CA2449843A1 - Non-peptide gnrh agents, pharmaceutical compositions and methods for their use, and processes for preparing them - Google Patents

Non-peptide gnrh agents, pharmaceutical compositions and methods for their use, and processes for preparing them Download PDF

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CA2449843A1
CA2449843A1 CA002449843A CA2449843A CA2449843A1 CA 2449843 A1 CA2449843 A1 CA 2449843A1 CA 002449843 A CA002449843 A CA 002449843A CA 2449843 A CA2449843 A CA 2449843A CA 2449843 A1 CA2449843 A1 CA 2449843A1
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unsubstituted
nhc
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alkyl
heterocycloalkyl
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Eric T. Sun
Mark B. Anderson
Kenna Lynn Anderes
Lance Christopher Christie
Quyen-Quyen Thuy Do
Jun Feng
Thomas Goetzen
Yufeng Hong
Eugenia Anatolievna Iatsimirskaia
Haitao Li
David Robert Luthin
Genevieve D. Paderes
Ved P. Pathak
Ranjan Jagath Rajapakse
Scott Shackelford
Eileen Valenzuela Tompkins
Larry Kenneth Truesdale
Haresh Vazir
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Agouron Pharmaceuticals LLC
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Abstract

Non-peptide GnRH agents capable of inhibiting the effect of gonadotropin-releasing hormone are described. Such compounds and their pharmaceutically acceptable salts, prodrugs, and active metabolites are suitable for treating mammalian reproductive disorders and steroid hormone-dependent tumors as well as for regulating fertility, where suppression of gonadotropin release is indicated. Methods for synthesizing the compounds and intermediates useful in their preparation are also described.

Description

NON-PEPTIDE GnRH AGENTS, PHARMACEUTICAL COMPOSITIONS
AND METHODS FOR THEIR USE, AND
PROCESSES FOR PREPARING THEM AND THEIR INTERMEDIATES
TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY
OF THE INVENTION
This invention relates generally to compounds that affect the action of human gonadotropin-releasing hormone (GnRH). More particularly, it relates to non-lo peptide GnRH antagonists or agonists and to their preparation. These non-peptide GnRH agents have advantageous physical, chemical, and biological properties, and are useful medicaments for diseases or conditions mediated by modulation of the pituitary-gonadal axis. The invention also relates to methods for treating individuals needing therapeutic regulation of GnRH--i.e., methods for treating diseases and 15 conditions mediated by GnRH regulation. The invention further relates to processes for synthesizing intermediate compounds useful for making GnRH agents.
BACKGROUND OF THE INVENTION
Gonadotropin-Releasing Hormone (GnRII), also known as luteinizing hormone-releasing hormone (LH-RH), plays a central role in the biology of 2o reproduction. A large variety of analogs have been used for an increasing number of clinical indications. The GnR_H_ decapeptide (pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 or p-EHWSYGLRPG-NH2) is produced in neurons of the medial basal hypothalamus from a larger precursor by enzymatic processing. The decapeptide is released in a pulsatile manner into the pituitary portal circulation 2s system where GnR_H_ interacts with high-affinity receptors (7-Transmembrane G-Protein Coupled Receptors) in the anterior pituitary gland located at the base of the brain. In the pituitary, GnR_H_ triggers the release of two gonadotropic hormones (gonadotropins): luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
In testes and ovaries, LH stimulates the production of testosterone and estradiol, 3o respectively. FSH stimulates follicle growth in women and sperm formation in men.
When correctly functioning, the pulse-timed release and concentration levels of GnRH are critical for the maintenance of gonadal steroidogenesis and for normal functions of reproduction related to growth and sexual development.

The pituitary response to GnRH varies greatly throughout life. GnRH and the gonadotropins first appear in the fetus at about ten weeks of gestation. The sensitivity to GnR_H_ declines, after a brief rise during the first three months after birth, until the onset of puberty. Before puberty, the FSH response to GnRH is greater than that of LH. Once puberty begins, sensitivity to GnR_H_ increases, and pulsatile LH
secretion ensues. Later in puberty and throughout the reproductive years, pulsatile release of GnRH occurs throughout the day, with LH responsiveness being greater than that of FSH. Pulsatile GnR_H_ release results in pulsatile LH and FSH release from the pituitary, and hence, estosterone and estradiol release from the gonads. After menopause, FSH and LH concentrations rise, and post-menopausal FSH levels are higher than those of LH.
Chronic administration of GnRH agonists and antagonists to animals or to man results in decreased circulating levels of both LH and FSH. GnRH agonists are compounds that mimic endogenous GnRH to stimulate receptors on the pituitary 15 gland, resulting in release of LH and FSH. After a transient rise in gonadal hormone production or "flare" response, chronic administration of GnRH agonists results in a down-regulation of GnRH receptors. GnRH receptor down-regulation and a desensitization of the pituitary results in a decrease of circulating levels of LH and FSH. In spite of the symptom-exacerbating hormonal flare experienced, GnRH
2o agonists have been the treatment of choice for sex-steroid-dependent pathophysiologies. For example, GnRH agonists have been used to reduce testosterone production, thereby reducing prostate volume in benign prostatic hyperplasia (BPH) and slowing tumor growth in prostate cancer. These compounds have also been used to treat breast and ovarian cancers.
2s Recently, GnitH antagonists have become available for clinical evaluation.
GnRH antagonists have an immediate effect on the pituitary without the observed flare associated with agonists. Use of GnRHantagonists (usually decapeptides) has been reported in the literature for treatment of breast, ovarian, and prostatic cancers.
Other uses of antagonists, like agonists, include endometriosis (including 3o endometriosis with pain), uterine myoma, ovarian and mammary cystic diseases (including polycystic ovarian disease), prostatic hypertrophy, amenorrhea (e.g., secondary amenorrhea), and precocious puberty. These compounds may also be useful in the symptomatic relief of premenstrual syndrome (PMS). Furthermore, antagonists may be useful to regulate the secretion of gonadotropins in male mammals to arrest spermatogenesis (e.g., as male contraceptives), and for treatment of male sex offenders: Importantly, GnR_H_ antagonists (and agonists) have found utility in treatments where a reversible suppression of the pituitary-gonadal axis is desired.
For over fifty years, androgen deprivation has been the most effective systematic therapy for the treatment of metastatic carcinoma of the prostate.
The rationale is simple the prostate gland requires androgens for proper growth, maintenance, and function. Yet, prostate cancer and benign prostate hyperplasia are common in men and develop in an environment of continuous androgen exposure.
Thus, utilizing a GnR_H_ antagonist to interrupt the pituitary-gonadal axis reduces 1o androgen production and results in tumor growth modulation. Furthermore, GnRH
antagonists may have a direct effect on tumor growth by blocking receptors on the tumor cells. For those cancer types that respond both to sex hormones and to GnRH
directly, antagonists should be effective in slowing tumor growth by these two mechanisms. Since GnR_H_ receptors are present on many prostate and breast cancer 1s cells, it has recently been speculated that GnR_H_ antagonists may also be effective in treating non-hormone-dependent tumors. Recent literature examples indicate that GnR_H_ receptors are present on a number of cancer cell lines, including:
~ prostate cancer: GnRH agonists exert both in vitro, and i~r vivo, a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and 2o androgen-independent (DU 145) human prostatic cancer cell lines [Montagnani et al., Arch. Ital..: Urol. Androl., 69(4), 257-263 (1997);
"GnR_H_ Antagonist Inhibit the Growth of Androgen-Independent PC-3 Prostate Cancer in Nude Mice," Jungwirth et al., Prostate, 32(3), 164-172 (1997)];
ovarian cancer: The demonstration of GnR_H_ receptors in human ovarian 2s cancers provides a rationale for the use of therapeutic approaches based on GnR_H_ analogues in this malignancy [Srkalovic et al., hrt. J. ~hcol., 12(3), 489-498 (1998)].
~ breast cancer: Breast cancer is the most common type of cancer in women over the age of forty and is the leading cause of cancer-related death in 3o women. Systematic endocrine intervention represents a major treatment option for the management of advanced breast cancer, especially with estrogen-dependent cancers. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer [Kottler et al., Iht. J. Cahce~, 71(4), 595-599 (1997)].
GnRIi agents may also be useful in treating cancer through generation of thymus re-growth and therefore induction of the development of new T-cells.
See s Norwood Abbey press release dated March 5, 2001. These white blood cells, which develop in the thymus gland, are a fundamental component of the immune system's involvement in a range of diseases, including viral infections, transplant organ rejection, cancer, and autoimmune diseases. Thus, for example, since the human immunodeficiency virus (HIV) preferentially infects and destroys T-cells, GnR_H_ to agents may be useful for treating HIV infection or acquired immune deficiency syndrome (AIDS). Additionally, GnRH agents may be useful in combating infection in tissue-transplant patients where immunosuppressive drugs, which remove T-cells, are being administered to counteract rejection of the transplanted tissue.
Similarly, since adequate and effective T-cells help defend against cancer, and chemotherapy is and radiation regimens detrimentally impact T-cells, GnRH agents may be useful in treating cancer. Furthermore, GnRH agents may be useful for treating autoimmune diseases such as multiple sclerosis (MS), where T-cells are produced that react against a molecule surrounding nerve cells.
Heretofore, available GnR_H_ antagonists have primarily been peptide analogs 20 of GnRH. See, e.g., International Publication Nos. WO 93/03058, WO
99/50276, WO 00/12521, and WO 00/12522; Koppan et al., Prostate, 38(2),151-8 (1999); and Nagy et al., Proc Natl Acad Sci USA, 97(2),829-34 (2000). Though peptide antagonists of peptide hormones are often quite potent, the use of peptide antagonists is typically associated with problems because peptides are degraded by physiological 2s enzymes and often poorly distributed within the organism being treated.
The first non-peptide antagonist of the human leuteinizing hormone-releasing hormone (LHRH) receptor was reported by Cho et al. (JMed Chem, 41(22), 4190 (1998). Since then, other non-peptide GnRH antagonists have been reported in the literature. For example, quinolone-6-carboxamides were reported by Walsh et al. in 3o Bioorg & Med Chem Lt~s., 10, 443-447 (2000). Tricyclic diazepines and cyclic pentapeptides were reported in International Publication Nos. WO 96/38438 and WO
96/34012, respectively. Tetrahydroisoquinoline derivatives were reported in U.S.
Patent No. 5,981,521. For additional examples of non-peptide GnRH antagonists, see International Publication Nos. WO 97/21435, WO 97/21703, WO 97/21704, WO

97/21707, WO 99/44987, WO 00/04013, WO 00/12522, WO 00/12521, WO
00/04013, and WO 00/20358.
Despite recent advances, there continues to be a need for non-peptide antagonists of the peptide hormone GnR_H_ with desirable properties. For example, there is a need for non-peptide GnRH agents having advantageous physical, chemical and biological properties compared to peptides, which are useful medicaments for treating diseases mediated via the pituitary-gonadal axis and by directly targeting the receptor on tumor cells. There is also a need for GnR_H_ agents that act upon these receptors to treat both hormone-dependent and hormone-independent cancers.
1o SUM1VIARY OF THE INVENTION
In one general aspect, the invention is directed to compounds represented by the following Formula I:
x Ar~Z ~ ~ V~Y~Ri wherein the variables are as defined in the claims.
is q In another general aspect, the invention is directed to compounds represented by Formula (II):
x R ~Z ~ ~ V~YiArz z wherein the variables are as defined in the claims.
In a further general aspect, the invention is directed to compounds 20 represented by Formula (III):
wherein the variables are as defined in the claims.
In addition to compounds of Formulas I, II, and III, the invention is also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, 25 and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. Such compounds, salts, prodrugs and metabolites are at times collectively referred to herein as "GnRH agents."
The invention also relates to pharmaceutical compositions each comprising a therapeutically effective amount of a GnRT-T agent of the invention in combination with a pharmaceutically acceptable carrier or diluent. Moreover, the invention relates to methods for regulating the secretion of gonadotropins in mammals, comprising administering therapeutically effective amounts of GnR_H_ agents of the invention.
Other aspects, features, and advantages of the invention will become apparent from the detailed description of the invention and its preferred embodiments.
1o DETAILED DESCRIPTION OF INVENTION AND PREFERRED
EMBODIMENTS
As used herein, the terms "comprising" and "including" are used herein in their open, non-limiting sense.
The term "alkyl" refers to a straight- or branched-chain alkyl group having 1s from 1 to 12 carbon atoms in the chain. Exemplary alkyl groups include methyl (Me, which also may be structurally depicted by ~, ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
The term "heteroalkyl" refers to a straight- or branched-chain alkyl group 2o having from 2 to 12 atoms in the chain, one or more of which is a heteroatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like.
The term "alkenyl" refers to a straight- or branched-chain alkenyl group having from 2 to 12 carbon atoms in the chain. Illustrative alkenyl groups include 25 prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
- The term "alkynyl" refers to a straight- or branched-chain alkynyl group having from 2 to 12 carbon atoms in the chain. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.
The term "aryl" (Ar) refers to a monocyclic, or fused or spiro polycyclic, 3o aromatic carbocycle (ring structure having ring atoms that are all carbon) having from 3 to 12 ring atoms per ring. Illustrative examples of aryl groups include the following moieties:

° ~\
\ ~ \ \ ~ \ \ \
~ ~ , ~ ~ ~ , ~ ~ , \ \
~ , and the like.
The term "heteroaryl" (heteroAr) refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from 3 to 12 ring atoms per ring. Illustrative examples of aryl groups include the following moieties:
NON I \ N \ S \ N
~N ~ NON , / ~ , I ,i ~ , I ~ ~~ , N
~N~ ~S~ ~O N\O~ ~N ~S N\S~
U,U~~N ,U,UN ~UN ,U~
N~N O Nw \ N~ N~ N
\ ~ ~ ~ ~ / NI ~ C ~ I / N ~N
> > > 'N , N > >
io S
N ~ ~ ~N
i / , and the like.
S N
The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from 3 to 12 ring atoms per ring.
Illustrative examples of cycloalkyl groups include the following moieties:

> > > ' D~ 0 ' > >
U ~.
> > >
s \ , and the like.
A "heterocycloalkyl" refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from~3 to 12 ring atoms per 1o ring selected from C atoms and N, O, and S heteroatoms. Illustrative examples of heterocycloalkyl groups include:

~Si N
S N~N N O O O
~U, ~ > > >~U~~S~
N N // O O // CO N
U ' ~N ~ U , ~N > > U ~ N-N
O
O S
N N~O 0 U c~ c~
, ~ ~~C>> >UU
N N N N N
~O
N~S;O N N ~ O
N , I / ~ , and the like.

IS
The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.

The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents.
Preferred GnRH agents of the invention include those having a I~1 value of about 10 wM or less. Especially preferred GnRH agents are those having a I~;
value in the nanomolar range.
It is understood that while a compound may exhibit the phenomenon of tautomerism, the formula drawings within this specification expressly depict only one of the possible tautomeric forms. It is therefore to be understood that a formula is intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific compound form depicted by the structural formula.
It is also understood that a compound of Formula I, II or III may exist as an "E" or "Z" configurational isomer, or a mixture of E and Z isomers. It is therefore to 1s be understood that a formula is intended to represent any configurational form of the depicted compound and is not to be limited merely to a specific compound form depicted by the formula drawings.
Some of the inventive compounds may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers 2o and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. In one preferred embodiment, the inventive compounds that are optically active are used in optically pure form.
As generally understood by those skilled in the art, an optically pure 2s compound having one chiral center (i.e., one asymmetric carbon atom) is one that -- consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a 3o form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).

