1H), 4.29 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 6.8 Hz, 1H), 3.40 (d, J = 11.6 Hz, 1H), 1.53-1.62 (m, 1H), 1.56 (t, J = 4.8 Hz, 1H), 0.80-0.77 (m, 1H). HRMS calculated for C18H17N5O3Cl2I (M + H) +: 547.9753; found 547.9747. Ethyl (1S,2R,3S,4R,5S)-4-(6-((3-chlorobenzyl)amino)-2-iodo-9H-purin-9- yl)-2,3-dihydroxybicyclo[3.1.0]hexane-1-carboxylate1H NMR (DMSO-d6, 400 MHz) δ 8.73 (s, 1H), 8.02 (s, 1H), 7.41 (s, 1H), 7.35-7.29 (m, 3H), 5.33 (s, 1H), 4.99 (d, J = 5.6 Hz, 1H), 4.88 (s, 1H), 4.59-4.58 (br s, 3H), 4.16-4.11 (m, 2H), 4.11 (br s, 1H), 2.04-2.00 (m, 1H), 1.66 (t, J = 5.2 Hz, 1H), 1.46-1.43 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H). HRMS calculated for C21H22N5O4ClI (M + H) +: 570.0405; found 570.0407. 2-((1S,2R,3S,4R,5S)-4-(6-((3-chlorobenzyl)amino)-2-((5-chlorothiophen-2- yl)ethynyl)-9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)acetonitrile1H NMR (CD3OD, 400 MHz) δ 8.21 (s, 1H), 7.42 (s, 1H) (d, J = 2.4 Hz, 1H), 7.33-7.22 (m, 4H), 7.00 (d, J = 4.0 Hz, 1H), 4.81 (s, 1H), 4.68 (d, J = 6.8 Hz, 1H), 3.96 (d, J = 6.4 Hz, 1H), 3.17 (d, J = 8.8 Hz, 1H), 2.98 (d, J = 8.8 Hz, 1H), 1.78-1.75 (m, 1H), 1.64 (t, J = 5.2 Hz, 1H), 0.90-0.87 (m, 1H). HRMS calculated for C26H21N6O2Cl2S (M + H) +: 551.0824; found 551.0818. (1R,2R,3S,4R,5S)-4-(6-((1H-pyrrol-1-yl)amino)-2-iodo-9H-purin-9-yl)-1- (hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.47 (s, 1H), 6.78-6.77 (m, 2H), 6.16-6.14 (m, 2H), 4.87 (s, 1H), 4.78 (d, J = 6.4 Hz, 1H), 4.28 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 6.8 Hz, 1H), 3.38 (d, J = 11.6 Hz, 1H), 1.62-1.59 (m, 1H), 1.55 (d, J = 4.8 Hz, 1H), 0.79-0.75 (m, 1H). HRMS calculated for C16H18N6O3I (M + H) +: 469.0485; found 469.0485. (1R,2R,3S,4R,5S)-1-(hydroxymethyl)-4-(2-(pyrrolidin-1-yl)-6-(pyrrolidin-1- ylamino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H), 4.82-4.80 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 6.8 Hz, 1H), 3.65-3.61 (m, 4H), 3.35 (d, J = 11.6 Hz, 1H), 3.05 (br s, 4H), 2.00- 1.98 (m, 4H), 1.97-1.93 (m, 4H), 1.57-1.54 (m, 1H0, 1.49 (t, J = 4.8 Hz, 1H), 0.75-0.72 (m, 1H). HRMS calculated for C20H30N7O3 (M + H) +: 416.2410; found 416.2408.4-(cyclopentylamino)-7-((1S,2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)bicyclo[3.1.0] hexan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile1H NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 8.30 (s, 1H), 5.06 (s, 1H), 4.73 (d, J = 6.4 Hz, 1H), 4.58-4.52 (m, 1H), 4.31 (d, J = 11.6 Hz, 1H), 3.79 (d, J = 6.4 Hz, 1H), 3.28 (d, J = 11.6 Hz, 1H), 2.19-2.12 (m, 2H), 1.85-1.79 (m, 2H), 1.78-1.69 (m, 2H), 1.66-1.60 (m, 2H), 1.57- 1.54 (m, 2H), 0.77-0.72 (m, 1H). HRMS calculated for C19H24N5O3(M + H) +: 370.1879; found 370.1877. 