Indian Patents
Title of Invention

ARYL ANILINE B2 ADRENERGIC RECEPTOR AGONIST COMPOUND
Abstract An aryl aniline (32 adrenergic receptor agonist compound of formula (I): wherein each of R<sup>1</sup>_R<sup>5</sup> is independently selected from the group consisting of hydrogen, C<sub>1</sub>-<sub>5</sub>alkyl, C<sub>1</sub>-<sub>5</sub>alkenyl, C<sub>1</sub>-<sub>5</sub>alkynyl, C<sub>1</sub>-<sub>10</sub>aryl, C<sub>3</sub>-<sub>10</sub>cycloalkyl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and 0, heterocyclyl containing 3 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and 0 and R3.
Full Text Field of the Invention The invention is directed to an aryl aniline 02 adrenergic receptor agonist compound. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 02 adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.
Background of the Invention P2 adrenergic receptor agonists are recognized as effective drugs for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema). Pa adrenergic receptor agonists are also useful for treating pre-term labor, and are potentially useful for treating neurological disorders and cardiac disorders. In spite of the success that has been achieved with certain 02 adrenergic receptor agonists, current agents possess less than desirable potency, selectivity, speed of onset, and/or duration of action. Thus, there is a need for additional 02 adrenergic receptor agonists having improved properties. Preferred agents may possess, among other properties, improved duration of action, potency, selectivity, and/or onset.
Summary of the Invention The invention provides novel compounds that possess 132 adrenergic receptor agonist activity. Accordingly, this invention provides an aryl aniline 02 adrenergic receptor agonist compound of formula (I):

wherein:
each of R*-R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and R3;

or R1 and R2, R2 and R3, R3 and R4, or R4 and R5 together form a group
selected from the group consisting of -C(Rd)=C(Rd)C(=0)NRd-,
-CRdRd-CRdRd-C(=0)NRd, NRdC(-0)C(Rd)=C(Rd)-, NRdC(=0)CRdRd-CRdRd-,
-NRdC(=0)S-, -SC(=0)NRd-, -(CRVV, -S(CRdRd)q-, -(CRdRd)qS, -S(CRdRd)rO,
-0(CRdRd)rS, and -NHC(RJ)=C(Rk)-;
R6 is hydrogen, alkyl, or alkoxy;
R7 is hydrogen or alkyl;
R8 is hydrogen or alkyl; or R8 together with R9 is -CH2- or -CH2CH2-;
R9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl,
aryl, heteroaryl, cycloalkyl, heterocyclyl, and Ra, or R9 together with R8 is -CH2- or
-CH2CH2-;
R10 is hydrogen or alkyl;
each R11, R12, and R13 is independently selected from the group consisting of
hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -NO2,
halo, -NRdRe, -C(=OJRd, -C02Rd, -OC{=0)Rd, -CN, -C(=0)NRdRe, -NRdC(=0)Re, -
OC(=0)NRdRe, -NRdC(=0)ORe, -NRdC(=OJNRdRe, -ORd, -S(OJmRd, -NRd-NRd-
C(=0)Rd, -NRd-N=CRdRd, -N(NRdRe)Rd, and-S{0) 2NRdRc ;
or R11 and R12 together with the atoms to which they are attached form a fused
benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 Re;
or R" and R12 together with the atoms to which they are attached form a heterocyclic ring;
wherein for RJ-R6, R9, and Ru-R13, each alkyl, alkenyl, and alkynyl is optionally substituted with Rm or with 1, 2, 3, or 4 substituents independently selected from Rb; for R]-R6, R9, and Rn-R13, each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rc and for RJ-R6, R9 and Ru-R13 each cycloalkyl and heterocyclic ring is optionally substituted with 1,2, 3, or 4 substituents independently selected from Rb and Rc ; each Ra is independently-ORd,-N02, halo, -S(0)raRd, -S(0)2ORd, -S(0}mNRdRe, -NRdRe, -OtCRfReJnNRdR*, -C(=0)Rd, -C02Rd, -C02(CRfRe)nCONRdRe, -OC(=0)Rd, -:N, -C(=0)NRdRe, -NRdC(=O)Re-0C(=0)NRdRe, -NRdC(=OJ NRdRe, -CRd{=N-ORe), -CF3| or -OCF3;
each Rb is independently Ra, oxo, or =N-ORe;

each Rc is independently Ra, alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted withl, 2,3, or 4 substituents independently selected from Rb;
each Rd and R* is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted withl, 2,3, or 4 substituents independently selected from Rh ; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen;
each Rf and Rs is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1,2, 3, or 4 substituents independently selected from Rh ; or Rf and Rs together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen;
each Rh is independently halo, Ci ealkyl, C1-4salkoxy, -S-C1-4salkyl, aryl, (aryl)-C1-46alkyl, (aryl)-C1-48alkoxy, heteroaryl, (heteroarylJ-C1-4ealkyl, (heteroaryl)-C, salkoxy, hydroxy, amino, -NHC1-4ealkyl, -N(C1-46alkyl)2, -OC(=0)C1-46alkyl, -C(=0)C1-4 ealkyl, -C(=0)OC1-46alkyl, -NHC (=0)C1-46alkyl, -C(=0)NHC1-46alkyl, carboxy, nitro, -CN, or-CF3 ;
R> and Rk together with the carbon atoms to which they are attached form a phenyl ring that is optionally substituted with 1,2, 3, or 4 Rc ;
each Rm is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1,2, 3, or 4 substituents selected from the group consisting of Rc, and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1,2, 3, or 4 substituents selected from Rb;
mis 0, 1, or 2 ;
n is 0, 1,2, 3,4, 5,6, 7,8, 9,or 10 ;
p is 3, 4, or 5 ; q is 2, 3, or 4 ;
r is 1,2, or 3 ; and
wisO, 1, 2,3, or 4 ;

or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
Accordingly, this invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of claims 1 to 14 and a pharaiaceutically-acceptable carrier, wherein said compound constitutes form about 0.1% to about 30% of the composition.
Accordingly, this invention provides compounds of formula (!}:


0)
wherein:
each of R -R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aiyl, heteroaryl, cycloalkyl, heterocyclyl, and R*;
orR1 and R2, R2 and R3, R3 and R\ or R4 and R5 are joined together to form a group selected from the group consisting of -C(Rd)=C(Rd)C(=0)NRd-, -CRdRd-CRV-C(=0)NRd-,-NRdC(=0)C(Rd)=C(RdX -NRdC(=0)CRdRd-CRdRd-, -NRdC(=0)S-, -SC(=0)NRd-, -(CRdRd)p-. -S(CRdRd)q-, -(CRdRd)qS-, -SfCRV)^-, -0(CRdRd)rS-, and -NHCtR^tR*)-;
R6 is hydrogen, alkyl, or alkoxy;
R7 is hydrogen or alkyl;
Re is hydrogen or alkyl; or R8 together with R9 is -CH2- or -CH:CH2-;
R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and Ra, or R9 together with R is -CH2- or
-CH3CHr;
R10 is hydrogen or alkyl;
each R,l,R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, aikynyl, aryl, heteroaryl, heterocyclyl, -NO:, halo, -NR"Re, -C(:=0)R\ -CO,Rd, -OC(=0)Rrt, -CN, -C(=0)NRV, -NRaC(=0)Re, -OC(=0)NRdR°, -NR"C(=0)OR°, -NR"C(=0)NR*R\ -ORa, -S(0)mR", -NRd-NRJ-C(=0)R\ -NR*-N=CRV. -NCNR^R", and -S(0),NRdR°;
or R11 and R12 together with the atoms to w-hich they are attached form a fused benzoring, which benzo ring can optionally he substituted with J, 2, 3, 0r4R";
or R1" and R12 together with the atoms to which they are attached form a heterocyclic ring;
wherein for R"-R6, R9, and R"-R13, each alkyl, alkenyl, and alkynyl is optionally substituted with Rm, or with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from Rh; for R"-R6, R9, and Rn-R13icach aryl and heteroaryl is optionally

substituted with I, 2, 3, or 4 substituents independently selected from R", and for R"-R6, R9, and RM-R,3each cycloalky! and heterocyclic ring is optionally substituted with 1,2, 3, or 4 substituents independently selected from Rb and R°;
each R" is independently -ORd, -NO,, halo, -S(0)„Rd, -S(0),ORd, -S(0)-NRiR\ -NRdRe, -0{CR"R").NRdR\ -C(=0)R*. -CO^R*, -CCyCR"R"XCONRV, -OC(=0)Rd, -CN, -C(=0)NR*R\ -NR"Cf=0)R") -OC(=0)NRaR\ -NR"C(=0)OR\ -NRdC(=0)NRdR", -CR"(=N-OR°)," -CF„ or -OCF3;
each Rb is independently R*, oxo, or =N-ORc;
each Rc is independently R", alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with I, 2, 3, or 4 substituents independently selected from R";
each Rd and R° is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alky], alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from R"; or Rd and R" together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
each R" and R" is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyi, or heterocycfyl; wherein each alkyi, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RK; or R" and R" together with the caibon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionaily contains 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
each Rh is independently halo, C,.aalkyl, C1-4alkoxy, -S-C,.salkyl, aryl, (aryl)-Cualkyl, (aryl)-C, BaIkoxy, heteroaryl, (heteroaryl)-C, ,alkyl, (heteroaryl)-C1.,alkoxy, hydroxy, amino, -NHCMalkyl, -N(C,^alkyl);, -OC(=0)CMalkyl, -C(=0)CMnlkyl, -C(=0)OC,,alkyl, -NHC{=0)CMalkyl, -Cf=0)NHC,4alkyl, carboxy, nitro. -CN, or -CF,;
R1 and Rk together with the carbon atoms to which they are attached form a phenyl ring that is optionally substituted with 1, 2, 3,or4Rc;
each Rm is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from the

group consisting of Rc, and wherein each cydoalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents selected from Rb;
misO, I, or2;
n is 0,1, 2, 3,4, 5, 6, 7, 8, 9, or 10;
p is 3,4, or 5;
q is 2, 3, or 4;
r is 1,2, or 3;
wisO, 1,2, 3, or 4;
or a pharmaceuticaily-acceptable salt or solvate or stereoisomer thereof.
The invention also provides compounds of formula (H):

wherein:
R4 is -CHzOH or -NHCHO and R5 is hydrogen; or R4 and R5 taken together are -NHC(=0)CH=CH-;
R11 is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, -ORd, -CN, -N03, -SOzR11, -C(=0)Rd, -C(=0)NR"V, and C|_3aifcyi, wherein Q.j&lkyl is optionally substituted with 1 or 2 substituents selected from cnrboxy, hydroxy, and amino, and each Rd and Rf is independently hydrogen or. Cj.jalkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 Ci-jalkyl substituents; and
R12 is hydrogen or -OCi-5alkyl;
or a pharmaceuticaily-acceptable salt or solvate or stereoisomer thereof.
The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceuticaily-acceptable carrier.
The invention also provides a method of treating a disease or condition associated with 32 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder.

or inflammation) in a mammal, comprising administering to the mammaJ, a therapeutically effective amount of a compound of the invention.
The invention also provides a method of treating a disease or condition associated with fa adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal, comprising administering to the mamma), a therapeutically effective amount of a pharmaceutical composition of the invention.
This invention also provides a method of modulating a J52 adrenergic receptor, the method comprising stimulating a $2 adrenergic receptor with a modulatory amount of a compound of the invention.
In separate and distinct aspects, the invention also provides synthetic processes and novel intermediates, including compounds of formulas (HI), (TV), and (VH) described herein, which are useful for preparing compounds of the invention.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition associated with p2 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a enrdiac disorder, or inflammation) in a mammal.
Detailed Description of the Invention
When describing the compounds, compositions and methods of the invention, .the following terms have the following meanings, unless otherwise indicated.
The term "alky!" refers to a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Such alkyl groups preferably contain from 1 to 20 carbon atoms; more preferably, from ! !o 8 carbon atoms; and still more preferably, from 1 to 4 carbon atoms. Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobuty], fert-buty], n~ pentyl, n-hexyl, /i-heptyl, n-octyl, n-nonyl, n-decyl and the like.
The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond, typically 1 or 2 carbon-carbon double bonds, and which may be linear or branched or combinations thereof. Such alkenyl

groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon aioms; and stil] more preferably, from 2 to 4 carbon atoms. Representative alkenyl groups include, by way of example, vinyl, ally], isopropenyl, btit-2-eny], n-pent-2-enyl, n-hex-2-enyl, n-hept-2-enyl, rt-oct-2-enyl, n-non-2-enyl, «-dec-4-enyi, «-dec-2,4-dieny/ and the like.
The term "alkynyi" refers to a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, typically 1 carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Such alkynyi groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; and still more preferably, from 2 to 4 carbon atoms. Representative alkynyi groups include, by way of example, ethynyl, propargyl, but-2-ynyl and the like.
The term "alkoxy" refers to a group of the formula -OR, where R is an aJkyl group as defined herein. Representative aJJcoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, jec-butoxy, isobutoxy, rerr-butox.y, n-pentoxy, ;i-hexoxy and the like.
The term "cycloalkyl" refers to a monovalent saturated carbocyclic group which may be monocyclic or multicyclic. Each ring of such cycloalkyl groups preferably contains from 3 to 10 carbon atoms. This term also includes cycloalkyl groups fused to an nryl or heleroaryl group in which the point of attachment is on the non-aromatic (cycloalkyl) portion of the group. Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, ],2,3,4-tetrakydronapbth-2-yl, decahydronaphthyl, indan-1-yJ, adamantyl, norbomyl and the like.
The term "aryl" refers to a monovalent carbocyciic group which may be monocyclic or multicyclic (i.e., fuseci) wherein at least one ring is aromatic. Such aryj groups preferably contain from 6 to 20 carbon atoms; more preferably, from 6 to 10 carbon atoms. This term includes multicyclic carbocyclic ring systems wherein one or more rings are not aromatic, provided the point of attachment is on an aromatic ring. Representative aryl groups include, by way of example, phenyl, napthyl, azulenyl, indan-5-yl, l,2,3,4-tetrabydronaphth-6-yl, and the like.
The term "heteroaryl" refers to a monovalent aromatic group that contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from N, S and O, and which may be monocyclic or multicyclic (i.e., fused). Such heteroaryl groups preferably contain from

5 to 20 atoms; more preferably, from 5 to 10 atoms. This term also includes heteroaryl groups fused to a cycloalkyl or aryl group, in which the point of attachment is on the aromatic (heteroaryl) portion of the group. Representative heteroaryl groups include, by way of example, pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl (or, equivalently, pyridinyl), oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, tnazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl and the like.
The term "heterocyclyl" or "heterocyclic ring" refers to a saturated or partially unsaturated cyclic non-aromatic group, which may be monocyclic or multicyclic (i.e., fused or bridged), and which contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from N(X), S and O, wherein each X is independently hydrogen or alkyl. Such heterocyclyl groups preferably contain from 3 to 20 atoms; more preferably, from 3 to 10 atoms. This term also includes such a heterocyclyl group fused to one or more cycloalkyl, aryl, or heteroaryl groups. The point of attachment of the heterocyclyl group may be any carbon or nitrogen atom in a heterocyclyl, cycloalkyl, aryl or heteroaryl portion of the group, Representative heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidiny!, morpholiny], indolin-3-yl, 2-imkla7.olinyl, i,2,3,4-teirahydroisoquinolin-2-y!, quinuclidinyl, 2-oxobenzopyran, and the like.
The term "halo" refers to a fluoro, chloro, bromo or iodo.
The term "oxo" refers to a group of the formula =0.
The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
The term "treatment" as used herein refers to the treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), and includes:
(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., eliminating or t ausing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.

The phrase "disease or condition associated with Pa adrenergic receptor activity" includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with p^ adrenergic receptor activity. Such disease states include, but are not limited to, bronchoconstrictive or pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as neurological disorders and cardiac disorders. p3 Adrenergic receptor activity is also known to be associated with pre-term labor (see, for example, U.S. Patent No. 5,872,126) and some types of inflammation (see, for example, WO 99/30703 and U.S. Patent No. 5,290,83 5).
The term "pharmaceutically-acceptable salt" refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from p/iarmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
Salts derived from pharmaceutically-acceptable acids include acetic, benzenesuffonic, benzoic, camphosulfonic, citric, ethanesulfonic, fbmaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (I-fiydroxy-2-naphthoic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, xinafoic, tartaric, citric, malic, maleic, succinic, and benzoic acids.
Salts derived from pharmaceutical!/- accept able inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N"-dibenzylethy!enediamine, diethyl amine, 2-diethylarrnnoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-elhylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucarnine, morpboline, piperazine, piperadine, polyamine

resins, procaine, purines, theobromine, trielhyfamine, (rimethylamine, Iripropyiamine, tromethamine and the like.
The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, i,e. a compound of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
The term "leaving group" refers to a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
The term "amino-protecting group" refers to a protecting group suitable for preventing undesired reactions at an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl; alkoxycarbonyl groups, such as fert-butoxycarbonyl (Boc); arylmetlioxycarbonyl groups, such as benzyl ox ycarbonyf (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and l,I-di-(4"-methoxyphenyl)methyl; silyl groups, such as trimethy]silyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
The term "hydroxy-protecting group" refers to a protecting group suitable for preventing undesired reactions at a hydroxy group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and /erf-butyl; acyl groups, for example aikanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn),/j-methoxybenzy! (PMB), 9-fluorenyl methyl (Pm), and diphenylmethy] (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and rm-butyldimethylsilyl (TBS); and the like.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only, they do not exclude other defined values or other values within defined ranges for the radicals and substittients.

A specific value for R is hydrogen.
A specific value for R2 is hydrogen.
A specific value for R3 is hydroxy.
A specific value for R4 is -CH2OH or -NHCHO.
A specific value for Rs is hydrogen,
A specific value for R* and Rs together are -NHC(=0)CH=CH- or -SC(=0)NH-.
A specific value for R6 is hydrogen.
A specific value for R7 is hydrogen.
A specific value for RB is hydrogen.
A specific value for w is 0.
Another specific value for w is 1 or 2.
A specific value for R9 together with Rg is -CH2- or -CH2CH2-.
A specific value for R10 is hydrogen.
Another specific vaJue forR10isalkyJ.
A specific value for R1" is hydrogen.
Another specific value forR" is alkyl, aJkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -NO,, halo, -NRJR", -C(=0)R\ -C02R°, -OC(=0)Rd, -CN, -C(=0)NRdR\ -NRdC(=0)Rc, -OC(=0)NRdR°, •NRdC(=O)0Rc1 -NRdC(=0)NRdR", -0Rd, -S(0)mR*, -NRl"-NRd-C{=0)R,", -NRu-N=CRJR", -N(NRV)Rd, or -S(0);NRdR".
Another specific value forR" is hydrogen, alkyl, heterocyclyl. -ORJ, -S{0)BRd, or
Another specific value for R1" is heterocyclyl, -OR*, -S(0)mRd- or -S(0)2NRdRe.
Another specific value for R1" is -ORd.
Another specific value for R1" is -S(0)nRd.
A specific value for Ru is hydrogen.
Another specific value for Ru is alkyl, alkenyl, alkynyl, aryi, heteroaryl, heterocyclyl, -NO,, halo, -NRX -C(=0)Rd, -CO,R", -OC(=0)Rtf, -CN. -C(=0)NRsR=. -NR°C(=0)Rc, -OC(=0)NRdRc, -NRdC(=0)OR\ -NR"C{=0)NRdR", -ORd, -S(0)X -NR°-NRd-C(=0)Rd, -NRJ-N=CR"RJ, -N(NRJRc)Ra,ior -S(0),NRdRc.
Another specific value for R12 is hydrogen, alkyl, heterocyclyl, -OR*, -S(0)nRd, or -S(0)2NRdRc.
A specific value for R12 is heterocyclyl, -ORd, -S(0)mRd, or -S(0),NR"Rc.
Another specific value for R " is -OR".

Another specific value for R12 is -S(0)mRd-Another specific value for R|: is -S(0)jNR*R*. A specific value for R" is hydrogen.
Another specific value for R13 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -N02,halo, -NRV, -C(=0)R4, -C03Rd, -OC(=0)R\ -CN, -C(=0)NRV, -NRdC(=0)Ra, -OCC=0)NRdR", -NRdC(=0)OR", -NRtfC(=0)NRdR", -OR*, -S(0)mRd, -NRd-NRd-C0=O)Rd, -NRd-N=CRdR°, -N(NR^°)Rd, or -SfCOjNR"R".
Another specific value for R13 is hydrogen, alkyl, heterocyclyl, -ORd, -StO^R4, or -S(0):NRdRAnother specific value for R13 is heterocyclyl, -ORd, -S(0)mRa. or -SCO^NRV. A specific value forR13 is -ORJ. A specific value for Rn is -S^R".
A specific group of compounds of the invention are compounds wherein each of R"-R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxy, A^-dimethylaminocarbonyloxy, -CH2OH, and -NHCHO, and R5 is hydrogen; or R1 is hydrogen, R2 is hydrogen, R3 is hydroxy, and R4 and R5 together are -NHC{=0)CH=CH- or -SC(=0)NH-.
A specific group of compounds of the invention are compounds wherein R is hydrogen; R2 is chlnm; R3 is amino; R4 is chloro; and Rs is hydrogen.
A specific group of compounds of the invention are compounds wherein R is hydrogen; R2 is /^.//-dimethylaminocarbonyloxy; R3 is hydrogen; R is N,N~ dimethylaminocarbonyloxy; and Rs is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen, fluoro, or chloro; R2 is hydroxy; R3 is hydrogen; R4 is hydroxy; and Rs is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is chloro; R2 is hydrogen; R3 is hydroxy; R4 is hydrogen; and Rs is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is hydrogen; R3 is hydroxy; R4 is -CHiOH; and R5 is hydrogen.
A specific group of compounds of the invention arc compounds wherein R1 is hydrogen; R2is hydrogen; R3is hydroxy; R4 is-NHCHO; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R is hydrogen; R2 is hydrogen; R3 is hydroxy; and R4 and R5 together are -NHC(=0)CH=CH-.

A specific group of compounds of (he invention are compounds wherein R is hydrogen; R2 is hydrogen; R3 is hydroxy; and R4 and R5 together are -SC(=0)NH-.
A specific group of compounds of the invention are compounds wherein R11 is hydrogen, R12 is -SRd; R13 is hydrogen; and R" is alkyl, aryl, or heteroaryl.
A specific group of compounds of the invention are compounds wherein R " is -SRd, R12 is hydrogen; RIJ is hydrogen; and R" is alkyl, aryl, heteroaryl. When part of the group -SRJ, a specific value for Rd is alkyl. When part of the group -SRd, another specific value for R* is C,-Salkyl. When part of the group -SRd, another specific value for Rd is C1-4alkyl. When part of the group -SR", another more specific value for Rd is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C(J,alkyl, C1-4alkoxy, hydroxy, amino, -N(C1HSa!kyl),, nitro, -CN, and -CFr
When part of the group -SRd, another more specific value for R* is phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from fluoro and Cloalkyl.
A specific group of compounds of the invention are compounds wherein R or R12 is methylthio, 2-methylphenylthio, 4-methyl-2-pyrimidylthio, 4-fluorophenyIthio, or 4-methyIphenylthio.
A specific group of compounds of the invention are compounds wherein R" is hydrogen or alkyl, R12 is -SO.NR"R1; and Rl] is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 is -SO,NRJR\ R12 is hydrogen or alkyl; and R13 is hydrogen.
When part of the group -SOjNR"R6, a specific value for R° is alkyl, aryl, or
heteroaryl; and for R" is hydrogen, alkyl, aryl, or heteroaryl; wherein each alkyl, aryl, or
heteroaryl, is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents
independently selected from Rh; or Rd and R° together with the nitrogen atom to which
they are attached is a heterocyclic ring having from 5 to 7 ring atoms, wherein the
heterocyclic ring optionally contains 1 or 2 additional heleroatoms independently selected
From oxygen, sulfur or nitrogen. i
When part of the group -SO,NRJR°. a specific value for RJ and R" independently is hydrogen, alkyi, aryl, or heteroaryl; wherein each alkyl, aryl, or heteroaryl, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rh.

As a substituent as part of the group -S02NRBRfl, a specific value for R" is halo, C,.tal!cyl, C1-4alkoxy, -S-C,.,alkyl, aryl, hydroxy, amino, -NHCMalkyl, -NtC1-4atkyl),, -OC(=0)Cualkyl, -C(=0)CMalkyl, -C(=0)OC,salkyl, -NHC(=0)C,salkyl, -C(=0)NHC1HSalkyl, carboxy, nitro, -CN, or -CFr
Another specific value for R* in the above context is halo, C1-4alkyl, Cualkoxy, or -CF,
When part of the group -SO^fR^R", a specific value for Rd and R" together with the nitrogen atom to which they are attached is a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen.
When part of the group -SOJNR"R*, a specific value for Rd and Re independently is alkyl; wherein each alkyl is optionally substituted with 1 or 2 alkoxy substituents.
When part of the group -SO^iR"K", a specific value for R" or R= is phenyl, or naphthyl; wherein each phenyl and naphthyi is optionally substituted with 1,2, 3, or 4 substituents independently selected from halo. Chalky], C1-4alkoxy, and -CF,.
When part of the group -SOj^^R^ a specific value for Rd or R" is heteroaryl; wherein each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, Chalky], Cl(ialkoxy, and -CFV Preferably heteroaryl is pyridyl, pyrimidyl, or thiazolyl.
A preferred group of compounds are compounds wherein R or R12 is -SOJNRJR":; wherein R* is 4-heptyl-6-methyl-2-pyrimidyl, 5-methoxy-2-pyrimidyl, 2-pyridyl, phenyl, 2,6-dimethylpheny!, 2-thiazoyl, 2-trifluoromethylphenyl, or 3,5-dichlorophenyl; and R° is hydrogen or ethyl.
Another preferred group of compounds are compounds of the invention wherein R" or R12 is -SOjNR"R"; wherein Rd and R" together with the atoms to which they are attached are piperidino or morpholino.
A specific group of compounds of the invention are compounds wherein R1" is hydrogen or alkyl; R12 is -SO,Rd; and R13 is hydrogen.
Another specific group of compounds of the invention are compounds wherein R" is -S03Rd; R12 is hydrogen or alkyl; and RIJ is hydrogen.
When pail of ihe group -SO^R", a specific value for Rd is alky!, aryl, or heteroaryl.

When part of the group -SOjRd, a specific value for Rd is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C,.(alky], ClHlaikoxy, and-CFr
When part of the group -SOjRd, a specific value for Rd is phenyl optionally substituted with 1 or 2 substituents independently selected from halo and C1-4alkyl.
A preferred group of compounds of the invention are compounds wherein R1" or R12 is -SOjRd; wherein Rd is phenyl, 4-chlorophenyl, methyl, or 4-fluorophenyl.
A specific group of compounds of the invention aie compounds wherein at least one of R1", R11, and R13 is -ORd and each of the other two of R11, R12, and R" is independently selected from the group consisting of hydrogen, alkyl, -O-alkyl, and halo; wherein any alkyl or -O-alkyl is optionally substituted with aryl, or with one or more (e.g. 1,2, 3, or 4) halo substituents.
A specific group of compounds of the invention are compounds wherein R1" is -ORd.
A specific group of compounds of the invention are compounds wherein R!2 is -OR"
A specific group of compounds of the invention are compounds wherein Rn is -OR"
A specific group of compounds of the invention are compounds wherein Rl! is hydrogen; R12 is -OR"; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein RN is -OR"; R1 is hydrogen; and R13 is hydrogen.
When part of the group -ORd, a specific value for Rd is alkyl, optionally substituted with one ^rmore (e.g. 1, 2, 3, or 4) halo substituents and also optionally substituted with 1, 2, 3, or 4 aryl substituents, wherein each aryl is optionally substituted with 1,2, 3, or 4 substituents independently selected from halo, C1-4alkyl, C,.6alkoxy, hydroxy, amino, -NHC1-4alkyl, -NXC1-4alkyl)^ -OC(=0)CuaIkyi, -C(=0)C,.6alky], -C(=O)0C,.6alky], -NHC(=0)C,6alkyI, -C(=0)NHC,.6alkyI, carboxy, nilro, -CN, and -CFr
When part of the group -ORd, a specific value for R° is alkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo substituents and also optionally substituted with 1 or 2 phenyl substituents, wherein each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, C1-4aikyl, C1-4alkoxy, hydroxy, -CN, and -CF5.

A specific group of compounds of the invention are compounds wherein R and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered ring comprising one or more carbon atoms and 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen; and R13 is selected from the group consisting of hydrogen, alkyl, -O-alkyl, and halo; wherein any alky! or -O-alkyl is optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo substituents.
A more specific group of compounds of the invention are compounds wherein Rn and R12 together are -OCH.O-, -OCB£Kp-, or -OCH^CH, CRp-.
A specific group of compounds of the invention are compounds wherein R11, R12, or R13 is methoxy, ethoxy, benzyloxy, or isopropoxy.
A specific group of compounds of the invention are compounds wherein Rn, R12, and R." are each hydrogen.
A specific group of compounds of the invention are compounds wherein at least one of R11, R12, and R11 is alkyl and each of the other two of Rn, R1Z, and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2 -O-alkyl substituents; or wherein R11 and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring.
A specific group of compounds of the invention are compounds wherein at least one of R!l, R12, and R" is alkyl and each of the other two of Ru. R12, and R" is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g." 1, 2, 3, or 4) halo, or with 1 or 2 -O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein R11 and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring; and R13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2 -O-alkyi substituents.
A specific value for R 3 is hydrogen.
A specific group of compounds of the invention are compounds wherein Rl l is hydrogen; R12 is alkyl; and R"1 is hydrogen.

A specific group of compounds of the invention are compounds wherein R is aikyl; R12 is hydrogen; and R1J is hydrogen.
A preferred group of compounds of the invention are compounds wherein R1" or R12 is methyl, ethyl, isopropyl, or cyclohexyl; or wherein R11 and R12 taken together are -CI^CH^CH,-.
A specific group of compounds of the invention are compounds wherein at least one of R"", R12, and R15 is aryl; and each of the other two of R1", R12, and R" is independently selected from the group consisting of hydrogen, aikyl, -O-alkyI, and balo, wherein any aikyl or-O-alkyl is optionally substituted with aryl, with one or more (e.g. I, 2,3, or 4) halo, or with 1 or 2 -O-alkyl substituents;
or wherein R11 and R12 together with the atoms to which they are attached form a fused benzo ring, which benzo ring can optionally be substituted with 1,2, 3, or4Rc; and R11 is independently selected from the group consisting of hydrogen, alky], -O-alkyl, and balo, wherein any aikyl or -O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2 -O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein at least one of R", Rn, and R13is aryl; and each of the other two of R11, R12, and RIJ is independently selected from the group consisting of hydrogen, aikyl, -O-alkyl, and halo, wherein any alky] or-O-aJkyl is optionally substituted with aryl. with one or more (e.g. 1, 2, 3, or 4) halo, or with I or 2 -O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein R1" is phenyl, optionally substituted with 1, 2, 3, or 4 aikyl, -ORd, -NO:, halo, -NRdRB, -C(=0)Rd, -C02Rd, -OC(=0)Rd, -CN, -C(=0)NRdRe, -NRdC(=0)Re, -OC(=0)NRdRe,"-NRdC(=0)ORe, -NRdC(=0)NRc,R=, -CRd{=N-ORe), -CF3, or -OCF3; R12 is selected from the group consisting of hydrogen and -O-alkyl, optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1" is phenyl, optionally substituted with 1, 2, 3, or 4 aikyl, -ORd, halo, -CF3, or -OCF3; Ri2 is selected from the group consisiing of hydrogen and -O-alkyl, optionally substituted with aryl. or with one or more (e.g. 1, 2, 3, or 4) halo; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1" or R12 is phenyl.