As indicated above, GnRH agents in accordance with the invention also include active tautomeric and stereoisomeric forms of the compounds of Formula I, II
or III, which may be readily obtained using techniques known in the art. For example, optically active (R) and (S) isomers may be prepared via a stereospecific s synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
Additionally, Formulas I, II, and III are intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-to hydrated forms.
In addition to compounds of the Formulas I, II, and III, the GnR_H_ agents of the invention include pharmaceutically acceptable salts, prodrugs, and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. Such non-peptide agents are pharmaceutically advantageous over 1s peptide agents since they provide better biodistribution and tolerance to degradation . by physiological enzymes.
A "prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound. An "active metabolite" is a pharmacologically 2o active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med.
Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
Res., 34, 220-230 (1995); Bodor, Advances i~ Drug Res., 13, 224-331 (1984);
25 Bundgaard, Design of Prodrugs (Elsevier Press 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al.
eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 293 (2000); Sprain et al., J. Pharmaceutical & Biomedical Av~alysis, Vol. 3, No. 2, 103-112 (1992).
3o The term "pharmaceutically acceptable salts" refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being administered the GnRH agent. Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, malefic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and fumaric acid. Exemplary base-addition salts include those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide 1o such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from organic bases such as amines, benzylamines, piperidines, and pyrrolidines.
If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available yin the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, malefic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a 2o pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable 2s salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic 3o amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
A variety of known assays and techniques may be employed to determine the level of activity of various forms of the compounds in the GnRH system. Ligand s binding assays are used to determine interaction with the receptor of interest. Where binding is of interest, a labeled receptor may be used, where the label is a fluorescer, enzyme, radioisotope, or tfe like, which registers a quantifiable change upon the binding of the receptor. Alternatively, the artisan may provide for an antibody to the receptor, where the antibody is labeled, which may allow for amplification of the l0 signal. Binding may also be determined by competitive displacement of a ligand bound to the receptor, where the ligand is labeled with a detectable label.
Where agonist and/or antagonist activity is of interest, an intact organism or cell may be studied, and the change in an organismic or cellular function in response to the binding of the compound of interest may be measured. Various devices are available 1s for detecting cellular response, such as a microphysiometer available from Molecular-Devices, Redwood City, California. In vitNO and in vivo assays useful in measuring GnR_H_ antagonist activity are known in the art. See, e.g., Bowers et al., "LH
suppression in cultured rat pituitary cells treated with 1 ng of LHRH,"
Endocrinology, 1980, 106:675-683 (in vitro,) and Corbin et al., "Antiovulatory activity (AOA) in 20 rats," Endoc~~. Res. Commun., 2:1-23 1975.. Particular test protocols that may be used are described below.
For example, GnRH-receptor 7antagonists may be functionally assessed by measurement of change in extracellular acidification rates as follows. The ability of compounds to block the extracellular rate of acidification mediated by GnRH in HEK
2s 293 cells expressing human GnRH receptors is determined as a measure of the -- compound's antagonist activity i~ vit~~o. Approximately 100,000 cellslchamber are immobilized in agarose suspension medium (Molecular Devices) and perfused with unbuffered MEM media utilizing the Cytosensor~ Microphysiometer (Molecular Devices). Cells are allowed to equilibrate until the basal acidification rate remains 30 stable (approximately one hour). Control dose-response curves are performed to GnR_H_ (10-11 M to 10-' M). Compounds are allowed to incubate 15 minutes prior to stimulation with GnRH, and are assessed for antagonist activity. After incubation with test compounds, repeat dose-response curves to GnRH in the presence or absence of various concentrations of the test compounds are obtained. Schild regression analysis is performed on compounds to determine whether compounds antagonize GnRH-mediated increases in extracellular acidification rates through a competitive interaction with the GnR_H_ receptor.
In another test, accumulation of total inositol phosphates may be measured by formic acid extraction from cells, followed by separation of the phosphates on Dowex columns. Cells are split using trypsin into two 12-well plates and pre-labeled with 3H-myoinositol (0.5 Ci to 2 mCi per mL) for 16-18 hours in inositol-free medium.
The medium is then aspirated and the cells rinsed with either 1X HBSS, 20 mM
HEPES (pH 7.5), or serum-free DMEM, 1X HBSS, 20mM HEPES (pH 7.5) to containing test compound, and 20 mM LiCI is then added and the cells are incubated for the desired time. The medium is aspirated and the reaction stopped by addition of ice-cold 10 mM formic acid, which also serves to extract cellular lipids.
lnositol phosphates are separated by ion-exchange chromatography on Dowex columns, which are then washed with 5 mL of 10 mM myoinositol and 10 mM formic acid. The 1s columns are then washed with 10 mL of 60 mM sodium formate and 5 mM borax, and total inositol phosphates are eluted with 4.5 mL 1M ammonium formate, O.1M
formic acid.
It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition 2o formulated, the mode of administration, and the particular site, host, and disease being treated. Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body 25 weight, with courses of treatment repeated at appropriate intervals.
Administration of prodrugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds.
To treat diseases or conditions mediated by GnR_H_ agonism or antagonism, a pharmaceutical composition of the invention is administered in a suitable formulation so prepared by combining a therapeutically effective amount (i.e., a GnR_H_ modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one GnR_H_ agent of the invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations. Optionally, one or more additional active ingredients, such as a second GnRH agent, may be employed in a pharmaceutical composition according to the invention.
The pharmaceutical carriers employed may be either solid or liquid.
Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, 1o hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavaliability enhancer, such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxymethylcellulose), PG (propyleneglycol), or PEG
(polyethyleneglycol), may be added. Gelucire~, a semi-solid vehicle that protects 1s active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
2o If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., 25 parenteral or oral administration.
To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or 3o combinations of cosolvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I, II, or III is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, s preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by 1o combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), 1s optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, 20 sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, 25 polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, -- lacquer solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
Pharmaceutical preparations which can be used orally include push-fit so capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fariy oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
s For administration intranasally or by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a 'pressurized aerosol the dosage unit may be determined by providing a valve to deliver a~ metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations fox injection may be presented in unit-dosage form, e.g., in ampoules or in mufti-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing andlor dispersing agents.
2o Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
2s Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
3o For administration to the eye, a GnR_u_ agent may be delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, irislcilary, lens, choroid/retina and selera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous and aqueous humor.
s Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
1o In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an 15 acceptable oil) or ion-exchange resins, or as sparingly ~ soluble derivatives, for example, as a sparingly soluble salt.
A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD
2o is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5%
dextrose in water solution. This co-solvent system dissolves, hydrophobic compounds well, and itself produces low toxicity upon systemic administration. The proportions of a 2s co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone;
3o and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on s their chemical nature, release the compounds for a few weeks up to over 100 days.
Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium 1o carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, 15 malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
The compounds of Formulas I, II and III and their intermediates may be prepared by advantageous processes described below. Preferred intermediates useful for synthesizing the inventive compounds include 5-(2-methylphenoxy)-2-furoic acid, 20 5-[2-bromo-5-(tert-butyl)phenoxy]-2-furoic acid, 5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furoic acid, 5-(4-chloro-5-isopropyl)-2-methylphenoxy)-2-furoic acid, 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furoic acid, and 6-methyl-2-[(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthalenyl)oxy]-4-pyrimidinecarboxylic acid. Additional preferred nitro and amine intermediates useful 25 for synthesizing of GnRH agents of the present invention are:
__ ~p ~O ~O
H N N ~O H2N~ 'N HZN 'N
I N~N J w0~~0~0~ ~ ~'~ OH
O ~ , O N 0~
~O ~O
O~O I N~ HaN I 'N
CI and CI
Methods for electrophilic aromatic nitration are described in the art. See, for example, Coon et al., J. O~g. Chem., 38: 4243 (1973); Yarbro et al., J.
Fluo~ihe Chem. 6:187 (1975); Hakimelahi et al., Hel. Chim. Acta 61: 906 (1984); Suri et al., Synthesis 743(1988); Umenoto et al, Tetrahed~o~c Lett. 31:3579 (1990);
Shackelford et al., Abstracts of the 11 th Rocky Mou~taih Regional America~r. Chemical Society Meeting, Albuquerque, NM, July 10-12, 1992; and Adams et al., Tetf ahedroh Lett.
s 34: 6669 (1993). These methods have drawbacks, however. For example, the Yarbro et al. and Hakimelahi et al. methods generate anhydrous nitronium triflate using toxic, gaseous nitryl chloride, NOZCI, and corrosive triflic chloride (acid chloride).
Various drawbacks of prior methods have been overcome by the nitration process of the present invention, which comprises forming a nitrating reagent by to adding trifluoromethanesulfonic anhydride to 2-tetramethylammonium nitrate in a polar solvent and reacting the nitrating reagent with an aryl or heteroaryl compound.
Advantages of the present method are, e.g.: a) simplified and more rapid aqueous work-up, thereby eliminating chromatographic column separation and/or plug filtration; b) improved reactant solubility and reduced byproduct formation as a 1s result of organic solvents rather than aqueous or easily hydrolyzed, corrosive anhydride solvents; c) facilitated synthesis of regioisomeric nitrated products sometimes not available when .using other nitration procedures; d) enables the preparation of novel nitroaromatic and nitroheterocyclic compounds; e) achieves selective and exclusive mono-nitration from mild reaction conditions; ~
provides 2o higher product yields than many conventional nitration procedures; g) higher crude nitrated product purity; and h) scaleable over a wide range to provide small or large product quantities.
This nitration method described herein may be used to provide nitrated benzene derivatives (e.g., Compound II) and aromatic heterocyclic intermediates.
2s Such nitrated intermediates are reduced (e.g., Compound II to Compound III) to provide intermediates useful for preparing final GnR_H_ agents of the invention (e.g., Compound V--the compound of Example B52).

O O O\ O O~O
NITRATION / I~~ \ REDUCTION /
NYN '~ NYN ~ NYN
CI ICI CI
NH
.O ~ ~ ?O.
NYN l O CI O O O
O III ~ N CI
OH HATU,TEA I ~ I / HN /
IV V O\
General Procedure for the Tetramethylammonium Nitrate-Generated Nitronium Triflate Nitration of Aromatic Compounds (General Procedurel:
R
R
00 0o OOo Oo a a cNZc~z a a (CH3)QNN03 + CF3SOSCF3 RT,--t~ NOZOSCF3 -1- N(CH3)qOSCF3 a,~B~CtoRT ~ + HOSCF3 O O ~ ~ cHZci2 N02 O
[HBO soluble] [H20 soluble]
Under nitrogen at room temperature, 2.26-2.39 g trifluoromethanesulfonic anhydride was added dropwise from a pressure-equalized addition funnel to a stirred suspension of 1.12 g tetramethylammonium nitrate (96%) in 24 mL commercial anhydrous (or low water) dichloromethane (DCM) with a slight temperature rise 1o resulting. The addition funnel was rinsed with 8 mL anhyd. DCM, and this rinse was added to the reaction suspension. After stirring for at least 1.5 hours, the stirred suspension was cooled in a dry ice/acetone bath to at least -69°C. The aromatic substrate, 7.50 mmol of in 10 mL DCM, was added dropwise to the stirred nitronium triflate suspension keeping the reaction temperature at -65.0°C or less. The addition 15 funnel was then rinsed with 2 mL anhyd. DCM; this rinse also was added to the stirred reaction suspension. The dry ice/acetone bath could then be removed;
however, many reactions proceeded more cleanly if the bath was kept in place 30 to 60 minutes and was then allowed to warm unattended to room temperature over the next 15 to 48 hours. In several reactions, the acetone bath was kept in place one hour 2o and then was replaced with a dry ice/acetonitrile cold bath. The reaction was quenched by adding 15 mL of 5% sodium bicarbonate solution and stirring until bubbling ceased with an aqueous layer pH = 8 (With acidic compounds containing phenolic and carboxylic acid groups, only water was added to maintain an acidic pH).

The reaction contents were transferred with 25 mL DCM and 50 mL H20. The lower DCM layer was separated and washed with 5 x 25 mL H20. The combined H20 washes were back-extracted with 25 ml DCM, and the combined DCM portions dried over anhyd. MgS04. DCM removal by rotary evaporation gave crude product. This s procedure proportionally can be scaled to larger quantities by directly increasing reactant and solvent amounts while keeping reaction time periods the same.
Compound II, shown below, was obtained in 98% crude yield with an isolated 99% crude product purity from reactant I. Originally synthesized on a 7.5 mmole scale, its synthesis has been scaled up to 2864 mmoles, again, with a resultant 98%
1o crude product yield. One preliminary attempt to synthesize Compound II by the traditional HN03/acetic anhydride solvent procedure was not successful.

H3C0 I ~ OCH3 H3CO~OCH3 H3CO~OCH3 NYN INY'IN NYN
CI CI CI
2-chloro-4,6-dimethogy-5-nitropyrimidine (Compound I1J: Reacted 1.31g (7.50mmo1) I with 1.50 equivalents of nitronium triflate for 48 hours at room 15 temperature to obtain 1.61g II, (98%). FW = 219.6; 1H NMR (DMSO-d6) 8 4.06 (s, 6H); GCIMS (CI, m/z) 220 (Mk and base peak); FTIR (KBr) 3126, 3073, (aromatic CH); 3000, 2958, 2924, 2852 (aliphatic CH); 1524, 1354, (NOa), crri 1; mp uncorrected = 131.8 to 132.0 °C; Elem. Anal. for C6H6C1N3O4 (crude product) calculated C 32.82%, H 2.75%, N 19.14%, Cl 16.15, found C 33.12 %, H 2.81%, N
20 18.95%, Cl 16.43.
2-chloro-4,6-trimethogypyrimidin-5-amine (Compound III): A 500 mL three-__ necked, round bottom flask containing a Teflon-coated magnetic stirring bar and a thermometer was charged with 10.00 g (45.54 mmol) 2-chloro-4,6-dimethoxy-5-nitropyrimidine, 100 mL 190 proof ethanol, and 50 mL saturated, aqueous ammonium 25 chloride solution. The resultant suspension was stirred at room temperature for several minutes while iron powder (-325 mesh) was added in several portions over a 22 minute period such that the reaction temperature from a slow rising exotherm did not exceed 56 °C. After addition of all the iron powder, the reaction was stirred for two and one-half hours in a room temperature environment. The reaction suspension 3o was suction filtered, and the isolated iron powder was washed with 2 x 25 mL of
3 PCT/US02/17846 ethanol, followed by 3 x 25 mL of ethyl acetate. Too the organic filtrate was added 200 mL water and 50 mL more ethyl acetate to effect separation. The upper organic layer was separated, and the lower aqueous layer was extracted with 3 x 50 mL
of ethyl acetate. All ethyl acetate portions were combined and dried over anhydrous magnesium sulfate. Suction filtration, washing the spent magnesium sulfate with 15 mL ethyl acetate, and rotary evaporation left a pinkish, wet solid. The wet solid was dissolved in 75 mL dichloromethane, and the dichloromethane was washed with 3 x 25 mL of water. The combined water washings were back-extracted with 25 mL
dichloromethane. The combined dichloromethane portions were dried over anhydrous magnesium sulfate. Suction filtration, washing the spent magnesium sulfate with 25 mL dichloromethane, and rotary evaporation afforded 8.21 g (95%) of a cream-colored solid shown to be 98% pure by HPLC analysis. The NMR and mass spectrometry data consistent with the desired product is as follows: FW =
189.6; 1H
NMR (DMSO-d6) 8 4.59 (s, 2H), 3.89 (s, 6H); FILMS (APCI, nZ/z) 192.0, 190.0 is (M++1); FTIR (ATR film) 3420, 3342, 3290 (NH) 3180, 3010, (aromatic CH);
2960, 2871 (aliphatic CH); 1587, 1488, 1458, 1398, 1375, 1314, 1197, 1067, 942 (fingerprint) cm 1 ; Elem. Anal. for C6H8C1N302 calculated: C 38.01%, H 4.25%, Cl 18.70, N 22.16%, found C 38.24 %, H 4.32%, Cl 18.70, N 22.09%.
NOp H3CO~OCH3 H3CO~OCH3 N~.N INI~.NI

VI VII
2o The synthesis of VII was also achieved by direct nitronium triflate nitration of VI
in a 73% crude yield with 85% crude yield purity. This represents the first synthesis of VII by direct nitration. Use of the acetic anhydride/nitric acid nitration procedure gave several byproducts plus VII in only 16% purity. The only other literature preparation appearing in the Beilstein electronic data base for 2s VII produced it from VI and gave a 66% yield [Cherkasov, V. M.; Remennikov, G. Ya.; Kisilenleo, A. A. Chena. Heterocycl. Compd. (Engl. Transl.); EN; 526 (1982)].
2,4,6-trimethogy-5-nitropyrimidine (Compound VIIJ: Into a 5-L three necked, round bottom flask fitted with an overhead mechanical stirrer, was placed 920 3o g (0.675 mole) of tetramethylammonium nitrate and 1 L DCM. The reaction flask was fitted with a thermometer and addition funnel. The suspension was stirred under nitrogen gas for 15 minutes at room temperature. Into the addition funnel was placed 190 g (0.675 mole, 118mL) of trifluoromethanesulfonic anhydride that was added dropwise to the stirred suspension over a 35 minute duration so the temperature did not rise more than 5 °C. The addition funnel was rinsed with a small amount of DCM, s and this rinse was added to the stirred reaction suspension. The resultant suspension was stirred at room temperature for 1.5 hours. The addition funnel was charged with 76.9 g (0.452 mole) dissolved in a minimum amount of DCM and was added dropwise at room temperature over 85 minutes such that the reaction temperature did not rise more than 5 °C, and a bright crimson red suspension resulted.
The reaction 1o was stirred overnight at room temperature. Work up entailed adding 5 kg of ice to the stirred reaction suspension followed by 10% NaHC03 solution until a pH 8 was reached and the reaction turned from a burgundy to purple to blue to green to yellow color change. The lower DCM layer was separated and washed with 3 x 1.5 L of water. The DCM portion was then dried sodium sulfate, filtered, and the DCM
15 solvent was removed by rotary evaporation giving ca. 70 g of green solid.
Recrystallization from methanol/water in two crops afforded 50.5 g of purified product for an overall 52% yield. The NMR and mass spectrometry data consistent with the desired product is as follows: FW = 215.2; 1H NMR (CDC13) 8 4.06 (s, 6H),
4.02 (s, 3H); FI/MS (APCI, m/z) 216 (M++1 and base peak); FTIR (ATR film) 3047, 20 3009, 2999 (aromatic CH); 2957, 2877, 2847 (aliphatic CH); 1578, 1338 (N02), cm 1;
Elem. Anal. for C~H9N305 calculated: C 39.07%, H 4.22%, N 19.53%, found C
39.14 %, H 4.19%, N 19.61%.
O

VIII
Compound VIII represents another class of aromatic heterocycle product 2s that was obtained by the above mentioned nitronium triflate method and demonstrates that a pendant ester group also is not attacked nor modified by these nitration conditions.