7-((1S,2R,3S,4R,5R)-5-cyano-3,4-dihydroxybicyclo[3.1.0]hexan-2-yl)-4- (cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile1H NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.94 (s, 1H), 4.99-4.96 (m, 2H), 4.58-4.52 (m, 1H), 4.06 (d, J = 6.8 Hz, 1H), 2.39-2.36 (m, 1H), 2.19-2.12 (m, 2H), 1.98 (t, J = 5.2 Hz, 1H), 1.85-1.81 (m, 2H), 1.79-1.70 (m, 2H), 1.66-1.59 (m, 2H), 1.50-1.46 (m, 1H). HRMS calculated for C19H21N6O2 (M + H) +: 365.1726; found 365.1724. (1S,2R,3S,4R,5S)-4-(6-amino-2-iodo-9H-purin-9-yl)-1-(3-methyl-1,2,4- oxadiazol-5-yl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 7.99 (s, 1H), 5.42 (d, J = 6.4 Hz, 1H), 4.91 (s, 1H), 4.14 (d, J = 6.8 Hz, 1H), 2.41-2.38 (m, 4H), 2.16 (t, J = 5.2 Hz, 1H), 1.73-1.69 (m, 1H). HRMS calculated for C14H15N7O3I (M + H) +: 456.0281; found 456.0284. (1S,2R,3S,4R,5S)-4-(6-(cyclopentylamino)-2-iodo-9H-purin-9-yl)-1-(3- methyl-1,2,4-oxadiazol-5-yl)bicyclo[3.1.0]hexane-2,3-diol1H NMR (CD3OD, 400 MHz) δ 7.92 (s, 1H), 5.41 (d, J = 6.8 Hz, 1H), 4.89 (s, 1H), 4.47 (br s, 1H), 4.12 (d, J = 7.2 Hz, 1H), 2.38 (s, 3H), 2.16 (t, J = 5.2 Hz, 1H), 2.10-2.04 (m, 2H), 1.82- 1.70 (m, 2H), 1.69-1.66 (m, 3H), 1.62-1.56 (m, 2H), 1.27-1.23 (m, 1H). HRMS calculated for C19H23N7O3I (M + H) +: 524.0907; found 524.0902. (1R,2R,3S,4R,5S)-1-((2H-1,2,3-triazol-2-yl)methyl)-4-(6-(((R)- cyclobutyl(cyclopropyl) methyl)amino)-2-iodo-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3- diol1H NMR (CD3OD, 400 MHz) δ 7.84 (s, 1H), 7.76 (s, 2H), 5.13 (d, J = 14.4 Hz, 1H), 4.79 (s, 1H), 4.54-4.51 (m, 2H), 3.91 (d, J = 6.4 Hz, 1H), 3.78 (br s, 1H), 2.72-2.66 (m, 1H), 2.12- 2.09 (m, 1H), 2.02-1.90 (m, 4H), 1.87-1.80 (m, 2H), 1.64 (d, J = 4.8 Hz, 1H), 0.95-0.87 (m, 2H), 0.58-0.53 (m, 1H), 0.40-0.37 (m, 3H). HRMS calculated for C22H28N8O2I (M + H) +: 563.1380; found 563.1376.REFERENCES:[0199[ Tosh, D.K.. Calkins, M.M., Campbell, R.G.. Chen, E.. Gao, Z.G., McCorvy, J.D., Jacobson, K.A. Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: A6, C2 and 5 '-modified (N)-methanocarba- adenosine derivatives, Eur. J. Med.Chem., 2023, 259, 115691.