A specific group of compounds of the invention are compounds wherein R and R 2 together with the atoms to which they are attached form a fused benzo ring.
A specific group of compounds of the invention are compounds wherein at least one of R1", R12, and R" is heterocyclyl; and each of the other two of R11, a"2, and R1" is independently selected from the group consisting of hydrogen, alkyl, -O-alkyl, and halo, wherein any alkyl or -O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2 -O-alkyl substituents;
or wherein R " and R together with the atoms to which they are attached form a heterocyclic ring.
A specific group of compounds of the invention are compounds wherein R"and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered ring comprising carbon atoms and optionally comprising 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen, wherein said ring can optionally be substituted on carbon with one or two oxo (=0), and wherein said ring is fused to a benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 Rc; and R11 is independently selected from the group consisting of hydrogen, alkyl, -Oalkyl, and halo, wherein any alkyl or -O-alkyl is optionally substituted with aryl, with one or more halo, or with 1 or 2 -O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein R1" or R12 is 2,3-dihydro-5-methyl-3-oxo-l-pyrazofyl; or wherein R11 and R12 together with the atoms to which they are attached form a 2-oxobenzopyran ring.
Another specific group of compounds of the invention are compounds wherein R: or R12 is anilino, trifluorometboxy, or methoxycarbonyl.
A sub-group of compounds of the invention are compounds of formula (I) wherein each of R -R is independently selected from the group consisting of hydrogen, alkyl, and Rs; wherein each R" is independently -OR", halo, -NRdR\ -NRdC(=0)Re, or -OC(=0)NRdR";
or R1 and R2, or R and R5, are joined together to form a group selected from the group consisting of -C0)NR,i-, -CRdRd-CRdRd-C(=0)NRd-, -NRdC(=0)C(RVC(Rd}-, -NRdC{=0)CRdRd-CRdRd-, -NRdC(=0)S-, and -SC(=0)NRd-;
R6, Ra, and R10 are each hydrogen;
each of R1 "and R12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -NO,, halo,

-NRdR\ -CO^R", -OC(=0)RJ, -CN, -C(=0)NRdR\ -NRdC(=0)Rs, -OR1, -S(0)„Rd, -NRd-NR",-CC=O)R0, -NRd-N=CR"Rd, -N(NRdRe)Rd, and -S(Oy*R*R";
wherein for R"-RJ, R11, and R12, each alkyl is optionally substituted with Rm, or with 1,2, 3, or 4 substituents independently selected from Rb; for R11 and Rl!, each aryl and beteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Re, and for R1" and R12, each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rb and R°; . R13 is hydrogen; the group comprising -NR10 is meta or para to the group comprising R7; and w is 0, 1, or 2.
Preferably within the above sub-group of compounds, each of R ] and R1Z is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, -ORd, -S(0),R", and -StoyWR6; wherein each alkyl is optionally substituted with 1 or 2 substituents independently selected from Rb, each aryl is optionally substituted with I or 2 substituents independently selected from Rc, and each heterocyclyl is optionally substituted with 1 or 2 subslituents independently selected from Rb and Rc; and m is 0 or 2.
More preferably for such compounds, R7 is hydrogen; each of Rn and R|: is independently selected from the group consisting of hydrogen, C1-4alkyl, cyclohexyl, phenyl pyrazolinyl, -ORd, -S(0)inRa, and -S(0);NRV; w is 0; and
Rd and Rc are independently selected from the group consisting of hydrogen, Ci^alkyl, phenyl, -CF3, and C,.3alk.yl, pyridyl, thiazolyl, pyrimidinyl, and pyrazolinyl, where each phenyl is optionally substituted with 1 or 2 substitutents independently selected from halo, -CF3, and Chalky], each pyrimidinyl is optionally substituted with 1 or 2 substitutents independently selected from Cj ^alkyl and OC|_ialkyl, and each pyrazolinyl is optionally substituted with 1 or 2 substitutents independently selected from Ci.jalkyl and carboxy; or
Rd and Re, together with the nitrogen atom to which they are attached are rnorpholino orpiperidino.
Within the more preferred sub-group, one most preferred sub-group of compounds are compounds wherein R" is -SR and R " is hydrogen, or R11 is hydrogen and R1 is -SRd, wherein Rd is selected from the group consisting of Chalky!, phenyl, and

pyrimidinyl, and wherein each phenyl is optionally substituted with 1 or 2 substitutents independently selected from halo and Q.3 alky!, and each pyrimidinyl is optionally substituted with Chalky!.
Another most preferred sub-group of compounds are compounds wherein R1" is -S(0)2NRdRB and R12 is hydrogen or alkyl, or R1" is hydrogen or alkyl and R12 is -S(0)2NRdRe, wherein Rd and Re are independently selected from the group consisting of hydrogen, C|.3alkyl, phenyl, pyridyl, thiazolyl, and pyrimidinyl, and wherein each phenyl is optionally substituted with 1 substitutent selected from halo and C1-3 alkyl, and each pyrimidinyl is optionally substituted with 1 substitutent selected from C1_3 alkyl and 0-C1_3 alkyl; or R and Re, together with the nitrogen atom to which they are attached are morpholino or piperidino.
Another most preferred sub-group of compounds are compounds wherein R1" is -S02Rd and R12 is hydrogen, or R*" is hydrogen and R12 is -S02Rd, wherein Ra is C1.3alkyl or phenyl, and wherein each phenyl is optionally substituted with ! substituent selected from halo and Chalky!.
Another most preferred sub-group of compounds are compounds wherein R!" is -ORd and Rn is hydrogen or -ORd; or R1"is hydrogen and R12 is-ORd, wherein Rd is CoaJkyl.
Anolher most preferred sub-group of compounds are compounds wherein R" is C1-3alkyl and R1 is hydrogen or Cioalkyl; or R11 is cyclohexane and R12 is hydroxy.
Another most preferred sub-group of compounds are compounds wherein R11 is hydrogen or phenyl; and R13 is -OCj.jalkyl; or wherein Rn is phenyl and R1 is hydrogen.
Yet another most preferred sub-group of compounds within the more preferred" sub-group defined above are compounds wherein Rl2is hydrogen and Rn is SOiNRdRe, wherein Rd and Re, together with the nitrogen atom to which they are attached, are morpholino or piperidino.
Another preferred group of compounds of formula (I) are compounds of formula (ID:

wherein:
R4 is -CH2OH or -NHCHO and R5 is hydrogen; or R4 and Rs taken together are -NHC(=0)CH=CH-;
R1" is phenyl or heteroaryl, wherein each phenyl is optionally substituted with I or 2 substituents selected from halo, -ORd. -CN, -N02l -S02Rd, -C(=0)Rd, -C(=0)NRdR8, and Q-jalkyl, wherein Ci.3alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each Rd and Re is independently hydrogen or C|.3alkyl; and wherein each heteroaryl is optionally substituted with 1 or2Ci.3alkyl substituents; and
R12 is hydrogen or -OCualkyl.
More preferably, for compounds of formula (H), R1" is phenyl, optionally substituted with 1 or 2 substituents selected from halo, -ORd, -CN, -N02, -S02Rd, -C(=0)Rd, and Ci^alkyl, wherein Chalky! is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and R is hydrogen or Ct^alkyl; or R11 is pyridyl, thiophenyi, furanyl, pyrrolyl, isoxazoly!, orindolyl, each of which is optionally substituted with I or 2 Chalky! substituents.
Most preferable are compounds of formula (IT), wherein Rn is phenyl, pyridyl, of thiophenyi, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, -OCH3, -CN, and -CHiNH^; and R12 is hydrogen, -OCH3, or -OQ1H5. Among most preferred compounds, particularly preferred are compounds of formula (IT) wherein R4 and R5 taken together are -NHC(-0)CH=CH-, R"" is phenyl or pyridyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, -OCH3, -CN, and -CH3NH:, and R12 is -OCH3.
A preferred compound is any one of compounds 1-102 shown in the Examples below.
Most preferred compounds of the invention include the following:
A"-{2-[4-(3-pheiiyI-4-niethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxy methy 1-4- hydroxyphenyl)ethyl amine;
A,-{2-[4-(4-etboxyphenyl)aminopheny!]ethyl)-2-hydroxy-2-{3-bydroxymethyl-4-hydroxyphenyl)ethyI amine;
/^-(2-[4-(3-phenylpheny!)aminophenyl]ethyi}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyI)ethylaminc;

jV-{2-[4-(3-phenyM-raethoxyphenyI)aminophenyI]ethyI[-2-hydroxy-2-(8-hydroxy-2(ltf)-quinolinon-5-yl)ethylamine;
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
W-{2-[4-(3-pheDyl-4-elhoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydcgxymethyl-4-hydroxyphenyl)ethylamiae;
N-{2-[4-(3-phenyl-4-methoxypheQyl)aminophenyl]ethyl)-2-hydroxy-2-(3-formaraido-4-hydroxyphenyl)ethyIamiDe;
N-12-[4-(4-ethoxyphenyl)aminophenyl]ethyl) -2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
^-{2-[4-(3-pheny]phenyI)aminophenyJ]elhyJ}-2-bydroxy-2-(3-fDnnamido-4-hydroxyphenyl)ethylamine;
W-{2-[4-(3-phenyl-4-ethoxyphcnyI)aniinophetiyl]ethyl}-2-hydraxy-2-(3-formamido-4-hydroxy phenyl)etbyl amine;
jY-(2-[4-(4-methoxyphenyl)a[ninophenyl]ethyl|-2-[iydroxy-2-(3-formamido-4-hydroxyphenyljethylamine;
//-{2-[4-(4-ethoxypheny])aminophenyl]ethy])-2-hydroxy-2-(8-hydroxy-2(l/0-quinolinon-5-y!)etriyl amine;
/V-{2-f4-(3-phcnyIpheny!);)minoplienyIfe(/iy(J-2-!iydroxy-2-(S-hyciroxy-2((//)-quinolinon-5-yOetbylamine;
A"-{2-[4-(3-phenyI-4-elhoxyphenyl)aminophenyl]ethyl]-2-hydroxy-2-(8-hydroxy-2(lff)-quinolinon-5-yl)ethylamine; and
Ar-[2-[4-(4-methoxyphenyl)aminophenyI]ethyl|-2-hydroxy-2-(8-fiydroxy-2{lH)-quino]Jnon-5-y])ethy]amJne;
W-{2-[4-(3-phenyl-4-methoxyphenyl)arainophenyl]ethyl}--(/?)-2"hydroxy-2-(3-hydroxyme(hyl-4-hydroxypheny])ethyIamine;
A"-{2-[4-(4-ethoxyphenyl)aminophe.nyl]e!hy!l-(R)-2-hydioxy"2-(3-hyciroxymethyI-4-hydroxyphenyl)ethylamine;
N- [ 2-[4-(3-phenyI)aminophenyl]etbyl ] -(/?)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethyiamine;
/V-{2-[4-(3-phenyl-4-methoxypheny])aminophenyl]ethyl)-(/?)-2-hydroxy-2-(8-hydrQxy~2(lff)-qiiirioliaon-5-yl"jtz(!iylamine;

//-{2-[4-(4-methoxyphenyl)aminophenyJ]etfayI}-(^)-2-hydroxy-2-(3-hydroxymethyI-4-hydroxyphenyl)ethy!amine;
W-{2-[4-(3-phenyI-4-ethoxyphenyl)amiriophenyl]ethyl)-CR)-2-hydroxy-2-(3-hydroxymethyI-4-hydroxypheQyl)ethyIamine;
A"-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(ff>2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
W-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-CW)-2-hydroxy-2-(3-fonnamido-4-hydroxyphenyl)ethylamine;
Ar-{2-[4-(3-phenyJphenyI)ami"nop/ienyl]e(hy[J-C1-4)-2-hydroxy-2-(3-forniamido-4" . hydroxyphenyl)ethylamine;
//-(2-[4-(3-phenyl-4-ethoxyphenyi)aminophenyl]ethyl)-(^)-2-hydroxy-2"(3-forraamido-4-hydroxyphenyI)ethylamine;
N- {2-[4-(4-methoxyphenyl)aminophenyl]ethyl J -{^)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethyIamine;
//-{2-[4-(4-ethoxyphenyl)aniinophenyl]ethyl}-(i?)-2-hydroxy-2-(8-hydroxy-2(l//)-quinolinon-5-yl)ethylamme;
//-|2-I4-{3-pbeny]phei)yJ)aminopbeny]Jelhy]}-(^)-2-hydroxy-2-{8-hydroxy-2{lH)-quinolinon-5-yl)ethylamine;
/vr-{2-[4-(3-phenyl-4-elhoxyphenyI)ami]iophefiyl]ethyl)-(/?)- 2-hydmxy-2-(S-hydroxy-2(l#)-qL)inolinon-5-yl)ethyIamine;
A"-{2-[4-(4-me[hoxyphenyl)aminophenyl]ethyl]-(/f)-2-hydroxy-2-(8-hydroxy-2(17/)-quino]iiion-5-yl)ethy]amine;
//-(2-[4-(3-(2-ch]orophenyl)phenyl)aminophenyl]ei!iyl)-(^)-2-hydroxy-2-(8-hydroxy-2(l//)-quinolinon-5-y0ethy]amine;
A"-12-[4-{3-(2-methoxyphenyl)pheny])aminophenyl]ethyl)-(^)-2-hydroxy-2-(8-liydroxy-2{l#)-quinolinon-5-yI)ethyIamine;
N-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl|-{^)-2-hydroxy*2-(8-hydroxy-2(lH)-quinoIinon-5-yl)ethylamine;
jV-{2-(4-(3-(4-aminomethylpheny])phenyl)aminophenyl]ethyl)-(/?)-2-hydroxy-2-
(S-hydroxy-2(l//)-quino]inon-5-yl)eih>"lamine;
W-{2-[4-(3"(3-ch]oropheny0pheny])aminophenyl]ethyl!-(^)-2-]iydroxy-2-(S-
hydroxy-2(]//)-quino!inon-5-yl)ethy]amine;

W-{2-[4-(3-(4-aminomethylp!ieny])-4-methoxyphenyl)arninophenyl]ethyl}-(ff)-2-hydroxy-2-(H- hydroxy- 2(lH)-qmnol"moa-5-yl)ethy}ainine;
N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyI)aminophenyl]ethyl}-{^)-2-hydroxy-2-(8-hydroxy-2(l//)-quJDo]inon-5-y])ethyJamine;
//-{2-[4-(3-(4-hydioxypbenyl)-4-methoxyphenyl)aminophenyl]ethyIJ-(R)-2-hydroxy-2-(8-hydroxy-2(l^)-quinolinon-5-yl)ethyl amine;
Ar-{2-[4-(3-(3-pyridyI)phenyl)aminophenyl]ethyl)-(i?)-2-hydroxy-2-(8-hydroxy-2( 1 #)-quinoU non-5-yl)ethylamine;
Af-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)arninopbeny]]ethylJ-(«)-2-hydroxy-2-(8-hydroxy-2(l/i)-quinoUnon-5-yl}ethyIamine;
Ar-(2-[4-(3-(4-pyridyl)-4-methoxyphenyl)arninophenyl]ethyl)-(K)-2-hydroxy-2-{8-hydroxy-2(lH)-quinoiinon-5-yl)etbylainine;
W-(2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(^)-2-hydroxy-2-(8-hydroxy-2(1^0-quinolinon-5-yl)ethylamine; and
Af-f2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminopheny]]ethyl}-(^)-2-hydroxy-2-(8-hydroxy-2(lH)-quinolinon-5-yl)ethylamine.
The compounds of (he invention contain one or more chiral centers Accordingly, the invention includes racemic mixtures, pure stereoisomers (i.e. individual enarttiomers or diasrereomers), and stcrcoisomer-enriched mixtures of such isomer.-;, unless otherwise indicated. When a particular stereoisomer is shown, it will be understood by those skilled in the art, that minor amounts of other stereoisomers may be present in the compositions of this invention unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. In particular, compounds of the invention contain a chiral center at the alkylene carbon in formulas (I) and (II) to which the hydroxy group is attached. When a mixture of stereoisomers is employed, it is advantageous for the amount of the stereoisomer with the (R) orientation at the chiral center bearing the hydroxy group to be greater than the amount of the corresponding (S) stereoisomer. When comparing stereoisomers of the same compound, the (R) stereoisomer is preferred over the (S) stereoisomer.
General Synthetic Procedures
The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be

appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in"the art, conventional protecting groups may be used to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. Representative examples of amino-protecting groups and hydroxy-protecting groups are given above. Typical procedures for their removal include the following. An acyl amino-protecting group or hydroxy-protecting group may conveniently be removed, for example, by treatment with an acid, such as trifluoroacetic acid. An arylraethyl group may conveniently be removed by hydrogenolysis over a suitable metal catalyst such as palladium on carbon. A silyl hydroxy-protecting group may conveniently be removed by treatment with a fluoride ion source, such as tetrabutylammonium fluoride, or by treatment with an acid, such as hydrochloric acid.
In addition, numerous protecting groups (including amino-protecting groups and hydroxy-protecting groups), and their introduction and removal, are described in Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, NY, 1991, and in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973.
Processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.

wherein R15 is an amino-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I), comprising deprotecting a corresponding

compound of formula (HI), wherein R,s is an amino-protecting group (e.g. l,l-(4-methoxyphenyl)methyl or benzyl).
A compound of formula (I) wherein R is hydroxy can be prepared by deprotecting a corresponding compound of formula (I) wherein R3 is -OPg" and Pg" is a hydroxy-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I) wherein R3 is hydroxy, comprising deprotecting a corresponding compound of formula (I) wherein R3 is -OPg" and Pg1 is a hydroxy-protecting group (e.g. benzyl).
A compound of formula (I) wherein R3 is hydroxy can also be prepared by deprotecting a corresponding compound of formula (IH) wherein R13 is an amino-protecting group and wherein R3 is -OPg1 wherein Pg1 is a hydroxy-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I), comprising deprotecting a corresponding compound of formula (Iff) wherein R is an amino-protecting group (e.g. benzyl) and R3 is -OPg1 wherein Pg" is a hydroxy-protecting group (e.g. benzyl).
The invention also provides an intermediate compound of formula (10) wherein R1S is an amino-protecting group (e.g. l,l-di-(4"-methoxypbenyl)metbyl or benzyl); as well as an intermediate compound of formula (I) wherein R3 is -OPg1 and Pg is a hydroxy-protecting group; and an intermediate compound of formula (UT) wherein R15 is an amino-protecting group (e.g. benzyl), R3 is -OPg1, and Pg1 is a hydroxy-protecting group (e.g. benzyl).
An intermediate compound of formula (HI) can be prepared by reacting an amine of formula (V) with a compound of formula (IV), wherein R16 is hydrogen or a hydroxy-protecting group (e.g. /ert-butyldimethylsilyi) and X is a suitable leaving group (e.g. bromo).


Accordingly, the invention provides a method for preparing a compound of formula (EI), comprising reacting a corresponding aniline of formula (V) with a corresponding compound of formula (IV), wherein X is a suitable leaving group (e.g. bromo) and R is an amino-protecting group, in the presence of a transition metal catalyst. When R16 is a hydroxy-protecting group, the intermediate formed by the reaction of a compound of formula (V) with a compound of formula (W) is subsequently deprotected to form the intermediate of formula (HI). Suitable conditions for this reaction as well as suitable leaving groups are illustrated in the Examples and are also known in

Accordingly, the invention provides a method for preparing a compound of formula (HI), comprising reacting a corresponding amine of formula (VH), wherein RM is hydrogen and R is an amino-protecting group, with a corresponding compound of formula (VI), (VIH), or (IX), wherein R16 is hydrogen or a hydroxy-protecting group and Z is a suitable leaving group (e.g. bromo). When Rlfi is a hydroxy-protecting group, the intermediate formed by the reaction of a compound of formula (VIT) with a compound of formula (VI) is subsequently deprotected to form the intermediate of formula (III).

The invention also provides a method for preparing a compound of formula (I), wherein R3 is -OPg1 and Pg1 is a hydroxy-protecting group, comprising reacting a corresponding compound of formula (VD) wherein RH and RIS are each hydrogen with a corresponding compound of formula (VI), wherein R3 is -OPg! and Pg1 is a hydroxy-protecting group and R1 is a hydroxy-protecting group.
Depending on the specific values of the substituents, variations on the synthetic schemes described above can be employed, particularly in the order of coupling and deprotection reactions, to produce a compound of the invention. For example, a compound of formula (I) wherein R3 is hydroxy and R12 and R13 are hydrogen can be prepared by reacting an intermediate of formula (I) wherein R is -OPg , where Pg is a hydroxy-protecting group, and R is a suitable leaving group (e.g. bromo) with an appropriately substituted boronic acid to form an intermediate, which is subsequently deptotected, as illustrated in Examples 65-102,
Additionally, a useful intermediate for preparing a compound of formula (VH), wherein RM is hydrogen and R is an ammo-protecting group, is a corresponding compound of formula (VD*) wherein RH is an amino-protecting group that can be removed in the presence of R15. A compound of formula (VII) wherein RM is hydrogen and R15 is an amino-protecting group is itself also a useful intermediate for the preparation of a compound of formula (VH) where both RH and R15 are hydrogen. Thus, the invention also provides novel intermediates of formula (VU), wherein R 4 is hydrogen or an amino-protecting group, R15 is hydrogen or an amino-protecting group, and wherein R7-R13 and w have any of the values defined herein, or a salt thereof.
A preferred compound of formula (VU) is a compound wherein R 4 and R are both hydrogen. Another preferred compound of formula (VU) is a compound wherein RH is an alkoxycarbonyl protecting group (e.g. /ert-butoxy carbonyl), and R,s is an arylmethyl protecting group (e.g. benzyl). Another preferred compound of formula (VU) is a compound wherein R14 is hydrogen, and RIS is an alkoxycarbonyl protecting group (e.g. terl-butoxy carbonyl).

Pharmaceutical Compositions
The invention also provides pharmaceutical compositions comprising a compound of the invention. Accordingly, the compound, preferably in the form of a pharmaceutically-acceptable salt, can be formulated for any suitable form of administration, such as oral or parenteral administration, or administration by inhalation.
By way of illustration, the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of powders, tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. Such pharmaceutical compositions will contain from about 0.05 to about 90% by weight of the active compound, and more generally from about 0.1 to about 30%. The pharmaceutical compositions may contain common carriers and excipients, such as cornstarch or gelatin, lactose, magnesium sulfate, magnesium stearate, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid. Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, cornstarch, sodium starch glycolate and alginic acid.
A liquid composition will generally consist of a suspension or solution of the compound or pharmaceutical!y-acceptable salt in a suitable liquid carrier(s), for example ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, optionally with a suspending agent, a solubilizing agent (such as a cyclodextrin), preservative, surfactant, wetting agent, flavoring or coloring agent. Alternatively, a liquid formulation can be prepared from a reconstitutable powder.
For example a powder containing active compound, suspending agent, sucrose and-a sweetener can be reconstituted with water to form a suspension; a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example polyvinylpyrrolidone. The tablet can also be provided with a color film coating, or color included as partiof the carrier(s). In addition, active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example by incorporation of active compound and

excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose. Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. Additionally, it may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.
The compounds of the invention and their pharmaceutically-acceptable salts that are active when given parenterally can be formulated for intramuscular, intrathecal, or intravenous administration.
A typical composition for intra-muscular or intrathecal administration will consist of a suspension or solution of active ingredient in an oil, for example arachis oi! or sesame oil. A typical composition for intravenous or intrathecal administration will consist of a sterile isotonic aqueous solution containing, for example active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples are lactated Ringer"s injection, lactated Ringer"s plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer"s injection, and the like. Optionally, a co-solvent, for example, polyethylene glycol; a chelating agent, for example, ethylenediamine tetracetic acid; a solubilizing agent, for example, a cyclodextrin; and an anti-oxidant, for example, sodium meiabisulphite, may be included in the formulation. Alternatively, the solution can be freeze dried and then reconstituted with a suitable solvent just prior to administration.
The compounds of this invention and their pharmaceutically-acceptable salts which are active on topical administration can be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous or discontinuous infusion of

the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent No. 5,023,252. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
One preferred manner for administering a compound of the invention is inhalation. Inhalation is an effective means for delivering an agent directly to the respiratory tract. There are three general types of pharmaceutical inhalation devices: nebulizer inhalers, dry powder inhalers (DPI), and metered-dose inhalers (MDI)> Nebulizer devices produce a stream of high velocity air that causes a therapeutic agent to spray as a mist which is carried into the patient"s respiratory tract. The therapeutic agent is formulated in a liquid form such as a solution or a suspension of microoized particles of respirable size, where micronized is typically defined as having about 90 % or more of the particles with a diameter of less than about 10 u,m. A typical formulation for use in a conventional nebulizer device is an isotonic aqueous solution of a pharmaceutical salt of the active agent at a concentration of the active agent of between about 0.05 Jlg/mL and about 10 mg/mL.
DPI"s typically administer a therapeutic agent in the form of a free flowing powder that can be dispersed in a patient"s air-stream during inspiration. In order to achieve a free flowing powder, the therapeutic agent can be formuialed with a suitable excipient, such as lactose or starch. A dry powder formulation can be made, for example, by combining dry lactose having a particle size between about I u.m and about 100 (im with micronized particles of a pharmaceutical salt of the active agent and dry blending. Alternative, the agent can be formulated without excipients. The formulation is loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
Examples of DPI delivery devices provided commercially include Diskhaler (GlaxoSmithKJine, Research Triangle Park, NC) (see, e.g., U.S. Patent No. 5,035,237); Diskus (GlaxoSmithKJine) (see, e.g., U.S. Patent No. 6,378,519; Turbubaler (AstraZencca, Wilmington, DF.) (see, e.g., U.S. Patent No. 4,524,769); and Rotahaler : (GlaxoSmithKJine) (see, e.g., U.S. Patent No. 4,353,365). Further examples of suitable DPI devices are described in U.S. Patent Nos. 5,415,162, 5,239,993, and 5,715,810 and references therein.

MDI"s typically discharge a measured amount of therapeutic agent using compressed propellant gas. Formulations for MDI administration include a solution or suspension of active ingredient in a liquefied propellant. While chlorofluorocarbons, such as CCI3F, conventionally have been used as propellants, due to concerns regarding adverse affects of such agents on the ozone layer, formulations using hydrofluoroalklanes (HFA), such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3,-heptafluoro-n-propane, (HFA 227) have been developed. Additional components of HFA formulations for MDI administration include co-solvents, such as ethanol or pentane, and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin. (See, for example, U.S. Patent No. 5,225,183, EP 0717987 A2, and WO 92/22286.)
Thus, a suitable formulation for MDI administration can include from about 0.01 % to about 5 % by weight of a pharmaceutical salt of active ingredient, from about 0 % to about 20 % by weight ethanol, and from about 0 % to about 5 % by weight surfactant, with the remainder being the HFA propellant. In one approach, to prepare the formulation, chilled or pressurized hydrofluoroalkane is added to a vial containing the pharmaceutical salt of active compound, ethanol (if present) and the surfactant (if present). To prepare a suspension, the pharmaceutical salt is provided as micronized particles. The formulation is loaded into an aerosol canister, which forms a portion of an MDI device. Examples of MDI devices developed specifically for use with HFA propellants are provided in U.S. Patent Nos. 6,006,745 and 6,143,277.
In an alternative preparation, a suspension formulation is prepared by spray drying a coating of surfactant on micronized particles of a pharmaceutical salt of active compound. (See, for example, WO 99/53901 and WO 00/61108.) For additional " examples of processes of preparing respirable particles, and formulations and devices suitable for inhalation dosing see U.S. Patent Nos. 6,268,533, 5,983,956, 5,874,063, and 6,221.398, and WO 99/55319 and WO 00/30614.
It will be understood that any form of ihe compounds of the invention, (i.e. free base, pharmaceutical salt, or solvate) that is suitable for the particular mode of administration, can be used in the pharmaceutical compositions discussed above.
The active compound is effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen

route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient"s symptoms, and the like.
Suitable doses of the therapeutic agent for inhalation administration are in the general range of from about 0.05 u:g/day to about 1000 [tg/day, preferably from about 0.5 Hg/day to about 500 jig/day. A compound can be administered in a periodic dose: weekly, multiple times per week, daily, or multiple doses per day. The treatment regimen may require administration over extended periods of time, for example, for several weeks or months, or the treatment regimen may require chronic administration. Suitable doses for oral administration are in the general range of from about 0.05 Hg/day to about 100 mg/day, preferably 0.5 to 1000 n.g/day.
The present active agents can also be co-administered with one or more other therapeutic agents. For example, for the treatment of asthma or of chronic obstructive pulmonary disease, the present agents can be administered in combination with a muscarinic receptor antagonist (e.g. ipatropium bromide or tiotropium) or a steroidal anti¬inflammatory agent (e.g."fluticasone propionate, beclometbasone, budesonide, mometasone, ciclesonide, or triamcinolone). In addition, the present active agents can be co-administered with an agent having anti-inflammatory and/or bronchodilating or other beneficial activity, including but not limited to, a phosphodiesterase (PDE) inhibitor (e.g. theophylline); a PDE4 inhibitor (e.g. cilomilast or rofhimilast); an immunoglobulin antibody (algE antibody); a leukotriene antagonist (e.g. monteJeukast); a cytokine antagonist therapy, such as, an interleukin antibody (alL antibody), specifically, an aIL-4 therapy, ancdL-13 therapy, or a combination thereof; a protease inhibitor, such as an elastase or tryptase inhibitor; cromolyn sodium; nedocromil sodium; and sodium cromoglycate. Further, the present agents can be co-administered with an antiinfective agent or antihistamines. Suitable doses for the other therapeutic agents administered in combination with a compound of the invention are in the range of about 0.05 fig/day to about 100 mg/day.
Accordingly, the compositions of the invention can optionally comprise a compound of the invention as well as another therapeutic agent as described above. Additional suitable carriers for formulations of the active compounds of the present invention can be found in Remington: The Science and Practice ofPhammcy,20th

Edition, Lippincott Williams & Wilkins, Philadelphia, PA, 2000. The following non-limiting examples illustrate representative pharmaceutical compositions of the invention.