Anhydrous Electrophilic Aromatic Nitration with Tetramethvlammonium Nitrate:
Nitration of non-heterocyclic aromatic compounds are also achieved with this anhydrous, one-pot, two-step method in which the nitronium triflate XVI
nitrating reagent is generated ih-situ under a static nitrogen gas blanket from s tetramethylammonium nitrate XIV and trifluoromethanesulfonic anhydride (triflic anhydride) XV. The aromatic compound to be nitrated is then introduced XVII.
Nitration occurs to produce the desired product XVIII plus the tetramethylammonium tiflate salt byproduct XIX.
Step 1 R Step 2 + ~ ~ CH2CI2 + - ~ ~ CHZCI2 (CH3)4NN03 + CF3SOSCF3 ~ N020SCF3 + ~ , N as O O N2 gas 2 9 RT New ReaCgent -7$ °C to Reflex Generation Method XIV XV XVI XVII
R O
+- ii \ + (CH3)4NOSCF3 ' \NO2 O
XVIII XIX
1o When using the tetramethylammonium nitrate reagent XIV, the resulting salt byproduct XIX is water soluble and is removed during an aqueous work-up leaving only the desired nitrated product XVIII after drying. Under similar reaction conditions, higher homologues of XIV (e.g. tetra-rc-butylammonium nitrate and tetraethylammonium nitrate) require additional, time intensive purification by column is chromatography or short column Silica Gel filtration to remove the analogous XIX
byproduct. The one lower homolog, ammonium nitrate, gives irreproducible results under analogous nitration conditions.
Most reactions have been conducted in methylene chloride solvent at room temperature. However, chloroform, dichloroethane, and nitromethane also would be 2o suitable solvents and would permit higher temperatures to be achieved by refluxing the reaction in step 2 with electron-deficient aromatic ring systems or when attempting to effect aromatic dinitration.
From 1.05 to 1.50 equivalents of nitronium triflate have been used for mononitration of the aromatic or heterocyclic reactant with excess reagent having no 2s deleterious effect. The less reactive the reactant, the larger the excess of nitronium triflate is needed for complete conversion. More than 1.5 equivalents of nitronium triflate could be used; no upper limit has been determined.
This reaction method (General Procedure) has been scaled linearly from the 7.5 mmole size (aromatic compound to be nitrated) to 92.9 mmoles. To date, no s upper limit has been established. It appears this method is limited only by the size of equipment available.
Additional Nitration Examples:
The following mono-substituted benzene compounds were evaluated for directing effects and substituent stability during the reaction conditions of this nitration method (ND = not detected). Table 1 illustrates the wide scope of mono-substituted benzenes nitrated with this method and reveals the directional susceptibility of nitronium triflate nitration to aromatic pendant group effects.
The nitrations were conducted with 1.05 equivalents of nitronium triflate as described by the General Procedure. Reaction conditions were not optimized for 1s these exploratory reactions, and isomeric percentages were determined by proton NMR analysis of the isolated crude products.
Table 1. Tetramethylammonium Nitrate Nitration of Mono-Substituted Benzenes (7.5 mmol scale).
Compound No. Conversion Isolated o/m/t~-IsomersTime fhrs.l (%1 Yield (%1 (%1 R = OCH3 1 100 97 63/5/32 24 Br 4 95 90 33/0/67 26 ____ 6 ___ 68 7/89/4 48 S02CH3 8 57 89" 13/84/3 102 ND = not determined because of reactant volatility and its loss during solvent removal.
A= Actual yield in a pure isolated mixture contained only reactant (43%) and product isomers (57%).
OMe OH CH3 Br HO CF3 C02H S02CH3 \ \ \ \ \ \ \ \

This one-pot tetramethylammonium nitrate-based nitration also was applied to multiple-substituted aromatic compounds under the same reaction conditions. Table 2 displays the results obtained.
Table 2. Tetramethylammonium Nitrate Nitration of Multiple-Substituted Benzenes (7.5 mmol scale).
Com op and % Converted Product s Reaction Time Isolated Yield (%1 Isolated Puritv (961 100 % I ~ 17 hrs. 71 % 92~
~NOz OCH3 OCI-~ OCH3 100 % ~ I ~ NOz _____ hrs. 82%
H3C0 ~ H3C0 ~ ~ OCH3 10 No2 95% 5%
11a 11b OH OH
NOZ
100 °~ I ~ 27 hrs. 94% 91%
0 CHZBr O CHZBr H3co cN ocH3 58 °~A H3co ~N ocH3 15 hrs. 43% -'-"
I i 96 °~A I ~ NOz 46 hrs. 80 % 81 OCH3 100 °!°B oCH3 53 hrs. 82% 95%

A. NOzOTf equivalents = 1.05 relative to the reactant 14.
B. NOZOTf equivalents = 1.50 relative to the reactant 14.
Compound purity was determined by HPLC analysis. Crude product 9 was purified further by preparative HPLC to greater than 99%. Compound 13 was purified by recrystallization from hexane. Both 9 and 13 gave acceptable elemental analyses. The only previous synthesis of 13 by direct nitration used fuming nitric acid at 5 °C for one hour, and gave a 70% crude product yield with an apparent purification obtained from an ethanol recrystallizati0n as described by Garg et al., J. Chem. Soc., 607, (1969). Compound 10 and its products lla and llb reveal that the sterically crowded position between 1,3-disubstituted methoxy groups is not attacked when less sterically hindered positions are available.
When 2o no alternative is available, nitration readily occurs between two 1,3-di-substituted methoxy groups as shown by 2,4,6-trimethoxybenzonitrile 14 where product 15 is obtained in good yield and purity. Other than the equivalents of NOZOTf, used, the main difference in reaction conditions between the latter two runs of reactant 14 was reactant 14 had a slower warming profile that gave the highest crude yield 2s and purity for product 15. In the first two reactions with 14, the dry ice/acetone cooling bath was removed immediately after adding reactant 14 like that described in the General Procedure. The better result in the third reaction of 14 was obtained by replacing the dry ice/acetone cooling bath with a dry ice/acetonitrile cooling bath for 2.5 hours (-50°C to -35°C), allowing the bath to warm to 9°C over S the next 2.5 hours, then removing the cooling bath completely and stirring the reaction for 48 hours. Product IS has not previously been reported in the chemical literature and represents a new compound.
This General Procedure scales directly from 7.5 to 100 millimoles by proportionally increasing the amounts of reagent and solvent while keeping to reaction times the same. Results of large-scale reactions appear in Table 3.
Unless stated otherwise, product particles were determined by HPLC analysis.
Table 3. Tetramethylammonium Nitrate Nitration at Large-Scale (86 to 100 mmol scale).

Reactant Scale Eauiv. of 3 Product IsolatedIsolated s Reaction Time Yeld Puritv OH H

~
NO2 91 % 88/ (nmr) 93 mmoles 1.1 I i 23 hrs.

CH2Br CHzBr O O

24 hrs. 94% 93% (nmr) 05 I ~ I ~

l ~N02 NO
es .
mmo z 23 100% 0%

24a 24b CN CN
H3CO~OCH3 H3CO~OCH3 90-100 1.5-1.7 ~ 48-52 hrs.2-84 0-95 %
%

mmoles H Ox OCH OC

CN CN CN

H3C0 ~ H3C0 ~ H3C0 100 mmoles 1.5 I ~ N02 OZN 91-96/ 78-82 %
I ~ 52 hrs.

26a 26b - CN CN

~ OCH3 H3C0 H3C0 ~ OCH3 I I 100 97 %
100 mmoles 1.5 ~ NOz 48-52 %
hrs.

As shown in Tables 2 and 3, the brominated acetyl group of reactant I2 was stable to the mild nitronium triflate electrophilic nitration conditions.
The carbonyl group in aldehyde, and carboxylic actid groups are compatible with this nitration procedure (Table 1), as is an ester group, and the unsaturated cyano 2o group is compatable with this reaction.

In the smaller 7.5 milligram scale nitration of reactant 10, nine percent of product isomer llb was obtained and was removed by recrystallization. No formation of product 11b was obtained in the larger scale reaction, see Table 3.
Compound 23 selectively produced the one isomeric product 24a in an excellent yield. In contrast, a literature nitration of 23 using the nitronium tetrafluoroborate reagent (N02+ BF4 ) produced 5% 24b by product as an impurity as described in Olah et al, J. Am. Chem. Soc., 86, 1067, (1964).
Compound 29 nitrated by this method gave different results when compared with the standard acetic anhydride/nitric acid nitration system. Each method gave the different xegioisomer in exclusive or a nearly exclusive yield. The nitronium triflate method heavily favored o>"tho-nitration with respect to the methylsulfamide group 30a, while the standard acetic anhydridelnitric acid method provided exclusive papa-nitration 30b.

NOZ* OS02CF3 1.05 eq., CHZCIz, Nz (g) ~ ~ N-S02CH3 H3C0 -72°C toRT HCO

H 30a + pace of 30b H3C0 CH3COCC1-lo / HN03 HaCO
H
29 RT 02N ~ ~ N-S02CH3 H3C0 30b In the oxidative environment of this in-situ nitration method, axomatic alkylsulfides 31 are cleanly oxidized to their analogous sulfoxide 32, and the sulfoxide 32 is then oxidized to a sulfone 33 in an apparent stepwise fashion.
Once the fully oxidized sulfone 33 is obtained, nitration can then occur to provide the mono-nitrated sulfone 34. This is illustrated by the three following non-optimized reactions.
O~ ~CHg O
+ - II CH2CIz, N2 (g) ~ 100 % CONVERSION
I / ~.. N02 O ii CF3 _7a °C~ I ~ g7 % CRUDE YIELD
31 ~ 32 1.05 equivalents __ _ ~ CH
O CH3 + - S CH2C12, Nz (g) ' O S O O~' 3 + N02 OSOCF
3 -75 °C to RT
I / ~ I / "f I / 64 % CONVERSION
NOT OPTIMIZED
32 1.05 equivalents 64 % 36 O=s=OO O=S=O O=s=O

\ -I- - CHzCIz, Nz (g) \
\

+ ~ ~ / 56 % CONVERSION
/ N02 OSOCF3 _73 G~ ~ / NOT OPTIMIZED

O

33 1.05 equivalents56 % 44 In each reaction step, only the product and unconverted reactant were detected with no byproducts present. With the correct number of nitronium triflate s equivalents, unique aromatic sulfones could be made during a clean, one-pot reaction.
SR

O O=S=O
\ -F - I I CH2CIz, Nz (g) \
NOp O ~~ CF3 -74Ct~

O /

multiule equivalents NOZ

d HO~OH + _ ~ GH2ch, Nz (g) \ OH
Fi0 I YN ..f. NOp O ii CF3 I
a4C to RT NYN

SCH3 O O=S=O

mul- tiule equivalentsCH3 The nitrated products obtained by this nitration method shown in Tables 2 and 3 were characterized as follows:
l0 1,4-Dimethogy-2-nitrobenzene (9): Reacted 1.04 g (7.50 mmol) 8 with 1.05 equivalents of nitronium triflate to obtain an isolated yield of 0.97 g (71%).
FW =
183.1; 1H NMR (DMSO-d6) 8 7.46 (s, 1H), 7.28 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H).
GC/MS (CI, m/z) 183 (M+ and base peak); FTIR (KBr,) 3071, 3024 (aromatic CH), 2982, 2946, 2844 (aliphatic CH), 1528, 1355 (N02) cni l; mp uncorrected, (crude =
15 68.6 to 70.0°C), (hplc purified = 70.8 to 71.2 0 °C), lit. mp = 71-73°C, 68-70 °C, 71 °C; Elem Anal for C$H9N04 calcd C 52.46%, H 4.95%, N 7.65%, found C
52.55%, H 4.94%, N 7.63.
1,3-Dimethogy-4-nitrobenzene (11a): Reacted 1.04 g (7.50 mmol) 10 with 1.05 equivalents of nitronium triflate to obtain an isolated yield of 1.13 g (82%
with 5%
20 llb isomer). FW = 183.1; 1H NMR (DMSO-d6) 8 7.97 (d, J = 9Hz, 1H), 6.80 (d, J =
2Hz, 1H), 6.67 (dd, Jl = 9Hz, J2 = 3Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H); GC/MS
(CI, n~/z) 183 (MF and base peak).
1,3-Dimethogy-2-nitrobenzene (11b): FW = 183.1; 1H NMR (DMSO-d6) 8 7.48 (t, 1H), 6.89 (d, 2H), 3.86 (s, 6H); GC/MS, (CI, m/z) 183 (M'~ and base peak).
2s 2-Bromo-1-(4-hydroxy-3-nitrophenyl)ethanone (13): Small Scale: Reacted 1.70 g (97.91 mmol) 12 with 1.15 equivalents of nitronium triflate to obtain an isolated yield of 1.93 g (93%). Lame Scale: Reacted 19.98 g 12 with 1.10 equivalents of nitronium triflate to obtain an isolated yield of 21.90 g (91%).
Recrystallized from hot hexane. FW = 260.0; 1H NMR (DMSO-d6) 8 12.18 (brd. s, 1H), 8.49 (s, 1H), 8.13 (d, 1H), 7.24 (d, 1H), 4.89 (s, 2H); ES/MS (CI, m/z) s (M'), 258 (base peak); FTIR (I~Br) 3279 (OH), 3086, (aromatic CH); 2997, (aliphatic CH), 1695 (C=O), 1568, 1329 (NOa) crri 1; mp uncorrected = 87.8 to 89.4 °C, (lit. mp = 91.5 to 92.0°C), Elem Anal for C$H6BrN04 calcd C
36.95%, H 2.33%, N 5.39%, Br 30.73%, found, C 37.28 %, H 2.34%, N 5.44%, Br 30.90%.
2,4,6-Trimethogy-3-nitrobenzonitrile (15): Small Scale: Reacted 1.48 g (7.51 1o mmol) 14 (98%) with 1.50 equivalents of nitronium triflate to obtain an isolated yield of 1.54 g (86%). Large Scale: Reacted 17.80 g (90.29 mmol) 14 (98%) with 1.66 equivalents of nitronium triflate to obtain an isolated yield of 17.59 g (82%).
Recrystallized from methanol. FW = 238.2; 1H NMR (DMSO-d6) 8 6.79 (s, 1H), 4.02 (s, 6H), 4.01 (s, 1H); FI/MS (APCI, mlz) 209 (Mh-30 and base peak); FTIR
is (ATR film) 3114, (aromatic CH); 2994, 2957, 2924, 2984 (aliphatic CH), 2228 (CN), 1529, 1349 (N02) cm 1; mp uncorrected = 195.2 to 195.6 °C; Elem Anal for CloHION2O5 calcd C 50.42%, H 4.23%, N 11.76%, found C 50.60 %, H 4.18%, N
11.80%.
4-tart-Butyl-2-nitrophenol (24a): FW = 193.3; Reacted 12.2 g (82.3 mmol) 23 20 with 1.04 equivalents of nitronium triflate to obtain an isolated yield of 15.0 g (94%).
1H NMR (CDC13) 8 7.84 (s, 1H), 7.40 (d, 1H), 7.12 (d, 1H), 2.42 (s 3H), 1.21 (s, 9H);
GC/MS (CI, m/z) 194 (M++1), 178 (base peak).
2,4-Dimethoay-5-nitrobenzonitrile (26a): Small Scale: Reacted 1.23 g (7.54 mmol) 25 (98%) with 1.25 equivalents of nitronium triflate to obtain an isolated yield 2s of 1.40 g (89% with 9% 26b isomer)._Lar eg Scale: Reacted 16.65 g (100.0 mmol) 25 (98%) with 1.50 equivalents of nitronium triflate to obtain an isolated yield of 18.99 g (91%). Recrystallized from methanol. FW = 208.2; 1H NMR (DMSO-d6) 8 8.46 (d, J
= 3Hz, 1H), 6.99 (s, J = 3Hz, 1H), 4.06 (s, 6H); GC/MS (CI, mlz) 208 (M~, 161 (base peak); FTIR (ATR film): 3126, 3073 (aromatic CH) 3000, 2958, 2924, 2852, 30 (aliphatic CH), 2232 (CN), 1524, 1354 (N02) cm 1; mp uncorrected = 195.8 to 196.4 °C; Elem Anal for C9H8N204 calcd C 51.93%, H 3.87%, N 13.46%, found, C
51.93 %, H 3.85%, N 11.45%.
2,6-Dimethogy-3-nitrobenzonitrile (28): Reacted 16.82 g (100.0 mmol) 27 (97%) with 1.50 equivalents of nitronium triflate to obtain an isolated yield of 20.85 g 3s (100%). Recrystallized from methanol. FW = 208.2; 1H NMR (DMSO-d6) b 8.34 (d, 1H), 7.18 (d, 1H), 4.03 (s, 6H); FI/MS (APCI, m/z) 209 (M'-+1), 208 (M'~, 179 (base peak); GC/MS (CI, m/z) 208 (M'~), 178 (base peak); FTIR (ATR film) 3114 (aromatic CH), 2994, 2957, 2924, 2854 (aliphatic CH), 2228 (CN), 1529, 1349 (NOa) cm 1;
mp uncorrected, crude = 115.4 to 115.6 °C); Elem Anal for C9H$N204 calcd C
50.42%, H
40 4.23%, N 11.76%, found C 50.60 %, H 4.18%, N 11.80%.