[0200] D. K. Tosh. A. Ciancetta, E. Warnick, S. Crane, Z. G. Gao, and K. A. Jacobson, Structure- based scaffold repurposing for G protein-coupled receptors: Transformation of adenosine derivatives into 5HT2B / 5HT2C serotonin receptor antagonists. J. Med. Chem. 59 (2016) 11006-11026.

[0201] D. K. Tosh, A. Ciancetta, P. Mannes, E. Warnick, A. Janowsky. A. J. Eshleman, E. Gizewski, T. F. Brust. L. M. Bohn, J. A. Auchampach. Z. G. Gao, and K. A. Jacobson, Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists. ACS Omega, 3 (2018) 12658-12678.

[0202] D. K. Tosh, A. Janowsky , A. J. Eshleman, E. Warnick, Z. G. Gao, Z. Chen, E. Gizewski, J. A. Auchampach, D. Salvemini, and K. A. Jacobson, Scaffold repurposing of nucleosides (adenosine receptor agonists): enhanced activity at the human dopamine and norepinephrine sodium symporters. J. Med. Chem. 60 (2017) 3109-3123.

[0203] D. K. Tosh, Rao, FL, Bitant, A., V. Salmaso, P. Mannes, D. I. Lieberman, K. L. Vaughan, J.A. Mattison, A. C. Rothwell, J. A. Auchampach, A. Ciancetta, N. Liu, Z. Cui, Z. G. Gao, M.L. Reitman, O. Gavrilova, and K. A. Jacobson, Design and in vivo characterization of Al adenosine receptor agonists in the native ribose and conformationally- constrained (N)-methanocarba series. J. Med. Chem. 62 (2019) 1502-1522.

[0204] K. A. Jacobson, X. D. Ji, A. H. Li, N. Melman, M. A. Siddiqui, K. J. Shin, V. E. Marquez, and R. G. Ravi, Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J. Med. Chem. 43 (2000) 2196-2203.

[0205] E. Pottie, Ph.D. thesis, University of Gent, 2022.

[0206] J. Besnard, G. F. Ruda, V. Setola, K. Abecassis, R. M. Rodriguiz, X. P. Huang, S. Norval, M.F. Sassano, A. I. Shin, L. A. Webster, F. R. Simeons, L. Stojanovski, A. Prat, N. G. Seidah, D. B. Constam, G. R. Bickerton, K. D. Read, W. C. Wetsel, I. H. Gilbert, B. L. Roth, and A.L. Hopkins, Automated design of ligands to polypharmacological profiles.Nature 492 (2012) 215-220.[02071 K. A. Jacobson, Z. G. Gao, S. Tchilibon, H. T. Duong, B. V. Joshi, D. Sonin, and B. T. Liang, Semirational design of (N)-methanocarba nucleosides as dual acting Al and A3 adenosine receptor agonists: Novel prototypes for cardioprotection. J. Med. Chem. 48 (2005) 8103-8107.

[0208] D. K. Tosh, S. Kiran, K. S. Toti, B. Hurst, J. G. Julander and K. A. Jacobson, Structure activity relationship of novel antiviral nucleosides against Enterovirus A71, Bioorg. Med. Chem. Lett. 30 (2020) 127599.

[0209] Jacobson, K.A., Salmaso, V., Suresh, R.R., Tosh, D.K. Expanding the repertoire of methanocarba nucleosides from purine receptors to diverse targets. RSC Med. Chem. 2021, 12: 1808-1825.

[0210] D. K. Tosh. V. Salmaso, H. Rao. R. Campbell. A. Bitant, Z. G. Gao, J. A. Auchampach, and K. A. Jacobson, Direct comparison of (N)-methanocarba and ribose- containing 2- arylalkynyladenosine derivatives as A3 receptor agonists. ACS Med. Chem. Lett. 11 (2021) 1935-1941.[02111 D. K. Tosh. Rao, H., Bitant, A., V. Salmaso, P. Mannes. D. I. Lieberman. K. L. Vaughan, J. A. Mattison, A. C. Rothwell, J. A. Auchampach, A. Ciancetta, N. Liu, Z. Cui, Z. G. Gao, M. L. Reitman, O. Gavrilova, and K. A. Jacobson, Design and in vivo characterization of Al adenosine receptor agonists in the native ribose and conformationally- constrained (N)-methanocarba series. J. Med. Chem. 62 (2019) 1502-1522.[02121 J. Besnard, G. F. Ruda. V. Setola, K. Abecassis. R. M. Rodriguiz. X. P. Huang. S. Norval, M. F. Sassano, A. I. Shin, L. A. Webster, F. R. Simeons, L. Stojanovski, A. Prat, N. G. Seidah, D. B. Constam, G. R. Bickerton, K. D. Read, W. C. Wetsel, I. H. Gilbert, B. L. Roth, and A. L. Hopkins, Automated design of ligands to polypharmacological profiles. Nature 492 (2012) 215-220.