Formulation Example E This example illustrates the preparation of a representative pharmaceutical composition for injection of a compound of this invention.
A reconstituted solution is prepared by adding 20 mL of sterile water to 1 g of the compound of this invention. Before use, the solution is then diluted with 200 mL of an intravenous fluid that is compatible with the active compound. Such fluids are chosen from 5% dextrose solution, 0.9% sodium chloride, or a mixture of 5% dextrose and 0.9% sodium chloride. Other examples are lactated Ringer"s injection, lactated Ringer"s plus 5% dextrose injection, Normosol-M and 5% dextrose, Isolyte E, and acylated Ringer"s injection.

Formulation Example F This example illustrates the preparation of a representative pharmaceutical composition containing a compound of this invention.
An injectable preparation is prepared having the following composition:
Ingredients
Active Compound 0.1-5.0 g
Hydroxypropyl-p-cyclodextrin 1-25 g
5% Aqueous Dextrose Solution (sterile) q.s. to 100 mL
The above ingredients are blended and the pH is adjusted to 3.5 ± 0.5 using 0.5 N HClor0.5NNaOH.
Formulation Example G This example illustrates the preparation of a representative pharmaceutical composition for topical application of a compound of this invention.
Ingredients grams
Active compound 0.2-10
Span 60 2
Tween 60 2
Mineral oil 5
Petrolatum 10
Methyl paraben 0.15
Propyl paraben 0.05
EHA (butylated hydroxy anisole) 0.01
Water q.s. to 100
All of the above ingredients, except water, are combined and heated to 60°C with stirring. A sufficient quantity of water at 60CC is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. 100 g.
Formulation Example H This example illustrates the preparation of a representative pharmaceutical
composition containing a compound of the invention.
An aqueous aerosol formulation for use in a nebulizer is prepared by dissolving
0.1 mg of a phannaceutical salt of active compound in a 0.9 % sodium chloride solution

acidified with citric acid. The mixture is stirred and sonicated until the active salt is dissolved. The pH of the solution is adjusted to a value in the range of from 3 to 8 by the slow addition of NaOH.
Formulation Example I
This example illustrates the preparation of a dry powder formulation containing a compound of the invention for use hi inhalation cartridges.
Gelatin inhalation cartridges are filled with a pharmaceutical composition having the following ingredients:
Ingredients
mg/cartridge
Pharmaceutical salt of active compound 0.2
Lactose 25
The pharmaceutical salt of active compound is micronized prior to blending with lactose. The contents of the cartridges are administered using a powder inhaler.
Formulation Example J
This example illustrates the preparation of a dry powder formulation containing a compound of the invention for use in a dry powder inhalation device.
A pharmaceutical composition is prepared having a bulk formulation ratio of micronized pharmaceutica! salt to lactose of 1:200. The composition is packed into a dry powder inhalation device capable of delivering between about 10 fig and about 100 Jig of active drug ingredient per dose.
Formulation Example K
This example illustrates the preparation of a formulation containing a compound of the invention for use in a metered dose inhaler.
A suspension containing 5 % pharmaceutical salt of active compound, 0.5 % lecithin, and 0.5 % trehalose is prepared by dispersing 5 g of active compound as micronized particles with mean .size less than 10 (im in a colloidal solution formed from
i 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 mL of demineralized water. The
suspension is spray dried and the resulting material is micronized to particles having a

mean diameter less than 1.5 fim. The particles are loaded into canisters with pressurized 1,1,1,2-tetrafluoroethane.
Formulation Example L
This example illustrates the preparation of a formulation containing a compound of the invention for use in a metered dose inhaler.
A suspension containing 5 % pharmaceutical salt of active compound and 0.1 % lecithin is prepared by dispersing 10 g of active compound as micronized particles with mean size less than 10 urn in a solution formed from 0.2 g of lecithin dissolved in 200 mL of demineralized water. The suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 u.m. The particles are loaded into canisters with pressurized 1,1,3,2,3,3,3-heptafluoro-n-propane.
Biological Assays
The compounds of this invention, and their pharmaceutically-acceptable salts, exhibit biological activity and are useful for medical treatment. The ability of a compound to bind to the p2 adrenergic receptor, as well as its selectivity, agonist potency, and intrinsic activity can be demonstrated using in vitro Tests A-C below, in vivo Test D, below, or can be demonstrated using other tests that are known in the art.
Abbreviations

%Eff % efficacy
ATCC American Type Culture Collection
BSA Bovine Serum Albumin
cAMP Adenosine 3":5"-cyclic monophosphate
DMEM Dulbecco"s Modified Eagle"s Medium
DMSO Dimethyl sulfoxide
EDTA Ethylenediaminetetraacetic acid
Emax maximal efficacy
FBS Fetal bovine serum
Gly Glycine
HEK-293 Human embryonic kidney - 293
PBS Phosphate buffered saline
rpm rotations per minute
Tris Tris(hydroxymethyl)arninomethane

Membrane Preparation From Cells Expressing Human Pi or p2 Adrenergic Receptors
HEK-293 derived ceil lines stably expressing cloned human jit 01 ^2 adrenergic
receptors, respectively, were grown to near confluency in DMEM with 10% dialyzed FBS
in the presence of 500 [ig/mL Geneticin. The cell monolayer was lifted with Versene
1:5,000 (0.2 g/L EDTA in PBS) using a cell scraper. Cells were pelleted by centrifugation
at 1,000 rpm, and cell pellets were either stored frozen at -80°C or membranes were
prepared immediately. For preparation, cell pellets were resuspended in lysis buffer (10
mM Tris/HCL pH 7.4 @ 4DC, one tablet of "Complete Protease Inhibitor Cocktail Tablets
with 2 mM EDTA" per 50 mL buffer (Roche cat.# 1697498, Roche Molecular
Biochemicals, Indianapolis, IN)) and homogenized using a tight-fitting Dounce glass
homogenizer (20 strokes) on ice. The homogenate was centrifuged at 20,000 x g, the
pellet was washed once with lysis buffer by resuspension and centrifugation as above. The
final pellet was resuspended in membrane buffer (75 mM Tris/HCI pH 7.4,12.5mM
MgCl2,1 mM EDTA @ 25°C). Protein concentration of the membrane suspension was
determined by the method of Bradford (Bradford MM., Analytical Biochemistry, 1976,
72, 248-54). Membranes were stored frozen in aliquots at -80°C.
Test A
Radioligand Binding Assay on Human pi and PJ Adrenergic Receptors
Binding assays were performed in 96-well microliter plates in a total assay volume
of 100 JiL wilb 5 [Ag membrane protein for membranes containing the human p2
adrenergic receptor, or 2.5 Jig membrane protein for membranes containing the human Pi
adrenergic receptor in assay buffer (75 rnM Tris/HCI pH 7.4 @ 25°C, 12.5 mM MgCl:,
1 mM EDTA, 0.2% BSA). Saturation binding studies for determination of Kj values of
the radioligand were done using [""rTJdihydroalprenolo] (NET-720, 100 Ci/mmol,
PerkinElmer Life Sciences Inc., Boston, MA) at 10 different concentrations ranging from
0.01 nM - 200 nM. Displacement assays for determination of pK, values of compounds
were done with [Tijdihydroalprenolol at i nM and 10 different concentrations of
compound ranging from 40 pM - 10 (i.M. Compounds were dissolved to a concentration
of 10 mM in dissolving buffer (25 mM Gly-HCI pH 3.0 with 50% DMSO), then diluted to
1 mM in 50 mM Gly-HCI pH 3.0, and from there serially diluted into assay buffer. Non-

specific binding was determined in the presence of 10 pM unlabeled alprenolol. Assays were incubated for 90 minutes at room temperature, binding reactions were terminated by rapid filtration over GF/B glass fiber filter plates (Packard BioScience Co., Meriden, CT) presoaked in 0.3% polyethyleneimine. Filter plates were washed three times with filtration buffer (75 mM Tris/HCl pH 7.4 @ 4°C, 12.5 mM MgCl2,1 mM EDTA) to remove unbound radioactivity. Plates were dried, 50 |iL Microscint-20 liquid scintillation fluid (Packard BioScience Co., Meriden, CT) was added and plates were counted in a Packard Topcount liquid scintillation counter (Packard BioScience Co., Meriden, CT). Binding data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA) using the 3-parameter model for one-site competition. The curve minimum was fixed to the value for nonspecific binding, as determined in the presence of 10 uM alprenolol. K,- values for compounds were calculated from observed ICso values and the Kj value of the radioligand using the Cheng-Prusoff equation (Cheng Y, and Prusoff WH„ Biochemical Pharmacology, 1973, 22, 23, 3099-108). The receptor subtype selectivity was calculated as the ratio of Ki(Pi)/Ki(p2)- All of the compounds tested demonstrated greater binding at the fJ2 adrenergic receptor than at the fli adrenergic receptor, i.e. K;(P]) > Kjfp;). Most preferred compounds of the invention demonstrated a selectivity greater than about 20.
TestB
Whole-cell cAMP Flashplate Assay With a Cell Line Heterologously Expressing Human pz Adrenergic Receptor
For the determination of agonist potencies, a HEK-293 cell line stably expressing cloned human p2 adrenergic receptor (clone H24.14) was grown to confluency in medium consisting of DMEM supplemented with 10% FBS and 500 [ig/mL Geneticin. The day before the assay, antibiotics were removed from the growth-medium.
cAMP assays were performed in a radioimmunoassay format using the Flashplate Adenylyl Cyclase Activation Assay System with 125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA), according to the manufacturers instructions.
i
On the day of the assay, cells were rinsed once with PBS, lifted with Versene 1:5,000 (0.2 g/L EDTA in PBS) and counted. Cells were pelleted by centrifugation at 1,000 rpm and resuspended in slimulation buffer prewarmed to 37"C at a final concentration of 800,000 cells / mL. Cells were used at a final concentration of 40,000

cells / well in the assay. Compounds were dissolved to a concentration of 10 mM in dissolving buffer (25 mM Gly-HCI pH 3.0 with 50% DMSO), then diluted to 1 mM in 50 mM Gly-HCI pH 3.0, and from there serially diluted into assay buffer (75 mM Tris/HCl pH 7.4 @ 25°C, 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA). Compounds were tested in the assay at 10 different concentrations, ranging from 2.5 jiM to 9.5 pM. Reactions were incubated for 10 min at 37DC and stopped by addition of 100 u.1 ice-cold detection buffer. Plates were sealed, incubated over night at 4°C and counted the next morning in a topcount scintillation counter (Packard BioScience Co., Meriden, CT). The amount of cAMP produced per mL of reaction was calculated based on the counts observed for the samples and cAMP standards, as described in the manufacturer"s user manual. Data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA) using the 4-parameter model for sigmoidal dose-response with variable slope. Agonist potencies were expressed as pECjo values. All of the compounds tested demonstrated activity at the P2 adrenergic receptor in this assay, as evidenced by pEC50 values greater than about 5. Most preferred compounds of the invention demonstrated pECso values greater than about 7.
TestC
Whole-cell cAMP Flashplate Assay With a Lung Epithelial Cell Line Endogenously Expressing Human p; Adrenergic Receptor
For the determination of agonist potencies and efficacies (intrinsic activities) in a cell line expressing endogenous levels of p2 adrenergic receptor, a human lung epithelial ceil line (BEAS-2B) was used (ATCC CRL-9609, American Type Culture Collection, Manassas, VA) (January B, et al., British Journal of Pharmacology, 1998,123, 4,701-11). Cells were grown to 75-90% confluency in complete, serum-free medium (LHC-9 MEDIUM containing Epinephrine andRetinoic Acid, cat # 181-500, Biosource International, Camanllo, CA), The day before the assay, medium was switched to LHC-8 (No epinephrine or retinoic acid, cat # 141-500, Biosource International, Camarillo, CA).
cAMP assays were performed in a radioimmunoassay format using the Flashplate Adenylyl Cyclase Activation Assay System with 125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA), according to the manufacturers instructions.
On the day of the assay, cells were rinsed with PBS, lifted by scraping with 5mM EDTA in PBS, and counted. Cells were pelleted by centrifugation ;it 1,000 rpm and resuspended in stimulation buffer prewarmed to 37°C at a final concentration of 600,000

cells / mL. Cells were used at a final concentration of 30,000 cells / well in the assay. Compounds were dissolved to a concentration of 10 mM in dissolving buffer (25 mM Gly-HCl pH 3.0 with 50% DMSO), then diluted to I mM in 50 mM Gly-HCl pH 3.0, and from there serially diluted into assay buffer (75 mM Tris/HCl pH 7.4 @ 25°C, 12.5 mM MgCi2, 1 mM EDTA, 0.2% BSA).
Compounds were tested in the assay at 10 different concentrations, ranging from 10 |lM to 40 pM. Maximal response was determined in the presence of 10 fiM Isoproterenol. Reactions were incubated for 10 min at 37°C and stopped by addition of 100 fll ice-cold detection buffer. Plates were sealed, incubated over night at 4°C and counted the next morning in a topcount scintillation counter (Packard BioScience Co., Meriden, CT). The amount of cAMP produced per mL of reaction was calculated based on the counts observed for samples and cAMP standards, as described in the manufacturer"s user manual. Data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA) using the 4-parameter model for sigmoidal dose-response with variable slope. Compounds of the invention tested in this assay demonstrated pECso values greater than about 7.
Compound efficacy (%Eff) was calculated from the ratio of the observed Emax (TOP of the fitted curve) and the maximal response obtained for 10U.M isoproterenol and was expressed as 9&E1T relaLive lo isoproterenol. The compounds tested demonstrated a %Eff greater than about 20.
TestD
Assay Of Bronchoprotection Against Acetylcholine-Induced Bronchospasm In A Guinea Pig Model
Groups of 6 male guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan, Madison, WI) weighing between 250 and 350 g were individually identified by cage cards. Throughout the study animals were allowed access to food and water ad libitum.
Test compounds were administered via inhalation over 10 minutes in a whole-body exposure dosing chamber (R&S Molds, San Carlos, CA). The dosing chambers were arranged so (hat an aerosol wag simultaneously delivered to 6 individual chambers from a central manifold. Following a 60 minute acclimation period and a 10 minute exposure to nebulized waier for injection (WFI), guinea pigs were exposed to an aerosol of test compound or vehicle (WFI). These aerosols were generated from

aqueous solutions using an LC Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, VA) driven by a mixture of gases
(C02 = 5%, 02= 21% and N2 = 74%) at a pressure of 22 psi. The gas flow through the nebulizer at this operating pressure was approximately 3 L/minute. The generated aerosols were driven into the chambers by positive pressure. No dilution air was used during the delivery of aerosolized solutions. During the 10 minute nebulization, approximately 1.8 mL of solution was nebulized. This was measured gravimetrically by comparing pre-and post-nebulization weights of the filled nebulizer.
The bronchoprotective effects of compounds administered via inhalation were evaluated using whole body plethysmography at 1.5, 24,48 and 72 hours post-dose. Forty-five minutes prior to the start of the pulmonary evaluation, each guinea pig was anesthetized with an intramuscular injection of ketamine {43.75 mg/kg), xylazine (3.50 mg/kg) and acepromazine (1.05 mg/kg). After the surgical site was shaved and cleaned with 70% alcohol, a 2-5 cm midline incision of the ventral aspect of the neck was made. Then, the jugular vein was isolated and cannulated with a saline-filled polyethylene catheter (PE-50, Becton Dickinson, Sp^ks, MD) to allow for intravenous infusioos of a 0.1 mg/mL solution of acetylcholine (Ach), (Sigma-Aldrich, St, Louis, MO) in saline. The trachea was then dissected free and cannulated with a 14G teflon tube (#NE- 014, Small Parts, Miami Lakes, FL). If required, anesthesia was maintained by additional intramuscular injections of the aforementioned anesthetic cocktail. The depth of anesthesia was monitored and adjusted if the animal responded to pinching of its paw or if the respiration rate was greater man 100 breaths/minute.
Once the cannuiations were complete, the animal was placed into a plethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, CT) and an esophageal pressure cannula was inserted to measure pulmonary driving pressure (pressure). The teflon tracheal tube was attached to the opening of the plethysmograph to allow the guinea pig to breathe room air from outside the chamber. The chamber was then sealed. A heating lamp was used to maintain body temperature and the guinea pig"s lungs were inflated 3 times with 4 mL of air using a 10 mL calibration syringe (#5520 Series, Hans Rudolph, Kansas City, MO) to ensure that the lower airways had not collapsed and that the animal did not suffer from hyperventilation.
Once it was determined that baseline values were within the range 0.3 - 0.9 mL/cm H?0 for compliance and within the range

0.1 - 0.199 cm H20/mL per second for resistance, the pulmonary evaluation was initiated. A Buxco pulmonary measurement computer progam enabled the collection and derivation of pulmonary values. Starting this program initiated the experimental protocol and data collection. The changes in volume over time that occured within the plethysmograph with each breath were measured via a Buxco pressure transducer. By integrating this gna] over time, a measurement of flow was calculated for each breath. This signal, >gether with the pulmonary driving pressure changes, which were collected using a ensym pressure transducer (#TRD4100), was connected via a Buxco (MAX 2270) reamplifier to a data collection interface (#"s SFT3400 and SFT3813). All other pulmonary parameters were derived from these two inputs.
Baseline values were collected for 5 minutes, after which time the guinea pigs were challenged with Ach. Ach was infused intravenously for 1 minute from a syringe pump (sp210iw, World Precision Instruments, Inc., Sarasota, FL) at the following doses and prescribed times from the start of the experiment: 1.9 ng/minute at 5 minutes, 3.8 |ig/minute at 10 minutes, 7.5 jig/minute at 15 minutes, 15.0 ug/minute at 20 minutes, 30 (ig/minute at 25 minutes and 60 jig/minute at 30 minutes. If resistance or compliance had not returned to baseline values at 3 minutes following each Ach dose, the guinea pig"s lungs were inflated 3 times with 4 mL of air from a 10 mL calibration syringe. Recorded pulmonary parameters included respiration frequency (breaths/minute), compliance (mlVcmHiO) and pulmonary resistance (cm H20/mL per second) (Giles et al, 1971). Once the pulmonary function measurements were completed at minute 35 of this protocol, the guinea pig was removed from the plethysmograph and euthanized by CO2 asphyxiation.
The quantity PD2, which is defined as the amount of Ach needed to cause a doubling of the baseline pulmonary resistance, was calculated using the pulmonary resistance values derived from the/few and the pressure over a range of Ach challenges using the following equation. This was derived from the equation used to calculate PC20 values in the clinic (Am. Thoracic Soc, 2000).



C1-4 = Final concentration of Ach (concentration resulting in a 2-fold increase in pulmonary resistance (RJ)
R„ = Baseline RL value
R, = RL value after C,
Rj = RL value after C2
Statistical analysis of the data was performed using a One-Way Analysis of Variance followed by post-hoc analysis using a Bonferroni / Dunn test. A P-value Dose-response curves were fitted with a four parameter logistic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, California)
Y = Min + (Max-Min)/(1 + 10*((log ED50-X)* Hillslope)),
where X is the logarithm of dose, Y is the response (PD2), and Y starts at Min and approaches asymptotically to Max with a sigmoidal shape.
Representative compounds of the invention were found to have significant bronchoprotective activity at time points beyond 24 hours post-dose.
The following synthetic examples are offered to illustrate the invention, and are not to be construed in any way as limiting the scope of the invention.
Examples In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meaning. Unless otherwise stated, all temperatures are in degrees Celsius.
Bn = benzyl
Boc = rerf-butoxycarbonyl
DMSO - dimethyl sulfoxide
EtOAc = ethyl acetate
TFA = trifluoroacetic acid
THF = tetrahydrofuran
MgSO* = anhydrous magnesium sulfate
NaHMDS = sodium hexamethyldisiiazane
TMSC1 = trimethylsilyl chloride
EjMF = dimethyl formamide
Boc - rerf-butoxycarbonyl
TBS = lert-butyldimethylsilyl

General: Unless noted otherwise, reagents, starting material and solvents were
purchased from commercial suppliers, for example Sigraa-Aldrich (St. Louis, MO), J. T.
Baker (Phillipsburg, NJ), Honeywell Burdick and Jackson (Muskegon, MI), Trans World
Chemicals, Inc. (TCI) (Rockville, MD), Mabybridge pic (Cornwall, UK), Peakdale
Molecular Limited (High Peak, UK), Avocado Research Chemicals Limited (Lancashire,
UK), and Bionet Research (Cornwall, UK) and used without further purification;
reactions were run under nitrogen atmosphere; reaction mixtures were monitored by thin
layer chromatography (silica TLC), analytical high performance liquid chromatography
(anal. HPLC), or mass spectrometry; reaction mixtures were commonly purified by flash
column chromatography on silica gel, or by preparative HPLC as described below; NMR
samples were dissolved in deuterated solvent (CDjOD, CDC13, or DMSO-d6), and spectra
were acquired with a Varian Gemini 2000 instrument (300 MHz) using the residual
protons of the listed solvent as the internal standard unless otherwise indicated; and mass
spectrometric identification was performed by an electrospray ionization method (ESMS)
with a Perkin Elmer instrument (PE SCLEX API 150 EX).

To 62 mg (0.1 mmol) of compound bb and 0.1 mmol of A?l-(4-heptyJ-6-methyl-2-pyrimidinyDsulfanilamJde (available from Sigma-Aldrich Library of Rare Chemicals) 0.15 mL of toluene were added 9.3 mg (0.015 mmol) of racemic-2,2"-bis(diphenylpbosphino)-1,1 "-binaphtbyl (Aldrich) in 0.15 mL toluene, 4.6 mg (0.05 mmol) of tris(dibenzylidineacetone)dipalladium(0) (Aldrich) in 0.1 mL toluene, and 29 mg (0.3 mmol) of sodium terf-butoxide slurried in 0.4 mL toluene. The mixture was shaken and heated at 80"C for 5 hours. Acetic acid (80% at;,, 0.6 mL) was added and the mixture was shaken and heated at 80°C for 5 hours. The crude reaction was diluted to a total volume of 2 mL with DMF, filtered, and purified by reversed phase HPLC, using a mass-triggered, automated collection device. The product containing fractions were

/

To 110 g (0.46 mol) of compound xx in 1.0 L of THF a! -7S°C was added 236 mL (0.51 mol) of 2.14 M n-BuU in hexanes via a dropping funiiel. After 30 minutes, 71 g (0.69 mol) of A,-MethyI-/V-methoxyacetamide (available from TCI) was added. After 2 hours, the reaction was quenched with waler, diluted with 2.0 L oil .0 M aqueous phosphate buffer (pH-7.0), and extracted once with diethyl ether. The diethyl ether phase


was washed once with brine, dried over NajSO*. filtered, and concentrated under reduced pressure to give a light orange oil. The oil was dissolved in a minimum volume of ethyl acetate, diluted with hexanes, and the product crystallized to give compound yy as a white solid. "H NMR (300 MHz, CDC13) 8 7.79 (m, 1H), 7.65 (m, 1H), 6.85 (d, 1H), 4.88 (s, 2H), 2.54 (s,3H), 1.56 (s,6H).



To 32 g (0.113 mo!) of compound zz in 300 mL methylene chloride at 0°C was added 31.6 mL (0.23 mol) of triethylamine, followed by 16,0 mL (0.10 mol) of 4-bromophenethylamine (Aldrich). After 2 hours, 27 g (0.10 mol) of the 4,4"-dimetboxychlorodiphenylmethane was added. After 30 minutes, the slurry was



Using a coupling procedure similar to that described in Example 1, except replacing the N -(4-heptyl-6-niethyl-2-pyrirnidiny])suIfaiii[amide with 2-SLilfarsilamidopyrimidine (sulfapyridine, available from Aldrich), a TFA salt of compound 4 was prepared. niJz: [M + H+] calcd for C2sH3oN405S 535.2; found 535.2.



/
Using a coupling procedure similar to that described in Example I, except replacing the W"-^heptyJ-C-methyl^-pyrimidinylJsulfaTiilarnide with 4-(piperidinosulfonyl)aniline (available from Maybridge), a TFA salt of compound 7 was prepared, m/z: [M + H*] calcd for C38H35N305S 526.2; found 526.2.

Using a coupling procedure similar to that described in Example 1, except ;p)acing (he Afl-(4-heptyl-6-methyl-2-pyrimidinyl)sulfaniIamide with ^"-(2,6-imethylpheny])-4-armnobenzene-l-suIfonamide (available from Maybridge), a TFA salt f compound 9 was prepared, m/z: [M + H+] calcd for C3,H35N305S 562.2; found 562.2.
















Using a coupling procedure similar lo that described in Example 1, except replacing the A"l-(4-hep[y!-6-meth),l-2-pyrimJdinyl)sulfanilamide 4-(m-lolylthio)aniline


Using a coupling procedure similar 10 that described in Example 1, except replacing the V-(4-heptyI-6-methy]-2-pyrimidinyl)5ulfanilamide with 4-[(4-flL)oropbenyl)suIfony)J aniline {available from Bionet), a TFA salt of compound 20 was prepared.




Using a coupling procedure similar lo that described in Example 1, except replacing the W,-C4-heptyl-6-methyl-2-pyrimidinyl)sulfani]amide with 4-(4-chloro-benzenesulfonyl)-phenylamine (available from Sigma-Aldrich Library of Rare Chemicals), a TFA salt of compound 23 was prepared, m/z: [M + H*] calcd for C29H29C1N20JS 553.2; found 553.1.




Using a coupling procedure simiiar lo that described in Example 1, except replacing the fV"-^-beptyl-e-methyW-pyrimidinyOsuIfanUamide with 4-methoxyaniIine (p-anisid"me, available from Afdrich), a TFA salt of compound 28 was prepared.


" Using a coupling procedure similar to that described in Example I, except
i replacing the jVl-(4-heptyl-6-methyl-2-pyrimidinyl)su]fanilainide with 3-chloro-4-methoxyaniline (available from Aldrich), a TFA salt of compound 31 was prepared.






butoxide was added 35 mi of toluene, and the mixture was heated at 95°C for 5,5 hours under a nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHS04 and diethyl ether, and the phases were separated. The diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHS04 and brine, dried over Na2S04, filtered, and concentrated to a dark oil. The oil was purified by chromatography, using 15% EtOAc / 85% hexanes as eluent, to give 2.52 g(73%)ofcompoundCasadarkorangeoiI. "HNMR (300MHZ, DMSO-d6) 5 7.64 (s, 1H), 7.28-7.13 (m,5H), 6.91-6.72 (m, 8H), 4.27 (s, 2H), 3.92 (q, 2H), 3.25 (s, 2H), 3.15 (m, 2H), 2.52 (m, 2H), 1.31 (s, 9H), 1.21 (t, 3H). m/z: [M + H4] calcd for CzgH^Oj 447.3; found 447.8.

To 2.93g (6.56 mmol) of compound C in 15 ml of CH2CI2 at 0°C was added 15 ml of trifluoroacelic acid. After 40 minutes, the solution was concentrated under reduced" pressure, and the residue was partitioned between 1M NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried overNa2S04, filtered, and concentrated to an orange oil. The oil was dissolved in 20 ml of isopropanoi, 1.86 g (6.56 mmol) of the epoxide a was added, and the solution was heated at 78°C overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give compound E as an orange oil that was used without purification in the next step.


To a solution of 200 mg of compound Q (0.36 mmol) in 5.0 mL methanol was added 45 mg of 10% palladium on carbon. The reaction was piaced under 1 atm H2 gas. After 20 h, an additional 25 mg of 10% palladium on carbon was added and the reaction was stirred under 1 atm H2 for an additional 24 h after which time the reaction was filtered. The filtrate was concentrated and purified by reversed phase preparative HPLC (gradient of 15-50% acetonitrile in 0.1 % TFA). Fractions containing pure product were combined and lyophilized to afford a TFA salt of compound 6 as a powder. A sample of



was added 35 mL of toluene, and the mixture was heated at 95°C for 16 hours under an nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHSC>4 and diethyl ether. The diethyl ether phase was washed once each with saturated NaHCOj and brine, dried over MgSCU, filtered, and concentrated to a dark oil. The oil was purified by silica gel chromatography, using 15% EtOAc / 85% hexanes as eluant, to give compound Y as a dark orange oil.

To 1.0 g of compound Y(2.8mmol)in 5 mL CH2C\2 was added 4 mLTFA. After 15 minutes, the solution was concentrated, diluted with 50 mL isopropyl acetate and washed twice with 1.0 M aqueous NaOH. The isopropyl acetate layer was dried over MgSO^, filtered, and concentrated to a brown oil. The oil was dissolved in 5.0 mL of isopropanol and 390 mg (1.3 mmol) of epoxide P {Example 15, part a) were added. The solution was heated to 70 °C. After 36 h, the solution was concentrated and the product purified by reversed phase HPLC (gradient of 20-70% acetonitrile in 0.1 % TFA). Fractions containing pure product were combined and concentrated to remove acetonitrile. The aqueous residue was diluted with brine and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSC>4 and concentrated to afford compound Q as a yellow foam.













was added 50mL of toluene, and the mixture was heated at 95°C for 5.5 hours under an nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHSC>4 and diethyl ether, and the phases were separated. The diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHS04 and brine, dried over NajSOj, filtered, and concentrated to a dark oil. The oil was purified by silica gel chromatography, using 12% EtOAc / 88% hexanes as eluent, to give compound D as a yellow foam, "H NMR (300 MHz, DMSO-dff) 5 7.76 (s, IE), 7.38-7A3 (m, IOH). 6.95-6.81 (m, 7H), 4.28 (s, 2H), 3.61 (s. 3H), 3.16 (m, 2H), 2.53 (m, 2H), 1.29 (s, 9H).

To 2.60 g (5.1 ImmoJ) of compound Din 15 mLof CHiCU at 0°C was added 15 mL of trifluoroacetic acid. After 40 minutes, the solution was concentrated under reduced pressure, and the residue was partitioned between IM aqueous NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried over Na2SO.i, filtered, and concentrated to an orange residue. The residue was dissolved in 15mL of isopropanol, 1.45 g (5.11 mmol) of the epoxide a (Example 37, part b) was added, and the solution was heated at 78DC overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give compound G as an orange oil which was used in the next step without purification.


To a mixture of 825 mg (1.22 mmol) of compound N in 15 mLof ethanol was
added 260 mg of 10% palladium on carbon under a stream of nitrogen. The flask was
fitted with a balloon of hydrogen gas, and the reaction was vigorously stirred for 3 hours.
The reaction was filtered through celite, using methanol to rinse, and the filtrate was I
concentrated under reduced pressure. The residue was dissolved in 10 mL isopropanol, 0.67 mL of 4.0 M HC1 in dioxane was added, and the product was precipitated by adding the solution to a large volume of EtOAc. The solids were isolated by filtration to give a



To 2.28 g (12.2 mmol) of compound J in 45 mL of dimethylformamide at 0°C wasadded734mg(18.4mmo])of60%NaHinoiI. After lOminutes, 1.90g(12.2mmol) of iodoethane was added. After 20 minutes, the solution was partitioned between diethyl ether and 5% aqueous N32S03, and the phases were separated. The diethyl ether phase was washed once each with I.OM aqueous NaOH, water, and brine, dried over I^SO^, and concentrated to give compound K as a dark brown oil. !H NMR (300 MHz, DMSO-d6) 5 7.37-7.19 (m, 5H), 6.73 (d, 1H), 6.47-6.42 (m, 2H), 4.65 (s, 2H), 3.73 (q, 2H), 1.07 (t, 3H).