N-(3,5-dimethoxy-2-nitrophenyl)methanesulfonamide (30a): Reacted 1.75 g (7.51 mmol) 29 with 1.05 equivalents of nitronium triflate to obtain an HPLC
purified yield of 0.25 g (11%). FW = 276.3; 1H NMR (CDC13) 8 8.31 (s, 1H), 6.88 (d, J =
3Hz, 1H), 6.32 (d, J = 3Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.03 (s 3H); 13C
NMR
(CDC13, 300 MHz) 164.01 (1C), 156.35 (1C), 134.75 (1C), 97.65 (1C), 96.45 (1C), 57.18 (1C), 56.47 (1C), 40.57 (1C); FI/MS (ANCI, m/z) 275 (M'-1).
N-(3,5-dimethoxy-4-nitrophenyl)methanesulfonamide (30b): Reacted 0.544 g (2.35 mmol) 29 with fuming nitric acid in acetic anhydride in an ice bath for minutes, removed ice bath for 4 hrs, and worked up reaction to obtain an HPLC
1o purified yield of 0.070 g (10%). FW = 276.3; 1H NMR (CDC13) 8 6.48m (s, 2H), 6.87 (s, 6H), 3.07 (s, 3H); 13C NMR (CDCl3, 300 MHz) 153.49 (2C), 140.26 (1C), 126.28 (1C), 95.85 (2C), 57.07 (2C), 40.12 (1C); FI/MS (APCI, m/z) 277 (MF+1).
Procedural Notes:
Reactant 14 (Table 2): the first two runs were conducted by removing the dry ice/acetone bath as described in the General Procedure. The best small-scale result with 14 used a slower warming profile by replacing the dry ice/acetone cooling bath with a dry ice/acetonitrile cold bath fro 2.5 hours (-49.6°C to -35.0°C), allowing the bath to warm to 9.0°C over the next 2.5 hours (-35.0°C-9.0°C), then removing the bath 2o completely and stirring for 48 hours. This led to the following temperature warming modification for the large-scale nitrations with reactants 14, 25, and 27.
After addition of aromatic reactant, the reaction was kept one hour in the dry ice/acetone bath; then, it was then replaced with a dry ice/acetonitrile bath (ca. --45°C) for three hours, after which, the bath was permitted gradually to warm unattended to room 2s temperature (RT) over the nexr 48 hours. For compound 23, the dry ice/acetone bath was removed as soon as addition was complete arid was stirred in a RT
environment for 24 hours. For compound 12 (large scale), the dry ice/acetone bath was not removed following its addition, but was left in place to warm gradually, unattended to RT over the next 23 hours.
Synthesis Of GnR_H_ Reagents And Compounds:
The inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of preferred compounds 3s of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other protein kinase inhibitors of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art. For example, the preparation of free amines from common salt forms and stock reagent solutions can be useful for small-scale reactions. See also Abdel-Magid et al., "Reductive Amination of Aldehydes and 1o Ketones with Sodium Triacetoxyborohydride," J. O~g. Chem. 61: 3849 (1996).
Methanolic solutions of the free bases can be prepared from hydrochloride, dihydrochloride, hydrobromide, or other salts when the free base is soluble in methanol. In this procedure, once the sodium methoxide is added, care should be taken to prevent exposure to air, since amine free bases, particularly primary amines, absorb carbon dioxide from the air to form salts. A 10~-mL quantity of a O.1M
solution of a free base in methanol may be prepared as follows. Weigh 1.0 mmol of a monohydrochloride salt into a tared Erlenmeyer flask containing a stirring bar, and ad~i 7 mL of methanol. To the stirred slurry, add 229 mL (1.0 mmol, 1 equiv.) of sodium methoxide in methanol (25 wt %, 4.37 M), stopper the flask, and stir the 2o mixture vigorously for 2 hours. The slurry will sometimes change in appearance as a finer, milky precipitate of sodium chloride is formed. Filter the slurry through a 15-mL medium fritted glass funnel, wash the filter case with 1-2 mL methanol, transfer the filtrate to a 20-mL vial, and dilute to 10 mL with methanol. The theoretical yield of sodium chloride is nearly 59 mg, but the recovery is usually not quantitative, owing 2s to a slight solubility in methanol. For a dihydrochloride salt, a second equivalent of sodium methoxide is required (458 mL).
A 0.5 M solution of sodium borohydride in ethanol may be prepared as follows. Sodium borohydride (520 mg, 13.8 mmol) is stirred in pure (non-denatured) anhydrous ethanol (25 mL) for ~2-3 minutes. The suspension is filtered through a 3o medium fritted glass funnel to remove a small amount of undissolved solid (typically about 5% of the total mass of borohydride, or 25 mg). The filtrate should appear as a colorless solution that evolves only a little hydrogen. This solution should be used immediately, as it decomposes significantly over a period of a few hours, resulting in the formation of a gelatinous precipitate. Sodium borohydride is hygroscopic, so avoid exposure to air by making the solution at once after weighing the solid.
Sodium borohydride has a solubility of about 4% in ethanol at room temperature. This corresponds to a little over 0.8 M. However, sometimes a small percentage of the solid remains undissolved regardless of the concentration being prepared, even after stirring for > 5 minutes.
Material and Methods:
In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius and all parts and percentages are by weight, unless indicated otherwise.
1o Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were purchased from Aldrich in SureSeal~ bottles and used as received. All solvents were purified by using standard methods in the art, 1s unless otherwise indicated.
The reactions set forth below were performed under a positive pressure of nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks are fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and/or Exemplary GnR_H_ Agents:
The following compounds were prepared according to Scheme A set forth below:
Scheme A

\ H KOH ~ \ OK
R i / R i / . R ~ / ~O-' -\ ~z RI
R
NaOH, CH3OH \ O _ R i H EDCI or II?.TU /

SOCIz, benzene Catalytic DMF
~~2 R [~'I
i /
\ O
R

TEA, DCM

Potassium phenogide 10: A mixture of potassium hydroxide (2.55g, 44.8 mmol) and the appropriate phenol 9_ (52.9 mmol) was heated in an oil bath at °C for 1-2 hours. The dark colored liquid was then evacuated at 130-140 °C to s remove water. The residue (potassium phenoxide ~ was dried i~c vacuo overnight.
Alternatively, the phenoxide 10 may be prepared by reaction with potassium t butoxide in tetrahydrofuran.
Condensation 12: A mixture of potassium phenoxide 10 (7 mmol), prepared as described above, and methyl 5-bromo-2-furoate 11 (5.8 mmol) in DMSO (10 mL) to was heated at 85 °C under nitrogen atmosphere. The reaction mixture was then diluted with water, and the aqueous mixture was acidified with concentrated HCI, and then extracted with diethyl ether. The combined ether extracts were concentrated and the product 12 was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexanes (1:5 to 1:1 v/v). Yield was in the range of 50-80%.
Saponification 13: The methyl ester 12 obtained from above was dissolved in methanol (4 mmol in 15 mL of solvent). An aqueous solution of sodium hydroxide (0.7g in 5 mL water) was added. The mixture was monitored by TLC for completion of reaction. It was concentrated, diluted with water, and extracted with diethyl ether.
The aqueous layer was then acidified with concentrated HCI, and extracted with ethyl 2o acetate. The ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated to give a solid residue. The product 5-substituted-2-furoic acid 13 may be purified, if necessary, by silica gel chromatography. Yield was greater than 90%.
Amide Formation: Procedure l: The furoic acid 13 from above (1 mmol) was dissolved in dimethylformamide (5 mL). To this solution was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 1 mmol), followed by the addition ofthe appropriate aniline or aniline hydrochloride (1 mmol), and triethylamine (1.1 mmol). The reaction mixture was stirred'at room temperature overnight. DIVIF' was removed on a rotovap. The residue was suspended in ethyl acetate, and washed with 10% HCl (aqueous), aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. The solvent was removed on a rotovap. The product 15 was purified by silica gel chromatography using a mixture of ethyl acetate/hexanes (2/1 v/v) as the eluting solvent.
Procedure 2: The furoic acid 13 from above (1 mmol) was dissolved in to dimethylformamide (5 mL). To this solution was added HATU (1 mmol), followed by the addition of the appropriate aniline or aniline hydrochloride ( 1 mmol), and triethylamine (2-3 mmol). The reaction mixture was stirred at room temperature overnight. D1VIF was removed on a rotovap. The residue was suspended in ethyl acetate, and washed with 10% HCl (aqueous), aqueous sodium bicarbonate, brine, and 1s dried over magnesium sulfate. The solvent was removed on~a rotovap. The product 15 was purified by silica gel chromatography using a mixture of ethyl acetate/hexanes (2/1 v/v) as the eluting solvent.
This procedure may be applied to the synthesis of anilides of the present invention. Alternatively, the appropriate amide 15 may be prepared via carboxylic 20 acid chloride 14. A suspension of 13 (300mmol) in anhydrous benzene (100m1) containing a ew drops of anhydrous DMF was heated to relax under nitrogen as thionyl chloride(l.l eq.) in benzene (35m1) was added dropwise. The solution was refluxed for 10 hours and then cooled to room temperature and concentrated under vacuum to give 14. A mixture of the appropriate aniline or aniline hydrochloride salt 25 (l.2eq.) and triethylamine (2.Se~ in dichloromethane was stirred at 0°C under nitrogen as a solution of 14 in dichloromethane was added dropwise. The solution was allowed to warm to room temperatureand further stirred for 12 hours. The resulting suspension was washed several times with 2N hydrochloric acid, saturated soduim bicarbonate, brine and water successively. The organic layer was dried over 3o anhydrous sodium sulfate, concentrated under vacuum to give 15 which was then purified by column chromatography.
Example Al: 5-(3,5-dichlorophenogy)-N-(2,4,6-trimethogyphenyl)-2-furamide I
00 , ci I ~ o 0 \/
A1 c~
Compound A1 was made according to Scheme A where:
\o c1 ~ off \o ~ i o~
and CI
were used as the starting materials Yield of the purified product was 70-85%.
NMR
and mass spectrometry data consistent with the desired title product were as follows:
1H NMR (300 MHz, CDC13): 8 7.39 (s, 9H), 5.78 (d, 1H), 6.15 (s, 2H), 7.00 (s, 2H), 7.16 (d, 2I~, 7.24 (s, 1H), APCI-MS m/z 438 (M+H)+.
Example A2: 5-(2,6-dimethylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide o\

\ o o \
I H
/O
Compound A2 was synthesized in a manner analogous to that of A1, according Scheme A. Yield of the purified product was 17%. NMR and mass spectrometry data consistent with the desired title product were as follows:

(300 MHz, CDCl3): 8 2.24 (s, 6H), 3.83 (s, 3H), 3.85 (s, 6H), 4.96 (d, 1H), 6.20 (s, 2H), 7.05 (d, 1H), 7.10 (s, 3H), 7.20 (lir s, 1H), APCI-MS m/z 398.1 (M+H)+.
15 Example A3: 5-(5-isopropyl-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide i H \
/o Compound A3 was synthesized in a manner analogous that of Al, according to Scheme A. The yield of the purified product was 48%. NMR and mass 2o spectrometry data consistent with the desired title product were as follows: 1H NMR
(300 MHz, CDC13): ~ 1.25 (d, 6H), 2.26 (s, 3H), 2.88 (m, 1H), 3.81 (s, 9H),
5.38 (d, 1H), 6.18 (s, 2H), 6.95 (br s, 1H), 7.0 - 7.21 (m, 4H), APCI-MS m/z 426.1 (M+H)+.

Example A4: 5-(2-methyl-6-propylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I

\/
A4 -o Compound A4 was synthesized in a manner analogous to that of Al, according to Scheme A. NMR data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDC13): ~ 0.95 (t, 3H), 1.58 (sextet, 2H), 2.26 (s, 3H), 2.56 (t, 2H), 3.81 (s, 3H), 3.83 (s, 6H), 4.96 (d, 1H), 6.18 (s, 2H), 7.10 (d, 1H), 7.13 (s, 3H), 7.22 (br s, 1H), APCI-MS m/z 426.1 (M+H)+.
Example A5: 5-[(1-bromo-3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N-(2,4,6-trimethoxypyrimidin-5-yl)-2-furamide I I
e~ o ° %~ °
O O N
I ~ \ ~ " O
A
Compound AS was synthesized in a manner analogous to that of Al, using similar starting compounds and where the pyrimidine is made from nitro compound VII which was further reduced to the amine in a manner analogous to that of compound III. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (CH30D): S 1.18 (s, 6H), 1.57 (d, 2H, J = 6.04 Hz), 1.77 (d, 2H, J = 6.42, 3.40 Hz), 2.27 (s, 3H), 2.68 (m, 2H, J = 6.80,
6.42 Hz), 3.86 (s, 6H), 3.91 (s, 3H), 5.32 (d, 1H, J = 3.40 Hz), 7.09 (d, 1H, J = 4.91 Hz), APCI-MS m/z 546 (M+H)+.
2o Example A6: 5-(4-bromo-2,6-dimethylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I ~ ~ I~I ~ \ / ~\

A6 \
Compound A6 was synthesized in a manner analogous to that of Al, according to Scheme A, via the acid chloride as set forth above. The yield of the 2s purified product was 35%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDC13): ~ 2.15 (s, 6H), 3.76 (s, 3H), 3.77 (s, 6H), 4.92 (d, 1H), 6.12 (s, 2H), 6.98 (d, 1H), 7.11 (br s, 1H),
7.19 (d, 2H), APCI-MS nalz 475.9 (M+H)+.
Example A7: 5-[(1-bromo-3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N-(2,6-dimethoxyphenyl)-2-furamide I
°
°
°
A7 ~
Compound A7 was synthesized in a manner analogous to that of Al, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR
(CH30D):
8 1.18 (s, 6H), 1.56 (m, 2H), 1.78 (m, 2H), 2.28 (s, 3H), 2.68 (d, 2H, J =
6.42 Hz), 3.75 (s, 6H), 5.31 (d, 1H, J= 3.78 Hz), 6.61 (d, 2H, J = 8.69 Hz), 7.06 (d, 1H, J =
3.40 Hz), 7.10 (s, 1H), 7.1? (t, 1H, J = 8.69, 8.31 Hz), APCI-MS m/z 515 (M+H)~".
Example A8: 5-[(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamic~e I
o I
w ~b A8 ~
1s Compound A8 was synthesized according to Scheme A. The yield of the purified product was 25%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDCl3): 81.22 (s, 6H), 1.28 (s, 6H), 1.66 (s, 4H), 3.80 (s, 9H), 5.41 (d, 1H), 6.15 (s, 2H), 7.06 (s, 1H), 7.18 (d, 1H), 7.51 (s, 1H), APCI-MS m/z 558.3 (M+H)+.
2o The requisite phenol, 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenol, was prepared as follows:
/ C CI~~~\~I //~~// 7.5 mol% AICI° / C BBr3, CHZCI~ / OH
I Br + ~CI CH ~ I gr -78 °~ ~ I Br 6-bromo-7-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (~: A solution of 2-bromoanisole, 2,5-dichloro-2,5-dimethylhexane (1.l equiv.) in 25 dichloromethane (2 mL/mmol) was stirred at 0 °C under nitrogen as anhydrous A1C13 (7.5 mol%) was added portionwise while keeping the temperature below 5 °C. The suspension was allowed to warm to room temperature and further stirred for about 15 hours. The resulting white suspension was poured into ice water (50 mL) and the aqueous l~.yer was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The white solid thus obtained was recrystallized from toluene to give 6-s bromo-7-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene in 78%
isolated yield. NMR data consistent with the desired title product were as follows: 1H
NMR
(300 MHz, CDCl3): b 1.21 (s, 6H), 1.27 (s, 6H), 1.61 (s, 4H), 3.80 (s, 3H), 6.80 (s, 1H), 7.40 (s, 1H).
3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenol ii : 6-1o Bromo-7-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene in CH2C12 (3 mL/mmol) was demethylated by adding borontribromide (1.2 equiv.) in CHZCl2 at-78 °C. The reaction mixture was allowed to warm to room temperature and further stirred for 15 hours. The solution was diluted with CH2Clz, washed with saturated NaHCO3. The organic layer was dried (Na2S04) and concentrated to give 3-bromo-1s 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenol in 90% yield. NMR
data consistent with the desired title product was as follows: 1H NMR (CDC13): 8 1.25 (s, 12H), 1.68 (s, 4H), 5.28 (s, 1H), 6.94 (s, 1H), 7.32 (s, 1H).
Example A9: N-(2,6-dimethoxyphenyl)-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy)-2-furamide o _0 0 I ~ I I " \
2o A9 \
Compound A9 was synthesized according to Scheme A via HATU. The yield for purified product was 27%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (CDC13): & 1.23 (s, 6H), 1.28 (s, 6H), 1.67 (s, 4H), 3.85 (s, 3H), 5.34 (d, 1H), 6.62 (d, 2H), 7.01 (s, 1H), 7.13 (d, 1H), 7.15 25 (s, 1H), 7.23 (s, 1H), 7.26 (s, 1H), 7.34 (br s, 1H), APCI-MS m/z 464.1 (M+H)+.
OH CI~ ~ / 0 °C to rt, 2 h ~ OH
+ %~CI + AICI3 CH2CI2 v 1.1 equiv 10 mol%

Example A10: 6-methogy-3,3-dimethyl-1-ogo-N-(2,4,6-trimethoxypehnyl)-5-indanecarboxamide Compound A10 was synthesized in a manner analogous to that of Al, according to Scheme A, using similar starting compounds and reaction conditions.
The overall yield is 5%. NMR and mass spectrometry data consistent with the desired s title product were as follows:1H NMR (300 MHz, CDC13): ~ 1.48 (s, 6H), 2.62 (s, 2H), 3.81 (s, 9H), 3.92 (s, 3H), 5.69 (d, 1H), 6.24 (s, 2H), 7.20 (s, 1H), 7.32 (s, 1H), APCI-MS m/z 482.1 (M+H)+.
OH / OH
I OH ~O PPA O
O O

Example All: N-(benzyloxy)-5- f (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-1o naphthalenyl)oxy}-2-furamide HN-~O
All Compound Al l was synthesized in a manner analogous to that of Al, according to Scheme A, using similar starting compounds and reaction conditions.
The overall yield was 33%. NMR and mass spectrometry data consistent with the 15 desired title product were as follows: 1HNMR(300 MHz, CDC13): S 1.20 (s, 6H), 1.26 (s, 6H), 1.78 (s, 4H), 2.21 (s, 3H), 5.00 (s, 2H), 5.30 (d, 2H), 6.90 (s, 1H), 7.10 (s, 1H), 7.14 (d, 1H), 7.40 (m, SH), 8.56 (br s, 1H), APCI-MS m/z 434.1 (M+H)+.
Example A12: 5-[(7-chloro-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide i ~ ° \ / H \ / °v O N ~ CI
2o A12 Compound A12 was synthesized in a manner analogous to that of A1, according to the following scheme:

OMe OH
I OMe + O / E>3N~ THF ~ ~ ~ CI AICo3 _ I

H2N~C1 ~ O H
3A 3B 3C 3D (49% yield from 3A) O HO ~ O O
general scheme 1A I ~ O \O/ H ~ / O\ Mel~NaH I ~ O \O/ H O / O\

H OI \ O N CI

To a solution of Compound 3A (10g) and 3B (7.5g) in THF (200 ml) was added EtN3 (6.5g). The solution was stirred at room temperature overnight. The reaction mixture s was extracted with EtOAc, dried and concentrated to give 16 g of 3C as brown oil...The residue was dissolved in 100 ml of CHZC12. To this solution was added A1C13 (33g). The solution was concentrated. The mixture was heated to 130°C in an oil bath under NZ overnight. The mixture was cooled to room temperature and extracted with EtOAC. Compound 3D was precipitated in ~H3CN (7.3g). To a to solution of Compound 3A (10g) and 3B (7.5g) in THF (200 ml) was added EtN3 (6.5g). The solution was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc, dried and concentrated to give 16 g of 3C as brown oil...The residue was dissolved in 100 ml of CH2Clz. To this solution was added A1C13 (33g). The solution was concentrated. The mixture was heated to 130°C in an ~s oil bath under N2 overnight. The mixture was cooled to room temperature and extracted with EtOAC. Compound 3D was precipitated in CH3CN (7.3g). NMR and mass spectrometry data consistent with the desired title product were as follows: 1H
NMR (MeOD): 8 1.29 (s, 6H), 2.54 (s, 2H), 3.41 (s, 3H), 3.88 (s, 9H), 5.45 (d, 1H), 6.21 (s, 2H), 7.10 (s, 1H), 7.14 (d, 1H), 7.19 (s, 1H), APCI-MS rrmlz 515.2 (M+H)+.
2o Example A13: 5-[(7-chloro-1,4,4-trimethyl-1,2,3,4-tetrahydro-6-quinolinyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide /
0o i I o\
I w o \o/ H
~cl Compound A13 was synthesized in a manner analogous to that of Al, according to the following scheme:

~ ~(7~ ~0 LAFi ~ OH ~~~OMe ~~ general scheme 1A ~~~ \ /
n ni ci mo .oa,rv ~ N CI
_. , . , ..,.,.
1o3 104 O O i l.Mel, ICzC03, DMF
\O/ OHgeneralschemelA I ~ O \O/
2. NaOH N ~ CI N ~ CI
I

NMR and mass spectrometry data consistent with the desired title product were as follows: lHhIMR (DMSO-d6): 8 1.20 (s, 6H), 1.69 (t, 2H), 3.22 (t, 2H), 3.71 (s, 6H), 3.78 (s, 3H), 5.29 (d, 1H), 6.26 (s, 2H), 6.63 (s, 1H), 7.21 (d, 1H), 8.9 (s, 1H), APCI-MS m/z 501.1 (M+I~~.
Example A14: 5-[(1-acetyl-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)oxy]-N-(2,6-dimethoxyphenyl)-2-furamide a " .0 0 N I ~ CI I~/ HN
A14 ~o -o Compound A14 was synthesized in a manner analogous to that of Al, 1o according to Scheme A, using similar starting compounds and reaction conditions:
NMR and mass spectrometry data consistent with the desired title product were as follows:1HNMR (DMSO-d6): 8 1.17 (s, 6H), 1.68 (t, 2H, J = 6.04 Hz), 2.15 (s, 3H), 3.64 (s, 2H), 3.65 (m, 6H), 5.54 (d, 1H, J = 3.40 Hz), 6.63 (d, 2H, J = 8.50 Hz), 7.17 (d, 2H, J = 16.81 Hz), 7.35 (s, 1H), 7.83 (s, 1H), 9.04 (s, 1H), APCI-MS m/z is (M+H)+.
OMe II CI O \ I OMe ~Br ~ \ I OMe ~ N CI
H2N- v 'CI E N, CH2C12 ~HN~CI LDA, THF
rt, 5h 2C (66°~ yield AICI3 I ~ OH from 2A) 130°C ' ~ CI
O
2D(87%) To a solution of 2A (11 g) and triethylamine (8.5 g) in CH2C12 was added acetylchlorode (6.6 g) slowly at room temperature. The solution was stirred for I hour, 2o extracted with CH2Cla and concentrated to give compound 2B. Without purification the crude product was dissolved in THF (100 mL). To this solution was added LDA
(1.3 eq.) followed by addition of allylbromide (11.3 g) at rt. The solution was stirred overnight. Compound 2C (12.4g) was isolated by column chromatography (hexaneBtoAC 2/1) Compound 2C (9g, 33.7 mmol) and A1C13 (9.1g, 67.4 mmol) was dissolved in 100 ml of CH3N02. The solvent was evaporated and the dried mixture was heated to 135°C for 1.5 hours. The mixture was cooled to room temperature, dissolved in CH3NO2, poured into ice slow water and extracted with EtOAc.
Column chromatography (hexane: EtOAc: 2:1) gave 2D (7.8g) in 87% yield.
Example A15: 5-[(1-methoxy-3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide o~ o \ / H \ /

to Compound A15 was synthesized in a manner analogous to that of Al, according to Scheme A and the scheme set forth below:
Br Br O
OH BrZ AcOH I W OH general scheme 1A I w O \O/ OH
>90°/

O
Br O OMe O OMe 0 ~
I ~ O \O/ H NaOMe_ I ~ O ~O/ OH general scheme 1A I ~ O \O/
CuBr NMR and mass spectrometry data consistent with the desired title product 1s were as follows: 1H NMR (CH30D): 8 1.37 (s, 6H), 1.64 (d, 2H, J = 10.20 Hz), 1.77 (d, 2H, J = 9.07 Hz), 2.17 (s, 3H), 2.71 (dd, 2H, J = 6.04, 5.67 Hz), 3.81 (s, 6H), 3.85 (s, 3H), 3.90 (s, 3H), 5.07 (d, 1H, J = 3.78 Hz), 6.26 (s, 2H), 6.75 (s, 1H), 7.11 (s, 1H), APCI-MS fnlz 496 (M+H)+.
Example A16: N-(2,6-dimethoxyphenyl)-5-[(1-methoxy-3,8,8-trimethyl-5,6,7,8-2o tetrahydronaphthalen-2-yl)oxy]-2-furamide I
of ° ° i ° N
I / \ I H O

Compound A16 was synthesized in a manner analogous to that of A15, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR
(CH30D): 8 25 1.12 (s, 6H), 1.55 (d, 2H, J = 5.67 Hz), 1.72 (d, 2H, J = 4.15 Hz), 2.10 (s, 3H), 2.65 (dd, 2H, J = 6.42, 6.04 Hz), 3.63 (s, 3H), 3.73 (s, 6H), 5.32 (d, 1H, J = 3.78 Hz), 6.60 (m, 2H), 6.84 (s, 1H), 7.02 (s, 1H), 7.17 (t, 1H, J = 8.69, 8.31 Hz), APCI-MS
m/z 466 (M+~+.
Example A17: 5-[(1-bromo-3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I I
o ~ o sr o ° ° \
\ / H
A17 °w Compound A17 was synthesized in a manner analogous to that of A15, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR
(CH30D): 8 1.18 (s, 6H), 1.56 (m, 2H), 1.77 (m, 2H), 2.29 (s, 3H), 2.69 (t, 2H, J = 6.42 Hz), 3.70 (s, 6H), 3.75 (s, 3H), 5.32 (d, 1H, J = 3.78 Hz), 6.22 (s, 2H), 7.04 (d, 1H, J
= 3.02 Hz), 7.10 (s, 1H), APCI-MS m/z 553 (M+H)+.
k The following compounds were prepared according to Scheme B set forth below:
Scheme B
Br 11 I \ H / O i \ NaOH, CH30H
R-R I / CszC03. DMF / O
90-120°C 12 \ ~2 I / I \
J' R I / ~ / OH EDCI or HATU /
SOCIy benzene Catalytic DMF
~~z R I~'~I
O
RI
I / ~ / C1 14 DCM or DMF
Scheme B is a modification of Scheme A. Numbered compounds and identified reagents of Scheme B are analogous to those similarly identified compounds and reagents of Scheme A.
2o Example Bl: N-(2,4,6-trimethoxyphenyl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furamide I
~I ~
C><~ H
I I N o Compound B1 was made according to Scheme B wherein:
~o and ~O ~ ~ O/
were used as the starting materials and the synthesis of the phenol is shown below.
5 NMR and mass spectrometry data consistent with the desired title product were as follows: 1HNMR (300 MHz, CD30D): 8 7.38 (1H, d, J = 3.6 Hz), 7.32 (1H, s), 7.21 (1H, s), 6.52 (2H, s), 5.54 (1H, d, J = 3.6 Hz), 4.07 (3H, s), 4.05 (6H, s), 2.97 (2H, t, J
= 6.23 Hz), 2.45 (3H, s), 2.10-1.89 (4H, m), 1.49 (6H, s), APCI-MS m/z: 466.2 (M+H)+.
10 The requisite phenol was synthesized according to the procedure shown and described below:
~ b. ~ Br c.
/ ~/

d.
a. 1y, heat, 110°C, 30mtn., neat ' b. Brz, AICI3, CH3NCz c. NaOMe, Cu(I)Br,EtOAc, reflux,12h H
d. BBr3, -78°C, ovar night, quench with MeOH
v- 30 7-bromo-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene 29: 1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene was synthesized from beta-ionone as 1s discussed in Parlow, TETRAB; Tetrahedron, EN, 49; 13; 2577-2588 (1993). To a solution containing 1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene 28 (1.0 eq, 7.5 g, 43.1 mmol, 0.2 M) in nitromethane, bromine (1.0 eq, 2.21 mL, 43.1 mmol) was added dropwise over 2 minutes. The solution was then stirred vigorously and aluminum trichloride (0.07 eq, 375 mgs, 2.81 mmol) was added solid. The mixture was stirred 20 overnight and quenched with sodium thiosulfate and extracted with methylene chloride. The organic solvent was evaporated in vacuo and the crude mixture was dissolved in minimal amount of hexanes. The resulting liquid was loaded onto a silicagel (700 mL) plug column and eluted with hexanes to yield 50% 7-bromo-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene 29 (5.50 g).

7-methoxy-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene 76: To a flask containing 7-bromo-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene (1.0 eq, 60 g, 228 mmol), sodium methoxide (521 mL) was added along with ethyl acetate (80 mL) and Cu(I)Br (0.03 eq, 1g, 7.0 mmol). The solution was refluxed 24 hours and quenched with concentrated HCI. The solution was diluted with water and extracted with ethyl acetate. The crude was purified by silica gel using ethyl acetate hexane elution to yield 7-methoxy-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene 76 (19.88 g, 97 mmol, 43% yield).
3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenol 30: 7-methoxy-1,1,6-~ trimethyl-1,2,3,4-tetrahydronaphthalene (1.0 eq, 5.67 g, 27.8 mmol) was dissolved in methylene chloride (0.2 M) and cooled to -78°C. To this solution, BBr3 (1.0 eq, 1 M, 27 mL) was added at once and stirred overnight slowly bringing the solution to room temperature. The solution was then quenched with methanol and passed through a silicagel plug to yield 3,8,8-trimethyl-5,6,7,8 tetrahydro-2-naphthalenol 30 (4.68 g, 88%).
Example B2: 5-(3-Benzenesulfonylamino-phenoxy)-furan-2-carboxylic acid (2,4,6-trimethoxy-phenyl)-amide 2o Compound B2 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
Example B3: 5- f [(6s)-3,5,5,6,88-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl] oxy}-N-(2,4,6-trimethoxyphenyl)-2-furamide \ / °\

Compound B3 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
Yield of purified product was 89%. NMR data consistent with the desired title product were as follows: 1H (300 MHz, CDCl3): 8 0.94 (d, 3H, J = 6.42 Hz), 1.08, 1.22, 1.25, 1.30 (4s, 3H each), 1.30 - 1.37 (m, 1H), 1.63 (t, J =12.8 Hz), 1.78-1.93 (m, 1H), 2.23 (s, 3H), 4.6 (s, 1H, OH), 6.75 and 7.15 (2s, 1H each).
The requisite phenol was prepared by the following scheme:
O mCPBA ~ OH
Ii Ii 3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenol: To the solution of fixolide (25.84 g, 100 mmol) in dichloromethane (500 mL) was added m-chloroperbenzoic acid (57-86 % taken mean value of 71%, 12.08 g, 100 mmol).
The resulting mixture was stirred for 16 hours at room temperature. The solvent was evaporated, and the residue was dissolved in methanol (200 mL). Sodium methoxide (457 mL of 25%, 200 mmol) was added. The mixture was stirred for 2 hours, and methanol evaporated. The residue was diluted with water and neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was filtered through a plug of silica gel. The solvent was evaporated and the residue on crystallization with ethyl acetate-hexane mixture gave white powder, 20.9 g.
Example B4: N-(2,6-dimethoxyphenyl)-5-[(5,5,8,8-tetramethyl-5,6,7,8-s tetrahydro-2-naphthalenyl)oxy]-2-furamide a o i Compound B4 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the desired title product were as follows:

(300 MHz, CDC13): 8 1.26 (s, 12H), 1.68 (s, 4H), 3.83 (s, 6H), 5.53 (d, 1H), 6.60 (d, 2H), 6.90 (d, 1H), 7.15 (s, 1H), 7.19 (d, 1H), 7.22 (t, 1H), 7.28 (d, 1H), APCI-MS m/z 450.3 (M+I~+.
Example B5: ethyl 4-[(5-~[5-(4-chloro-3-isopropyl-2-methoxy-6-methylphenoxy)-2-furoyl]amino)-4,6-dimethoxy-2-pyrimidinyl)amino]butanoate o~ o -N
~O~ H ~ /~NH O
N
CI ~ O

Compound BS was synthesized by coupling of the pyrimidine derivative, the preparation of which is described below, to a substituted furoic acid according to s Scheme B. NMR and mass spectrometry data consistent with the desired title product were as follows: 1HNMR (CDC13): 8 1.26 (3H, t), 1.40 (6H, d), 1.98 (2H, sextet), 2.19 (3H, s), 2.39 (2H, t), 3.48 (2H, c~, 3.58 (1H, heptet), 3.83 (3H, s), 3.89 (6H, s), 4.12 (2H, c~, 5.08 (1H, br t); 5.11(1H, d), 6.91 (1H, s), 7.03 (1H, s), 7.08 (1H, d), FI-PCI m/z 592.2 & 593.2 (M+H)+.
o ~ o i0 I N~C~ ,O N~N~LO~ i0 NYN O
N ~ SIN I iN
OaN OaN H2N
i0 i0 i0 ~~ 117 118 Displacement of 4-chloride: To a solution of 4-chloro-2,4-dimethoxy nitropyrimidine (3.28 g, 15 mmol) in DMF (30 mL) was added triethylamine (2.09 mL, 15 mol) and ethyl 4-aminobutyrate hydrochloride (2.51 g, 15 mmol). The reaction mixture was stirred at room temperature overnight. Most of DMF was removed on a rotovap. The concentrate was redissolved in ethyl acetate, washed with water, brine, dried over magnesium sulfate. The solvent was removed on a rotovap.
The product was purified by flash chromatography (solvent: 1 ethyl acetate: 3 hexanes to 1 ethyl acetate: 2 hexanes): 2.38 g (50.5%). NMR data consistent with the desired title product were as follows:1H NMR (CDCl3): 8 1.27 (3H, t), 1.98 (2H, sextet), 2.41 (2H, t), 3.49 (2H, c~, 3.94 (3H, s), 4.01 (3H, s), 4.15 (2H, ~, 5.50 (1H, br t).
Hydrogenation: The nitro pyrimidine compound obtained from above (2.38 g, 7.58 mmol) was dissolved in methanol (25 mL). 10% palladium on carbon catalyst (.4 g) was carefully added to the methanolic solution and the mixture was hydrogenated at 45-50 psi overnight. The mixture was then filtered through Celite and then washed with methanol. The combined filtrate was concentrated to a dark oil, 1.76 g (82%).