[0213] Tosh, D.K., Toti, K.S., Hurst, B., Julander, J.G., Jacobson, K.A. Structure activity relationship of novel antiviral nucleosides against Enterovirus A71, Bioorg. Med. Chem. Lett. 2020, 30: 127599. PMCID: PMC7534897 [=0150],

[0214] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.10215 | The use of the terms "a" and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be constmed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherw ise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.| 0216| Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary' skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted bv context.

Claims

CLAIMS:

1. A compound of formula (I) or formula (II). a salt thereof, or an optical isomer thereof.wherein, in the compound of formula (I),R1is selected from the group consisting of aryl, arylalkyl, cycloalky l, cycloalkyl alky l, di-cycloalkylalkyl, di-bicycloalkyl, tricycloalkyl, alkyl, (cycloalkyl)(alkyl)alkylenyl, and H, wherein the aryl, alkyl, and cycloalkyl moieties can be optionally substituted with one or more of alky l, halo, and cyano groups;R2is selected from the group consisting of H, halo, alkylthio, arylalkylthio, heteroaryl, tetrahydropyrroly 1, cyano, and thienylalkyny 1, wherein each of said moieties, other than H and halo, can be optionally substituted with one or more of alkyl, halo, and cyano groups; andR3is selected from the group consisting of optionally substituted 5 -membered aromatic heterocyclyl, 3-alkyl-l,2,4-oxadiazol-5-yl, triazolylalkyl, cyano, alkydaminocarbonyl, alkydaminothiocarbony l, alkyloxycarbonyl, alky doxythiocarbonyl, hydroxyalkyl, monohaloalkyl, dihaloalky 1, cyanoalkyl, and cyanothioalky 1; andY = N or CH; and in the compound of formula (II),R1is cycloalkyl or di-cycloalkylalkyl;R2is halo;X is NH, O, S, Se, or CH2, andR3is COXR4or CSXR4, and R4is H, alkyl, or alkyloxy; andY = N or CH; and wherein the optical isomer of compound or salt of formulas (I) and (II) can have R or S configuration at the -NH- moiety of -NH-R1; with the provisos:(i) in formula (II), when R3is CH2OH and R1is H, alkyl, di-cycloalkyl alky l, or (cycloalkyl)(alkyl)alkylenyl, then R2is not chloro or H;(ii) in formula (I), when R3is alkylaminocarbonyl and R1is di-cycloalkyl alkyl, or (chloro substituted aryl) alkyl, then R2is not chloro; and(iii) in formula (I), when R3is alkylaminocarbonyl and R1is (chloro substituted aryl) alkyl, then R2is not (halo substituted thienyl)alkynyl.

2. The compound, salt, or optical isomer according to formula (I) of claim 1 , wherein the aryl moiety' of aryl and arylalkyl in R1is phenyl, biphenyl, naphthyl, anthracenyl, or pyrenyl.

3. The compound, salt, or optical isomer according to formula (I) of claim 1 or 2, wherein R1is phenyl optionally substituted with one or more of alkyl, halo, and cyano groups.

4. The compound, salt, or optical isomer according to formula (I) of any one of claims 1-3, wherein R3is an optionally substituted 5-membered aromatic heterocyclyl.

5. The compound, salt, or optical isomer according to formula (I) of claim 4, wherein R3is selected from the group consisting of thienyl, furyl, oxadiazolyl, diazolyl, thiazolyl, triazolyl, pyrazolyL and pyrrolyl, each of which is optionally substituted with halo, C1-C6 alkyl, C1-C6 alkydthio, aryl, or aryl C1-C6 alkylthio.

6. The compound, salt, or optical isomer according to formula (I) of claim 5, wherein R3is 3-alkyl-l,2,4-oxadiazol-5-yl or triazolylalkyl.

7. The compound, salt, or optical isomer according to formula (I) of claim 1, wherein:R1is selected from the group consisting of phenyl, phenylalkyl, halophenyl, dihalophenyl, halobenzyl, C3-C8 cycloalkyl, di-C3-C8 cycloalkyl C3-C8 alkyl, and C3-C8 alkyl;R2is selected from the group consisting of chloro, bromo, iodo, C1-C8 alkylthio, aryl C1-C8 alkylthio, heteroaryl, thienylalkynyl, pyrrolidinyl, and halothienylalkynyl; andR3is selected from the group consisting of 3-methyl-l,2,4-oxadiazol-5-yl, cyano, hydroxy C1-C8 alkyl, cyano C1-C8 alkyl, and cyanothio C1-C8 alkyd.