To a flask containing 3.97 g (10.7 mmol) of compound B (Example 13, part b), 2.27 g (12.2 mmol) of compound K, 0.46 g (0.5 mmol) of tris(dibenzylidineacetone)dip;iiladium (0), 0.95 g (!.5nimol) of rncemic-2,2"-bis(diphenylphosphJno)-I,r-binaphthyl, and 1.27 g (13.3 mmol) of sodium /ert-butoxide was added 48 mL of toluene, and the mixture was heated at 95°C for 5.5 hours under an nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHSOj and diethyl ether, and the phases were separated. The diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHS04 and brine, dried over Na2SCU, filtered, and concentrated to a dark oil. The oil was purified by silica gel chromatography, using 10% EtOAc/ 90% hexanes as eluent, to give 4.13 g (77%) of compound L as a yellow foam. "H NMR (300 MHz, DMSO-rffi) 5 7.76 (s, 1H), 7.42-7.13 (m, 10H), 6.93-6.81 (m, 7H). 4.27 (s, 2H), 3.86 (q, 2H), 3.25 (m, 2H), 2.53 (m, 2H), 1.28 (s,9H), 1,13 (t,3H).


To 2.68 mniol of crude compound M in 20 mL of tetrahydrofuran at 0°C was added 7.0 mL (7.0mmol) of 1.0 M lithium aluminum hydride in tetrahydrofuran. After 2 hours, trie reaction was quenched by slow addition of sodium sulfate decahydrate. The slurry was diluted with diethyl ether, dried over Na2S04, filtered, and concentrated to an orange oil. The oil was purified by silica gel chromatography, using 50% EtOAc / 50% hexanes as eluent, to give 835 mg of compound N as a while foam. *H NMR (300 MHz, DMSO-d6) 5 7.73 (s, 1H), 7.42-6.77 (m, 25H), 5.00 (s, 2H), 4.93 (m, lk), 4.66 (d, 1H), 4.51 Cm, 1H).4.47 (m, 2H), 3.86 (q, 2H), 3.62 (m, 2H), 2.55 (m. 6H), 1.13 (t, 3H).



To 944 mg (1.85 mmol) of compound D (Example 52, part a) in 6 mLof CH2CI2 at 0°C was added 6 mL of trifluoroacetic acid. After 40 minutes, the solution was concentrated under reduced pressure, and the residue was partitioned between I.OM aqueous NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried over Na2SO.i, filtered, and concentrated to an orange oil.
The residue from above was dissolved in 5 mL of isopropanot, 500 mg (1.85 rnmol) of the epoxide b was added, and the solution was heated at 78°C overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give an orange oil. The oit was purified by silica gel chromatography, using 50 EtOAc / 50 hexanes as eluent, to give 825 mg (66%) of compound I as a white foam. "H NMR (300 MHz, DMSO-tf The intermediate epoxide b can be prepared as described in U.S, Patent No. 6,268,533 B1, and in R. Kelt, et aj.. Organic Process Research and Development, 1998, 2, 96-99.

To a mixture of746mg(L 07 mmol) of compound O in 15 mLof ethanol and 5 mLof EtOAc was added 260mg of 10% palladium on carbon under a stream of nitrogen. The flask was fitted with a balloon of hydrogen gas, and the reaction was vigorously stirred for 3 hours. The reaction was filtered through celite, using methanol to rinse, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 mL isopropanol, 0.58 mL of 4.0 M HCI in dioxane was added, and the product was precipitated by adding the solution to a large volume of EtOAc. The solids were isolated by filtration to give a hydrochloride salt of compound 55 as an off while solid. "HNMR (300MHz, DMSO-d6) 5 10.12 (br s, IH), 9.62 (s, IH), 8.90 (br s. IH), S.67 (br s, IH),


To 1.4 g (2.68 mmol) of compound L {Example 53, parte) in 6 mL of CH2CI2 at 0"C was added 6 mL of trifluoroacetic acid. After 40 minutes, the solution was concentrated under reduced pressure, and the residue was partitioned between 1.0 M aqueous NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried over NajSGi, filtered, and concentrated to an orange residue. The residue was dissolved in 5 mL of isopropano!, 721 mg (2.68 mmol) of epoxide I) (Example 54, part a) was added, and the solution was heated at 78°C overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give an orange oil, The oil was purified by silica gel chromatography using 50 EtOAc / 50 hexanes as eluent, to give 756 mg of compound O as a white foam. H NMR (300 MHz, DMSO-rf6)5 9.45{d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.72 (s, 1H). 7.45-6.76 (m, 25H), 5.10 (s, 2H). 5.04 (m, IH), 3.94 (q, 2H), 3.61 (s, 2H), 2.50 (s. 6H), 1.13 (t, 3H).
1


To a solution of 840mg of compounds (1.2 mmol) in 40 mLof 1:1 methano!:THF was added 170 mg of 10% palladium on carbon. The reaction was shaken under an atmosphere of 35 psi H2. After 24 h, the reaction was filtered and the filtrate purified by reversed-phase HPLC (gradient of 10 to 70% acetonitrile in 0.1% aqueous TFA). Fractions containing pure product were combined and lyophilized to afford a TFA salt of compound 56 as a powder.
A sample of the TFA salt (75 mg) was dissolved in acetonitrile (1.0 mLJ and diluted with water (2.0 mL) followed by 0.1 N I-IC1 (3.0 mL). The solution became cloudy. Addition of 1.5 mL acetonitrile afforded a clear solution which was frozen and lyophiiized. The residue was redissolved in ncetonitriJe (1.0 mL) and diluted with water (2.0 mL) followed by 0.1 N I-IC1 (4.0 mL), The solution became cloudy. Addition of 1.0 mL acetonitrile afforded a clear solution which was frozen and lyophilized. The hydrochloride salt of compound 56 (50 mg) was obtained as a gray solid, "HNJVfJi (300MHz, DMSO-46) 5 10.55 (brs, 1H), 9.30 (br s, 1H), 8.80, (br s, 1H), 8.24 (d, 1H), 7.25-7.48 (m, 5H), 6.92-7.18 (m 9H), 6.55 (d, 1H), 5.55 (d, 1H), 3.69 (s, 3H) 2.80-3.20 (m, 6H) m/z: [M + H+J cakd for C32H31N3O4 522.24; found 522.3.
The intermediate compound S was prepared as follows.


Using a coupling procedure similar to that described in Example 1, except i replacing the A"^4-heptyl-6-mirlhyI-2-pyrimidinyl)sulfanilamide with methy]-4-iiminobenzoate (available from AJdrich), a TFA saJt of compound 57 was prepared, m/z: [M + H+] calcd for CssH^O; 437.2; found 437.2.


To a mixture ofcompoundjj (0.2 g, 0.27 mmol) in 6 mLDMF/EtOH (1:1) was added 50 mg of 10% palladium on carbon. The reaction was agitated under H2 at 40 psi for 8 hours. The slurry was filtered and purified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in 0.1 % aqueous TFA). Fractions containing pure product were combined and JyophiJized to afford compound 59 as a TFA salt. The TFA salt product was solubjlized in acetonitrile/water (1:1, 2 mL) to which 1.5 mLof 0.1 N aqueous HC1 was added. The solution was frozen and lyophilized to afford compound 59 as an HC1 salt. ni/v. fM+r-njcalcd for C30H29N5O5S 572.7; found 572.3.
The intermediate jj was prepared as follows.


To a mixture of compound pp {0.3 g, 0.45 mmol) in 10 mL anhydrous ElOH was added 100 mg of 10% palladium on carbon. The reaction was agitated under Hz at 40 psi for 18 h. The reaction was filtered and purified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in 0.1% aqueous TFA). Fractions containing pure product were combined and lyophilized to afford compound 60 as a TFA salt. The TFA salt product wassolubilized in acetonitriIe/water(I:2, 100 mL) to which 6 mL of 0.1 N aqueous HCI was added. The solution was frozen and lyophilized to afford compound 60 as an MCI salt. m/v. [M+H+] calcd for C^H^NiC^ 4S8.6; fo


After I h, the solution was concentrated, diluted with 15 mL Cl-^Ch and washed with 1.0 N aqueous sodium hydroxide. The aqueous was collected and washed again with CH2CI2 (10 mL) followed by a wash with ethyl acetate (10 mL). The organic layers were

combined and dried over MgSOj, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (gradient of 2-10% MeOH in CH2CI2) to afford an oil (2.1 g). A portion of this product (0.5 g, 1.26 mmol) was solubilized in 10 mL of 1:1 methanol:THF. Bromohydrin GG (Example 13, part d) (0.42 g, 1.20 mmol) and K2CO3 (0.44 g, 3.15 mmol) were added and the slurry was stirred at room temperature for 1.5 h. The reaction was concentrated and the residue was diluted with 30 mL water and extracted twice with 30 mL portions of toluene. The toluene extracts were combined, dried over Na3SO^, filtered, and concentrated. The residue was heated to 120°C. After 2 h, the reaction was cooled to room temperature and the crude compound was purified by silica gel chromatography (gradient of 5-10% MeOH in CH2CI2) to afford compound pp as a tan colored solid (0.7 g).

To a solution of 200 mg of compound T (0.28 mmol) in 4 mL of acetic acid was added 100 mg of 10% palladium on carbon. The reaction was shaken under an atmosphere of 40 psi H2. After 17 h, the reaction was filtered and the filtrate purified by reversed-phase HPLC (gradient of 10 lo 70% acetonitrile in 0.1% aqueous TFA). Fractions containing pure product were combined and lyophilized to afford compound 61 as a powder.
The intermediate compound T was prepared as follows:


To 1.13 g of compound D (2.2mmol, Example 52, part a) in 4 mL CH2CI2 was added 4 mL TFA. After 30 minutes, the solution was concentrated and diluted with 20 mL ethyl acetate and 20 mL water. The pH was raised to 11 by addition of 6.0 N aqueous sodium hydroxide and the layers were separated. The ethyl acetate layer was washed once with 1.0 N aqueous sodium hydroxide, dried over MgSO*r filtered, and concentrated to a brown oil. The oil was dissolved in 7.0 mL of isopropanol and 600 mg (2.0 mmol) of epoxide P (Example 15, part a) were added. The solution was heated to 70 °C. After 34 h, the solution was concentrated and the product partially purified by silica gel chromatography (gradient of 1 to 2% methanol in CHiC\2). Fractions containing product were combined and concentrated to afford T as a yellow oil.
Example 61B: Synthesis of A^-{2-[4-(3-phenyI-4-
methoxyphenyJ)aminopl]cnyl]e()iyl)-(^)-2-hydro.xy-2-(8-hydroxy-2(J/i)-quinolinon-5-yI)e(hylamine (60)
To a solution of//-{2-[4-(3-pheny]-4-methoxyphenyl)aminophenylJethy]}-(fi)-2-
hydroxy-2-(8-benzyloxy-2(IjVJ-quinolinon-5-yi)ethyIamine (PP) (4.0g, 6.5 mmol) in
tetrahydrofuran (100 mL) and water (16 mL) was added 10% palladium on carbon (800
mg). The reaction was stirred vigorously under one atmosphere of hydrogen for 6.5 h.
The solids were filtered off and washed wiih tetrahydrofuran (4x25 mL) and then 50%
metbanol/teirahydrofuran (2x25 mL). The combined filtrates were evaporated to dryness
and the crude product was purified by reverse-phase HPLC. Fractions containing pure
product were combined and lyophilized. The product from several runs was combined to .
give 4.68 g which was dissolved in acetonitrile (200 mL) and water (200 mL). 1.0 N HC1
(18.7 mL) was added, and the solution was lyophilized. The residue was again dissolved
in acetonitrile(]25mL)and warer (125 mL). 1.0 N HCI was added and the solution was
lyophilized to give a hydrochloride salt of compound 61 as an off white powder. H NMR


A slurry of aluminum chloride (85.7 g, 640 mmol) in 1,2-dichIoroethane (280 mL) was cooled in ice, and compound CC (56.8 g, 280 mmol) was added. The mixture was warmed to room temperature, and then heated at 85°C. After 30 minutes acetyl chloride (1.5 mL, 21 mmol) was added anil the mixture was heated an additional 60 minutes. The reaction mixture was then cooled and added to EN HC1 (3 L) at 0°C with good stirring. After stirring for 2 hours, the solids were collected on a Buchner funnel, washed with water (3x25DmL) and dried under reduced pressure. The crude product isolated from



(10.4 mL, 82.0 mmoJ) was added via syringe and the mixture was wanned to room temperature to give a thick suspension. The suspension was heated at 45°C (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dicbloromethane (100 mL) was added over 40 minutes. The mixture was kept 45dC for an additional 15 minutes and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4x 100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2x50 mL) and methanol (2x50 mL). The solid was dried under reduced pressure to give 5-(2-bromo-l-oxy)ethyl-8-benzyloxy-2(Itf)-quinolinone (R) (34.1 g) as an off"white powder.

Using a procedure described in Mathreet al., J. Org. Chem., 1991,56, 751-762, a catalyst was prepared as follows. (R)-(+)-ct, a -Diphenylprolinol (10.0 g, 39 mmol) and trimethylboroxine (3.7 mL, 26 mmol) were combined in toluene (200 mL) and stirred at room temperature for 30min. The mixture was placed in a 150"Coil bath and 150 mL liquid was distilled away. Toluene (50 rnL) was added, and another 50 mL of distillate was collected. Another portion of toluene (50 mL) was added and a further 50 mL of distillate was collected. A 1.00 mL aliquot of the material remaining in the pot was evaporated to dryness and weighed (241,5 mg) to determine that the concentration of catalyst was 0.87 M.
5-(2-Bromo-l-oxy)ethyl-8-benzyloxy-2(l//)-quinolinone(R) (30.0E, 81 mmol) was suspended in, tetrahydrofuran (;1.2 L) under a nitrogen atmosphere and the catalyst from above (13 mL, 11 mmol) was added. The suspension was cooled to -5°C in an ice/isopropanol bath and borane (1.0 M in THF, 97 mL, 91 mmol) was added over 3 h. The reaction was stirred an additional 45 min at -5°C, then methanol (200 mL) was added



2.5 mmol) was added, followed by trjs(dibenzylideneacetone)c!ipalladium{0) (760 mg, 0.83 mmol) and finally sodium tert-butoxide (5.3 g, 55 mmol). The mixture was heated at 90°C for 150 min and then cooled to room temperature. Water (150 mL) was added followed by ethyl acetate (150 mL) and the phases partitioned. The aqueous foyer was extracted with ethyl acetate (150 mL) and the combined organics washed three times with 0.5 M sodium bisulfate (200 mL), once with saturated sodium bicarbonate (150 mL) and twice with saturated sodium chloride (150 mL). The organics were dried over magnesium sulfate (50 g) and the volatiles removed under vacuum to give W-fer(-butoxycarbonyl-2-[4-(3-[phenyl-4-methoxypheQyI)aminophenyl]ethylamine (LL) (8.4 g) which was used without further purification.

Under nitrogen, compound LL (94.6 g) was treated will] dichloromethane (500 mL) and cooled in an ice bath. Hydrogen chloride (4 M in dioxane, 125 mL, 500mmol) was added in 10 portions over 20 min. The reaction was kept at room temperature for 130 minutes, during which time the product precipitated. The solid was filtered and washed with dichloromethane (350 mL) and dried under vacuum in the dark to give the dihydrochloride salt of 2-[4-(3-[phenyl-4-methoxyphenyl)aminophenyl]ethylamine (MM) (37.1 g). "H NMR (300MHZ, DMSO-dtf) 5 8.29 (br s, 2H), 8.04 (br s, 1H) 7.25-7.50 (m, 5H), 6.90-7.08 (m, 7H) 3.69 (s, 3H), 2.93 (m, 2H), 2.75 (m, 2H); tn/z: [M + H+] calcd for Ci,HHNzO 319.13; found 319.3.


hydrochloric acid {170 mL) was added in portions (exothermic). The solution turned orange and cloudy after the addition and more methanol (100 mL) was added until a clear solution was obtained. The mixture was stirred at room temperature overnight, in which

time a brown guru had formed. The solvent was removed under vacuum, and ethyl . acetate (300 mL) was added. The resulting mixture was cooled in an ice bath, and neutralized (pH 7) with 10 N sodium hydroxide. The pH was then raised to 10 with 1 M sodium hydroxide to give a clear biphasic mixture. The phases were separated and the aqueous layer was extracted with ethyl acetate (300 mL), The combined organic layers were dried over sodium sulfate, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (500 g, 0-10% methanol in dichloromethane)togiveA"-(2-[4-(3-pheny]-4-methoxyphenyI)aminophenyl]ethyl]-(^|)"2-hydroxy-2-(8-benzyloxy-2(l/i)-quinolinon-5-yl)ethyIamine (PP) (5.6 g).
Example 61C: Synthesis of N-{2-[4-(3-pheny]-4-
methoxyphenyl)aminophenyI]ethyl}-(i?)-2-hydroxy-2-(8-benzyloxy-2(lff)-quino!inon-5-yI)ethylamine (PP)
The intermediate compound PP was prepared as follows: a. Synthesis of 5-(2-bromo-(fl)-I-hydroxy)ethyI-8-benzyIoxy-2(l//)-quinoIinone (FF)
(R)-(+)-cc,a-Dipheny!proIinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 minutes. The mixlure was placed in a 150°C oil bath and liquid was distilled off. Toluene was added in 20 mL aliquols, nnc! distillation was continued for 4 hours. A total of 300 mL toluene was added. The mixture was finally cooled to room temperature. A 500 U.L aliquot was evaporated to dryness, weighed (246 mg) to determine that the concentration of catalyst was 1.8 M,
5-(2-Bromo-l-oxy)ethy]-8-benzyloxy-2(l/f)-quinolinone (R) (90.0 g, 243 mmol) was placed under nitrogen, letrahydrofuran (900 mL) was added followed by the catalyst from above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to -10±5°C in anice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 hours. The reaction was stirred an additional 45 minutes at -10°C, then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum. The residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under reduced pressure to give 5-(2-biomo-(tf)-]-hydroxy)ethyl-8-benzyloxy-2(l/7)-qumolinone (FF) (72.5g, 196 mmol, 81% yield, 95% ee, 95% pure by HPLC area ratio).


Compound HH (136.5 g, 279 mmo]), 4-bromophenethyIamine (123 g, 615 mmol)
and dimethyl sulfoxide (180 mL) were mixed at room temperature under nitrogen.
Another 40 mL of dimethyl sulfoxide was added. The mixture was heated to 85°C for
5 hours. The reaction was partitioned between ethyl acetate (1 L) and 10% aqueous acetic
acid (500 mL). The organies were washed with 10% aqueous acetic acid (3x500 mL),
then with 1N sodium hydroxide (3x500 mL). The last wash was filtered through Celite |
(100 g). The organic layer was concentrated to 300 mL and cyclohexane (2x500 mL) was added and the solution concentrated to 300 mL. Sufficient cydohexane was added to form 1.8 L final volume which was filtered through O.lite i"tf) d A cnhwinn nf Hri in

isopropanol, prepared by slowly adding concentrated HC1 (23.5 mL) to isopropanol (180 mL) at 10°C (internal), was added to the crude product and the reaction mixture was stirred for 5 hours, washed with cyclohexane (2x500 mL) and dried under reduced pressure for 24 hours to give Ar-[2-(4-bromophenyl)ethyl}-(fl)-2-rerr-butyIdimethylsiIoxy-2-(8-benzyIoxy-2(lJ^-quinolinon-5-yI)ethylanune (JJ) hydrochloride (145 g, 80 mo] %, 106 wt %, HPLC purity 97.9 %).
d. Synthesis of Ar-{2-[4-(3-phenyi-4-methoxyphenyl)arninophenyl]ethyl}-(/?)-2-fert-butyldimethy!silyl-2-(8-benzyloxy-2(lfO-quinoIinon-5-y])ethyIamine(NN)
To compound JJ hydrochloride (73.7 g, lI4mmoI) and 4-methoxy-3-
phenylaniline hydrochloride (32.4 g, 137 mmol), toluene (380 mL) was added with mild
agitation for 5 minutes, followed by sodium /ert-butoxide (49.3 g, 513 mmol) in portions
over 1 minute, and finally 2,2"-bis(diphenylphosphino)-l,l"-binaphthyl (10.65 g, 17 mmol)
and tris(dibenzylideneacetone)dipa]ladium(0) {5.22 g, 5,7 mmol). The resulting mixture
was stirred and heated to 85-89°C (internal) for 2.5 hours. The solution was cooled to
room temperature, water (400 mL) was added and the mixture was stirred for 5 minutes,
filtered through Celite (80 g), and partitioned with toluene (100 mL). The organic layer
was collected and concentrated tmder reduced pressure in a40"C bath to giveA"-{2-[4-(3-
phenyl-4-methoxypbenyl)aminoph("nyIlet!]yl]-(/?)-2-/^rf-butyldimethy!silyI-2-(8-
benzyloxy-2(lr/)-qmnolinon-5-yl)eihyIarnine (NN) as a dark viscous oil.
e. Synthesis of Ar-{2-[4-(3-phenyW-methoxyphenyl)aminophenyl]ethyI)-(/?)-2-hydroxy-2-(8-benzyloxy~2(lri)-quinolinon-5-y])ethyIainine(PP)
Compound NN from the previous step was dissolved in 280 ml of THF.
Triethylamine trihydrofluoride (27.6 g, 171 mmol) was added to the solution, an
additional 20 mL of THF was used to rinse down residual reagent, and the reaction was
stirred at 25"C under nitrogen for 16 hours. The reaction mixture was concentrated under
reduced pressure in a 25°C bath to give a dark viscous oil to which dichlorometiiane (400
mL) was added, followed by IN aqueous NaOH (200 mL). The reaction mixture was
stirred for 5 hours. The top layer was discarded and the organic layer was concentrated to
a viscous oil.
The oil was dissolved in dichloromethane to give a total volume of 630 mL. A
60 mL aliquot was taken and concentrated to 30 mL. Toluene (60 mL) was added,

followed by a mixture of concentrated hydrochloric acid (2.7 mL) and methanol (4.5 mL) to give a thick paste covered in a free-flowing liquid. The liquid was carefully removed and the paste washed with toluene,(50 mL). The gum was partitioned between dichloromethane (40 mL) and IN aqueous sodium hydroxide (40 mL) and the organic solvents were removed under reduced pressure. The residue was purified chromatographically over silica using a gradient of 0-10% methanol in dichloromethane to give N- {2-[4-(3-phenyi-4-methoxypbenyl)aminophenyl]ethyl} -(tf ^-hydroxy^-fS-benzyloxy^ClHJ-quinoIinon-S-yOethylamine (PP).



A solution of compound kk (2.88 g, 5.24 mmcl) in 20 mL CH2Cl2 was cooled (o 0 "C and 20 mL of TFA was added. After 20 min, the reaction was concenlraled and the residue dissolved in isopropyl acetate. The isopropyl acetate solution was washed twice with 1.0 N aqueous NaOH followed by water and then dried over MgSC>4, filtered and concentrated to an oil. The oil was dissolved in 2 mL DMF and intermediate AA (337 mg, 0.69 mmol), diethyl isopropyl amine (179 mg, 1.38 mmol) and potassium iodide (172 mg, 1.04 mmol) were added. The reaction was heated to 100°C. After 18 h, the reaction was cooled and added to vigorously stirred ice water. Compound mm


To a solution of 730 mg of compound rr(1.05 mmol) in 10 mL of glacial acetic acid was added 100 mg of 10% palladium on carbon. The reaction was stirred under an atmosphere of H2. After 65 h, the reaction was filtered and the filtrate purified by reversed-phase HPLC (gradient of 10 to 50% acetonitrile in 0.1 % aqueous TFA) to afford 90 mg (0.14 mmol) the TFA salt. The TFA salt product was solubilized in acetonitrile/water (1:2, 10 mL) to which 3 mL of 0.1 N aqueous HC1 was added. The solution was frozen and lyophilized to afford compound 63 as an HC1 salt, m/v [M+H*] calcd for Cs^HjgNjO^ 512.6; found 512.3.


To a solution of compound qq (2.0 6, 5.0 mraol) in 27 mL DMF were added
bromoketone R (from Example 56, part a) (1.71 g, 4.5 mmol) and K2C03 (1.91 g, 13,8
mmol). The reaction was heated to 50°C. After 1 h, the reaction was allowed to cool to
room temperature and the KSCOB was filtered off. The filtrate was diluted with CHjCh
(50 mL) and was washed with 0.1 N HC1 (30 mL). The organic layer was washed once I
with saturated sodium bicarbonate solution, followed by aqueous saturated sodium chloride, dried over Na^SCXj and concentrated under reduced pressure to afford an oil. The product (1.14 g, 1.65 mmol) was solubilized in 12 mLTHF/EtOH (1:1) and NaBRt

(380 mg, 10.0 mmol) was added. After 20 minutes of vigorous stirring. The reaction was quenched with saturated aqueous NHjCI which was added until effervescence of the reaction mixture ceased. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed twice with saturated sodium bicarbonate, followed by saturated sodium chloride, dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2% MeOH in CH2C]2) to yield 230 mg of intermediate rr.

To a mixture of 580 mg (0.93 mmol) of compound V in 25 mL of ethanol was added 173 mg of 10% palladium on carbon under a stream of nitrogen. The flask was fitted with a balloon of hydrogen gas, and the reaction was vigorously stirred for 4 days. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC using ;i gradient of 10 to 50% rtcetoriitrile in 0.1% aqueous TFA. Fractions containing pure product were combined and lyopliilized to afford a TFA salt of compound 64 as an off-white powder.
A sample of the TFA salt of compound 64 (150 mg) was dissolved in acetonitrile (2,0 mL) and water (2,0 mL). 0, IN HC1 (7.0 mL, 0.70 mmol) was added, and the resulting precipitate was redissolved by the addition of acetonitrile. The resulting solution was lyopliilized to give a solid which was again dissolved in acetonitrile {5.0 mL) and water (5.0 mL). 0, IN HC1 (7.0mL," 0.7 mmol) was added and the resulting solution was lyophilized to give a hydrochloride salt of compound 64 as an off white powder. "H NMR (300MHz, DMSO- The intermediate compound V was prepared as follows.


Compound W (55.2 mg, 0.094 mmol), phenyl boronic acid (13.2 mg, 0.113 mmol) and [l,]"-bis(dipheny]pho.sphinoferrocenc)dich]oropal]adium (II), complex with dichloromeihajie (PdCMdppO-DCM) {5.0 mg, 0.006 mmol) were combined in a small pressure tube and purged with N2. 1,2-Dimethoxyethane (1.0 mL) and 2.0 N cesium carbonate (150 \iL, 0.3 mmol) were added. The tube was sealed, and then p/aced in an oil


Compound HH (Example 61B, part f) (9.1g, 18.62mmoi), 4-aminophenethyIamine {9.8 mL, 74.8 mmol) and sodium iodide (4.2 g, 27.93 mmol) were placed in a flask and purged with nitrogen. Methyl sulfoxide {25 mL) was added, and (he solution was placed in an oil bath heated at 140°C. The solution was the stirred for 20 min at 140DC. The reaction was allowed to cool to room temperature, then ethyl acetate (300 mL) and II20 (300 mL) were added. The phases were partitioned, and the organic layer was washed with water (4 x 200mL) and saturated sodium chloride (4 x 200mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to yield compound U (10.5g).