8r O
I ~ OH NBS, (iPrhNH OH NaOMe, CuBr OH
CH CI I ~ CH OH

SOZCIZ
--~ ~OH

CI
NMR and Mass spectrometry data consistent with the title product were as follows: 1H NMR (CDCl3): ~ 1.24 (3H, t), 1.98 (2H, sextet), 2.39 (2H, t), 2.49 (2H, br s), 3.48 (2H, q), 3.90 (6H, s), 4.12 (2H, q), 4.60 (1H, br t), FI-PCI
m/z 285.2 (M+H)+.
Example B6: 4-bromo-5-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide o i B6 Br Compound B6 was synthesized in a manner analogous to that of B 1, according 1o to Scheme B. NMR and mass spectrometry data consistent with the desired title product were as follows: IH NMR (300 MHz, CD30D): 8 1.52 (s, 12H), 1,96 (s, 4H), 4.06 (s, 6H), 6.94 (d, 2H), 7.09 (d, 1H), 7.28 (s, 1H), 7.54 (t, 2H), 7.62 (d, 1H), APCI-MS m/z 528.3 (M+H)+.
Example B7: 4-bromo-5-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-15 naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide o , O
Fi O\
B7 Br Compound B7 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the desired title product were as follows: IH
2o NMR (300 MHz, CD30D): 8 1.26 (s, 12H), 1,70 (s, 4H), 3.77 (s, 3H), 3.80 (s, 6H), 6.25 (s, 2H), 6.81 (d, 1H), 7.01 (s, 1H), 7.27 (s, 1H), 7.32 (d, 1H), APCI-MS
mlz 558.4 (M+H)+.
Example B8: 5-[(3,5,5,8',8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2H-tetrazol-5-yl)-2-furamide a o NH

Compound B8 was synthesized in a manner analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions. NMR
data consistent with the desired title product were as follows: 1H NMR (CD30D-d4):

1.25 (s, 6H), 1.30 (s, 6H), 1.72 (s, 4H), 2.23 (s, 3H), 5.41(d, 1H), 7.08 (s, 1H), 7.28 (s, 1H), 7.45 (d, 1H), LC-MS, APCI, (M+H)+: 396.
Example B9: 5-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2h-chromen-6-yl)oxy]-n-(2,4,6-trimethoxyphenyl)-2-furamide I
° ° \ °\
° ° ~ i ~I H
O~ O\

1o Compound B9 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H
NIvIR (300 MHz, CDC13): ~ 1.32 (s, 6H), 1.81 (t, 2H), 2.05 (s, 3H), 2.11 (s, 6H), 2.62 (t, 2H), 3.81 (s, 9H), 4.91 (d, 1H), 6.19 (s, 2H), 7.08 (d, 1H), 7.22 (s, 1H), APCI-MS
m/z 496.1 (M+H)+.
Example 810: N-(2,4,6-trimethoxyphenyl)-5-[(4,4,7-trimethyl-3,4-dihydro-2h-chromen-6-yl)oxy]-2-furamide p ~b B10 ° ~ -°
Compound B 10 was synthesized in a manner analogous to that of B 1, 2o according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 26%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDCl3):
~ 1.32 (s, 6H), 1.84 (dd, 2H, J = 4.14, 6.23 Hz), 2.21 (s, 3H), 3.81 (br s, H20), 3.81 (s, 9H), 4.2 (dd, 2H, J = 4.23, 6.23 Hz), 5.22 (d, 1H, J = 3.4 Hz), 6.19 (s, 2H), 6.69 (s, 1H), 7.03 (s, 1H), 7.17 (d, 1H, J = 3.02 Hz), 7.31 (br s, 1H), APCI-MS m/z 468.2 (M+H)+.

Example B11: N-(2,4,6-trimethoxyphenyl)-5-[(4,4,8-trimethyl-3,4-dihydro-2h-chromen-6-yl)oxy]-2-furamide d H~ , Bll Compound B 11 was synthesized in a manner analogous to that of B 1, s according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 26%.
The requisite chromanophenol was synthesized according to the following method:
CHCI3-MeOH(9:1) TBDMS-CI, OH / reilux, 16 h Imidazale, DMF
HO I ~ + ' 16% of inseparable mixture ~ O~ CH3MgI, 81%
/~ + s ~O SI~O i Non-separable mixture O
~ f~H
O~SI~ \ O~ AICI9,CH3N02 ,90%
~p I ~ / ~ + ~gp0 ~ / Non-separable mixture -i-OH
\ OH ~~OH
> ~~i + o l i 1o The mixture of these chromanophenols was treated with methyl bromofuroate.
The final products were separated using HPLC. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDCl3): 8 1.24 (s, 6H), 1.75 (t, 2H, J = 5.29 Hz), 2.10 (s, 3H), 3.73 (s, 9H), 4.13 (t, 2H, J = 5.29 Hz), 4.25 (br s, HZO), 5.32 (d, 1H, J = 3.59 Hz), 6.08 (s, 2H), 6.69 (d, 15 1H, J = 3.03 Hz), 6.84 (d, 1H, J = 3.03 Hz), 7.10 (d, 1H, J = 3.59 Hz), 7.31 (br s, 1H), APCI-MS m/z 468.2 (M+H)+.
Example 812: N-[(5-methyl-2-pyrazinyl)methyl]-5-[(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide ~ '~ O O O H
B12 a' v \
2o Compound B 12 was synthesized in a manner analogous to that of B 11, according to Scheme B, using similar starting compounds and reaction conditions.

The yield of the purified product was 12%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDCl3):
~ 1.30 (s, 6H), 1.83 (t, 2H, J = 5.48 Hz), 2.18, 2.62 (2s, 3H each), 4.19 (t, 2H, J = 5.48 Hz), 5.06 (br s, H20), 5.19 (d, 1H, J = 3.58 Hz), 6.68 (s, 1H), 6.99 (s, 1H), 7.11 (d, 1H, J = 3.58 Hz), 7.13 (br s, 1H), 8.48, 8.60 (2s, 1H each), APCI-MS m/z 408.1 (M+H)+.
Example B13: N-[(5-methyl-2-pyrazinyl)methyl]-5-[(4,4,8-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide H
O' 1o Compound B 13 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 11%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (300 MHz, CDC13):
8 1.32 (s, 6H), 1.85 (dd, 2H, J = 5.29, 5.47 Hz), 2.18, 2.63 (2s, 3H each), 4.23 (dd, 1s 2H, J = 5.29, 5.48 Hz), 4.78 (d, 2H, J = 5.47 Hz), 5.39 (d, 1H, J = 3.59 Hz), 6.14 (br s, H20), 6.66 (d, 1H, J = 2.83 Hz), 6.92 (d, 1H, J = 3.02 Hz), 7.13 (d, 1H, J =
3.58 Hz), 7.17 (br s, 1H), 8.50, 8.62 (2s, 1H each), APCI-MS m/z 408.1 (M+H)+.
Example B14: N-(2,6-dimethoxyphenyl)-5-[(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide 2o B14 Compound B 14 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 66%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H NMR (CDC13): S
1.29 (s, 2s 6H), 1.81 (t, 2H, J = 5.48 Hz), 2.19 (s, 3H), 3.84 (s, 6H),'4.17 (t, 2H, J
= 5.29 Hz), 5.21 (d, 1H, J = 3.59 Hz), 6.62 (m, 2H), 7.01 (s, 1H), 7.15 (d, 1H, J = 3.4 Hz), 7.21 (t, 1H, J = 8.5 Hz), 7.40 (br s, 1H), MS m/z 438.2 (M+H)+.

Example B15: 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(3-{ [(2-{ [(2R)tetrahydro-2-furanylmethyl] amino}-4-pyrimidinyl)amino]methyl}benzyl)-2-furamide Compound B 15 was synthesized according to Scheme B.
~N
THF Op N"', O
CI~N~CI H2N U r.t O O
O I, HZN I W NI12 + ~ ~ ~ FsC~H I ~ NHZ CI~'O~
g p ~N
O O ~ N~O~ CI~:N~H ~V
II II [(ZG~g F30~H I \ H~O~ I H ~CI
/ I, NHZ
~N
~I I /~ /'~..
~Hi°,.~ ICOH H2N I / H I N H
HO'~'OH,fl 109 Preparation of 2-chloro-N-[(2R)-tetrahydro-2-furanmethyl]-4-pyrimidinamine & 4-chloro-N-[(2R)-tetrahydro-2-furanmethyl]-2-pyrimidinamine: To a 250 mL round bottom flask was placed 2,4-dichloropyrimidine (5.0g, 33.56 mmol) and 200 mL THF. To this solution was added triethylamine (14.0 mL, 100.68 mmol) and [R]-tetrahydrofurfiuylamine.
The solution was stirred overnight. The reaction mixture was poured into water and extracted with methylene chloride. The separated organic layer was washed with brine, dried over magnesium sulfate, and concentrated on a rotary evaporator. The crude compound was purified by silica gel chromatography with hexane/ ethyl acetate (4:1 v/v to 1:1 v/v) to yield chloro-N-[(2R)-tetrahydro-2-furanmethyl]-2-pyrimidinamine (1.3 g) and 2-chloro-N-[(2R)-tetrahydro-2-furanmethyl]-4-pyrimidinamine (3.98 g). Preparation of N-[3-(aminomethyl)benzyl]-2,2,2-trifluoroacetamide: To a solution of m-xylene diamine (28.76g, 211.15 mmol) in THF (300 mL, .7IV1) was added dropwise a solution of ethyl trifluoroacetate (10g, 70.38 mmol) in THF (50 mL, 1.41V1]. The solution was stirred at room temperature overnight. The reaction was monitored by TLC. The solvent was concentrated and residue was acidified to pH 2 with 4N HCl and dissolved in water and washed with ethyl acetate. The separated aqueous layer was basified to pH 11 using NH40H and compound was extracted with dichloromethane. The separated organic layer was wash with water/brine, dried over magnesium sulfate and concentrated to yield N-[3-(aminomethyl)benzyl]-2,2,2-trifluoroacetamide ( 8.718, 53% yield). Preparation of ethyl 3-(aminomethyl)benzylcarbamate: To a solution of N-[3-(aminomethyl)benzyl]-2,2,2-trifluoroacetamide (10.6g, 43.1 mmol) was added ethyl chloroformate (leq.) followed by triethylamine.. Reaction was stirred at room temperature for 30 min. Crude product was extracted with methylene chloride and concentrated to give ethyl 3-{[(trifluoroacetyl)amino]methyl} benzylcarbamate 4. This crude product was dissolved in methanol (100 mL) and 2N I~zC03 ( 100 mL) and stirred overnight. Reaction mixture was basified to pH 14 with 20% NaOH, extracted with methylene chloride, wash with brine and dried over magnesium sulfate to yield ethyl 3-(aminomethyl)benzylcarbamate (5.2g).Prepaxation of ethyl 3-~[(2-f [(2R)-tetrahydro-2furanylmethyl]amino}-4-pyrimidinyl)amino]methyl}benzylcarbamate: To a solution of ethyl 3-(aminomethyl)benzylcarbamate and 4-chloro-N-[(2R)-tetrahydro-2-furarnnethyl]-2-pyrimidinamine in chlorobenzene was added triethylamine. Reaction mixture was reflux overnight. The solution was cooled to room temperature and loaded on a silica gel column and eluted with hexane/ethyl acetate (1:l v/v) to yield ethyl 3-([(2-{[(2R)-tetrahydro-2-furanylmethyl]amino}-4-pyrimidinayl)amino]methyl}benzylcarbamate (73% yield).
Ethyl 3-f [(2-{[(2R)-tetrahydro-2-furanylinethyl]amino}-4-pyrimidinayl) amino]methyl}benzylcarbamate was dissolved in ethylene glycol and potassium hydroxide (1:1 v/v). The solution washeated to 100°C overnight. The mixture was cooled to room temperature and extracted with chloroform, washed with brine, and dried over magnesium sulfate to yield N4-[3-(aminomethylObenzyl]-NZ-[(2R)-tetrahydro-2-furanylmethyl]-2,4-pyrimidinediamine (82 % yield). NMR and mass spectrometry data consistent with the desired title product were as follows: 1HNMR (CDC13): 8 1.20 (s, 6H), 1.25 (s, 6H), 1.66 (s, 4H), 1.87-1.99 (m, 4H), 2.21 (s, 3H), 3.74-3.89 (m, 2H), 3.75 (t, 1H), 3.87 (t, 1H), 3.88 (m, 1H), 4.5 (d, 2H), 4.58 (d, 2H), 5.30 (d, 1H), 5.73 (d, 1H), 6.57 (t, 1H), 6.94 (s, 1H), 7.08 (d, 1H), 7.14 (s, 1H), ?.23-7.34 (m, SH) (s, 1H), 7.76 (d, 1H), APCI-MS ynlz 624.4 (M+H)+.
Example B16: 5-[(3-isopropyl-1,1,2,6-tetramethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide o~

Compound B 16 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds where the nitro-pyrimidine is compound VII which was reduced to the amine in a manner analogous to that of s compund III and the synthesis of the phenol is shown below. The yield of the purified product was 61%.
The requisite phenol, 3-isopropyl-1,1,2,6-tetramethyl-5-indanol, was synthesized according to the following method:

1. mCPBA I ~ OH
i 2. NaOMe 1o To the solution of transeolide (5.16 g, 20 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (57-86% taken mean value of 71%, 5.83 g, 24 mmol) and sodium bicarbonate (1.7 g, 20 mmol). The reaction mixture was stirred fox 16 hours at room temperature. The solvent evaporated, the residue was dissolved in methanol (100 mL). Sodium methaoxide (13.72 mL of 25% methanolic soution, is mmol) was added and the mixture was stirred at room temperature for 2 hours, and solvent evaporated. The residue was diluted with water (150 mL), neutralized with diluted hydrochloric acid, and extracted with ethyl acetate (500 mL). The organic layer was dried and filtered through a small plug of silica gel to give desired phenol as white solid (4.29 g, 92%). NMR and mass spectrometry data consistent with the 2o desired title product were as follows: 1H (300 MHz, CDC13): 8 0.96 (d, 6H, J = 9.8 Hz), 1.01 (s, 3H), 1.09 (d, 3H, J = 9.0 Hz), 1.27 (s, 3H), 1.8-1.95 and 2.1-2.25 (2m, 1H each), 2.25 (s, 3H), 2.73 (d, 1H, J = 9.82 Hz), 3.95 (s, 6H), 3.98 (s, 3H), 5.32 (d, 1H, J = 3.58 Hz), 6.91 (s, 1H), 7.05 (s, 1H), 7.15 (d, 1H, J = 3.59 Hz), APCI-MS m/z 510.3 (M+I~+.
25 Example B17:4-[(5-~[5-(4-chloro-3-isopropyl-2-metho~ry-6-methylphenoxy)-2-furoyl]amino}-4,6-dimethogy-2-pyrimidinyl)amino]butanoic acid o~ o /
\ / " ~ ~'~~ ~a~
a ~,//\
OH

Compound B17 was synthesized from Compound B5. Compound BS (53 mg, 0.089 mmol) was dissolved in ethanol (1 mL) and an aqueous solution of sodium hydroxide (2 equivalents) was added. The reaction was monitored by TLC
(developing solvent: 5% methanol in methylene chloride) for completion of reaction.
After saponification was complete, the mixture was concentrated. The residue was diluted with water and washed with ether. The aqueous layer was then carefully acidified to pH 2 with 10% HCl and the product was extracted with methylene 1o chloride. The title product was purified by silica gel chromatography (solvent: 10%
methanol in methylene chloride). NMR and Mass spectrometry data consistent with the desired title product were as follows: 1H NMR (CDCl3):a8 1.35 (6H, d), 1.95 (2H, sextet), 2.19 (3H, s), 2.43 (2H, t), 3.47 (2H, q), 3.58 (1H, heptet), 3.83 (3H, s), 3.89 (6H, s), 5.11(1H, d), 5.30 (1H, br t); 6.93 (1H, s), 7.01 (1H, s), 7.08 (1H, d); FI-PCI
15 rn/z 564.2 & 565.2 (M+I~+.
s Example B18: 5-[(3-isopropyl-1,1,2,6-tetramethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide ~ /
O\

Compound B 18 was synthesized in a manner analogous to that of B 1, 20 according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 55%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H (300 MHz, CH30H-d4): 8 0.96 (d, 6H, ~J = 8.87 Hz), 0.99 (s, 3H), 1.01 (d, 3H, J = 6.98 Hz), 1.28 (s, 3H), 1.70-1.95 and 2.1-2.25 (2m, 1H each), 2.26 (s, 3H), 2.71 (d, 1H, J = 9.25 Hz), 3.80 (2s, 3H
25 each), 3.82 (s, 3H), 5.31 (d, 1H, J = 3.58 Hz), 6.27 (2s, 1H each), 6.92 and 7.06 (2s, 1H each), 7.15 (br s, 1H), APCI-MS rnlz 508.2 (M+H)+.
Example B19: N-(2,6-dimethoxy-3-pyridinyl)-5-((3-isopropyl-1,1,2,6-tetramethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide 0 0 -_ /