8. The compound, salt, or optical isomer according to formula (I) of any one of claims 1-7, wherein R1is selected from the group consisting of di-cyclopropylmethyl, di-bicyclobutylmethyl, di-bicyclopentylmethyl, di-bicyclohexylmethyl, (isopropyl)(cyclopropyl)methyl, (cyclopropyl)(cyclobutyl)methyl, and dicyclopentylmethyl.

9. The compound, salt, or optical isomer according to formula (I) of any one of claims 1-8, wherein R2is selected from the group consisting of methylthio, chloro, or iodo.

10. The compound, salt, or optical isomer according to formula (T) of any one of claims 1-9, wherein R3is selected from the group consisting of 3 -methyl- 1,2,4- oxadiazol-5-yl. cyano, dihalomethyl, hydroxymethyl, cyanomethyl, methylaminocarbonyl, trizolylmethyl, and cyanothiomethyl.

11. The compound, salt, or optical isomer according to formula (I) of any one of claims 1-10, wherein the compound is:

12. The compound, salt, or optical isomer according to formula (I) of claim 1 , wherein:R1is di(cyclopropyl)methyl, R2is Cl, and R3is CHF2;R1is isopropyl(cyclopropyl)methyl (R), R2is Cl, and R3is CHF2;R1is (cyclopropyl)(cyclobutyl)methyl ( / ?). R2is I, and R3is CHF2;R1is (cyclopropyl)(cyclobutyl)methyl (S), R2is I, and R3is CHF2; R1is m-chlorobenzyl, R2is I, and R3is CHF2; R1is H, R2is Cl, and R3is CN; R1is methyl, R2is I, and R3is CN; R1is n-propyl, R2is I, and R3is CN; R1is isopropyl(cyclopropyl)methyl (R), R2is Cl, and R3is CN; R1is isopropyl(cyclopropyl)methyl (R), R2is I, and R3is CN; R1is (cyclobutyl)(cyclopropyl)methyl (R), R2is I, and R3is CN; R1is (cyclobutyl)(cyclopropyl)methyl (R), R2is I, and R3is CH2SCN; R1is (cyclobutyl)(cyclopropyl)methyl (S), R2is I, and R3is CN; R1is (cyclobutyl)(cyclopropyl)methyl (R), R2is I, and R3is CH2CN; R1is (cyclopropyl)(cyclobutyl)methyl (S), R2is I, and R3is CH2CN; R1is cyclopentyl, R2is I, and R3is CN; R1is cyclopentyl, R2is I, and R3is CH2CN; R1is 3-difluorocyclopentyl (R), R2is I, and R3is CN; R1is 3-difluorocyclopentyl (R), R2is I, and R3is CH2CN; R1is 3-difluorocyclopentyl (S), R2is I, and R3is CN; R1is 3-difluorocyclopentyl (S), R2is I, and R3is CH2CN; R1is bicyclo [1.1.2] butyl, R2is I, and R3is CN; R1is bicyclo [1.1.2] butyl, R2is I, and R3is CH2CN; R1is m-chlorobenzyl, R2is I, and R3is CN; R1is m-chlorobenzyl, R2is I, and R3is CH2CN; R1is Me, R2is 5-Cl-thien-2-yl, and R3is CN; R1is nPr, R2is 5-Cl-thien-2-yl, and R3is CN;R1is Me, R2is 5-Cl-thien-2-yl-ethynyl, and R3is CN; R1is H, R2is S-CH2Ph, and R3is CH2OH; R1is Me, R2is S-CH2Ph, and R3is CH2OH; R1is Me, R2is S-CH2Ph, and R3is CH2CN; R1is (cyclopropyl)(cyclobutyl)methyl, R2is Cl, and R3is COOCH2CH3; R1is H, R2is I, and R3is CONHCH3; R1is Me, R2is I, and R3is CONHCH3; R1is phenylethyl, R2is I, and R3is CONHCH3; R1is Me, R2is 5-Cl-thien-2-yl, and R3is CONHCH3; R1is nPr, R2is 5-Cl-thien-2-yl, and R3is CONHCH3; R1is Me, R2is 5-Cl-thien-2-yl-ethynyl, and R3is CONHCH3; R1is nPr, R2is 4-pyridyl, and R3is CONHCH3; R1is Me, R2is I, and R3is COOCH2CH3; R1is (cyclopropyl)(isopropyl)methyl , R2is 5-Cl-thien-2-yl-ethynyl, and R3is CONHCH3; or R1is Me, R2is H (Z=C-I), and R3is COOCH2CH3.