Examples 66-69: Synthesis of Compounds 66-69
Using procedures similar to that described in Example 65, except replacing the phenylboronic acid with the appropriate substituted phenylboronic acid, TFA salts of " compounds 66-69 were prepared.
Compound 66: Af-{2-[4-(3-(2-chloropheny[)phenyl)aminophenyl]ethyl}-(/i)-2-hydroxy-2-(8-hydroxy-20//)-quinoIinon-5-yl)ethylamine (Formula (X) where R1" is 2-chlorophenyI): "H NMR (300MHZ, DMSO-t/6) 5 10.47 (s, 1H), 10.37 (s, IH), 8.55, (br s, 2H), 8.22, (s, IH), 8.06 (d, 1H)7,46 (m, IH), 7.32 (m, 3H), 7.22 (t, IH), 7.01 (m, 8H), 6.89 (d, IH), 6.74 (dd, IH), 6.51 (d, IH), 6.10 (d, IH), 3.18 (m,4H), 2.80 (m, 2H); m/z: p^+H4] calcd for C3|H2BC1N303 526.19; found 526.4.
Compound 67: Af-J2-[4-(3-(2-methoxyphenyl)phenyI)aminophenyl]ethyl)-(ff)-2-hydroxy-2-(8-hydroxy-2{l//)-qLiinolinon-5-yl)ethyIamJne (Formula (X) where RM is 2-methoxyphenyl): !H NMR (300MHz, DMSO-d6) 5 10.46 (s, IH), 10.40 (s, IH), 8.60 (brs, 2H), 8.12 (s,lH), 8.06 (d,lH), 7.16 (m, 13H), 6.80 (d, JH), 6.51 (d, IH) 6.11 (s. IH) 5.24 (d, IH), 3.69 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); i^v [M+H*] calcd for C3iH31N3Od 522.24; found 522.7.
Compound 68: Formula (X) where R11 is 4-hydroxymethyIphenyl: "H NMR (300MHz, DMSO-(5) 5 10.47 (s, IH). 10.39 (s, JH), 8.60 (brs, 2H), 8.18 (s, IH), 8.07 (d, IH), 7.46 (d, 2H), 7.30 (d, 2H), 7.20 (m, 2H), 7.00 (m, 8H). 6.51 (dd, IH), 6.1! (s, IH), 5.23 (d, IH), 4.44 (s, 2H), 3.10 (m. 4H), 2.80 (m, 2H); m/z: [M+H+] calcd for C32H3,N30,, 522.24; found 522.4.
Compound 69: Formula (X) where R1" is 4-methoxyphenyI: "H NMR (300MHz, DMSO-d6) 5 10.47 (s, IH), 10.39 (s, IH) 8.60 (brs, 2H), 8.16 (s, IH), 8.07 (d, 1H),7.44 (d, 2H), 6.85-7.20 (m. 12H), 6.51 (dd, IH), 6.12 (d, IH), 5.23 (d, IH), 3.70 (s, 3H), 3.10 (m, 4H). 2.80 (m, 2H); m/z: [M+H+] calcd for C32H31N304 522.24; found 522.4.
Example 70: Synthesis of compound 70
Compound 70: Formula (X) where R11 is 4-chlorophenyl Compound W {84.0 mg. 0.143 mmol), 4-chlorophenyl boronic acid (27.2 mg, 0.172 mmol) and [IJ^bisfdiphenylphospliinoferroceneJdichloropalladiiun (H), complex with dichloromethane (PdCl2(dppf)-DCM) (5.9 mg, 0.007 mmol) were combined in a small pressure tube and purged with Nj. 1,2-Dimcthoxyethnne (2.0 mL) and 2.0 N

; cesium carbonate (150 uL, 0.3 mmol) were added. The tube was sealed, and then placed 1 in an oil bath at 90°C for 4 hours. The solution was then cooled to room temperature and DCM (10 mL) was added. The solution was filtered and concentrated to dryness. To the residue there was added DMF (1.0 mL) and 10% palladium on carbon (10 nig), and the reaction was stirred under one atmosphere of hydrogen for 4 hours. At this time, watenacetonitrile 1:1 and 200 uL TFA was added and the solution was filtered to remove the catalyst. The filtrate was purified by reverse phase HPLC. Fractions containing pure product were combined and lyophilized to give compound 70 as a TFA salt. "H NMR (300MHz, DMSO-dS) 5 10.46 (s, 1H), 10.40 (s, 1H), 8.61 (br s, 2H), 8.22 (s, IH), 8.07 (d, IH), 7.53 (d, 2H), 7.42 (d, 2H), 7.23 (t, 1H), 7.14 (s, 1H), 6.85-7.10 (m, 8H), 6.51 (d, IH), 6.12 (s, 1H), 5.24 (d, JH), 3.10 (m, 4H), 2.80 (m, 2H); m/r. [M+H4] calcd for C3iH!aClN303 526.19; found 526.4.
Examples 71-72: Synthesis of compounds 71-72
Using procedures similar to that described in Example 70, except replacing the 4-chlorophenyiboronic acid with the appropriate substituted boronic acid, TFA salts of compounds 71-72 were prepared.
Compound7J: Formula(X) where RM is 5-indolyl: "lINMR (300MHz, DMSO-d6) 5 11.07 (s, IH), 10.47(5, IH), 10.40 (s, IH), 3.60 (br s, 211), 8.15 (s, IH), 8.11 (d, IH), 7.65 (s, IH), 7.15-7.40 (m, 511). 7.00-7.15 (ra, 5H), 6.89 (d, 2M), 6.51 (dd, IH), 6.39 (s, IH), 6.11 (s, IH), 5.24 (d, IH), 3.10 (m, 4H), 2.80 (m, 2H); m/c [M+H*] calcd for C33H30N4O3 531.24; found 531.4.
Compound 72: Formula (X) wliere R11 is 4-pyridyI: "H NMR (300MHz. DMSO-d6) 5 10 48 (s, IH) 10.38 (s, IH), 8.60 (brm, 4H), 8.32 (s, IH), 8.07 (d, IH), 7.69 (d, 2H), 7.31 (m, 2H), 7.16 (d, IH) 7,05 (m, 6H), 6.90 (d, IH), 6.52 (dd, IH), 6.11 (s, IH), 5.24 (d, IH), 3.10 (m, 411), 2.80 (m, 211); m/r [M+M+] calcd for C30H21N4O] 493.23; found 493.5.
Example 73: Synthesis of compound 73 I
Compound 73: Formula (X) where RM is hydrogen: A TFA salt of compound 73 was prepared: "H NMR (300MHz, DMSCwtf) 5 10.48 (s, IH), 10.39 (s, 111), 8.59 (brs, 211), S.07 (dd, 2H), 6.85-7.17 (m, 10H), 6.72 (t, III), 6.52 (dd, IH), 6.11 (d, IH), 5.22 (d,

IH), 3.10 (m, 4H), 2.80 (m, 2H); m/z: rM+H4] calcd for C25H25N3O3 416.20; found 416.3.
Example 74: Synthesis of N~{2-[4-(3-(3-
cyanophenyOphenyOaminophenylJetliyO-W^-hydroxy-^CS-hydroxy-Stl/O-quinolinon-5-yl)ethylamine (74)
Compound 74: Formula (X) where R11 is 3-cyanophenyl
Compound W (Example 65, part b) (58.1 mg, 0.100 mmol), 3-cyanophenyl
boronic acid (17.6 mg, 0.120 mmol) and [ 1,1"-
bis(diphenylphosphinoferrocene)dichloropalladium (II), complex with dichloromethane
(PdCl2(dppf)-DCM) (approximately 6 mg, 0.007 mmol) were combined in a small
pressure tube and purged with N2. 1,2-Dimethoxyethane (2.0 mL) and 2.0 N cesium
carbonate (200 uL, 0.4 mmol) were added, the tube was sealed, and then placed in an oil
bath at 90°C for 5 hours. The solution was then cooled to room temperature and DCM
(10 mL) was added. The solution was dried (Na2SO^) for 30 minutes, then filtered,
concentrated and dried under vacuum. The residue was dissolved in DCM (2mL) and
cooled to 0°C, then boron trichloride (1.0N in DCM, l.OmL, l.Ommol) was added. After
10 minutes the reaction was quenched with methanol (lOmL), and concentrated under
reduced pressure. The residue was purified by reverse phase HPLC. Fractions
containing pure product were combined and Jyophihzed to give compound 74 as a TFA
salt. "HNMR (300MHZ, DMSO-d6)8 10.45 (s, 1H), 10.40 (s, 1H), 8.70 (br 2, 2H), 8.34
(m, 1H), 8.09 (d, 1M), 7.97 (s. 1H), 7.85 (dt, 1H), 7.74 (dt, 1H), 7.58 (t, IH), 7.20-7.30
(m, 2H), 6.95-7.10 (m, 7H), 6.90 (d, IH), 6.50 (d, IH), 6.12 (s, IH), 5.25 (d, IH), 3.10
(m, 4H), 2.80 (m, 2H); m/v [M+H*] calcd for C32H2aN403 517,23; found 517.4.
Examples 75-93: Synthesis of compounds 75-93
Using procedures similar to that described in Example 74, except replacing the 3-cyanophenyl boronic acid with the appropriate substituted boronic acid, TFA salts of compounds 75-93 were prepared.
Compound 75: Formula (X) where R" is trans-2-phenylvinyl: m/z: [M+H+] calcd for CSSHJINJOS 518.25; found 518.3.
Compound 76: A"-(2-[4-[3-(3-pyridyl)pheny!)aminophenyI]ethy])-{^)-2-hydroxy-2-(8-hydroxy-2(I^)-quinolinon-5-y0ethy[amine (Formula (X) where R" is 3-pyridyI):

"H NMR (300MHz, DMSO-d6) 5 10.38 (br s, 2H), 8.84 (s, 2H), 8.67 (s, IH), 8.58 (d, IH), 8.25 (s, 1H), 8.14 (d, IH), 8.1 i (d, IH), 7.59 (dd, 1H), 7.27 (m, 2H), 7.05 (m, 7H), 6.90 (d, IH), 6.50 (d, IH), 5.28 (d, IH), 3.10 (m, 4H), 2.83 (m, 2H). m/z: [M+H+] calcd for C30H2BN4O3 493.23; found 493.5.
Compound 77: Formula (X) where R" is 4-cyanophenyI: "H NMR (300MHz, DMSO-rf Compound 78: Formula (X) where R11 is 3,5-dimelhylisoxazole-4-yl: m/z: [M+H+] calcd for C30H30N4O4 511.24; found 511.5.
Compound 79: Formula (X) where R11 is 2-furanyl: "H NMR (300MHz, DMSO-d6) 5 11.15 (s, IH), 10,47 (s, IH), 10.41 (s, IH), 8.64 (br s, IH), 8.10 (t, 2H), 7.08 (m, 9H),6.77(s, 1H),6.74(S, IH), 6.52 (d, IH), 6.30 (s, lH),6.12(s, IH), 6.02 (q, 1H),5.25 (d, IH), 3.10 (m, 4H), 2.85 (m, 2H). m/z [M+H+] calcd for C29H27N3O4 482.21; found 481.4.
Compound 80: Formula (X) where R11 is lhiophene-2-yl: "H NMR (300MHz. DMSO-d6) 5 10.47 (s, IH), 10.38 (s, III), 8.62 (brs, 211), 8.22 (s, IH), 8.07 (d, IH), 7.44 (d, IH), 7.U3 (d, IH), 7.35 (in, 2H), 7.06 (m, 7H), 6.90 (d, 2H), 6.50 (d, IH), 6.10 (d, IH), 5.23 (m, IH), 3,10 (m, 4H), 2.S5 (m, 211). m/z [M+H+] calcd for C^^NAS 498.19; found 498.5.
Compound 81: Formula (X) where R11 is 3-nitrophenyl: m/z: [M+H+] calcd for C3|H2aN405 537.22; found 537.3.
Compound 82: Formula (X) where RM is 4-formyIphenyl: m/z: [M+H*] calcd for C32H19N3O4 520.23; found 520.5.
Compound 83: Formula (X) where R11 is 2-pyrrolyl: Using a procedure similar lo
that described in Example 74, except replacing [lie 3-cyanophenylboronic acid with 1-
(ter/-butoxycarbony0pyrro]c-2-boronic acid, a TFA salt of compound 83 was prepared.
Deprotectton of the Boc group occurred under reaction conditions, "ll NMR (300MJ lz, I
DMSO-dS) 6 11.13 (s, IH), 10.46 (s, IH), 10.37 (s. IH), 8.58 (brs, 2H), 8.08 (s, IH), 8.05 (£, IH). 7.05 (m,9H). 6.75 (s. IH), 6.73 (s. IH). 6.51 (d, IH). 6.23 (s. IH). 6.08 (s,

1H). 6.01 (s, 1H), 5.22 (m, 1H), 3,12 (m, 4H), 2.80 (m, 2H). m/j: [M+H4] calcd for C29H2gN403 481.23; found 481.3,
Compound 84: Formula (X) where Rn is 4-carboxyphenyl: m/z: [M+H4] calcd for Q2H29N3O5 536.22; found 536.3.
Compound 85: Formula (X) where R1" is 4-methyIsulfonylpbenyI: "H NMR (300MHz, DMSO-dS) 5 10.45 (s, 1H), 10.38 (s, 1H), 8.58 (br s, 1H), 8.27 (s, 1H), 8.05 (d, 1H), 7.90 (d, 2H), 7.77 (d. 2H), 7.26 (m, 2H), 7.04 (m, 7H), 6.88 (d, 1H), 6.50 (d, 1H), 6.11 (s, 1H), 5.22 (d, 1H), 3.16 (s, 3H), 3.11 (m, 4H), 2.80 (m, 2H) . m/z: [M+H4] calcd for C32H3,N30jS 570.21; found 570.3.
Compound 86: Formula (X) where R1" is 4-hydroxyphenyl: Using a procedure similar to that described in Example 74, except replacing the 3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA salt of compound 86 was prepared. "H NMR (300MHz, DMSO-dS) 8 10.46 (s, 1H), 10.40 (s, 1H), 9.47 (s, 111), 8.71 (brs, 2H), 8.12 . (m, 2H), 7.32 (d, 2H), 7.02 (m, 9H), 6.75 (d, 2H), 6.51 (d."lH), 6.10 (s, 1H), 5.25 (d, 1H), 3.10(m,4H),2.80(mt2H). m/z: [M+H+] calcd for C31H29N3O4 508.23; found508.3. Compound 87: N-(2-[4-(3-(4-aminomethylphenyl)phenyl)aininophenyl]ethyi}-(/f)-2-hydroxy-2-(8-hydroxy-2(l//)-quinoIinon-5-yl)ethylamine (Formula (X) where R11 is 4-(aminomethyI)phenyl): m/z: [M+Ii*"] calcd for C^l-^N^Oj 521.26; found 521.3.
Compound 88: Formula (X) where R1" is 4-etho;>:ypheny[: m/z: [M+H4] cftlud fur C33H33N304 536.26; found 536.3.
Compound 89: Formula (X) where R1" is thiophene-3-yl: m/z: [M+H4] calcd for C29H27Na03S 498.19; found 498.3.
Compound 90: Formula (X) where R" is 2-indolyl: m/z: [M+H*] calcd for C33H30N4OJ531.24; found531.3.
Compound 91: //-(2-[4-(3-{3-chIorophenyI)phenyi)aminophenyl]ethyl)-(^)-2-hydroxy-2-(8-hydroxy-2(l//)-quinolinon-5-y])elhyIamine (Formula (X) where RM is 3-chlorophenyI): "H NMR (300MHz, DMSO-dfi) 5 10.45 (s, 1H), 10.38 (s, 1H), 8.58 (brs,2H),8.20(s, lH),8.06(d. 1H). 7.21 (m. 14H), 6.51 (d, lH),6.10(s, lH),5.23(d, ]H),3.10(m,4H),2.80(m,2H"). I [M+H] calcd forC3iH2gClN30;, 526.03; found 526.3.
Compound 92: Formula (X) where R11 is 3-methoxyphenyl: m/z: [M+H] calcd for CMHJJNJOI 522.24; found 522.0.


Example 94: Synthesis of A"-{2-[4-(3-(3-pyridyI)-4-methoxyphenyl)aminophenyl]ethyI)-(fi)-2-hydroxy-2-(8-hydroxy-2(l/0-(luinolmon-5-yl)ethylamine (94)
Compound 94: Formula (XI) where R1" is 3-pyridy!
a. Synthesis of 4-iodophenethyIamine
4-Iodoprieny/acetcnitrite (4.80 g, f 9.7 mmol) was dissolved in tetrahydrofuntn (25
mL) under nitrogen, and 1.0 M boranc in tetrahydrofuran (29.6 mL, 29.6 mmol) was
added via syringe. The reaction was heated at reflux for I hour, then cooled in ice and the
excess borane was quenched by the addition of methanol (100 mL). When hydrogen
evolution ceased, the solvents were removed under reduced pressure. The residue was
dissolved in tetrahydrofuran (25 mL) and 4N HCI in dioxane (6.0 mL, 24 mmol) was ■
added, followed by ether (75 mL). The hydrochloride salt of 4-iodophenethy!amine was
collected on a Buchner funnel, washed with ether (2x50 mL) and dried under reduced
pressure. To generate the free base, the solid was partitioned between dichloromethane
(200 mL) and IN NaOH (100 mL). The aqueous layer was extracted with
dichloromethane (2x100 mL). The combined organic layers were dried (Na2S04) and
concentrated lo give 4-iodophenethylamine (4.52 g) as a colorless oil.


To a solution of 4-iodophenethyIamine (4.5 g, 22 mmol) in methyl sulfoxide (13 mL) under nitrogen was added compound HH (from Example 6TB part f) (7.3 g, 15 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodium iodide (3.3 g, 22 mmol). The mixture was heated at 140°C in an oil bath for 25 minutes. After cooling to room temperature, water (100 mL) was added and the resulting mixture was extracted with ethyl acetate (2x150 mL). The combined extracts were washed with IN HCI (2x50 mL), water (50 mL) 10% sodium thiosulfate (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), The solution was dried (Na2S04) and concentrated. The crude product was purified in two lots by flash chromatography on silica gel (75 g) eluting with 0-5% methanol in dichloromethane containing 0.5% triethylamine. Compound QQ (6.1 g) was isolated as a dark yellow oil.
c. Synlhesis of 4-aminu-2-bromoani;;ole
To a mixture of 2-bromo-4-nilroanisoIe (5.0 g, 21.5 mmol, Lancaster), ethanol (25 mL) and water (25 mL), was added powdered iron (4.8 g, 86 mmol) and 12 N HCI (0.5 mL). The solution was heated at reflux for 20 minutes. lNNaOH(lOmL) was added and the reaction mixture was filtered through a pad of celite while still hot, and then rinsed with ethanol (2x50 mL). The ethanol was removed under reduced pressure and the residue extracted with dichloromethane (2x100 mL). The organic extracts were dried (Na2SOd) and concentrated. The crude product was purified by flash chromatography on silica gel (75 g) eluting with dichloromethane, to give 4-amino-2-bromoanisole as a light tan solid.


(73 mg, 0.12 mmol), [1,1 -bis(diphenylphosphJno)-ferrocene]dichloropaI]adLiim(II) dichloromelhane complex (10 mg) and 3-pyridylboronic acid (18 mg, 0.14 mmol). Dimelhoxyelbane (2.5 mL) wa.s added, followed by 2.0 N cesium carbonate (0.20 mL,

f 0.40 mmol). The mixture was heated at 90°C for 4 hours. The solution was then cooled
to room temperature and DCM (20 mL) was added. The solution was dried (NajSQj) for
30 minutes, then filtered, concentrated and dried under vacuum. The residue was
dissolved in DCM (2 mL) and cooled to 0°C, and then boron trichloride (1.0N in DCM,
1.0 mL, 1.0 mmol) was added. After 10 minutes the reaction was quenched with
methanol (10 mL), and concentrated under reduced pressure. The residue was purified by
reverse phase HPLC. Fractions containing pure product were combined and lyophilized
to give a TFA salt of A"-{2-[4-(3-(3-pyridylH-methoxyphenyl)aminophenyI]ethyl) -(tf)-2-
hydroxy-2-(8-hydroxy-2(I//)-quinolinon-5-yl)etliyIamine (94). "H NMR (300MHZ,
DMSCW6) 5 10.; m/z: [M+H*] calcd for C3|HMN,A 523.24; found 523.3.
A sample of the TFA salt (25 mg) was dissolved in acetonitrile (0.5 mL) and water
(0.5 mL), followed by IN HCI (0.10 mL, 0.10 mmol). The solution was lyophylized to a
powder which was redissolvcd in acetonitrile (0,5 mL) and water (0.5 mL). IN HCI was
then added (O.lOmL, O.lOmmol). Lyophylization gave a hydrochloride salt of compound
94 as an off white powder.. "H NMR (300MHz, DMSO-c/ lH),8.97(d. 1H), 8.78 (d.lH), 8.77 (brs, 1H), 8.61 (dt, 1H), 8.20 (d, 1H), 8.01 (dd, 1H),
6.90-7.15 (m. 8H), 6.47 (d, tfl),5.39 (d, 1H). 3.70 (s, 3H), 3.02 (m, 4H), 2.82 (m, 2H);
m/z: [M+H+]caicd for C31H30N4O4 523.24; found 523.6.
Example 95: Synthesis of A"-{2-[4-(3-(3-cynnophenyl)-4-tnethoxypl]en}"])nminophenyl]ethyO-(A)-2-l]ydroxy-2-(8-hytlroxy>2(If7)-quinonnon-5-yl)etliylamme (95)
Compound 95: Formula (XI) where R"" is 3-cyanophenyl.
Into a nitrogen purged lest tube with a screw cap was placed compound RR (from Example 94, part d) (100 mg, 0.163 mmol), [l,r-bis(dipbenylphosphino)-feirocene]dichloropalladium(Ii) dichloromethanc complex (10 mg) and 3-cyanophenylboronic acid (35 mg, 0.20 mmol). Dimethoxyethane (3 mL) was added, followed by 2.0 N cesium carbonate (0.30 mL, 0.60 mmol). The mixture was heated at 90nC for 4 hours. The solution was then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried (Na2SCXt), concentrated and dried under reduced pressure. The residue was dissolved in DCM (5 mL) and cooled to 0 °C, and then boron trichloride (1.0 N in DCM, 2.0mL, 2.0 mmol) was added. After 10
minutes the reaction was quenched with methanol (20 mL), and concentrated under
1

, reduced pressure. The residue was purified by reverse phase HPLC. Fractions
containing pure product were combined and iyophiJized to give a TFA salt of compound 95. "H NMR (300MHZ, DMSO-ttf) 5 10.47 (s, IH), 10.38 (s, 1H), 8.57 (br s, 2H) 8.05
1 (d, IH), 7.89 (m, IH), 7.82 (m, IH), 7.70 (m, 2H), 7.53 (t, 2H), 7.07 (d, IH), 6.95-7.00 (m, 4H), 6.85-6.92 (m, 3H), 6.50 (dd, IH), 6.09 (d, IH), 5.22 (d, IH), 3.65 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H+] calcd for CJJHSIMO* 547.24; found 547.5.
Examples 96-102: Synthesis of Compounds 96-102
Using procedures similar to that described in Example 95, except replacing the 3-cyanophenylboronic acid with the appropriate substituted phenylboronic acid, TFA salts of compounds 96-102 were prepared.
Compound 96: yv"-(2-[4-(3-C4-aminomethylphenyl)-4-methoxyphenyI)aminophenyl]elhyl)-C^)-2-hydroxy-2-(8-hydroxy-2fl//)-quinolinon-5-yl)ethylamine (Formula (XI) where R11 is 4-(aminomethyI)pbenyl): ]H NMR (300MHz, DMSO-dS) 8 10.47 (s, IH), 10.40 (s, IH), 8.58 (br s, 2H), 8.07 (m, 4H), 7.87 (s, IH), 7.40 (dd, 4H), 7.07 (d, IH), 6.84-7.05 (m, 8H), 6.50 (dd. IH), 6.11 (d, IH), 5.23 (d, IH), 3.98 (m, 2H), 3.62 (s, 3H), 3.05 (m, 2H), 2.95 (m, 2H), 2.75 (m, 2H); m/z: [M+H+] calcd for C33H34NA 551.27; found 551.5.
Compound 97 A/-{2-[4-(3-(4-pyridy!)-4-mefhoxyphenyI)ammophenyl]efhyl ]-(/?)-2-hydroxy-2-(8-bydroxy-2(l//)-quinoIinon-5-yl)ethylamine (Formula (XI) where R1" is 4-pyridyl): "HNMR (300MHZ, DMSO-cW) 5 10.46 (s, IH), 10.42 (s, IH), 8.65 (d, 2H), 8.62 (br s, IH), 8.06 (d, 2H). 7.97 (br s, IH), 7.73 (d, 2H) 6.95-7.10 (m, 7H), 6.90 (dd, 2H), 6.12 (br s, IH), 5.23 (d, 111), 3.69 (s, 3H), 3.10 (m, 4H), 2.80 (m, 211); m/z: [M+it] calcd for C31H30N4O4 523.24; found 523.6.
Compound 98: Formula (XI) where R1" is 4-formyIphenyI: "H NMR (300MHz,
DMSO-rftf) 5 10.46 (s, IH), 10.39 (s, IH), 9.95 (s, IH), 8.57 (br s, 2H), 8.05 (d, IH), 7.91
(brs, IH), 7.85 (d, 2H), 7.61 (d, 2H), 6.95-7.10 (m, 7H), 6.89 (dd. 2H), 6.50 (dd, IH).
6.10 (s, IH), 5.22 (d, IH), 3.65 (s, 3H), 3.05 (m. 4H), 2.75 (m, 2H) ; m/z: [M+H+] calcd
for C3jH3iN30s 550.24; found 550.6. I
Compound 99: Formula (XI) where R11 is 4-methylsuIfonyl: "H NMR (300MHz, DMSO-d6) o 10.46 (s. IH), 10.38 (s, IH), 8.55 (brs, 2H), 8.05 (d, IH), 7.91 (s. HI), 7.86 (d, 2H), 6.74 (d, 2M), 6.93-7.10 (m, 6H). 6.85-6.92 (m. 3H), 6.51 (dd, IH), 6.09 (d, IH),

5.22 (d, IH), 3.65 (s, 3H), 3.17 (s, 3H), 3.05 (m, 4H), 2.75 (m, 2H); m/Z: [M+H*] caJcd for CssHasNsOsS 600.22; found 600.5.
Compound 100: A^{2-[4-(3-(4-hydroxypheny])-4-methoxyphenyI)aminophenyl]ethyIJ-(^)-2-hydroxy-2-(8-hydroxy-2Clfl)-quinoIinon-5-yl)ethylamine (Formula (XI) where R1" is 4-hydroxyphenyl): Using a procedure similar to that described in Example 95, except replacing die 3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA salt of compound 100 was prepared. "H NMR (300MHz, DMSO-J6) 8 10.46 (s, 1H), 10.38 (s, 1H), 9.34 (s, IH), 8.57 (brs, 2H), 8.06 (d, 1H), 7.80 (s, 1H), 7.18 (d, 2H), 7.07 (d, IH), 6.97 (d, 2H), 6.80-6.90 (m, 6H), 6.69 (d, 2H), 6.51 (dd, 1H), 6.09 (s, 1H), 5.23 (d, IH), 3.60 (s, 3H), 3.05 (m, 4H), 2.78 (m, 2H); m/z: [M+H] calcd for C32H3iN305 538.24; found 538.5.
Compound 101: Af-{2-[4-(3-(thiophen-3-yI)-4-metboxypbenyl)amjnophenyI]ethyl} -(#)-2-bydroxy-2-(8-hydroxy~2( l/f)-quinolinon-5-yl)ethylamine (Formula (XI) where Rn is thiophen-3-yl): "H NMR (300MHz, DMSO-d6) 5 10.47 (s, 1H), 10.38 (s, 1H), 8.57 (br s, 2H), 8.06 (df 1H), 7.83 (s."lH), 6.74 (dd, 1H), 7.48 (dd, 1H), 7.31 (dd, IH), 7.13 (s, 1H), 7.06 (d, IH), 6,80-7.00 (m, 7H), 6.51 (dd, 1H), 6.01 (s, IH), 5.23 (d, IH), 3.70 (s, 3H), 3.07 (m, 4H), 2.77 (m, 2H); m/z: [M+H*] calcd for C30H29N3O4S 528.20; found 528.3.
Compound 102: Af-(2-[4-(3-(3"Chlorophenyl)-4-methoxypheny!)ammoplieny!]ethyl|-(y?)-2-hydroxy-2-(8-hydroxy-2(l//)-qLiinolinon-5-yl)ethylamine {Formula (XI) where R11 is 3-chlorophenyl): "H NMR (300MHz, DMSO-d6) 5 10.46 (s, IH), 10.38 (s, IH), 8,76 (br s, IH), 8.62 (br s, IH), 8,10 (s, IH), 7.88 (br s, IH), 7.15-7.23 (m, 5H), 6.85-7.10 (m, 1 IH), 6.50 (d, IH), 6.09 (br s, IH), 5.27 (d, IH), 3.65 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H"] calcd for C32H30ClN3O4 556.20; found 556.2.
Example 103: Synthesis of Ar-{2-[4-(3-(3-cyanophenyl)- mc(hoxyplicnyI)aminophenyI]ethyl]-(tf)-2-hydroxy-2-(8-hydroxy-2(U7)-qiiinolinon-5*yl)ethyIaminc (95)
Using procedures similar to those described in Example 61C and the deprotection step of Example 61B, except replacing the 4-meilioxy-3-phenylaniIinc hydrochloride with 3-(3-cyanophenyl)-4-metboxyaniline in Example 61C, part d, compound 95 was prepared.
The intermediate compound 3-(3-cyanophenyl)-4-mcthoxyaniline was prepared as follows:

a. Synthesis of 2-C3-cyanopheoylH-nitroanisote
[l,l"Bis(diphenylphosphino)ferrocenc]dicWoropaIIadium(]I), complex with dichloromethane(I;l)(1.43 g) was added to a stirred mixture of 3-cyanophenylboronic acid (10.0 g, 61.8 mmol) and 2-bromo-4-nitroanisoIe (14-.35 g, 62 mmol) in 2.0N cesium carbonate (92.7 mL, 185.4 mmol) and ethylene glycol dimethylether (200 mL). The flask was purged with nitrogen and heated at 90aC (oil bath) for 4 hours. The mixture was allowed lo cool to room temperature overnight, during which time the product precipitated from solution. The solid was collected on a Buchner funnel, washed with water and dried under reduced pressure to give 2-(3-cyanophenyl)-4-nitroanisoIe {15.7 g).
b. Synthesis of 3-(3-cyanophenyl)-4-niethoxyaniline
Zinc dust (20.26g, 3 lOmmol) was added in portions over five minutes to a solution of 2-(3-cyanopbenyl)-4-nitroanisole (15.7 g, 62 mmol) and ammonium formate (19.48 g, 310 mmol) in methanol (500 mL) and tetiahydofuran (500 mL). The reaction was complete after stirring for one hour at room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatoghraphy on silica gel eluting with 5% methanol in dichloromethane to give 3-(3-cyanophenyi)-4-methoxyantline (10 g, 44 mmol) as a yellow oil,
Example 104: Synthesis „f A"-{2-[4-(3-(4-iiminomethylphenyl)-"l-methoxyphcnyI)aminophenyl]e(liy])-(^)-2-liydroxy-2-(8-liy(lroxy-2(l//)-quinolinon-5-yl)ethylamine (96)
Using procedures similar to those descrihed in Example 61C and tire deprotection step of Example 6 IB, except replacing the 4-methoxy-3-pbenylaniiine hydrochloride with 3-(4-aminomethylphenyl)-4-methoxyaniline in Example 6IC, part d, compound 96 was prepared.
The intermediate compound 3~(4-aminomelliylphenyI)-4-methoxynniIine was prepared as follows:
a. Synthesis of 2-(4-aminomethyiphenyl)-4-nitronnisoie
A mixture of 2-bromo-4-nitroaniso!e (5.80 g, 25.0 mmol) and 4-(aminomethyl)phenylboronic acid hydrochloride (4-96 g, 26.6 minol) was slurried in 1-propanol (50 mL) under nitrogen. Triphenylphosphine (315 mg, 1.20 mmol) and palladium (11) acetaic (90 mg, 0.40 mmol) were added, followed by 2.0N sodium

carabonate(33mL, 66mmoi). The mixture was heated at 95°C (oil bath) under nitrogen

for 3 hours, at which time the reaction was judged to be complete by TLC. Water (25 mL) was added and the mixture was stirred open to air for 2 hours at room temperature. The mixture was extracted with ethyl acetate (100 mL, 2x50 mL) and the combined extracts were washed with sodium bicarbonate (25 mL) and brine (25 mL). The solution was dried with sodium sulfate, and concentrated to an oil which was purified by flash chromatography on silica gei (100 g) eluting with 0-4% methanol/0,5% triethylamirte/dichloromethane. Pure fractions were combined and concentrated to give 2-(4-aminometliyIphenyl>4-nitroanisole (4.6 g) as a yellow solid.
b. Synthesis of 3-(4-aminometbylphenyl)-4-methoxyani]ine
A solution of 2-(4-amino methyl phenyl)-4-nitroanisole (4.50g) in methanol (200 mL) was treated with 10% palladium on carbon (200mg). The reaction mixture was stirred under one atmosphere of hydrogen for 2,5 hours. The reaction mixture filtered through Celite, and the filter cake was washed with methanol (3x25mL). The filtrate was concentrated to dryness and Ihe residue was purified by flash chromatography on silica gel (80 g) eluting with 0-6% methanol/0.5% triethylnmine/dichlorometbane. Pure fractions were combined and concentrated to give 3-(4-aminomethylphenyl)-4-methoxyaniline as an off while powder.
Example 105: Synthesis of /V-(2-[4-(3-(3-cliIorophenyl)-4-
metlioxyplienyl)aminophenyI]ethyl}-(ff)-2-hydroxy-2-(8-hydroxy-2(i//)- |
quinoIinon-5-yI)ethylamiiic(I02)
Using procedures similar to those described in Example 61C and the deprotection
step of Example 6 IB, except replacing the 4-methoxy-3-phenyianiline hydrochloride with
3-(3-chIoropIienyI)-4-methoxyani!ine in Example 61C, part d, compound 102 was
prepared.
The intermediate compound 3-(3-chloropheny!)-4-me(hoxyaniIine was prepared as
follows:
a. Syndiesis of 2-(3-chlorophenyl)-4-nltroanisole
To a flask containing abi-phasic mixture of 2-broma-4-mtroanisolc (15.0 g, 64.6 mmol) and 3-chlorophenyiboronic acid (12.1 g, 77.6 mmol) in ethylene glycol dimethyl ether (187.5 mL) and 2.0 N aqueous cer

bis(r%henylphospbJno)feirocene)dichloro palladium (H), complex with dicbloromethajie (1:1) (1.5 g). The mixture was heated at reflux for 4 hours under a nitrogen atmosphere.
The crude reaction mixture was partitioned between ethyl acetate (350 rnL) and brine (250 mL) and then filtered through a Buchner funnel. Layers were separated and the organic layer was washed with brine (250 mL). The organic phase was dried overNajS04. filtered, and concentrated to a dark oil. The crude residue was purified by flash chromatography on silica gel using dicbloromethane as the eluent to afford 2-(3-chlorophenyl)-4-nitroanisole as a yellow solid (13.9 g, 59.4 mmol).
b. Synthesis of 3-{3-chIorophenyl>4-methoxyaniline
To a mixture of 2"(3-chlorophenyI)-4-nitroanisoIe (0,5 g, 1.9 mmol)in tetrabydrofuran (5 mL) and methanol (5 mL) was added platinum (IV) oxide (1 mg). The reaction was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours. The slurry was filtered through Celite and concentrated under reduced pressure to afford 3-(3-chloropbenyI)-4~metboxyaniline as a light yellow oil (405 mg, 1.7 mmol).
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from die trtie spirit and scope of the invention. In addition, many modifications may be made tu ;i(|;tpt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. Additionally, all publications, " patents, and patent documents cited hereinabove are incorporated by reference herein in full, as though individually incorporated by reference.