B19 \ _ - -o Compound B 19 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 28 %. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H (300 MHz, CH30H-d4): 8 0.95 (d, 6H, J = 7.18 Hz), 1.00 (s, 3H), 1.09 (d, 3H, J = 6.98 Hz), 1.27 (s, 3H), 1.80-1.95 and 2.1 - 2.25 (2m, 1H each), 2.25 (s, 3H), 2.71 (d, 1H, J = 8.31 Hz), 3.90 and 4.0 (2s, 3H each), 5.33 (d, 1H, J = 3.58 Hz), 6.33 (d, 1H, J = 8.31 Hz), 6.92 and 7.06 (2s, 1H each), 7.16 (d, 1H, J = 3.78 Hz), 8.05 (d, 1H, J = 8.5 Hz), APCI-MS
m/z 479.2 io (M+H)+.
Example B20: N-[2-(2,4-difluorophenoxy)-3-pyridinyl]-5-[(3-isopropyl-1,1,2,6-tetramethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide Compound B20 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was~2 %. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H (300 MHz, CH30H-d4): S 0.91 (d, 6H, J = 6.99 Hz), 1.00 (s, 3H), 1.04 (d, 3H, J = 6.80 Hz), 1.24 (s, 3H), 1.80-1.95 and 2.1-2.25 (2m, 1H each), 2.22 (s, 3H), 2.65 (d, 1H, J = 9.07 2o Hz), 5.36 (d, 1H, J = 3.78 Hz), 6.91 (s, 1H), 6.95-7.15 (m, 4H), 7.26 (d, 1H, J =
3.78 Hz), 7.26-7.37 (m, 1H), 7.80 (dd, 1H, J = 6.6, 1.7 Hz), 8.47 (dd, 1H, J =
9.44 and 1.70 Hz), APCI-MS m/z 547.2 (M+H)+.
Example B21: 4-bromo-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide \ l °\
2s B21 Compound B21 was synthesized in a manner analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 16 %. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H (300 MHz, CDCl3): b 0.97 (d, 3H, J = 6.61 Hz), 1.05, 1.20, 1.22, 1.31 (4s, 3H each), 1.30-1.45 (m, 1H), 1.50-1.70 (m, 1H), 1.80-2.0 (m, 1H), 2.33 (s, 3H), 3.79 (2s, 6H), 3.81 (s, 3H), 5.34 (d, 1H, J = 3.4 Hz), 6.15 (s, 2H), 6.79 (s, 1H), 7.08 (br s, 1H), 7.18 and 7.19 (2s, 1H
each), APCI-MS nalz 586.2 and 588.2 (M+H)+.
Example B22: 4-bromo-N-(2,4,6-trimethoxyphenyl)-5-[(3,8,8-trimethyl-5,6,7,8-l0 ' tetrahydro-2-naphthalenyl)oxy]-2-furamide \ / ~ \ / °\
i B22 Br o\
Compound B22 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 18%. NMR and mass spectrometry data 1s consistent with the desired title product were as follows: 1H (300 MHz, CDC13): 8 1.21 (s, 6H), 1.55 -1.66 (m, 2H), 1.73 - 1.83 (m, 2H), 2.29 (s, 3H), 2.70 (t, 1H, J =
6.24 Hz), 3.78 (s, 6H), 3.81 (s, 3H), 6.16 (s, 2H), 6.85,6.90, 7.07 (br) and 7.19 (4s, 1H
each), APCI-MS mlz 544.2 and 545.2 (M+H)+.
Example B23: 4-bromo-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,5-tetrahydro-2-20 naphthalenyl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide \ ~\
°\

Compound B23 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 8%. NMR and mass spectrometry data 25 consistent with the desired title product were as follows: 1H (300 MHz, CDCl3): S
0.98 (d, 3H, J = 6.61 Hz), 1.05, 1.20, 1.21, 1.32 (4s, 3H each), 1.30-1.45 (m, 1H), 1.61 (dd, 1H, J =12.8, 13.2 Hz), 1.77 - 1.92 (m, 1H), 2.32 (s, 3H), 3.94 (s, 6H), 3.94 (s, 3H), 6.77 (s, 1H), 6.93 (br s, 1H), 7.19 and 7.22 (2s, 1H each), APCI-MS m/z 588.2 and 590.2 (M+H)+.
Example B24: 4-bromo-N-(2,4,6-trimethoxyphenyl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]2-furamide o I ~ ~ / b \ /
B24 g' °\
Compound B24 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 21 %.
.M~ ASH
HO I ~ ~ O I ~ \ I ~ \ O I ~ H
HCI THF NaH
refluxovernight overnight DMF reflux OC to reflux NMR and mass spectrometry data consistent with the desired title product were as follows: 1H (300 M>=Iz, CDC13): 8 1.46 and 2.37 (2s, 6H and 3H respectively), 3.81 (s, 6H), 3.99 (s, 3H), 5.01, 6.16 (2s, 2H each), 6.62 and 7.05 (2s, 1H each), 7.09 (brs, 1H), 7.20 (s, 1H), APCI-MS m/z 533 and 534 (M+H)+.
Example B25: 4-bromo-N-methyl-N-(2,4,6-trimethoxyphenyl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide 0 o I
o I ~ ~ / N \ / °
far o\

Compound B25 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
2o The yield of the purified product was 20%. NMR and mass spectrometry data consistent with the desired title product were as follows: 1H (300 MHz, CDC13): 8 1.41 (s, 6H), 2.24 and 3.17 (2s, 3H each), 3.70 (s, 6H), 3.82 (s, 3H), 4.98, 6.04 (2s, 2H
each), 6.08 (s, 2H), 6.50 and 6.97 (2s, 1H each), APCI-MS m/z 533 and 546 and (M+H)+.
Example B26: 5-(3,3,6-Trimethyl-indan-5-yloxy)-furan-2-carboxylic acid (2-chloro-4,6-dimethoxy-pyrimidin-5-yl)-amide o N\Yci p O N ~ /N
/
/O

Compound B26 was synthesized in a manner analogousto that of B 1, according to scheme B.
Example B27: 5-(4-chloro-3-isopropyl-2-methoxy-6-methylphenoxy)-N-(2- f [3-(dimethylamino)propyl]amino}-4,6-dimethoxy-5-pyrimidinyl)-2-furamide O~ '~NYN~N~
O O N~N
/ ~/ TO
CI v~ ~

Compound B27 was synthesized in a manner analogousto that of B 1, 1o according to scheme B.
Example B28: N-{4,6-dimethoxy-2-[(pyridin-2-ylmethyl)amino]pyrimidin-5-yl}-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide HN ~ ~>--NH N-N
O

Compound B28 was synthesized in manner analogous to that of B52. NMR
~s and mass spectrometry data consistent with the title product were as follows: 1H NMR
(300 MHz, CDC13): 8 1.21 (s, 6H), 1.93(dd, 2H, J =14.35, 7.18, Hz), 2.24 (s, 3H), 2.84 (t, 2H, J = 14.35 Hz), 3.86 (s, 6H), 4.72 (d, 2H, J = 6.04 Hz), 5.28 (s, 1H), 5.84 (dd, 1H, J = 11.33, 5.67 Hz), 6.82 (s, 1H), 6.94 (s, 1H), 7.05 (s, 1H), 7.09 (d, 1H, J =
3.78 Hz), 7.18 (d, 1H, J =11.71 Hz), 7.35 (d, 1H, J = 7.93 Hz), 7.66 (dd, 1H, J'=
20 15.49, 7.93 Hz), 8.56 (d, 1H, J = 4.91 Hz), APCI-MS m/z 530.6 (M+H)+.
Example 829: N- f 4,6-dimethoxy-2-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl~-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide _N
I / I ~ HN ~ /~NH
~N ~N

Compound B29 was synthesized in manner analogous to that of B52. NMR
and mass spectrometry data consistent with the title product were as follows:

(300 MHz, CDC13): 8 1.21 (s, 6H), 1.93 (dd, 2H, J =1 4.35, 7.18 Hz), 2.24 (s, 3H), 2.50 (s, 4H), 2.59 (t, 2H, J = 12.09 Hz), 2.84 (dd, 2H, J =14.35, 7.18 Hz), 3.49 (dd, 1H, J =11.71, 5.67 Hz), 3.75 (tt, 4H, J = 9.07, 4.53 Hz), 3.88 (s, 6H), 5.27(d, 1H, J =
3.78 Hz), 5.36 (d, 1H, J = 10.20 Hz), 6.82 (s, 1H), 6.95 (s, 1H), 7.05 (s, 1H), 7.10 (d, 1H, J=3.40 Hz), APCI-MS m/z 552.6 (M+H)+.
Example B30: N (2,4,6-trimethoxyphenyl)-5-[(1,1,5-trimethyl-1H inden-6-yl)oxy]-2-furamide O
HaC Hs -NH \ / oCH3 to B30 ~"3 Compound B30 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.
CsZCOs, DMF, 120 °C ~ O O O -E- ~ O O-w OH \ 1i I/ O_ I~ I/ O
1i O O , Br ~ / O' Note: the reaction content were not degassed before heating NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): b 8.89 (bs, 1H), 7.24 (s, 2H), 7.18 (bd, 1H, J = 3 Hz), 6.63 (d, 1H, J
= 6 IIz), 6.45 (d, 1H, J = 6 Hz), 6.26 (s, 2H), 5.47 (d, 1H, J = 3 Hz), 3.79 (s, 3H), 3.71 (s, 6H), 2.24 (s, 3H), 1.23 (s, 6H).
Example B31: N (2,4,6-trimethoxyphenyl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide H3/~ ~ O ~0~ NH \ ~ oCH3 2o B31 cH3 Compound B31 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized according to the following method:

O O OH
OH ~OH ~ OH I ~ Hz, Pd/C ~ OH
cat. H,SO,, _ I
polyphosphoric acid '\~ O
60 110 °C major 61 6z 63 NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): 8 7.17 (bs, 1H), 7.10 (d, 1H, J = 3 Hz), 7.05 (s, 1H), 6.84 (s, 1H), 6.17 (s, 2H), 5.29 (d, 1H, J = 3.6 Hz), 3.81 (s, 9H), 2.84 (t, 2H, J = 7.2, 14.4 Hz), 2.25 (s, 3H), s 1.93 (t, 2H, J = 7.2, 14.4 Hz), 1.22 (s, 6H).
Example B32: N (2,6-dimethoxyphenyl)-5-[(1,1,3,3,6-pentamethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide O O /
H3C CHa / O O ~ NH \
O
CHa ~CHg B32 Hay cHa Compound B32 was synthesized in a manner analogous to that of B 1, 1o according to Scheme B, using similar starting compounds arid reaction conditions.
OH HCI (conc) OI ~ ~ OH AICI3 ~ ~ OH
OH 30 min OI ~ CH3N02 ' min NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): 8 7.33 (bs, 1H), 7.19 (t, 1H, J = 8.31, 8.35 Hz), 7.13 (d, 1H, J
= 3.6 1s Hz), 6.96 (s, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.59 (s, 1H), 5.34 (d, 1H, J
= 3.4 Hz), 3.84 (s, 6H), 2.28 (s, 3H), 1.92 (s, 2H), 1.30 (s, 6H), 1.26 (s, 6H).
Example B33: N (2,6-dimethoxyphenyl)-5-[(1,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-2-furamide ~ Ha O

O ~O~ NH
~CH3 O
B33 H'C CH3 CH

2o Compound B33 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was prepared according to the following method:

~OH A1CI3, CH3NOZ ~'~OH
[~ i~' ~ fl 'T~/
CI CSI

NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): ~ 7.35 (s, 1H), 7.20 (t, 1H, J = 9 Hz), 7.06 (d, 2H, J = 3 Hz), 6.63 (d, 2H, J =
9 Hz), 4.98 (d, 1H, J = 3 Hz), 3.86 (s, 6H), 2.36 (s, 3H), 2.17 (s, 3H), 1.66 (m, 4H), 1.40 (s, 6H), 1.28 (s, 6H).
Example B34: N-(4,6-dimethoxy-2-{[3-(4-methylpiperazin-1-yl)propyl]amino~pyrimidin-5-yl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-2-furamide I~ /~ N
O O ~N
N N~
N~, 1o B34 Compound B34 was synthesized in a manner analogous to that of compound B 1, according to scheme B, using similar starting compounds and reaction conditions.
Example 835: 5-(2-bromo-5-tert-butylphenoxy)-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide O

Ii ~ ~ O ~ O ~ NH ~ ~>-O
-N
Br O
1s B35 .~_ cH3 Compound B35 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
OH Br2/CCI4 / I OH
0 °C to rt ~ Br NMR data consistent with the desired title product were as follows: 1H NMR
20 (ppm, CDCl3): 8 7.54 (d, 1H, J = 6 Hz), 7.19-7.15 (m, 3H), 7.02 (bs, 1H), 5.46 (d, 1H, J = 3.6 Hz), 3.97 (s, 9H), 1.29 (s, 9H).
Example 836: N-(2,4,6-trimethoxy-5-pyrimidinyl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide CHg H3C ~ \ 0 ~ O 1 NH ~ ~~--O

B36 ~H3 Compound B36 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): ~ 7.13 (d, 1H, J = 3.6 Hz), 7.06 (s, 1H), 7.0 (bs, 1H), 6.83 (s, 1H), 5.30 (d, 1H, J = 3.6 Hz), 3.97 (s, 9H), 2.85 (t, 2H, J =14.54 Hz), 2.24 (s, 3H), 1.93 (t, 2H, J = 7.18 Hz), 1.22 (s, 6H).
Example B37: 5-[(1,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N (2,4,6-trimethoxyphenyl)-2-furamide H3C CH3 H3 0 ~ I O\CH3 \ O 0 NH~
~CH3 CH3 Compound B37 was synthesized in a manner analogous to that of Bl, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDCl3): ~ 7.19 (s, 1H), 7.05 (s, 1H), 7.04 (d, 1H, J = 3.6 Hz), 6.19 (s, 2H), is 4.96 (d, 1H, J = 3.6 Hz), 3.83 (s, 6H), 3.82 (s, 3H), 2.35 (s, 3H), 2.16 (s, 3H), 1.40 (s, 6H), 1.28 (s, 6H).
Example B38: 5-(2,4-dibromo-5-tent butylphenoxy)-N (2,4,6-trimethoxypyrimidin-5-yl)-2-furamide HsC ~ \ O ~ O ~ NH ~ ~ O
N~ CH3 Br ~ Br O
B38 ~"3 2o Compound B38 was synthesized in a manner analogous to that of Bl, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): ~ 7.85 (s, 1H), 7.23 (s, 1H), 7.16 (d, 1H, J = 3.6 Hz), 7.01 (bs, 1H), 5.51 (d, 1H, J = 3.6 Hz), 3.97 (s, 9H), 1.46 (s, 9H).

Example B39: 5-[(1,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]-N (2,4,6-trimethoxypyrimidin-5-yl)-2-furamide O

\ O I O I NH ~ ~~-p s -N

B39 "30 CH3 CH3 Compound B39 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): 8 7.07 (d, 1H, J = 3.8 Hz), 7.03 (s, 1H), 4.98 (d, 1H, J = 3.6 Hz), 3.99 (s, 6H), 3.98 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H), 1.66 (m, 4H, J =1.32 Hz), 1.40 (s, 6H), 1.28 (s, 6H).
1o Example B40: N-(2-{[3-(dimethylamino)propyl]amino}-4,6-dimethoxypyrimidin-5-yl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-2-furamide Ij /~ N .

o ~J~.
N NON

is Compound B40 was synthesized in a manner analogous to that of compound B 1, according to scheme B, using similar starting compounds and reaction conditions.
Example 841: 5-(2-bromo-5-tent-butylphenoxy)-N (2,4,6-trimethoxyphenyl)-2-furamide H C ~H3 O
HsC ~ \ O ~ O ~ NH ~ ~ O

Br O
2o B41 ~"3 Compound B41 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): 8 7.54 (d, 1H, J = 8.5 Hz), 7.18 (d, 1H, J = 3.6 Hz), 7.14-7.12 (m, 25 2H, J = 2.27, 4.72 Hz), 6.17 (s, 2H), 5.47 (d, 1H, J = 3.6 Hz), 3.81 (s, 9H), 1:28 (s, 9H).

Example 842: 5-[2-bromo-5-tent-butyl-4-(2,4-dibromo-5-tert-butylphenoxy)phenoxy]-N (2,4,6-trimethoxypydrimidin-5-yl)-2-furamide Compound B42 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
I \ OH CsZC03, DMF, 120 °C 0 O 0 ~ 0 p O
_ -I- ~ ~ / _ I ~ ~ / O Br ~ Br O
Br Br 0 O Br Br ~ O, Br \ I
Br NMR data consistent with the desired title product were as follows:1H NMR
(ppm, DMSO - d6): 8 9.24 (bs, 1H), 8.00 (s, 1H), 7.37 (s, 1H), 7.24 (d, 1H, J
= 3.6 Hz), 7.06 (s, 2H), 7.00 (s, 1H), 5.64 (d, 1H, J = 3.6 Hz), 3.91 (s, 3H), 3.87 (s, 6H), 1.38 (s, 9H), 1.37 (s, 9H).
Example B43: 5-(2-bromo-5-tent-butylphenoxy)-N (4-ethoxypyridin-3-yl)-2-furamide /N
H3C CH9 r O O /
H3C ~ ~ ~ NH~
/ O
/%~B~
B43 --,_ 1 H
Compound B43 was synthesized in a manner analogous to that of B 1, 1s according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): ~ 9.57 (bs, 1H), 8.30 (s, 1H), 8.27 (d, 1H, J = 5.48 Hz), 7.55 (d, 1H, J = 8.31 Hz), 7.21 (m, 2H), 7.15 (t, 1H, J = 2.17 Hz), 6.80 (d, 1H, J =
5:67 Hz), 5.46 (m, 1H), 4.20 (d, 2H, J =13.98 Hz), 1.48 (dd, 3H, J =13.98, 6.99 Hz), 1.28 (s, 9H).
Example B44: 5-(2-bromo-5-tert-butylphenoxy)-N quinolin-3-yl-2-furamide I

H I ~ O \ O' NH /N

Compound B44 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows:1H NMR
(ppm, CDC13): 8 8.86 (t, 1H, J = 7.18 Hz), 806 (d, 1H, J = 8.31 Hz), 7.83 (d, 1H, J
= 8.12 Hz), 7.65 (d, 1H, J = 8.31 Hz), 7.55 (ddd, 2H, J =12.84, 8.31, 7.18 Hz), 7.27 (d, 1H, J = 3.59 Hz), 7.22 (m, 1H), 7.18 (d, 1H, J = 10.58 Hz), 5.47 (d, 1H, J
= 3.6 Hz), 1.30 (s, 9H).
Example B45: N (2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-IH inden-5-yl)oxy]-2-furamide O O N"CI