13. The compound, salt, or optical isomer according to formula (I) of claim 1, wherein: R1is Me, R2is Cl-thienyl-ethynyl, and R3is CH2CN; R1is c-Bu, R2is I; and R3is CH2OH; R1is c-Bu, R2is I, and R3is CN; R1is c-Hex, R2is I, and R3is CH2OH; R1is c-Hex, R2is I, and R3is CN; R1is (CH2)2cPr, R2is I, and R3is CH2OH; R1is (CH2)2cPr, R2is I, and R3is CN;13c’: R1is (CH2)2cPr, R2is I, and R3is CH2CN; R1is (CH2)2cPr, R2is I, and R3is CH2Cl; R1is (CH2)2cPr, R2is I, and R3is CO2Et; R1is (CH2)2cPr, R2is I, and R3is CONHCH3; R1is (CH2)2cPr, R2is I, and R3is CH2SH; R1is Ph, R2is I, and R3is CH2OH; R1is Ph, R2is I, and R3is CN; R1is Ph, R2is I, and R3is CH2CN; R1is Ph, R2is I, and R3is CO2Et; R1is Ph, R2is Cl-thienyl-ethynyl, and R3is CONHCH3; R1is (cyclobutyl)(cyclopropyl)methyl, R2is Cl-thienyl-ethynyl, and R3is CH2OH; R1is (CH2)5Ph, R2is Cl-thienyl-ethynyl, and R3is CO2Et; R1is (3-F-Ph), R2is I, and R3is CH2OH; R1is (3-F-Ph), R2is I, and R3is CN; R1is (3,5-diCl-Ph), R2is I, and R3is CH2OH; R1is (3,5-F-Ph), R2is I, and R3is CN; R1is NH-(3,4-diCl-Ph), R2is I, and R3is CH2OH; R1is (3,4-diCl-Ph), R2is I, and R3is CN; R1is (3-Cl-Bn), R2is I, and R3is CN; R1is (3-Cl-Bn), R2is I, and R3is CO2Et; R1is (3-Cl-Bn), R2is Cl-thienyl-ethynyl, and R3is CH2CN; R1is pyrrolyl, R2is I, and R3is CH2OH;N R1tetrahydropyrrolyl H; R1is tetrahydropyrrol H2OH;R1is tetrahydropyrrolyl, R2is 2-H, Z=C-CN, and R3is CN; ONN orR1is (cyclopropyl)(cyclobutyl) (R), R2is .

14. The compound, sal, o formula (II) of claim 1, wherein R1is selected from the group consisting of cycloalkyl or di-cycloalkylalkyl; R2is halo; and R3is CH2OH or COOR4, wherein R4is alkyl.

15. The compound, salt, or optical isomer of claim 14, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R2is chloro, iodo, or methylthio; and R3is COOR4, or CONHR4, wherein R4is C1-C3alkyl.

16. A pharmaceutical composition comprising a compound, salt, or optical isomer of any one of claims 1-15 and a pharmaceutically acceptable carrier.

17. A method of antagonizing a 5-HT2B serotonin receptor in an animal in need thereof comprising administering a compound, salt, or optical isomer of any one of claims 1-15 or a pharmaceutical composition of claim 16.

18. A method of treating fibrosis of the lung, skin, coronary and or liver fibrosis, pulmonary arterial hypertension, valvular heart disease, pain, or cancer in an animal in need thereof, comprising administering a compound, salt, or optical isomer of any one of claims 1-15 or a pharmaceutical composition of claim 16.

19. Use of a compound, salt, or optical isomer of any one of claims 1-15 or a pharmaceutical composition of claim 16 for antagonizing a 5-HT2B serotonin receptor in an animal in need thereof.

20. Use of a compound, salt, or optical isomer of any one of claims 1-15 or a pharmaceutical composition of claim 16 treating fibrosis of the lung, skin, coronary and or liver fibrosis, pulmonary arterial hypertension, valvular heart disease, pain, or cancer in an animal in need thereof.

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