Using a coupling procedure similar lo that described in Example 1, except replacing the A"l-(4-hep[y!-6-meth),l-2-pyrimJdinyl)sulfanilamide 4-(m-lolylthio)aniline


Using a coupling procedure similar 10 that described in Example 1, except replacing the V-(4-heptyI-6-methy]-2-pyrimidinyl)5ulfanilamide with 4-[(4-flL)oropbenyl)suIfony)J aniline {available from Bionet), a TFA salt of compound 20 was prepared.




Using a coupling procedure similar lo that described in Example 1, except replacing the W,-C4-heptyl-6-methyl-2-pyrimidinyl)sulfani]amide with 4-(4-chloro-benzenesulfonyl)-phenylamine (available from Sigma-Aldrich Library of Rare Chemicals), a TFA salt of compound 23 was prepared, m/z: [M + H*] calcd for C29H29C1N20JS 553.2; found 553.1.




Using a coupling procedure simiiar lo that described in Example 1, except replacing the fV"-^-beptyl-e-methyW-pyrimidinyOsuIfanUamide with 4-methoxyaniIine (p-anisid"me, available from Afdrich), a TFA salt of compound 28 was prepared.


" Using a coupling procedure similar to that described in Example I, except
i replacing the jVl-(4-heptyl-6-methyl-2-pyrimidinyl)su]fanilainide with 3-chloro-4-methoxyaniline (available from Aldrich), a TFA salt of compound 31 was prepared.






butoxide was added 35 mi of toluene, and the mixture was heated at 95°C for 5,5 hours under a nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHS04 and diethyl ether, and the phases were separated. The diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHS04 and brine, dried over Na2S04, filtered, and concentrated to a dark oil. The oil was purified by chromatography, using 15% EtOAc / 85% hexanes as eluent, to give 2.52 g(73%)ofcompoundCasadarkorangeoiI. "HNMR (300MHZ, DMSO-d6) 5 7.64 (s, 1H), 7.28-7.13 (m,5H), 6.91-6.72 (m, 8H), 4.27 (s, 2H), 3.92 (q, 2H), 3.25 (s, 2H), 3.15 (m, 2H), 2.52 (m, 2H), 1.31 (s, 9H), 1.21 (t, 3H). m/z: [M + H4] calcd for CzgH^Oj 447.3; found 447.8.

To 2.93g (6.56 mmol) of compound C in 15 ml of CH2CI2 at 0°C was added 15 ml of trifluoroacelic acid. After 40 minutes, the solution was concentrated under reduced" pressure, and the residue was partitioned between 1M NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried overNa2S04, filtered, and concentrated to an orange oil. The oil was dissolved in 20 ml of isopropanoi, 1.86 g (6.56 mmol) of the epoxide a was added, and the solution was heated at 78°C overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give compound E as an orange oil that was used without purification in the next step.


To a solution of 200 mg of compound Q (0.36 mmol) in 5.0 mL methanol was added 45 mg of 10% palladium on carbon. The reaction was piaced under 1 atm H2 gas. After 20 h, an additional 25 mg of 10% palladium on carbon was added and the reaction was stirred under 1 atm H2 for an additional 24 h after which time the reaction was filtered. The filtrate was concentrated and purified by reversed phase preparative HPLC (gradient of 15-50% acetonitrile in 0.1 % TFA). Fractions containing pure product were combined and lyophilized to afford a TFA salt of compound 6 as a powder. A sample of



was added 35 mL of toluene, and the mixture was heated at 95°C for 16 hours under an nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHSC>4 and diethyl ether. The diethyl ether phase was washed once each with saturated NaHCOj and brine, dried over MgSCU, filtered, and concentrated to a dark oil. The oil was purified by silica gel chromatography, using 15% EtOAc / 85% hexanes as eluant, to give compound Y as a dark orange oil.

To 1.0 g of compound Y(2.8mmol)in 5 mL CH2C\2 was added 4 mLTFA. After 15 minutes, the solution was concentrated, diluted with 50 mL isopropyl acetate and washed twice with 1.0 M aqueous NaOH. The isopropyl acetate layer was dried over MgSO^, filtered, and concentrated to a brown oil. The oil was dissolved in 5.0 mL of isopropanol and 390 mg (1.3 mmol) of epoxide P {Example 15, part a) were added. The solution was heated to 70 °C. After 36 h, the solution was concentrated and the product purified by reversed phase HPLC (gradient of 20-70% acetonitrile in 0.1 % TFA). Fractions containing pure product were combined and concentrated to remove acetonitrile. The aqueous residue was diluted with brine and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSC>4 and concentrated to afford compound Q as a yellow foam.













was added 50mL of toluene, and the mixture was heated at 95°C for 5.5 hours under an nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHSC>4 and diethyl ether, and the phases were separated. The diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHS04 and brine, dried over NajSOj, filtered, and concentrated to a dark oil. The oil was purified by silica gel chromatography, using 12% EtOAc / 88% hexanes as eluent, to give compound D as a yellow foam, "H NMR (300 MHz, DMSO-dff) 5 7.76 (s, IE), 7.38-7A3 (m, IOH). 6.95-6.81 (m, 7H), 4.28 (s, 2H), 3.61 (s. 3H), 3.16 (m, 2H), 2.53 (m, 2H), 1.29 (s, 9H).

To 2.60 g (5.1 ImmoJ) of compound Din 15 mLof CHiCU at 0°C was added 15 mL of trifluoroacetic acid. After 40 minutes, the solution was concentrated under reduced pressure, and the residue was partitioned between IM aqueous NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried over Na2SO.i, filtered, and concentrated to an orange residue. The residue was dissolved in 15mL of isopropanol, 1.45 g (5.11 mmol) of the epoxide a (Example 37, part b) was added, and the solution was heated at 78DC overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give compound G as an orange oil which was used in the next step without purification.


To a mixture of 825 mg (1.22 mmol) of compound N in 15 mLof ethanol was
added 260 mg of 10% palladium on carbon under a stream of nitrogen. The flask was
fitted with a balloon of hydrogen gas, and the reaction was vigorously stirred for 3 hours.
The reaction was filtered through celite, using methanol to rinse, and the filtrate was I
concentrated under reduced pressure. The residue was dissolved in 10 mL isopropanol, 0.67 mL of 4.0 M HC1 in dioxane was added, and the product was precipitated by adding the solution to a large volume of EtOAc. The solids were isolated by filtration to give a



To 2.28 g (12.2 mmol) of compound J in 45 mL of dimethylformamide at 0°C wasadded734mg(18.4mmo])of60%NaHinoiI. After lOminutes, 1.90g(12.2mmol) of iodoethane was added. After 20 minutes, the solution was partitioned between diethyl ether and 5% aqueous N32S03, and the phases were separated. The diethyl ether phase was washed once each with I.OM aqueous NaOH, water, and brine, dried over I^SO^, and concentrated to give compound K as a dark brown oil. !H NMR (300 MHz, DMSO-d6) 5 7.37-7.19 (m, 5H), 6.73 (d, 1H), 6.47-6.42 (m, 2H), 4.65 (s, 2H), 3.73 (q, 2H), 1.07 (t, 3H).

To a flask containing 3.97 g (10.7 mmol) of compound B (Example 13, part b), 2.27 g (12.2 mmol) of compound K, 0.46 g (0.5 mmol) of tris(dibenzylidineacetone)dip;iiladium (0), 0.95 g (!.5nimol) of rncemic-2,2"-bis(diphenylphosphJno)-I,r-binaphthyl, and 1.27 g (13.3 mmol) of sodium /ert-butoxide was added 48 mL of toluene, and the mixture was heated at 95°C for 5.5 hours under an nitrogen atmosphere. The mixture was partitioned between 1.0 M aqueous NaHSOj and diethyl ether, and the phases were separated. The diethyl ether phase was diluted with one volume of hexanes, and was washed once each with 1.0 M aqueous NaHS04 and brine, dried over Na2SCU, filtered, and concentrated to a dark oil. The oil was purified by silica gel chromatography, using 10% EtOAc/ 90% hexanes as eluent, to give 4.13 g (77%) of compound L as a yellow foam. "H NMR (300 MHz, DMSO-rffi) 5 7.76 (s, 1H), 7.42-7.13 (m, 10H), 6.93-6.81 (m, 7H). 4.27 (s, 2H), 3.86 (q, 2H), 3.25 (m, 2H), 2.53 (m, 2H), 1.28 (s,9H), 1,13 (t,3H).


To 2.68 mniol of crude compound M in 20 mL of tetrahydrofuran at 0°C was added 7.0 mL (7.0mmol) of 1.0 M lithium aluminum hydride in tetrahydrofuran. After 2 hours, trie reaction was quenched by slow addition of sodium sulfate decahydrate. The slurry was diluted with diethyl ether, dried over Na2S04, filtered, and concentrated to an orange oil. The oil was purified by silica gel chromatography, using 50% EtOAc / 50% hexanes as eluent, to give 835 mg of compound N as a while foam. *H NMR (300 MHz, DMSO-d6) 5 7.73 (s, 1H), 7.42-6.77 (m, 25H), 5.00 (s, 2H), 4.93 (m, lk), 4.66 (d, 1H), 4.51 Cm, 1H).4.47 (m, 2H), 3.86 (q, 2H), 3.62 (m, 2H), 2.55 (m. 6H), 1.13 (t, 3H).



To 944 mg (1.85 mmol) of compound D (Example 52, part a) in 6 mLof CH2CI2 at 0°C was added 6 mL of trifluoroacetic acid. After 40 minutes, the solution was concentrated under reduced pressure, and the residue was partitioned between I.OM aqueous NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried over Na2SO.i, filtered, and concentrated to an orange oil.
The residue from above was dissolved in 5 mL of isopropanot, 500 mg (1.85 rnmol) of the epoxide b was added, and the solution was heated at 78°C overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give an orange oil. The oit was purified by silica gel chromatography, using 50 EtOAc / 50 hexanes as eluent, to give 825 mg (66%) of compound I as a white foam. "H NMR (300 MHz, DMSO-tf The intermediate epoxide b can be prepared as described in U.S, Patent No. 6,268,533 B1, and in R. Kelt, et aj.. Organic Process Research and Development, 1998, 2, 96-99.

To a mixture of746mg(L 07 mmol) of compound O in 15 mLof ethanol and 5 mLof EtOAc was added 260mg of 10% palladium on carbon under a stream of nitrogen. The flask was fitted with a balloon of hydrogen gas, and the reaction was vigorously stirred for 3 hours. The reaction was filtered through celite, using methanol to rinse, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 mL isopropanol, 0.58 mL of 4.0 M HCI in dioxane was added, and the product was precipitated by adding the solution to a large volume of EtOAc. The solids were isolated by filtration to give a hydrochloride salt of compound 55 as an off while solid. "HNMR (300MHz, DMSO-d6) 5 10.12 (br s, IH), 9.62 (s, IH), 8.90 (br s. IH), S.67 (br s, IH),


To 1.4 g (2.68 mmol) of compound L {Example 53, parte) in 6 mL of CH2CI2 at 0"C was added 6 mL of trifluoroacetic acid. After 40 minutes, the solution was concentrated under reduced pressure, and the residue was partitioned between 1.0 M aqueous NaOH and EtOAc. The phases were separated, and the EtOAc phase was washed once each with water and brine, dried over NajSGi, filtered, and concentrated to an orange residue. The residue was dissolved in 5 mL of isopropano!, 721 mg (2.68 mmol) of epoxide I) (Example 54, part a) was added, and the solution was heated at 78°C overnight. The mixture was cooled to room temperature, and concentrated under reduced pressure to give an orange oil, The oil was purified by silica gel chromatography using 50 EtOAc / 50 hexanes as eluent, to give 756 mg of compound O as a white foam. H NMR (300 MHz, DMSO-rf6)5 9.45{d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.72 (s, 1H). 7.45-6.76 (m, 25H), 5.10 (s, 2H). 5.04 (m, IH), 3.94 (q, 2H), 3.61 (s, 2H), 2.50 (s. 6H), 1.13 (t, 3H).
1


To a solution of 840mg of compounds (1.2 mmol) in 40 mLof 1:1 methano!:THF was added 170 mg of 10% palladium on carbon. The reaction was shaken under an atmosphere of 35 psi H2. After 24 h, the reaction was filtered and the filtrate purified by reversed-phase HPLC (gradient of 10 to 70% acetonitrile in 0.1% aqueous TFA). Fractions containing pure product were combined and lyophilized to afford a TFA salt of compound 56 as a powder.
A sample of the TFA salt (75 mg) was dissolved in acetonitrile (1.0 mLJ and diluted with water (2.0 mL) followed by 0.1 N I-IC1 (3.0 mL). The solution became cloudy. Addition of 1.5 mL acetonitrile afforded a clear solution which was frozen and lyophiiized. The residue was redissolved in ncetonitriJe (1.0 mL) and diluted with water (2.0 mL) followed by 0.1 N I-IC1 (4.0 mL), The solution became cloudy. Addition of 1.0 mL acetonitrile afforded a clear solution which was frozen and lyophilized. The hydrochloride salt of compound 56 (50 mg) was obtained as a gray solid, "HNJVfJi (300MHz, DMSO-46) 5 10.55 (brs, 1H), 9.30 (br s, 1H), 8.80, (br s, 1H), 8.24 (d, 1H), 7.25-7.48 (m, 5H), 6.92-7.18 (m 9H), 6.55 (d, 1H), 5.55 (d, 1H), 3.69 (s, 3H) 2.80-3.20 (m, 6H) m/z: [M + H+J cakd for C32H31N3O4 522.24; found 522.3.
The intermediate compound S was prepared as follows.


Using a coupling procedure similar to that described in Example 1, except i replacing the A"^4-heptyl-6-mirlhyI-2-pyrimidinyl)sulfanilamide with methy]-4-iiminobenzoate (available from AJdrich), a TFA saJt of compound 57 was prepared, m/z: [M + H+] calcd for CssH^O; 437.2; found 437.2.


To a mixture ofcompoundjj (0.2 g, 0.27 mmol) in 6 mLDMF/EtOH (1:1) was added 50 mg of 10% palladium on carbon. The reaction was agitated under H2 at 40 psi for 8 hours. The slurry was filtered and purified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in 0.1 % aqueous TFA). Fractions containing pure product were combined and JyophiJized to afford compound 59 as a TFA salt. The TFA salt product was solubjlized in acetonitrile/water (1:1, 2 mL) to which 1.5 mLof 0.1 N aqueous HC1 was added. The solution was frozen and lyophilized to afford compound 59 as an HC1 salt. ni/v. fM+r-njcalcd for C30H29N5O5S 572.7; found 572.3.
The intermediate jj was prepared as follows.


To a mixture of compound pp {0.3 g, 0.45 mmol) in 10 mL anhydrous ElOH was added 100 mg of 10% palladium on carbon. The reaction was agitated under Hz at 40 psi for 18 h. The reaction was filtered and purified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in 0.1% aqueous TFA). Fractions containing pure product were combined and lyophilized to afford compound 60 as a TFA salt. The TFA salt product wassolubilized in acetonitriIe/water(I:2, 100 mL) to which 6 mL of 0.1 N aqueous HCI was added. The solution was frozen and lyophilized to afford compound 60 as an MCI salt. m/v. [M+H+] calcd for C^H^NiC^ 4S8.6; fo


After I h, the solution was concentrated, diluted with 15 mL Cl-^Ch and washed with 1.0 N aqueous sodium hydroxide. The aqueous was collected and washed again with CH2CI2 (10 mL) followed by a wash with ethyl acetate (10 mL). The organic layers were

combined and dried over MgSOj, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (gradient of 2-10% MeOH in CH2CI2) to afford an oil (2.1 g). A portion of this product (0.5 g, 1.26 mmol) was solubilized in 10 mL of 1:1 methanol:THF. Bromohydrin GG (Example 13, part d) (0.42 g, 1.20 mmol) and K2CO3 (0.44 g, 3.15 mmol) were added and the slurry was stirred at room temperature for 1.5 h. The reaction was concentrated and the residue was diluted with 30 mL water and extracted twice with 30 mL portions of toluene. The toluene extracts were combined, dried over Na3SO^, filtered, and concentrated. The residue was heated to 120°C. After 2 h, the reaction was cooled to room temperature and the crude compound was purified by silica gel chromatography (gradient of 5-10% MeOH in CH2CI2) to afford compound pp as a tan colored solid (0.7 g).

To a solution of 200 mg of compound T (0.28 mmol) in 4 mL of acetic acid was added 100 mg of 10% palladium on carbon. The reaction was shaken under an atmosphere of 40 psi H2. After 17 h, the reaction was filtered and the filtrate purified by reversed-phase HPLC (gradient of 10 lo 70% acetonitrile in 0.1% aqueous TFA). Fractions containing pure product were combined and lyophilized to afford compound 61 as a powder.
The intermediate compound T was prepared as follows:


To 1.13 g of compound D (2.2mmol, Example 52, part a) in 4 mL CH2CI2 was added 4 mL TFA. After 30 minutes, the solution was concentrated and diluted with 20 mL ethyl acetate and 20 mL water. The pH was raised to 11 by addition of 6.0 N aqueous sodium hydroxide and the layers were separated. The ethyl acetate layer was washed once with 1.0 N aqueous sodium hydroxide, dried over MgSO*r filtered, and concentrated to a brown oil. The oil was dissolved in 7.0 mL of isopropanol and 600 mg (2.0 mmol) of epoxide P (Example 15, part a) were added. The solution was heated to 70 °C. After 34 h, the solution was concentrated and the product partially purified by silica gel chromatography (gradient of 1 to 2% methanol in CHiC\2). Fractions containing product were combined and concentrated to afford T as a yellow oil.
Example 61B: Synthesis of A^-{2-[4-(3-phenyI-4-
methoxyphenyJ)aminopl]cnyl]e()iyl)-(^)-2-hydro.xy-2-(8-hydroxy-2(J/i)-quinolinon-5-yI)e(hylamine (60)
To a solution of//-{2-[4-(3-pheny]-4-methoxyphenyl)aminophenylJethy]}-(fi)-2-
hydroxy-2-(8-benzyloxy-2(IjVJ-quinolinon-5-yi)ethyIamine (PP) (4.0g, 6.5 mmol) in
tetrahydrofuran (100 mL) and water (16 mL) was added 10% palladium on carbon (800
mg). The reaction was stirred vigorously under one atmosphere of hydrogen for 6.5 h.
The solids were filtered off and washed wiih tetrahydrofuran (4x25 mL) and then 50%
metbanol/teirahydrofuran (2x25 mL). The combined filtrates were evaporated to dryness
and the crude product was purified by reverse-phase HPLC. Fractions containing pure
product were combined and lyophilized. The product from several runs was combined to .
give 4.68 g which was dissolved in acetonitrile (200 mL) and water (200 mL). 1.0 N HC1
(18.7 mL) was added, and the solution was lyophilized. The residue was again dissolved
in acetonitrile(]25mL)and warer (125 mL). 1.0 N HCI was added and the solution was
lyophilized to give a hydrochloride salt of compound 61 as an off white powder. H NMR


A slurry of aluminum chloride (85.7 g, 640 mmol) in 1,2-dichIoroethane (280 mL) was cooled in ice, and compound CC (56.8 g, 280 mmol) was added. The mixture was warmed to room temperature, and then heated at 85°C. After 30 minutes acetyl chloride (1.5 mL, 21 mmol) was added anil the mixture was heated an additional 60 minutes. The reaction mixture was then cooled and added to EN HC1 (3 L) at 0°C with good stirring. After stirring for 2 hours, the solids were collected on a Buchner funnel, washed with water (3x25DmL) and dried under reduced pressure. The crude product isolated from



(10.4 mL, 82.0 mmoJ) was added via syringe and the mixture was wanned to room temperature to give a thick suspension. The suspension was heated at 45°C (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dicbloromethane (100 mL) was added over 40 minutes. The mixture was kept 45dC for an additional 15 minutes and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4x 100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2x50 mL) and methanol (2x50 mL). The solid was dried under reduced pressure to give 5-(2-bromo-l-oxy)ethyl-8-benzyloxy-2(Itf)-quinolinone (R) (34.1 g) as an off"white powder.

Using a procedure described in Mathreet al., J. Org. Chem., 1991,56, 751-762, a catalyst was prepared as follows. (R)-(+)-ct, a -Diphenylprolinol (10.0 g, 39 mmol) and trimethylboroxine (3.7 mL, 26 mmol) were combined in toluene (200 mL) and stirred at room temperature for 30min. The mixture was placed in a 150"Coil bath and 150 mL liquid was distilled away. Toluene (50 rnL) was added, and another 50 mL of distillate was collected. Another portion of toluene (50 mL) was added and a further 50 mL of distillate was collected. A 1.00 mL aliquot of the material remaining in the pot was evaporated to dryness and weighed (241,5 mg) to determine that the concentration of catalyst was 0.87 M.
5-(2-Bromo-l-oxy)ethyl-8-benzyloxy-2(l//)-quinolinone(R) (30.0E, 81 mmol) was suspended in, tetrahydrofuran (;1.2 L) under a nitrogen atmosphere and the catalyst from above (13 mL, 11 mmol) was added. The suspension was cooled to -5°C in an ice/isopropanol bath and borane (1.0 M in THF, 97 mL, 91 mmol) was added over 3 h. The reaction was stirred an additional 45 min at -5°C, then methanol (200 mL) was added



2.5 mmol) was added, followed by trjs(dibenzylideneacetone)c!ipalladium{0) (760 mg, 0.83 mmol) and finally sodium tert-butoxide (5.3 g, 55 mmol). The mixture was heated at 90°C for 150 min and then cooled to room temperature. Water (150 mL) was added followed by ethyl acetate (150 mL) and the phases partitioned. The aqueous foyer was extracted with ethyl acetate (150 mL) and the combined organics washed three times with 0.5 M sodium bisulfate (200 mL), once with saturated sodium bicarbonate (150 mL) and twice with saturated sodium chloride (150 mL). The organics were dried over magnesium sulfate (50 g) and the volatiles removed under vacuum to give W-fer(-butoxycarbonyl-2-[4-(3-[phenyl-4-methoxypheQyI)aminophenyl]ethylamine (LL) (8.4 g) which was used without further purification.

Under nitrogen, compound LL (94.6 g) was treated will] dichloromethane (500 mL) and cooled in an ice bath. Hydrogen chloride (4 M in dioxane, 125 mL, 500mmol) was added in 10 portions over 20 min. The reaction was kept at room temperature for 130 minutes, during which time the product precipitated. The solid was filtered and washed with dichloromethane (350 mL) and dried under vacuum in the dark to give the dihydrochloride salt of 2-[4-(3-[phenyl-4-methoxyphenyl)aminophenyl]ethylamine (MM) (37.1 g). "H NMR (300MHZ, DMSO-dtf) 5 8.29 (br s, 2H), 8.04 (br s, 1H) 7.25-7.50 (m, 5H), 6.90-7.08 (m, 7H) 3.69 (s, 3H), 2.93 (m, 2H), 2.75 (m, 2H); tn/z: [M + H+] calcd for Ci,HHNzO 319.13; found 319.3.


hydrochloric acid {170 mL) was added in portions (exothermic). The solution turned orange and cloudy after the addition and more methanol (100 mL) was added until a clear solution was obtained. The mixture was stirred at room temperature overnight, in which

time a brown guru had formed. The solvent was removed under vacuum, and ethyl . acetate (300 mL) was added. The resulting mixture was cooled in an ice bath, and neutralized (pH 7) with 10 N sodium hydroxide. The pH was then raised to 10 with 1 M sodium hydroxide to give a clear biphasic mixture. The phases were separated and the aqueous layer was extracted with ethyl acetate (300 mL), The combined organic layers were dried over sodium sulfate, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (500 g, 0-10% methanol in dichloromethane)togiveA"-(2-[4-(3-pheny]-4-methoxyphenyI)aminophenyl]ethyl]-(^|)"2-hydroxy-2-(8-benzyloxy-2(l/i)-quinolinon-5-yl)ethyIamine (PP) (5.6 g).
Example 61C: Synthesis of N-{2-[4-(3-pheny]-4-
methoxyphenyl)aminophenyI]ethyl}-(i?)-2-hydroxy-2-(8-benzyloxy-2(lff)-quino!inon-5-yI)ethylamine (PP)
The intermediate compound PP was prepared as follows: a. Synthesis of 5-(2-bromo-(fl)-I-hydroxy)ethyI-8-benzyIoxy-2(l//)-quinoIinone (FF)
(R)-(+)-cc,a-Dipheny!proIinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 minutes. The mixlure was placed in a 150°C oil bath and liquid was distilled off. Toluene was added in 20 mL aliquols, nnc! distillation was continued for 4 hours. A total of 300 mL toluene was added. The mixture was finally cooled to room temperature. A 500 U.L aliquot was evaporated to dryness, weighed (246 mg) to determine that the concentration of catalyst was 1.8 M,
5-(2-Bromo-l-oxy)ethy]-8-benzyloxy-2(l/f)-quinolinone (R) (90.0 g, 243 mmol) was placed under nitrogen, letrahydrofuran (900 mL) was added followed by the catalyst from above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to -10±5°C in anice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 hours. The reaction was stirred an additional 45 minutes at -10°C, then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum. The residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under reduced pressure to give 5-(2-biomo-(tf)-]-hydroxy)ethyl-8-benzyloxy-2(l/7)-qumolinone (FF) (72.5g, 196 mmol, 81% yield, 95% ee, 95% pure by HPLC area ratio).


Compound HH (136.5 g, 279 mmo]), 4-bromophenethyIamine (123 g, 615 mmol)
and dimethyl sulfoxide (180 mL) were mixed at room temperature under nitrogen.
Another 40 mL of dimethyl sulfoxide was added. The mixture was heated to 85°C for
5 hours. The reaction was partitioned between ethyl acetate (1 L) and 10% aqueous acetic
acid (500 mL). The organies were washed with 10% aqueous acetic acid (3x500 mL),
then with 1N sodium hydroxide (3x500 mL). The last wash was filtered through Celite |
(100 g). The organic layer was concentrated to 300 mL and cyclohexane (2x500 mL) was added and the solution concentrated to 300 mL. Sufficient cydohexane was added to form 1.8 L final volume which was filtered through O.lite i"tf) d A cnhwinn nf Hri in

isopropanol, prepared by slowly adding concentrated HC1 (23.5 mL) to isopropanol (180 mL) at 10°C (internal), was added to the crude product and the reaction mixture was stirred for 5 hours, washed with cyclohexane (2x500 mL) and dried under reduced pressure for 24 hours to give Ar-[2-(4-bromophenyl)ethyl}-(fl)-2-rerr-butyIdimethylsiIoxy-2-(8-benzyIoxy-2(lJ^-quinolinon-5-yI)ethylanune (JJ) hydrochloride (145 g, 80 mo] %, 106 wt %, HPLC purity 97.9 %).
d. Synthesis of Ar-{2-[4-(3-phenyi-4-methoxyphenyl)arninophenyl]ethyl}-(/?)-2-fert-butyldimethy!silyl-2-(8-benzyloxy-2(lfO-quinoIinon-5-y])ethyIamine(NN)
To compound JJ hydrochloride (73.7 g, lI4mmoI) and 4-methoxy-3-
phenylaniline hydrochloride (32.4 g, 137 mmol), toluene (380 mL) was added with mild
agitation for 5 minutes, followed by sodium /ert-butoxide (49.3 g, 513 mmol) in portions
over 1 minute, and finally 2,2"-bis(diphenylphosphino)-l,l"-binaphthyl (10.65 g, 17 mmol)
and tris(dibenzylideneacetone)dipa]ladium(0) {5.22 g, 5,7 mmol). The resulting mixture
was stirred and heated to 85-89°C (internal) for 2.5 hours. The solution was cooled to
room temperature, water (400 mL) was added and the mixture was stirred for 5 minutes,
filtered through Celite (80 g), and partitioned with toluene (100 mL). The organic layer
was collected and concentrated tmder reduced pressure in a40"C bath to giveA"-{2-[4-(3-
phenyl-4-methoxypbenyl)aminoph("nyIlet!]yl]-(/?)-2-/^rf-butyldimethy!silyI-2-(8-
benzyloxy-2(lr/)-qmnolinon-5-yl)eihyIarnine (NN) as a dark viscous oil.
e. Synthesis of Ar-{2-[4-(3-phenyW-methoxyphenyl)aminophenyl]ethyI)-(/?)-2-hydroxy-2-(8-benzyloxy~2(lri)-quinolinon-5-y])ethyIainine(PP)
Compound NN from the previous step was dissolved in 280 ml of THF.
Triethylamine trihydrofluoride (27.6 g, 171 mmol) was added to the solution, an
additional 20 mL of THF was used to rinse down residual reagent, and the reaction was
stirred at 25"C under nitrogen for 16 hours. The reaction mixture was concentrated under
reduced pressure in a 25°C bath to give a dark viscous oil to which dichlorometiiane (400
mL) was added, followed by IN aqueous NaOH (200 mL). The reaction mixture was
stirred for 5 hours. The top layer was discarded and the organic layer was concentrated to
a viscous oil.
The oil was dissolved in dichloromethane to give a total volume of 630 mL. A
60 mL aliquot was taken and concentrated to 30 mL. Toluene (60 mL) was added,

followed by a mixture of concentrated hydrochloric acid (2.7 mL) and methanol (4.5 mL) to give a thick paste covered in a free-flowing liquid. The liquid was carefully removed and the paste washed with toluene,(50 mL). The gum was partitioned between dichloromethane (40 mL) and IN aqueous sodium hydroxide (40 mL) and the organic solvents were removed under reduced pressure. The residue was purified chromatographically over silica using a gradient of 0-10% methanol in dichloromethane to give N- {2-[4-(3-phenyi-4-methoxypbenyl)aminophenyl]ethyl} -(tf ^-hydroxy^-fS-benzyloxy^ClHJ-quinoIinon-S-yOethylamine (PP).



A solution of compound kk (2.88 g, 5.24 mmcl) in 20 mL CH2Cl2 was cooled (o 0 "C and 20 mL of TFA was added. After 20 min, the reaction was concenlraled and the residue dissolved in isopropyl acetate. The isopropyl acetate solution was washed twice with 1.0 N aqueous NaOH followed by water and then dried over MgSC>4, filtered and concentrated to an oil. The oil was dissolved in 2 mL DMF and intermediate AA (337 mg, 0.69 mmol), diethyl isopropyl amine (179 mg, 1.38 mmol) and potassium iodide (172 mg, 1.04 mmol) were added. The reaction was heated to 100°C. After 18 h, the reaction was cooled and added to vigorously stirred ice water. Compound mm


To a solution of 730 mg of compound rr(1.05 mmol) in 10 mL of glacial acetic acid was added 100 mg of 10% palladium on carbon. The reaction was stirred under an atmosphere of H2. After 65 h, the reaction was filtered and the filtrate purified by reversed-phase HPLC (gradient of 10 to 50% acetonitrile in 0.1 % aqueous TFA) to afford 90 mg (0.14 mmol) the TFA salt. The TFA salt product was solubilized in acetonitrile/water (1:2, 10 mL) to which 3 mL of 0.1 N aqueous HC1 was added. The solution was frozen and lyophilized to afford compound 63 as an HC1 salt, m/v [M+H*] calcd for Cs^HjgNjO^ 512.6; found 512.3.


To a solution of compound qq (2.0 6, 5.0 mraol) in 27 mL DMF were added
bromoketone R (from Example 56, part a) (1.71 g, 4.5 mmol) and K2C03 (1.91 g, 13,8
mmol). The reaction was heated to 50°C. After 1 h, the reaction was allowed to cool to
room temperature and the KSCOB was filtered off. The filtrate was diluted with CHjCh
(50 mL) and was washed with 0.1 N HC1 (30 mL). The organic layer was washed once I
with saturated sodium bicarbonate solution, followed by aqueous saturated sodium chloride, dried over Na^SCXj and concentrated under reduced pressure to afford an oil. The product (1.14 g, 1.65 mmol) was solubilized in 12 mLTHF/EtOH (1:1) and NaBRt

(380 mg, 10.0 mmol) was added. After 20 minutes of vigorous stirring. The reaction was quenched with saturated aqueous NHjCI which was added until effervescence of the reaction mixture ceased. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed twice with saturated sodium bicarbonate, followed by saturated sodium chloride, dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2% MeOH in CH2C]2) to yield 230 mg of intermediate rr.

To a mixture of 580 mg (0.93 mmol) of compound V in 25 mL of ethanol was added 173 mg of 10% palladium on carbon under a stream of nitrogen. The flask was fitted with a balloon of hydrogen gas, and the reaction was vigorously stirred for 4 days. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC using ;i gradient of 10 to 50% rtcetoriitrile in 0.1% aqueous TFA. Fractions containing pure product were combined and lyopliilized to afford a TFA salt of compound 64 as an off-white powder.
A sample of the TFA salt of compound 64 (150 mg) was dissolved in acetonitrile (2,0 mL) and water (2,0 mL). 0, IN HC1 (7.0 mL, 0.70 mmol) was added, and the resulting precipitate was redissolved by the addition of acetonitrile. The resulting solution was lyopliilized to give a solid which was again dissolved in acetonitrile {5.0 mL) and water (5.0 mL). 0, IN HC1 (7.0mL," 0.7 mmol) was added and the resulting solution was lyophilized to give a hydrochloride salt of compound 64 as an off white powder. "H NMR (300MHz, DMSO- The intermediate compound V was prepared as follows.


Compound W (55.2 mg, 0.094 mmol), phenyl boronic acid (13.2 mg, 0.113 mmol) and [l,]"-bis(dipheny]pho.sphinoferrocenc)dich]oropal]adium (II), complex with dichloromeihajie (PdCMdppO-DCM) {5.0 mg, 0.006 mmol) were combined in a small pressure tube and purged with N2. 1,2-Dimethoxyethane (1.0 mL) and 2.0 N cesium carbonate (150 \iL, 0.3 mmol) were added. The tube was sealed, and then p/aced in an oil


Compound HH (Example 61B, part f) (9.1g, 18.62mmoi), 4-aminophenethyIamine {9.8 mL, 74.8 mmol) and sodium iodide (4.2 g, 27.93 mmol) were placed in a flask and purged with nitrogen. Methyl sulfoxide {25 mL) was added, and (he solution was placed in an oil bath heated at 140°C. The solution was the stirred for 20 min at 140DC. The reaction was allowed to cool to room temperature, then ethyl acetate (300 mL) and II20 (300 mL) were added. The phases were partitioned, and the organic layer was washed with water (4 x 200mL) and saturated sodium chloride (4 x 200mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to yield compound U (10.5g).



Examples 66-69: Synthesis of Compounds 66-69
Using procedures similar to that described in Example 65, except replacing the phenylboronic acid with the appropriate substituted phenylboronic acid, TFA salts of " compounds 66-69 were prepared.
Compound 66: Af-{2-[4-(3-(2-chloropheny[)phenyl)aminophenyl]ethyl}-(/i)-2-hydroxy-2-(8-hydroxy-20//)-quinoIinon-5-yl)ethylamine (Formula (X) where R1" is 2-chlorophenyI): "H NMR (300MHZ, DMSO-t/6) 5 10.47 (s, 1H), 10.37 (s, IH), 8.55, (br s, 2H), 8.22, (s, IH), 8.06 (d, 1H)7,46 (m, IH), 7.32 (m, 3H), 7.22 (t, IH), 7.01 (m, 8H), 6.89 (d, IH), 6.74 (dd, IH), 6.51 (d, IH), 6.10 (d, IH), 3.18 (m,4H), 2.80 (m, 2H); m/z: p^+H4] calcd for C3|H2BC1N303 526.19; found 526.4.
Compound 67: Af-J2-[4-(3-(2-methoxyphenyl)phenyI)aminophenyl]ethyl)-(ff)-2-hydroxy-2-(8-hydroxy-2{l//)-qLiinolinon-5-yl)ethyIamJne (Formula (X) where RM is 2-methoxyphenyl): !H NMR (300MHz, DMSO-d6) 5 10.46 (s, IH), 10.40 (s, IH), 8.60 (brs, 2H), 8.12 (s,lH), 8.06 (d,lH), 7.16 (m, 13H), 6.80 (d, JH), 6.51 (d, IH) 6.11 (s. IH) 5.24 (d, IH), 3.69 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); i^v [M+H*] calcd for C3iH31N3Od 522.24; found 522.7.
Compound 68: Formula (X) where R11 is 4-hydroxymethyIphenyl: "H NMR (300MHz, DMSO-(5) 5 10.47 (s, IH). 10.39 (s, JH), 8.60 (brs, 2H), 8.18 (s, IH), 8.07 (d, IH), 7.46 (d, 2H), 7.30 (d, 2H), 7.20 (m, 2H), 7.00 (m, 8H). 6.51 (dd, IH), 6.1! (s, IH), 5.23 (d, IH), 4.44 (s, 2H), 3.10 (m. 4H), 2.80 (m, 2H); m/z: [M+H+] calcd for C32H3,N30,, 522.24; found 522.4.
Compound 69: Formula (X) where R1" is 4-methoxyphenyI: "H NMR (300MHz, DMSO-d6) 5 10.47 (s, IH), 10.39 (s, IH) 8.60 (brs, 2H), 8.16 (s, IH), 8.07 (d, 1H),7.44 (d, 2H), 6.85-7.20 (m. 12H), 6.51 (dd, IH), 6.12 (d, IH), 5.23 (d, IH), 3.70 (s, 3H), 3.10 (m, 4H). 2.80 (m, 2H); m/z: [M+H+] calcd for C32H31N304 522.24; found 522.4.
Example 70: Synthesis of compound 70
Compound 70: Formula (X) where R11 is 4-chlorophenyl Compound W {84.0 mg. 0.143 mmol), 4-chlorophenyl boronic acid (27.2 mg, 0.172 mmol) and [IJ^bisfdiphenylphospliinoferroceneJdichloropalladiiun (H), complex with dichloromethane (PdCl2(dppf)-DCM) (5.9 mg, 0.007 mmol) were combined in a small pressure tube and purged with Nj. 1,2-Dimcthoxyethnne (2.0 mL) and 2.0 N

; cesium carbonate (150 uL, 0.3 mmol) were added. The tube was sealed, and then placed 1 in an oil bath at 90°C for 4 hours. The solution was then cooled to room temperature and DCM (10 mL) was added. The solution was filtered and concentrated to dryness. To the residue there was added DMF (1.0 mL) and 10% palladium on carbon (10 nig), and the reaction was stirred under one atmosphere of hydrogen for 4 hours. At this time, watenacetonitrile 1:1 and 200 uL TFA was added and the solution was filtered to remove the catalyst. The filtrate was purified by reverse phase HPLC. Fractions containing pure product were combined and lyophilized to give compound 70 as a TFA salt. "H NMR (300MHz, DMSO-dS) 5 10.46 (s, 1H), 10.40 (s, 1H), 8.61 (br s, 2H), 8.22 (s, IH), 8.07 (d, IH), 7.53 (d, 2H), 7.42 (d, 2H), 7.23 (t, 1H), 7.14 (s, 1H), 6.85-7.10 (m, 8H), 6.51 (d, IH), 6.12 (s, 1H), 5.24 (d, JH), 3.10 (m, 4H), 2.80 (m, 2H); m/r. [M+H4] calcd for C3iH!aClN303 526.19; found 526.4.
Examples 71-72: Synthesis of compounds 71-72
Using procedures similar to that described in Example 70, except replacing the 4-chlorophenyiboronic acid with the appropriate substituted boronic acid, TFA salts of compounds 71-72 were prepared.
Compound7J: Formula(X) where RM is 5-indolyl: "lINMR (300MHz, DMSO-d6) 5 11.07 (s, IH), 10.47(5, IH), 10.40 (s, IH), 3.60 (br s, 211), 8.15 (s, IH), 8.11 (d, IH), 7.65 (s, IH), 7.15-7.40 (m, 511). 7.00-7.15 (ra, 5H), 6.89 (d, 2M), 6.51 (dd, IH), 6.39 (s, IH), 6.11 (s, IH), 5.24 (d, IH), 3.10 (m, 4H), 2.80 (m, 2H); m/c [M+H*] calcd for C33H30N4O3 531.24; found 531.4.
Compound 72: Formula (X) wliere R11 is 4-pyridyI: "H NMR (300MHz. DMSO-d6) 5 10 48 (s, IH) 10.38 (s, IH), 8.60 (brm, 4H), 8.32 (s, IH), 8.07 (d, IH), 7.69 (d, 2H), 7.31 (m, 2H), 7.16 (d, IH) 7,05 (m, 6H), 6.90 (d, IH), 6.52 (dd, IH), 6.11 (s, IH), 5.24 (d, IH), 3.10 (m, 411), 2.80 (m, 211); m/r [M+M+] calcd for C30H21N4O] 493.23; found 493.5.
Example 73: Synthesis of compound 73 I
Compound 73: Formula (X) where RM is hydrogen: A TFA salt of compound 73 was prepared: "H NMR (300MHz, DMSCwtf) 5 10.48 (s, IH), 10.39 (s, 111), 8.59 (brs, 211), S.07 (dd, 2H), 6.85-7.17 (m, 10H), 6.72 (t, III), 6.52 (dd, IH), 6.11 (d, IH), 5.22 (d,

IH), 3.10 (m, 4H), 2.80 (m, 2H); m/z: rM+H4] calcd for C25H25N3O3 416.20; found 416.3.
Example 74: Synthesis of N~{2-[4-(3-(3-
cyanophenyOphenyOaminophenylJetliyO-W^-hydroxy-^CS-hydroxy-Stl/O-quinolinon-5-yl)ethylamine (74)
Compound 74: Formula (X) where R11 is 3-cyanophenyl
Compound W (Example 65, part b) (58.1 mg, 0.100 mmol), 3-cyanophenyl
boronic acid (17.6 mg, 0.120 mmol) and [ 1,1"-
bis(diphenylphosphinoferrocene)dichloropalladium (II), complex with dichloromethane
(PdCl2(dppf)-DCM) (approximately 6 mg, 0.007 mmol) were combined in a small
pressure tube and purged with N2. 1,2-Dimethoxyethane (2.0 mL) and 2.0 N cesium
carbonate (200 uL, 0.4 mmol) were added, the tube was sealed, and then placed in an oil
bath at 90°C for 5 hours. The solution was then cooled to room temperature and DCM
(10 mL) was added. The solution was dried (Na2SO^) for 30 minutes, then filtered,
concentrated and dried under vacuum. The residue was dissolved in DCM (2mL) and
cooled to 0°C, then boron trichloride (1.0N in DCM, l.OmL, l.Ommol) was added. After
10 minutes the reaction was quenched with methanol (lOmL), and concentrated under
reduced pressure. The residue was purified by reverse phase HPLC. Fractions
containing pure product were combined and Jyophihzed to give compound 74 as a TFA
salt. "HNMR (300MHZ, DMSO-d6)8 10.45 (s, 1H), 10.40 (s, 1H), 8.70 (br 2, 2H), 8.34
(m, 1H), 8.09 (d, 1M), 7.97 (s. 1H), 7.85 (dt, 1H), 7.74 (dt, 1H), 7.58 (t, IH), 7.20-7.30
(m, 2H), 6.95-7.10 (m, 7H), 6.90 (d, IH), 6.50 (d, IH), 6.12 (s, IH), 5.25 (d, IH), 3.10
(m, 4H), 2.80 (m, 2H); m/v [M+H*] calcd for C32H2aN403 517,23; found 517.4.
Examples 75-93: Synthesis of compounds 75-93
Using procedures similar to that described in Example 74, except replacing the 3-cyanophenyl boronic acid with the appropriate substituted boronic acid, TFA salts of compounds 75-93 were prepared.
Compound 75: Formula (X) where R" is trans-2-phenylvinyl: m/z: [M+H+] calcd for CSSHJINJOS 518.25; found 518.3.
Compound 76: A"-(2-[4-[3-(3-pyridyl)pheny!)aminophenyI]ethy])-{^)-2-hydroxy-2-(8-hydroxy-2(I^)-quinolinon-5-y0ethy[amine (Formula (X) where R" is 3-pyridyI):

"H NMR (300MHz, DMSO-d6) 5 10.38 (br s, 2H), 8.84 (s, 2H), 8.67 (s, IH), 8.58 (d, IH), 8.25 (s, 1H), 8.14 (d, IH), 8.1 i (d, IH), 7.59 (dd, 1H), 7.27 (m, 2H), 7.05 (m, 7H), 6.90 (d, IH), 6.50 (d, IH), 5.28 (d, IH), 3.10 (m, 4H), 2.83 (m, 2H). m/z: [M+H+] calcd for C30H2BN4O3 493.23; found 493.5.
Compound 77: Formula (X) where R" is 4-cyanophenyI: "H NMR (300MHz, DMSO-rf Compound 78: Formula (X) where R11 is 3,5-dimelhylisoxazole-4-yl: m/z: [M+H+] calcd for C30H30N4O4 511.24; found 511.5.
Compound 79: Formula (X) where R11 is 2-furanyl: "H NMR (300MHz, DMSO-d6) 5 11.15 (s, IH), 10,47 (s, IH), 10.41 (s, IH), 8.64 (br s, IH), 8.10 (t, 2H), 7.08 (m, 9H),6.77(s, 1H),6.74(S, IH), 6.52 (d, IH), 6.30 (s, lH),6.12(s, IH), 6.02 (q, 1H),5.25 (d, IH), 3.10 (m, 4H), 2.85 (m, 2H). m/z [M+H+] calcd for C29H27N3O4 482.21; found 481.4.
Compound 80: Formula (X) where R11 is lhiophene-2-yl: "H NMR (300MHz. DMSO-d6) 5 10.47 (s, IH), 10.38 (s, III), 8.62 (brs, 211), 8.22 (s, IH), 8.07 (d, IH), 7.44 (d, IH), 7.U3 (d, IH), 7.35 (in, 2H), 7.06 (m, 7H), 6.90 (d, 2H), 6.50 (d, IH), 6.10 (d, IH), 5.23 (m, IH), 3,10 (m, 4H), 2.S5 (m, 211). m/z [M+H+] calcd for C^^NAS 498.19; found 498.5.
Compound 81: Formula (X) where R11 is 3-nitrophenyl: m/z: [M+H+] calcd for C3|H2aN405 537.22; found 537.3.
Compound 82: Formula (X) where RM is 4-formyIphenyl: m/z: [M+H*] calcd for C32H19N3O4 520.23; found 520.5.
Compound 83: Formula (X) where R11 is 2-pyrrolyl: Using a procedure similar lo
that described in Example 74, except replacing [lie 3-cyanophenylboronic acid with 1-
(ter/-butoxycarbony0pyrro]c-2-boronic acid, a TFA salt of compound 83 was prepared.
Deprotectton of the Boc group occurred under reaction conditions, "ll NMR (300MJ lz, I
DMSO-dS) 6 11.13 (s, IH), 10.46 (s, IH), 10.37 (s. IH), 8.58 (brs, 2H), 8.08 (s, IH), 8.05 (£, IH). 7.05 (m,9H). 6.75 (s. IH), 6.73 (s. IH). 6.51 (d, IH). 6.23 (s. IH). 6.08 (s,

1H). 6.01 (s, 1H), 5.22 (m, 1H), 3,12 (m, 4H), 2.80 (m, 2H). m/j: [M+H4] calcd for C29H2gN403 481.23; found 481.3,
Compound 84: Formula (X) where Rn is 4-carboxyphenyl: m/z: [M+H4] calcd for Q2H29N3O5 536.22; found 536.3.
Compound 85: Formula (X) where R1" is 4-methyIsulfonylpbenyI: "H NMR (300MHz, DMSO-dS) 5 10.45 (s, 1H), 10.38 (s, 1H), 8.58 (br s, 1H), 8.27 (s, 1H), 8.05 (d, 1H), 7.90 (d, 2H), 7.77 (d. 2H), 7.26 (m, 2H), 7.04 (m, 7H), 6.88 (d, 1H), 6.50 (d, 1H), 6.11 (s, 1H), 5.22 (d, 1H), 3.16 (s, 3H), 3.11 (m, 4H), 2.80 (m, 2H) . m/z: [M+H4] calcd for C32H3,N30jS 570.21; found 570.3.
Compound 86: Formula (X) where R1" is 4-hydroxyphenyl: Using a procedure similar to that described in Example 74, except replacing the 3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA salt of compound 86 was prepared. "H NMR (300MHz, DMSO-dS) 8 10.46 (s, 1H), 10.40 (s, 1H), 9.47 (s, 111), 8.71 (brs, 2H), 8.12 . (m, 2H), 7.32 (d, 2H), 7.02 (m, 9H), 6.75 (d, 2H), 6.51 (d."lH), 6.10 (s, 1H), 5.25 (d, 1H), 3.10(m,4H),2.80(mt2H). m/z: [M+H+] calcd for C31H29N3O4 508.23; found508.3. Compound 87: N-(2-[4-(3-(4-aminomethylphenyl)phenyl)aininophenyl]ethyi}-(/f)-2-hydroxy-2-(8-hydroxy-2(l//)-quinoIinon-5-yl)ethylamine (Formula (X) where R11 is 4-(aminomethyI)phenyl): m/z: [M+Ii*"] calcd for C^l-^N^Oj 521.26; found 521.3.
Compound 88: Formula (X) where R1" is 4-etho;>:ypheny[: m/z: [M+H4] cftlud fur C33H33N304 536.26; found 536.3.
Compound 89: Formula (X) where R1" is thiophene-3-yl: m/z: [M+H4] calcd for C29H27Na03S 498.19; found 498.3.
Compound 90: Formula (X) where R" is 2-indolyl: m/z: [M+H*] calcd for C33H30N4OJ531.24; found531.3.
Compound 91: //-(2-[4-(3-{3-chIorophenyI)phenyi)aminophenyl]ethyl)-(^)-2-hydroxy-2-(8-hydroxy-2(l//)-quinolinon-5-y])elhyIamine (Formula (X) where RM is 3-chlorophenyI): "H NMR (300MHz, DMSO-dfi) 5 10.45 (s, 1H), 10.38 (s, 1H), 8.58 (brs,2H),8.20(s, lH),8.06(d. 1H). 7.21 (m. 14H), 6.51 (d, lH),6.10(s, lH),5.23(d, ]H),3.10(m,4H),2.80(m,2H"). I [M+H] calcd forC3iH2gClN30;, 526.03; found 526.3.
Compound 92: Formula (X) where R11 is 3-methoxyphenyl: m/z: [M+H] calcd for CMHJJNJOI 522.24; found 522.0.


Example 94: Synthesis of A"-{2-[4-(3-(3-pyridyI)-4-methoxyphenyl)aminophenyl]ethyI)-(fi)-2-hydroxy-2-(8-hydroxy-2(l/0-(luinolmon-5-yl)ethylamine (94)
Compound 94: Formula (XI) where R1" is 3-pyridy!
a. Synthesis of 4-iodophenethyIamine
4-Iodoprieny/acetcnitrite (4.80 g, f 9.7 mmol) was dissolved in tetrahydrofuntn (25
mL) under nitrogen, and 1.0 M boranc in tetrahydrofuran (29.6 mL, 29.6 mmol) was
added via syringe. The reaction was heated at reflux for I hour, then cooled in ice and the
excess borane was quenched by the addition of methanol (100 mL). When hydrogen
evolution ceased, the solvents were removed under reduced pressure. The residue was
dissolved in tetrahydrofuran (25 mL) and 4N HCI in dioxane (6.0 mL, 24 mmol) was ■
added, followed by ether (75 mL). The hydrochloride salt of 4-iodophenethy!amine was
collected on a Buchner funnel, washed with ether (2x50 mL) and dried under reduced
pressure. To generate the free base, the solid was partitioned between dichloromethane
(200 mL) and IN NaOH (100 mL). The aqueous layer was extracted with
dichloromethane (2x100 mL). The combined organic layers were dried (Na2S04) and
concentrated lo give 4-iodophenethylamine (4.52 g) as a colorless oil.


To a solution of 4-iodophenethyIamine (4.5 g, 22 mmol) in methyl sulfoxide (13 mL) under nitrogen was added compound HH (from Example 6TB part f) (7.3 g, 15 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodium iodide (3.3 g, 22 mmol). The mixture was heated at 140°C in an oil bath for 25 minutes. After cooling to room temperature, water (100 mL) was added and the resulting mixture was extracted with ethyl acetate (2x150 mL). The combined extracts were washed with IN HCI (2x50 mL), water (50 mL) 10% sodium thiosulfate (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), The solution was dried (Na2S04) and concentrated. The crude product was purified in two lots by flash chromatography on silica gel (75 g) eluting with 0-5% methanol in dichloromethane containing 0.5% triethylamine. Compound QQ (6.1 g) was isolated as a dark yellow oil.
c. Synlhesis of 4-aminu-2-bromoani;;ole
To a mixture of 2-bromo-4-nilroanisoIe (5.0 g, 21.5 mmol, Lancaster), ethanol (25 mL) and water (25 mL), was added powdered iron (4.8 g, 86 mmol) and 12 N HCI (0.5 mL). The solution was heated at reflux for 20 minutes. lNNaOH(lOmL) was added and the reaction mixture was filtered through a pad of celite while still hot, and then rinsed with ethanol (2x50 mL). The ethanol was removed under reduced pressure and the residue extracted with dichloromethane (2x100 mL). The organic extracts were dried (Na2SOd) and concentrated. The crude product was purified by flash chromatography on silica gel (75 g) eluting with dichloromethane, to give 4-amino-2-bromoanisole as a light tan solid.


(73 mg, 0.12 mmol), [1,1 -bis(diphenylphosphJno)-ferrocene]dichloropaI]adLiim(II) dichloromelhane complex (10 mg) and 3-pyridylboronic acid (18 mg, 0.14 mmol). Dimelhoxyelbane (2.5 mL) wa.s added, followed by 2.0 N cesium carbonate (0.20 mL,

f 0.40 mmol). The mixture was heated at 90°C for 4 hours. The solution was then cooled
to room temperature and DCM (20 mL) was added. The solution was dried (NajSQj) for
30 minutes, then filtered, concentrated and dried under vacuum. The residue was
dissolved in DCM (2 mL) and cooled to 0°C, and then boron trichloride (1.0N in DCM,
1.0 mL, 1.0 mmol) was added. After 10 minutes the reaction was quenched with
methanol (10 mL), and concentrated under reduced pressure. The residue was purified by
reverse phase HPLC. Fractions containing pure product were combined and lyophilized
to give a TFA salt of A"-{2-[4-(3-(3-pyridylH-methoxyphenyl)aminophenyI]ethyl) -(tf)-2-
hydroxy-2-(8-hydroxy-2(I//)-quinolinon-5-yl)etliyIamine (94). "H NMR (300MHZ,
DMSCW6) 5 10.; m/z: [M+H*] calcd for C3|HMN,A 523.24; found 523.3.
A sample of the TFA salt (25 mg) was dissolved in acetonitrile (0.5 mL) and water
(0.5 mL), followed by IN HCI (0.10 mL, 0.10 mmol). The solution was lyophylized to a
powder which was redissolvcd in acetonitrile (0,5 mL) and water (0.5 mL). IN HCI was
then added (O.lOmL, O.lOmmol). Lyophylization gave a hydrochloride salt of compound
94 as an off white powder.. "H NMR (300MHz, DMSO-c/ lH),8.97(d. 1H), 8.78 (d.lH), 8.77 (brs, 1H), 8.61 (dt, 1H), 8.20 (d, 1H), 8.01 (dd, 1H),
6.90-7.15 (m. 8H), 6.47 (d, tfl),5.39 (d, 1H). 3.70 (s, 3H), 3.02 (m, 4H), 2.82 (m, 2H);
m/z: [M+H+]caicd for C31H30N4O4 523.24; found 523.6.
Example 95: Synthesis of A"-{2-[4-(3-(3-cynnophenyl)-4-tnethoxypl]en}"])nminophenyl]ethyO-(A)-2-l]ydroxy-2-(8-hytlroxy>2(If7)-quinonnon-5-yl)etliylamme (95)
Compound 95: Formula (XI) where R"" is 3-cyanophenyl.
Into a nitrogen purged lest tube with a screw cap was placed compound RR (from Example 94, part d) (100 mg, 0.163 mmol), [l,r-bis(dipbenylphosphino)-feirocene]dichloropalladium(Ii) dichloromethanc complex (10 mg) and 3-cyanophenylboronic acid (35 mg, 0.20 mmol). Dimethoxyethane (3 mL) was added, followed by 2.0 N cesium carbonate (0.30 mL, 0.60 mmol). The mixture was heated at 90nC for 4 hours. The solution was then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried (Na2SCXt), concentrated and dried under reduced pressure. The residue was dissolved in DCM (5 mL) and cooled to 0 °C, and then boron trichloride (1.0 N in DCM, 2.0mL, 2.0 mmol) was added. After 10
minutes the reaction was quenched with methanol (20 mL), and concentrated under
1

, reduced pressure. The residue was purified by reverse phase HPLC. Fractions
containing pure product were combined and iyophiJized to give a TFA salt of compound 95. "H NMR (300MHZ, DMSO-ttf) 5 10.47 (s, IH), 10.38 (s, 1H), 8.57 (br s, 2H) 8.05
1 (d, IH), 7.89 (m, IH), 7.82 (m, IH), 7.70 (m, 2H), 7.53 (t, 2H), 7.07 (d, IH), 6.95-7.00 (m, 4H), 6.85-6.92 (m, 3H), 6.50 (dd, IH), 6.09 (d, IH), 5.22 (d, IH), 3.65 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H+] calcd for CJJHSIMO* 547.24; found 547.5.
Examples 96-102: Synthesis of Compounds 96-102
Using procedures similar to that described in Example 95, except replacing the 3-cyanophenylboronic acid with the appropriate substituted phenylboronic acid, TFA salts of compounds 96-102 were prepared.
Compound 96: yv"-(2-[4-(3-C4-aminomethylphenyl)-4-methoxyphenyI)aminophenyl]elhyl)-C^)-2-hydroxy-2-(8-hydroxy-2fl//)-quinolinon-5-yl)ethylamine (Formula (XI) where R11 is 4-(aminomethyI)pbenyl): ]H NMR (300MHz, DMSO-dS) 8 10.47 (s, IH), 10.40 (s, IH), 8.58 (br s, 2H), 8.07 (m, 4H), 7.87 (s, IH), 7.40 (dd, 4H), 7.07 (d, IH), 6.84-7.05 (m, 8H), 6.50 (dd. IH), 6.11 (d, IH), 5.23 (d, IH), 3.98 (m, 2H), 3.62 (s, 3H), 3.05 (m, 2H), 2.95 (m, 2H), 2.75 (m, 2H); m/z: [M+H+] calcd for C33H34NA 551.27; found 551.5.
Compound 97 A/-{2-[4-(3-(4-pyridy!)-4-mefhoxyphenyI)ammophenyl]efhyl ]-(/?)-2-hydroxy-2-(8-bydroxy-2(l//)-quinoIinon-5-yl)ethylamine (Formula (XI) where R1" is 4-pyridyl): "HNMR (300MHZ, DMSO-cW) 5 10.46 (s, IH), 10.42 (s, IH), 8.65 (d, 2H), 8.62 (br s, IH), 8.06 (d, 2H). 7.97 (br s, IH), 7.73 (d, 2H) 6.95-7.10 (m, 7H), 6.90 (dd, 2H), 6.12 (br s, IH), 5.23 (d, 111), 3.69 (s, 3H), 3.10 (m, 4H), 2.80 (m, 211); m/z: [M+it] calcd for C31H30N4O4 523.24; found 523.6.
Compound 98: Formula (XI) where R1" is 4-formyIphenyI: "H NMR (300MHz,
DMSO-rftf) 5 10.46 (s, IH), 10.39 (s, IH), 9.95 (s, IH), 8.57 (br s, 2H), 8.05 (d, IH), 7.91
(brs, IH), 7.85 (d, 2H), 7.61 (d, 2H), 6.95-7.10 (m, 7H), 6.89 (dd. 2H), 6.50 (dd, IH).
6.10 (s, IH), 5.22 (d, IH), 3.65 (s, 3H), 3.05 (m. 4H), 2.75 (m, 2H) ; m/z: [M+H+] calcd
for C3jH3iN30s 550.24; found 550.6. I
Compound 99: Formula (XI) where R11 is 4-methylsuIfonyl: "H NMR (300MHz, DMSO-d6) o 10.46 (s. IH), 10.38 (s, IH), 8.55 (brs, 2H), 8.05 (d, IH), 7.91 (s. HI), 7.86 (d, 2H), 6.74 (d, 2M), 6.93-7.10 (m, 6H). 6.85-6.92 (m. 3H), 6.51 (dd, IH), 6.09 (d, IH),

5.22 (d, IH), 3.65 (s, 3H), 3.17 (s, 3H), 3.05 (m, 4H), 2.75 (m, 2H); m/Z: [M+H*] caJcd for CssHasNsOsS 600.22; found 600.5.
Compound 100: A^{2-[4-(3-(4-hydroxypheny])-4-methoxyphenyI)aminophenyl]ethyIJ-(^)-2-hydroxy-2-(8-hydroxy-2Clfl)-quinoIinon-5-yl)ethylamine (Formula (XI) where R1" is 4-hydroxyphenyl): Using a procedure similar to that described in Example 95, except replacing die 3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA salt of compound 100 was prepared. "H NMR (300MHz, DMSO-J6) 8 10.46 (s, 1H), 10.38 (s, 1H), 9.34 (s, IH), 8.57 (brs, 2H), 8.06 (d, 1H), 7.80 (s, 1H), 7.18 (d, 2H), 7.07 (d, IH), 6.97 (d, 2H), 6.80-6.90 (m, 6H), 6.69 (d, 2H), 6.51 (dd, 1H), 6.09 (s, 1H), 5.23 (d, IH), 3.60 (s, 3H), 3.05 (m, 4H), 2.78 (m, 2H); m/z: [M+H] calcd for C32H3iN305 538.24; found 538.5.
Compound 101: Af-{2-[4-(3-(thiophen-3-yI)-4-metboxypbenyl)amjnophenyI]ethyl} -(#)-2-bydroxy-2-(8-hydroxy~2( l/f)-quinolinon-5-yl)ethylamine (Formula (XI) where Rn is thiophen-3-yl): "H NMR (300MHz, DMSO-d6) 5 10.47 (s, 1H), 10.38 (s, 1H), 8.57 (br s, 2H), 8.06 (df 1H), 7.83 (s."lH), 6.74 (dd, 1H), 7.48 (dd, 1H), 7.31 (dd, IH), 7.13 (s, 1H), 7.06 (d, IH), 6,80-7.00 (m, 7H), 6.51 (dd, 1H), 6.01 (s, IH), 5.23 (d, IH), 3.70 (s, 3H), 3.07 (m, 4H), 2.77 (m, 2H); m/z: [M+H*] calcd for C30H29N3O4S 528.20; found 528.3.
Compound 102: Af-(2-[4-(3-(3"Chlorophenyl)-4-methoxypheny!)ammoplieny!]ethyl|-(y?)-2-hydroxy-2-(8-hydroxy-2(l//)-qLiinolinon-5-yl)ethylamine {Formula (XI) where R11 is 3-chlorophenyl): "H NMR (300MHz, DMSO-d6) 5 10.46 (s, IH), 10.38 (s, IH), 8,76 (br s, IH), 8.62 (br s, IH), 8,10 (s, IH), 7.88 (br s, IH), 7.15-7.23 (m, 5H), 6.85-7.10 (m, 1 IH), 6.50 (d, IH), 6.09 (br s, IH), 5.27 (d, IH), 3.65 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H"] calcd for C32H30ClN3O4 556.20; found 556.2.
Example 103: Synthesis of Ar-{2-[4-(3-(3-cyanophenyl)- mc(hoxyplicnyI)aminophenyI]ethyl]-(tf)-2-hydroxy-2-(8-hydroxy-2(U7)-qiiinolinon-5*yl)ethyIaminc (95)
Using procedures similar to those described in Example 61C and the deprotection step of Example 61B, except replacing the 4-meilioxy-3-phenylaniIinc hydrochloride with 3-(3-cyanophenyl)-4-metboxyaniline in Example 61C, part d, compound 95 was prepared.
The intermediate compound 3-(3-cyanophenyl)-4-mcthoxyaniline was prepared as follows:

a. Synthesis of 2-C3-cyanopheoylH-nitroanisote
[l,l"Bis(diphenylphosphino)ferrocenc]dicWoropaIIadium(]I), complex with dichloromethane(I;l)(1.43 g) was added to a stirred mixture of 3-cyanophenylboronic acid (10.0 g, 61.8 mmol) and 2-bromo-4-nitroanisoIe (14-.35 g, 62 mmol) in 2.0N cesium carbonate (92.7 mL, 185.4 mmol) and ethylene glycol dimethylether (200 mL). The flask was purged with nitrogen and heated at 90aC (oil bath) for 4 hours. The mixture was allowed lo cool to room temperature overnight, during which time the product precipitated from solution. The solid was collected on a Buchner funnel, washed with water and dried under reduced pressure to give 2-(3-cyanophenyl)-4-nitroanisoIe {15.7 g).
b. Synthesis of 3-(3-cyanophenyl)-4-niethoxyaniline
Zinc dust (20.26g, 3 lOmmol) was added in portions over five minutes to a solution of 2-(3-cyanopbenyl)-4-nitroanisole (15.7 g, 62 mmol) and ammonium formate (19.48 g, 310 mmol) in methanol (500 mL) and tetiahydofuran (500 mL). The reaction was complete after stirring for one hour at room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatoghraphy on silica gel eluting with 5% methanol in dichloromethane to give 3-(3-cyanophenyi)-4-methoxyantline (10 g, 44 mmol) as a yellow oil,
Example 104: Synthesis „f A"-{2-[4-(3-(4-iiminomethylphenyl)-"l-methoxyphcnyI)aminophenyl]e(liy])-(^)-2-liydroxy-2-(8-liy(lroxy-2(l//)-quinolinon-5-yl)ethylamine (96)
Using procedures similar to those descrihed in Example 61C and tire deprotection step of Example 6 IB, except replacing the 4-methoxy-3-pbenylaniiine hydrochloride with 3-(4-aminomethylphenyl)-4-methoxyaniline in Example 6IC, part d, compound 96 was prepared.
The intermediate compound 3~(4-aminomelliylphenyI)-4-methoxynniIine was prepared as follows:
a. Synthesis of 2-(4-aminomethyiphenyl)-4-nitronnisoie
A mixture of 2-bromo-4-nitroaniso!e (5.80 g, 25.0 mmol) and 4-(aminomethyl)phenylboronic acid hydrochloride (4-96 g, 26.6 minol) was slurried in 1-propanol (50 mL) under nitrogen. Triphenylphosphine (315 mg, 1.20 mmol) and palladium (11) acetaic (90 mg, 0.40 mmol) were added, followed by 2.0N sodium

carabonate(33mL, 66mmoi). The mixture was heated at 95°C (oil bath) under nitrogen

for 3 hours, at which time the reaction was judged to be complete by TLC. Water (25 mL) was added and the mixture was stirred open to air for 2 hours at room temperature. The mixture was extracted with ethyl acetate (100 mL, 2x50 mL) and the combined extracts were washed with sodium bicarbonate (25 mL) and brine (25 mL). The solution was dried with sodium sulfate, and concentrated to an oil which was purified by flash chromatography on silica gei (100 g) eluting with 0-4% methanol/0,5% triethylamirte/dichloromethane. Pure fractions were combined and concentrated to give 2-(4-aminometliyIphenyl>4-nitroanisole (4.6 g) as a yellow solid.
b. Synthesis of 3-(4-aminometbylphenyl)-4-methoxyani]ine
A solution of 2-(4-amino methyl phenyl)-4-nitroanisole (4.50g) in methanol (200 mL) was treated with 10% palladium on carbon (200mg). The reaction mixture was stirred under one atmosphere of hydrogen for 2,5 hours. The reaction mixture filtered through Celite, and the filter cake was washed with methanol (3x25mL). The filtrate was concentrated to dryness and Ihe residue was purified by flash chromatography on silica gel (80 g) eluting with 0-6% methanol/0.5% triethylnmine/dichlorometbane. Pure fractions were combined and concentrated to give 3-(4-aminomethylphenyl)-4-methoxyaniline as an off while powder.
Example 105: Synthesis of /V-(2-[4-(3-(3-cliIorophenyl)-4-
metlioxyplienyl)aminophenyI]ethyl}-(ff)-2-hydroxy-2-(8-hydroxy-2(i//)- |
quinoIinon-5-yI)ethylamiiic(I02)
Using procedures similar to those described in Example 61C and the deprotection
step of Example 6 IB, except replacing the 4-methoxy-3-phenyianiline hydrochloride with
3-(3-chIoropIienyI)-4-methoxyani!ine in Example 61C, part d, compound 102 was
prepared.
The intermediate compound 3-(3-chloropheny!)-4-me(hoxyaniIine was prepared as
follows:
a. Syndiesis of 2-(3-chlorophenyl)-4-nltroanisole
To a flask containing abi-phasic mixture of 2-broma-4-mtroanisolc (15.0 g, 64.6 mmol) and 3-chlorophenyiboronic acid (12.1 g, 77.6 mmol) in ethylene glycol dimethyl ether (187.5 mL) and 2.0 N aqueous cer

bis(r%henylphospbJno)feirocene)dichloro palladium (H), complex with dicbloromethajie (1:1) (1.5 g). The mixture was heated at reflux for 4 hours under a nitrogen atmosphere.
The crude reaction mixture was partitioned between ethyl acetate (350 rnL) and brine (250 mL) and then filtered through a Buchner funnel. Layers were separated and the organic layer was washed with brine (250 mL). The organic phase was dried overNajS04. filtered, and concentrated to a dark oil. The crude residue was purified by flash chromatography on silica gel using dicbloromethane as the eluent to afford 2-(3-chlorophenyl)-4-nitroanisole as a yellow solid (13.9 g, 59.4 mmol).
b. Synthesis of 3-{3-chIorophenyl>4-methoxyaniline
To a mixture of 2"(3-chlorophenyI)-4-nitroanisoIe (0,5 g, 1.9 mmol)in tetrabydrofuran (5 mL) and methanol (5 mL) was added platinum (IV) oxide (1 mg). The reaction was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours. The slurry was filtered through Celite and concentrated under reduced pressure to afford 3-(3-chloropbenyI)-4~metboxyaniline as a light yellow oil (405 mg, 1.7 mmol).
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from die trtie spirit and scope of the invention. In addition, many modifications may be made tu ;i(|;tpt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. Additionally, all publications, " patents, and patent documents cited hereinabove are incorporated by reference herein in full, as though individually incorporated by reference.




We Claim:
1. An aryl aniline p2 adrenergic receptor agonist compound of formula (I):

wherein:
each of R:-R5 is independently selected from the group consisting of hydrogen, Ci-salkyl, C2-salkenyl, C2 salkynyl, C6-ioaryl, C3-iocycloalkyl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, heterocyclyl containing 3 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O and R3;
or R1 and R2, R2 and R3, R3 and R4, or R4 and R5 together form a group selected from the group consisting of-C(Rd)=C(Rd)C(=0)NRd-, -CRdRd-CRdRd-C(=0)NRd, NRdC(=0)C(Rd)=C(Rd)-, NRdC(=0)CRdRd-CRdRd-, -NRdC{=0)S-, -SC(=0)NRd-, -(CRdrV, -S(CRdRdJq-, -(CRdRd)qS, -S(CRdRd)rO, -0(CRdRd)rS, and -NHC(RJ)=C(Rk)-;
R6 is hydrogen, Ci-salkyl or alkoxy of a formula -OR where R is Ci-salkyl; R7 is hydrogen or Ci-aalkyl;
R8 is hydrogen or Ci-salkyl; of R8 together with R9 is -CH2- or -CH2CH2-; R9 is independently selected from the group consisting of Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce-ioaryl, C3-iocycloalkyl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, heterocyclyl containing 3 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, and Ra, or R9 together with R8 is -CH2- or -CH2CH2-; R10 is hydrogen or Ci-salkyl;

each Ru, R12, and R13 is independently selected from the group consisting of hydrogen, Ci-salkyl, C3-iocycloalkyl, C2-aalkenyl, C2-8alkynyl, Ce-ioaryl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, heterocyclyl containing 3 to 10 atoms including 1 to 4 heteroatoms selected N, S, and O, -NO2, halo, -NRdRe, -C(=0)Rd, -C02Rd, -OC{=0)Rd, -CN, -C(=0)NRdRe, -NRdC(=0)Re, -OC(=0)NRdRe, -NRdC(=0)0Re, -NRdC(=0)NRdRe, -ORd, -S(0)mRd, -NRd-NRd-C(=0)Rd, -NRd-N=CRdRd, -N(NRdRe)Rd, and-S(O) 2NRdRe ;
or R11 and R12 together with the atoms to which they are attached form a fused benzo ring, which benzo ring can be unsubstituted or substituted with 1, 2, 3, or 4 Re;
or Ru and R12 together with the atoms to which they are attached form a heterocyclic ring;
wherein for Rl-R6, R9, and Rn-R13, each alkyl, alkenyl, and alkynyl is unsubstituted or substituted with Rm or with 1, 2, 3, or 4 substituents independently selected from Rb; for R^R6, R9, and Rn-R13, each aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from Rc and for R^R6, R9 and Rn-R13 each cycloalkyl and heterocyclic ring is unsubstituted or substituted with 1,2, 3, or 4 substituents independently selected from Rb and Rc ;
each Ra is independently-ORd,-N02, halo, -S(0)mRd, -S(0)20Rd, -S(0)mNRdRe, -NRdRe, -0(CRfRs)nNRdRe, -C(=0)Rd, -C02Rd, -C02(CRfR8)nCONRdRe, -OC(=0)Rd, -CN, -C(=0)NRdRe, -NRdC(=0)Re-OC(=0)NRdRe, -NRdC(=0) NRdRe, -CRd(=N-ORe), -CF3, or -OCF3;
each Rb is independently Ra, oxo, or =N-ORe;
each Rc is independently Ra, O-salkyl, C2-salkenyl, or C2-8alkynyl; wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted withl, 2,3, or 4 substituents independently selected from Rb;
each Rd and Re is independently hydrogen, Ci-salkyl, C2-aalkenyl, C2-aalkynyl, Ce-ioaryl, C3-iocycloalkyl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O or heterocyclyl

containing 3 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is unsubstituted or substituted withl, 2,3, or 4 substituents independently selected from Rh ; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring may contain 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen;
each Rf and Re is independently hydrogen, Ci-salkyl, Ce-ioaryl, C3-locycloalkyl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, heterocyclyl containing 3 to 10 atoms including 1 to
4 heteroatoms selected from N, S, and O; wherein each alkyl, aryl, heteroaryl,
cycloalkyl and heterocyclyl is unsubstituted or substituted with 1,2, 3, or 4
substituents independently selected from Rh ; or Rf and Re together with the
carbon atom to which they are attached form a ring having from 5 to 7 ring
atoms, wherein the ring may contain 1 or 2 heteroatoms independently
selected from oxygen, sulfur or nitrogen;
each Rh is independently halo, Ci-salkyl, Ci-salkoxy, -S-Ci-salkyl, aryl, (aryl)-Ci-6alkyl, (arylJ-Ci-salkoxy, heteroaryl, (heteroaryl)-Ct-6alkyl, (heteroaryl)-C, aalkoxy, hydroxy, amino, -NHCi-ealkyl, -N(Ci-6alkyl)2, -OC(=0)Ci-6alkyl, -C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, -NHC (=0)Ci-6alkyl, -C(=0)NHCi-6alkyl, carboxy, nitro, -CN, or-CF3 ;
R> and Rk together with the carbon atoms to which they are attached form a phenyl ring that is unsubstituted or substituted with 1,2, 3, or 4 Rc ;
each Rm is independently Ce-ioaryl, C3-iocycloalkyl, heteroaryl containing
5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, or
heterocyclyl containing 3 to 10 atoms including 1 to 4 heteroatoms selected
from N, S, and O; wherein each aryl or heteroaryl is unsubstituted or
substituted with 1,2, 3, or 4 substituents selected from the group consisting of
Rc, and wherein each cycloalkyl and heterocyclyl is unsubstituted or
substituted with 1,2, 3, or 4 substituents selected from Rb;
m is 0, 1, or 2 ;

n is 0, 1,2, 3,4, 5,6, 7,8, 9,or 10 ;
p is 3, 4, or 5 ; q is 2, 3, or 4 ;
r is 1,2, or 3 ; and
wisO, 1, 2,3, or 4 ;
or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
2. The compound as claimed in claim 1 or 2 wherein R1 is hydrogen; R2 is hydrogen; R3 is hydroxy; and R4 and R5 together are-NHC (=0) CH=CH-.
3. The compound of claim 1 wherein each of RL-R5 is independently selected from the group consisting of hydrogen, Cigalkyl, and Ra ; wherein each Ra is independently -ORd, halo, NRdRe, -NRdC(=0)Re, or-OC (=0) NRdRe ;
or R1 and R2, or R4 and R5, together form a group selected from the group consisting of-C(Rd) =C (Rd)C(=0)NRd-, -CRdRd-CRdRd-C(=0)NRd-, -NRdC(=0) C(Rd) =C (Rd)-,-NRdC (=0) CRdRd-CRdRd-, -NRdC(=OJS-, and-SC(=0)NRd-;
R6,R8, and R10 are each hydrogen;
each of R11 and R12 is independently selected from the group consisting of hydrogen, Ci-salkyl, C3-iocycloalkyl, C2-salkenyl, C2-8alkynyl, Ce-ioaryl, heteroaryl containing 5 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, heterocyclyl containing 3 to 10 atoms including 1 to 4 heteroatoms selected from N, S, and O, -NO2, halo, -NRdRc, -C02Rd, -OC(=0)Rd, -CN, -C(=0)NRdRe, -NRdC(=0)Re, -ORd, -S(0)rnRd, -NRd-NRd-C(=0)Rd, -NRd-N=CRdRi, -N(NRdRe)Rd, and-S(0)2NRdRe ;
wherein for R]-R5, R", and R12, each alkyl is unsubstituted or substituted with Rm, or with 1,2, 3, or 4 substituents independently selected from Rb ; for R11 and R12, each aryl and heteroaryl is unsubstituted or substituted with 1,2, 3, or 4 substituents independently selected from Rc, and for Ru and R12, each cycloalkyl and heterocyclyl is unsubstituted or substituted with 1,2, 3, or 4 substituents independently selected from Rb and
Rc;
R13 is hydrogen;

the group comprising -NR10 is meta or para to the group comprising R7 ; and wis 0, 1, or 2.
The compound as claimed in any one of claims 1-8 wherein:
R7 is hydrogen;
each of R11 and R12 is independently selected from the group consisting of hydrogen, Ci-ealkyl, cyclohexyl, phenyl, pyrazolinyl, -ORd, -S(0)mRd, and-S(OJ2NRdRe;
w is 0;
and Rd and Re are independently selected from the group consisting of hydrogen, Ci-ealkyl, phenyl,-CF3, and Ci-3 alkyl, pyridyl, thiazolyl, pyrimidinyl, and pyrazolinyl, wherein each phenyl is unsubstituted or substituted with 1 or 2 substitutents independently selected from halo, -CF3, and C1-3 alkyl, each pyrimidinyl is unsubstituted or substituted with 1 or 2 substituents independently selected from Ci salkyl and OC1-3 alkyl, and each pyrazolinyl is unsubstituted or substituted with 1 or 2 substitutents independently selected from Ci-3alkyl and carboxy; or
Rd and Re, together with the nitrogen atom to which they are attached are morpholino or piperidino.
5. The compound as claimed in any one of claims 1 to 4 wherein Ru is
hydrogen or phenyl and R12 is-OCi-3alkyl; or R11 is phenyl and R12 is hydrogen.
6. A compound as claimed in claim 1, wherein said compound is a
compound of formula (II):


wherein:
R4 is -CH2OH or-NHCHO and R5 is hydrogen; or R4 andR5 taken together s -NHC(=OJCH=CH-;
R11 is phenyl or heteroaryl containing 5 to 10 atoms including 1 to 4 teroatoms selected from N, S, and O, wherein each phenyl is unsubstituted substituted with 1 or 2 substituents selected from halo, -ORd, -CN, -NO2, -S02Rd, -C (=0) Rd,-C (=0) NRdRe, and Ci-aalkyl, wherein C1-3 alkyl is unsubstituted or substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each Rd and Re is independently hydrogen or Ci 3alkyl ; and wherein each heteroaryl is unsubstituted or substituted with 1 or 2 Ci-3alkyl substituents; and
R12 is hydrogen or-OCi-ealkyl;
or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
7. The compound of claim 6 wherein R11 is phenyl, unsubstituted or
substituted with 1 substituent selected fromhalo,-ORd,-CN,-N02,-S02Rd,-C
(=0) Rd, and Ci-3alkyl,
wherein Ci-3alkyl is unsubstituted or substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and Rd is hydrogen or C1-3 alkyl.
8. The compound as claimed in claim 6 whereinR11 is phenyl, pyridyl, or thiophenyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro,-OCH3,-CN, and-CH2NH2| and R12 is hydrogen, -OCH3, or -OC2H5.
9. The compound as claimed in claim 8 wherein R4 and R5 taken together are -NHC(=0)CH=CH-; RU is phenyl or pyridyl, wherein each phenyl is unsubstituted or substituted with 1 substituent selected from the group consisting of chloro,-OCH3,-CN, and-CH2NH2 ; and R12 is-OCH3-.

10. The compound as claimed in any one of claims 6 to 9 wherein the compound is a mixture of stereosiomers wherein the amount of the stereoisomer having the (R) orientation at the chiral center to which the hydroxy group is attached is greater than the amount of the stereoisomer having the (S) orientation at the chiral center to which the hydroxy group is attached.
11. The compound as claimed in any one of claims 6 to 9 wherein the compound is the stereoisomer having the (R) orientation at the chiral center to which the hydroxy group is attached.
12. The compound of claim 6 wherein the compound is selected from the group consisting of:
JV{2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl}- (-R)-2-hydroxy-2- (3-
hydroxymethyl-4-hydroxyphenyl) ethylamine;
JV-{2- [4- (4-ethoxyphenyl) aminophenyfjethyl}- (£)-2-hydroxy-2- (3-
hydroxymethyl- 4-hydroxyphenyl) ethylamine;
JV-{2-[4-{3-phenyl) aminophenyl]ethyl}- (R)-2-hydroxy-2- (3-hydroxymethyl-4-
hydroxyphenyl) ethylamine ;
JV-{2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl]ethyl}- fi?)-2-hydroxy-2- (8-
hydroxy-2(l-H)-quinolinon-5-yl) ethylamine;
N-{2- [4- (4-methoxyphenyl) aminophenyl] ethyl}- (i^-2-hydroxy-2- (3-
hydroxymethyl-4-hydroxyphenyl} ethylamine;
N-{2- [4- (3-phenyl-4-ethoxyphenyl) aminophenyl]ethyl}- (i?)-2-hydroxy-2- (3-
hydroxymethyl-4-hydroxyphenyl) ethylamine;
N-{2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl}- (J^-2-hydroxy-2- (3-
formamido-4-hydroxyphenyl) ethylamine;
N-{2- [4- (4-ethoxyphenyl) aminophenyl] ethyl}-/K)-2-hydroxy-2-(3-formamido-4-
hydroxyphenyl) ethylamine;

JV- {2- [4- (3-phenylphenyl) aminophenyl]ethyl}- (£)-2-hydraxy-2- (3-formamido-
4- hydroxyphenyl) ethylamine;
JV- {2- [4- {3-phenyl-4-ethoxyphenyl) aminophenyl] ethyl}- (i^-2-hydroxy-2- (3-
formamido-4-hydroxyphenyl) ethylamine;
N-{2- [4- (4-methoxyphenyl) aminophenyl] ethyl}- (i?)-2-hydroxy-2- (3-
formamido-4- hydroxyphenyl) ethylamine;
JV-{2- [4- (4-ethoxyphenyl) aminophenyl] ethyl}-(i?)-2-hydroxy-2-(8-hydroxy-
2(1W)- quinolinon-5-yl) ethylamine;
JV-{2- [4- (3-phenylphenyl) aminophenyl] ethyl}- (i?^-2-hydroxy-2- (8-hydroxy-
2(1 Hj- quinolinon-5-yl) ethylamine ;
JV-{2-[4-(3-phenyl-4-ethoj^phenyl) aminophenyl] ethyl] ethyl}-(i?)-2-hydroxy-2-(8-
hydroxy-2 {1 H)-quinolinon-5-yl) ethylamine;
JV-{2- [4- (4-methoxyphenyl) aminophenyljethyl}- (i?)-2-hydroxy-2- (8-hydroxy-
2(lfl)-quinolinon-5-yl) ethylamine ;
N-{2- [4- (3- (2-chlorophenyl) phenyl) aminophenyl]ethyl}- (i?)-2-hydroxy-2- (8-
hydroxy-2 (lJ-f)-quinolinon-5-yl) ethylamine;
JV-{2- [4- (3- (2-methoxyphenyl) phenyl)aminophenyl] ethyl}- (i?)-2-hydroxy-2-
(8- hydroxy-2(l.H)-quinolinon-5-yl) ethylamine;
JV-{2-[4-(3-cyanophenyl) phenyl) aminophenyljethyl}- (i?)-2-hydroxy-2- (8-
hydroxy-2(1 fl)-quinolinon-5-yl) ethylamine;
JV- {2-[4- (3- (4-aminomethylphenyl) phenyl) aminophenyl] ethyl}-(i?)-2-hydroxy-
2- (8-hydroxy-2 (li^)-quinolinon-5-yl) ethylamine;
JV-{2- [4- (3- (3-chlorophenyl) phenyl) aminophenyljethyl}- (J?)-2-hydroxy-2- (8-
hydroxy-2(lH)-quinolinon-5-yl) ethylamine ;
JV-{2- [4- (3- (4-aminomethylphenyl)-4-methoxyphenyl) aminophenyl] ethyl}- (R\-
2-hydroxy-2- (8-hydroxy-2 (li-f)-quinolinon-5-yl) ethylamine;
JV-{2-(4-(3-(3-cyanophenyl)-4-methoxyphenyl) aminophenyl] ethyl}- (J^)-2-
hydroxy-2-(8-hydroxy-2 (l.H)-quinolinon-5-yl) ethylamine ;
JV-{2- [4- {3- (4-hydroxyphenyl)-4-methoxyphenyl) aminophenyl] ethyl}- (i^-2-
hydroxy-2- (8-hydroxy-2 (l.H)-quinolinon-5-yl) ethylamine;

iV-{2-[4-(3-(3-pyridyl) phenyl) aminophenyl] ethyl}- (J?J-2-hydroxy-2- (8-hydroxy-
2 (lfl)-quinolinon-5-yl)ethylamie ;
JV-{2- [4- (3- (3-pyridyl)-4-methoxyphenyl) aminophenyl] ethyl}- (i?J-2-hydroxy-2 -
(8- hydroxy-2 (2H)-quinolmon-5-yl)ethylamine ;
N~{2- [4- (3- (4-pyridyl)-4-methoxyphenyl) aminophenyl] ethyl}- (R)-2-hydroxy-2-
(8- hydroxy-2(lH)-quinolinon-5-yl) ethylamine;
N-{2- [4- (3- (thiophen-3-yl)-4-methoxyphenyl) aminophenyl]ethyl}- (R)-2-
hydroxy-2- (8-hydroxy-2 (lH)-quinolinon-5-yl) ethylamine ; and
iV-12- [4- (3- (3-chlorophenyl)-4-methoxyphenyl) aminophenyl] ethyl}- (R)-2-
hydroxy-2-(8-hydroxy-2(l/^-qumolinon-5-yl)ethylamine.
13. The compound of claim 6 wherein the compound is 7V-{2-[4-(3-phenyl-4-
methoxyphenyl) aminophenyl] ethyl}-(R)-2-hydroxy-2-(8-hydro;cy-2(l.H)-
quinolinon-5- yl)ethylamine.
14. The compound of claim 6 wherein the compound is iV-{2-[4-(3-(3-
chlorophenyl)-4-methoxyphenyl}aminophenyl]ethyl)-/i?)-2-hydroxy-2-(8-
hydroxy- 2(lH)-quiuoiinon-5-yl)ethylamine.
15. A pharmaceutical composition comprising a therapeutically effective
amount of a compound as claimed in any one of claims 1 to 14 and a
pharmaceutically-acceptable carrier, wherein said compound constitutes form
about 0.1% to about 30% of the composition.
16. The pharmaceutical composition of claim 15, wherein the composition is
formulated for administration by inhalation.
17. The pharmaceutical composition of claim 15, wherein the composition
comprises a therapeutically effective amount of a steroidal anti-inflammatory
agent.

18. The pharmaceutical composition of claim 15, wherein the composition
comprises a therapeutically effective amount of a compound selected from the
group consisting of a muscarinic receptor antagonist agent, a
phosphodiesterase inhibitor agent, an immunoglobulin antibody, a leukotriene
antagonist agent, a cytokine antagonist agent, a protease inhibitor, cromolyn
sodium, nedocromil sodium, and sodium cromoglycate.
19. A compound substantially as herein described and exemplified.
20. A pharmaceutical composition comprising a therapeutically effective
amount substantially as herein described and exemplified.

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Patent Number 227966
Indian Patent Application Number 1019/CHENP/2004
PG Journal Number 10/2009
Publication Date 06-Mar-2009
Grant Date 27-Jan-2009
Date of Filing 12-May-2004
Name of Patentee THERAVANCE, INC
Applicant Address 901 GATEWAY BOULEVARD, SOUTH SAN FRANCISCO, CALIFORNIA 94080,
Inventors:
# Inventor's Name Inventor's Address
1 MORAN, EDMUND J 131 CHAVES, SAN FRANCISCO, CA 94127,
2 LEADBETTER, MICHAEL, R 335 BEVERLY AVENUE, SAN LEANDRO, CA 94577,
3 TRAPP, SEAN G 1112 DE HARO, SAN FRANCISCO, CA 94107,
4 JACOBSEN, JOHN R 16 OAK VALLEY ROAD, SAN MATEO, CA 94402,
5 NODWELL, MATTHEW, B #8 1346 COTTON DRIVE, VANCOUVER, BRITISH COLUMBIA, CANADA V5L 3T7,
6 AGGEN, JAMES 1311 CALIFORNIA DRIVE, BURLINGAME, CA 94010,
7 CHURCH, TIMOTHY, J 3913 PASADENA DRIVE, SAN MATEO, CA 94403,
PCT International Classification Number CO7C229/60
PCT International Application Number PCT/US02/36237
PCT International Filing date 2002-11-12
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/338,194 2001-11-13 U.S.A.
2 60/343,771 2001-12-28 U.S.A.