O O NH~N
/ ,o HC
CHI
1o B45 Compound B45 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the desired title product were as follows: 1H NMR
(ppm, CDC13): 8 7.15 (d, 1H, J = 3.59 Hz), 7.07 (s, H), 6.83 (s, 1H), 5.29 (d, 1H, J
is 3.59 Hz), 4.01 (s, 6H), 2.85 (d, 2H, J =10.01 Hz), 2.24 (s, 3H), 1.94 (t, 2H, J =
7.27 Hz), 1.22 (s, 6H).
Example 847: 5-(2-bromo-5-tert-bntylphenoxy)-N-(2,6-dimethoxypyridin-3-yl)-2-furamide CH3 O / O~CH3 H3C O~~ \ IN
H3C ~ '(~~/ NH
O
B47 / Br H3c' 2o Compound B47 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR data consistent with the title product were as follows: 1H NMR (ppm, DMSO-d6): 8 9.26 (s, 1H) 7.81 (d, 1H, J = 8.31 Hz), 7.67 (d, 1H, J = 8.69 Hz), 7.34 (d, 1H, J = 1.89 Hz), 7.27 (d, 2H, J = 8.69 Hz), 6.38 (d, 1H, J = 8.31 Hz), 2s 5.64 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 1.25 (s, 9H).
Example 848: 5-(5-Chloro-1,1,7-trimethyl-indan-4-yloxy)-furan-2-carboxylic acid [2-(3-dimethylamino-propylamino)-4,6-dimethoxy-pyrimidin-5-yl]-amide acetic acid salt \ O 0 O ~N~N~N
N \ N \
ci Compound B48 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
Example 849: 5-[(3-isopropyl-1,1,4,6-tetramethyl-2,3-dihydro-1H-inden-5-yl)oxy] N (2,4,6-trimethoxyphenyl)-2-furamide Compound B49 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.
~ OH Cs2C03, DMF, 100 °C ~ O O O O + w O O O O
~i ~ ~~ ~~ HN ~ ~ ~ ~~ ~~ HN \ / O
O O O ~ ~ O O' 114 Br ~ ~ H
- O' NMR data consistent with the title product were as follows: 1H NMR (ppm, CDC13): ~ 7.19 (s, 1H), 7.04 (d, 1H, J = 3.59 Hz), 6.81 (s, 1H), 6.19 (s, ZH), 4.92 (d, 1H, J = 3.59 Hz), 3.83 (s, 6H), 3.82 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 1.33(s, 3H), 1.15 (s, 3H), 0.96 (d, 3H, J = 6.80 Hz), 0.60 (d, 3H, J = 6.80 Hz).
Example 850: 5-[(3-isopropyl-1,1,4,6-tetramethyl-2,3-dihydro-1H-inden-5-yl)oxy] N (2,4,6-trimethoxypyrimidin-5-yl)-2-furamide Compound B50 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
2o NMR data consistent with the title product were as follows: 1H NMR (ppm, CDCl3): 8 7.06 (d, 1H, J= 3.59 Hz), 7.03 (s, 1H), 6.80 (s, 1H), 3.98 (s, 6H), 3.97 (s, 3H), 4 ;92 (m, 1H), 2.90 (m, 2H, J =19.83, 11.90, 11.52, 4.72 Hz), 2.18 (s, 3H), 2.16 (s, 3H), 1.84 (dt, 1H, J =13.22, 8.88 Hz), 1.32 (s, 3H), 1.14 (s, 3H), 0.95 (m, 3H), 0.60 (d, 3H, J = 6.80 Hz).
Example 851: 5-(4-chloro-5-isopropyl-2-methylphenoxy)-N (2,4,6-trimethoxypyrimidin-5-yl)-2-furamide -N
H3C ~ ~ \O/ NH
/ ~N CH3 B51 ~"3 Compound B51 was synthesized in a manner analogous to that of Bl, according to Scheme B, using similar starting compounds and reaction conditions.
1o NMR data consistent with the title product were as follows: 1H NMR (ppm, CDC13): 8 7.24 (s, 1H), 7.14 (d, 1H, J = 3.40 Hz), 6.98 (s, 2H), 5.35 (d, 1H, J =
3.40 Hz), 3.97 (s, 9H), 3.33 (d, 1H, J = 6.80 Hz), 2.24 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H).
Example B52: N {4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-~s yl}-5-[3,3,6-trimthyl-2,3-dihydro-IH inden-5-yl)oxy]-2-furamide HaC I w C ~~ NH~N~--NH'W/~ ~O
CH3 p B52 ~H3 Compound B52 was synthesized according to a method analogous to Scheme B, using similar starting compounds and reaction conditions as shown and described below. NMR data consistent with the title product were as follows: 1H NMR
(ppm, 2o CDC13): ~ 7.09 (d, 1H, J = 3.40 Hz), 7.05 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 5.72 (bs, 1H), 5.29 (d, 1H, J = 3.40 Hz), 3.87 (s, 6H), 3.75 (dd, 4H, J = 9.07, 4.53 Hz), 3.47 (m, 2H), 2.84 (d, 2H, J = 7.18 Hz), 2.51 (d, 6H, J = 6.42 Hz), 2.23 (s, 3H), 1.93 (d, 2H, J =
7.18 Hz), 1.78 (t, 2H, J = 6.42 Hz), 1.21 (s, 6H).

OH I \ Og I
\ i ~
off OH
i i ~--~

polyphosphori c acid los 61 O

major IHZ, Pd/C
~'I~cst.
H2SOq O CsiC03, ~
p DMF OH
O Br~ p p ~
i i ~
~

O- ~ ~ 63 65 O .
- _64 NaOH, MeOH, tt.

O DMF, HATU.
O r.t ~
O ~ O O
OH O O ~O
I ~ I /
HN \ N~NMN
~

~O N
H

N (CompoundB52) O N
wp ~
~

SOC12,DCM, refluxed 120 C, 20 min. SmithSynthesize5 CsF, CH3CN, ' [N~NHz O

_7z ~O /
O _ ~
O HZN J~.~ w O ~ O
~~ O
O
O
~
~
~
N

,,, HN
CI \
O ~-CI
~

CI N

EtOAc, 69 DIEA, r.2. -O
or 120 ~C, 10 min. SmithSynthesizer 5-hydrogy-3,3,6-trimethyl-1-indanone 62: To a three-necked round bottom flask assembled with a condenser, thermometer and mechanic stirrer under nitrogen, s o-cresol (1197 mmol, 124 ml) and 3,3-dimethylacrylic acid (1520 mmol, 154 g) were added. The mixture was gently stirred and heated at 40 °C while adding polyphosphoric acid (3.9 L). After the addition of polyphosphoric acid was completed, the contents were rapidly heated to 105 °C, and the heating mantel was removed. The reaction mixture was monitored by TLC (1:3 ethyl acetate: hexane) 1o showing no starting materials. The reaction was quenched by pouring the hot mixture into a large bucket of ice water with constant stirring. The aqueous layer was extracted with ethyl acetate. The organic phase was concentrated, and the crude product was crystallized with ethyl acetate to obtain pure Compound 62 (21 g, 9.5 %).
NMR data consistent with the title product were as follows: II~TMR (300 MHz, 15 CDC13): 8 7.50 (s, 1H), 7.83 (s, 1H), 6.06 (bs, 1H), 2.55 (s, 2H), 2.27 (s, 3H), 1.36 (s, 6H).
3,3,6-trimethyl-5-indanol 63:A solution of 5-hydroxy-3,3,6-trimethyl-1-indanone (21.5 mmol, 4.1 g) and sulfuric acid (290 ~.~.1) in methanol (150 ml) were 7o degassed with nitrogen for at least twenty minutes following by the addition of catalyst palladium on carbon (4.3 mmol, 0.63 g). The ketone was reduced under psi of H2 overnight. The contents were filtered over celite. Methanol was removed in vacuum to give brown oil residue that was redissolved in ethyl acetate and washed with water until neutral and brine. The organic layer was dried over sodium sulfate and brought to dryness given light yellow oil. The crude product was purified by plug column chromatography (1:3 ethyl acetate: hexane) to give light yellow solid Compound 63 (3.6 g, 93%). NMR data consistent with the title product were as follows: iHNNIR (300 MHz, CDCl3): 8 6.94 (s, 1H), 6.57 (s, 1H), 4.58 (s, 1H), 2.78 (t, 2H), 2.21 (s, 3H), 1.89 (t, 2H), 1.21 (s, 6H).
Methyl 5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furoate 65:
In a one-necked round-bottom flask assembled with a condenser and gas outlet, a solution of 63 (22.73 mmol, 4.0 g), 64 (17.6 mmol, 3.6 g) and cesium carbonate ( 22.8 mmol, 7.4 g) in DMF ( 45 mL) was degassed with nitrogen gas for 20 minutes then 1s heated to 100 °C for 7 hours under N2. The mixture was cooled down to room temperature and quenched with 1M HCI. The content was extracted with ethyl acetate, water and brine. The organic phase was dried over sodium sulfate. The crude prbduct was purified by plug column chromatography (1:5 ethyl acetate: hexane) to obtain yellow oil Compound 65 (5.8 g, 84%). Note: The material from the baseline of 2o the column was 66. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR (300 MHz, CDCl3): S 1.21 (s, 6H), 1.89 (t, 2H), 2.20 (s, 3IT), 2.77 (t, 2H), 3.86 (s, 3H), 5.22 (d, 2H), 6.56 (s, 1H), 6.93 (s, 1H), 7.12 (d, 1H), APCI-MS mlz 302.2 (M+H)+.
5[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furoic acid 66: To a 25 solution of 65 (19.3 mmol, 5.8 g) in methanol (10 ml) in a one-necked round bottom flask assembled with a stir bar, 4M NaOH aqueous solution (20 ml) was added.
The contents were stirred at room temperature overnight. The clear brown solution was acidified with 2M HCl and stirred for 3 hours. The aqueous layer was extracted with ethyl acetate and brine then dried over sodium sulfate. The crude product was 3o crystallized with CH3CN to give pure light yellow solid Compound 66 (3.18 g, 57 %).
NMR data consistent with the title product were as follows: 1HNMR (CDCl3, ppm): 8 7.26 (d, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 2.84 (t, 2H), 2.20 (s, 3H), 1.93 (t, 2H), 1.21 (s, 6H).

N-~4,6-dimethogy-2-[(3-morpholin-4-ylpropyl)amino] pyrimidin-5-yl}-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)ogy]-2-furamide 68 (Compound B52): Procedure 1: To a solution of 66 (9.74 mmol, 2.8 g), 67 (8.0 mmol, 2.4g) and HATU (10.2 mmol, 3.4 g) in DMF (18 ml) prepared in a one-necked flask assembled with a gas outlet and a stir bar, diisopropylethylamine (33.5 mmol, 6 ml) was added slowly via a syringe under N2. The reaction mixture was stirred under N2 overnight.
The solvent was removed under vacuum pressure then purified by HPLC (32-95 70 min. - CH3CN: O.1M NH4oAC) without further work-up to give white solid product 68 (2.84 g, 52%). Compound 6~ was dissolved in methylene chloride and then 1o dried in vacuum, yielding an amorphous solid. NMR data consistent with the title product were as follows: 1HNMR (300 MHz, CDC13): 8 17.10 (d, 1H), 7.05 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 5.72 (bs, 1H), 5.29 (d, 1H), 3.87 (s, 6H), 3.75 (t, 4H), 3.48 (bt, 2H), 2.84 (t, 2H), 2.49 (m, 6H), 2.23 (s, 3H), 1.93 (t, 2H), 1.81 (t, 4H), 1.21 (s, 6H).
Procedure 2: Compound 68 was also be synthesized from 71. In a 5 ml microwave tube assembled with a stir bar, N (2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H inden-5-yl)oxy]-2-furamide 71( 0.35 g, 0.76 mmol), cesium fluoride (0.29 g, 1.9 mmol), acetonitrile (3.8 ml) and amine (0.14 g, 0.91 mmol) were added. The mixture was heated to 120 °C for 20 minutes by Smith 2o Synthesizer. Without work-up the crude product was purified by HPLC.
5-[(3,3,6-trimethyl-2,3-dihydro-1H inden-5-yl)oxy]-2-furoyl chloride 69:
In a one-necked round bottom flask assembled with a stir bar, condenser and gas inlet was added 5[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furoic acid 66 ( 18.6 mmol), thionyl chloride (6 ml), and methylene chloride (100 ml). The 2s mixture was refluxed overnight. After cooling down to room temperature, the contents were washed with water and brine to quench the excess thionyl chloride.
Organic solution was dried over Na2S04. Reddish-brown oil product was passed over a short silica gel plug with 1:1 (ethyl acetate: hexane). NMR data consistent with the title product were as follows: 1HNMR (300 MHz, CDC13): b 1.22 (s, 6H), 30 1.91-197 (m, 2H), 2.19 (s, 3H), 2.85 (t, 2H), 5.31 (d, 1H), 6.86 (s, 1H), 7.07 (s, 1H), 7.45 (d, 1H).
N (2-chloro-4,6-dimethogypyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H inden-5-yl)oxy]-2-furamide 71: 5-[(3,3,6-trimethyl-2,3-dihydro-lII inden-5-yl)oxy]-2-furoyl chloride 69 (2.66 g, 8.71 mmol) and 2-chloro-4,6-dimethoxypyrimidin-5-amine (1.65 g, 8.71 mmol) were added into a 25-ml round-bottam flask containing a stir bar and ethyl acetate (17.5 ml) following by slow addition of diisopropylethyl amine (3.2 ml). The mixture was stirred at room temperature overnight. An alternate route was to heat the mixture to 120 degree Celsius for 10 minutes by Smith Synthesizer microwave. Classical work up was carried out. Crude product was purified by flask chromatography (silica gel 1:5 ethyl acetate: hexane). Light brown product 71 was obtained (0.5 g, 13%). NMR data consistent with the title product were as follows: 1HNMR (300 MHz, CDC13): 8 1.22 (s, 6H), 1.94 (t, 2H), 2.24 (s, 3H), 2.85 (t, 2H), 4.01 (s, 6H), 5.30 (d, 1H), 6.83 (s, 1H), 7.08 (d, 2H), 7.15 (d, 1H).
Compound 67 was synthesized according to the nitration scheme below:
w W N CF3S020501,CFa _ OpN ~ DMP, r.t 02N W N
/~ (CH3)4~°a,DCM N
~O N"OI ~ N_"CI OJN~NHZ \O N HEN
~O

HZ, Pd/C. MeOH H2N
~O N H~N

2-chloro-4,6-dimethogy-5-nitropyrimidine 74: In a 12-L flask assembled with an overhead stirrer, thermometer, N2 inlet and addition funnel, tetramethylammonium nitrate (587 g, 4.31 mol) and dichloromethane (4 L) were added. The contents were stirred under N2 for 1 hour at room temperature (20°C).
Triflic anhydride (1.216 g, 4.31 mol, 725 ml) was added dropwise over a period of 45 minutes so that the temperature remained below 25°C. The addition funnel was rinsed with 100 ml of dichloromethane, and the dichloromethane was added to the reaction.
2o The contents were stirred at room temperature under N2 for 2 hours. The reaction mixture was then cooled to -78°C in a dry ice/acetone bath. The 2-chloro-4,6-dimethoxypyrimidine 73 (500 g, 2.87 mol) was dissolved in minimal amount of dichloromethane (3L). The solution of 73 was added dropwise aver a period of 1.5 hours. The addition rate was important to ensure the temperature did not rise above 5°C. After the addition of solution 73, the addition funnel was rinsed with 100 ml of dichloromethane and the rinse was added to the reaction. The acetone/dry bath was removed and the reaction was stirred for 38 hours under N2 as it warmed to room temperature. The reaction was monitored by TLC (3:1 CHCL3: Hexanes) and quenched by pouring reaction mixture into N2 kg of ice. The contents were neutralized with NaHC03 aqueous solution (pH = 8) and the dichloromethane layer was separated. The aqueous layer was extracted with 3x100 ml of dichloromethane.
The dichloromethane portions were combined and washed with 2xlL of H20. The combined dichloromethane portion was dried over MgS04, and brought to dryness.
Compound 74 was a white solid (615 g, 98 %).
4,6-dimethoxy-N-(3-morpholin-4-ylpropyl)-5-nitropyrimidine-2-amine 75:
A mixture of 2-chloro-4,6-dimethoxy-5-nitropyrimidine 74 (92.32 mmol, 20.2 g) in DMF -(23 ml) was cooled down to 0°C. 4-(3-Aminopropyl) morpholine 72 (92.4 to mmol, 13.5 ml) was added drop by drop via a syringe into the mixture 74.
The contents were warmed up to room temperature and stirred overnight under N2.
The organic solvents were removed by high vacuum, and the crude product was purified by flash column chromatography (2:5 methanol: ethyl acetate) without aqueous work up. Compound 75 had bright yellow solid (18 g, 60 %).
1s N-(5-amino-4,6-dimethoxy-2-pyrimidinyl)-N-(3-(~-morpholinyl)propyl]amine 67: A solution of 4,6-dimethoxy-N-(3-morpholin-4-ylpropyl)-5-nitropyrimidine-2-amine 75 (55 mmol, 18 g) in methanol (500 ml) was ddgassed for 15 minutes followed by the addition of catalyst Pd/C (5.5 mmol, 0.8 g).
The nitro-group was reduced under 30 psi of H2 overnight. The contents were filtered 20 over Celite, and the organic solvent was removed in vacuum. The product was dried under high vacuum to give brown solid Compound 67 (15 g, 90 %).
Exapample B53: 5-[(5-chloro-1,1,7-trimethyl-2,3-dihydro-1H-inden-4-yl)oxy]-N-(4,6-dimethoxy-2{[3-(4-methyl-1-piperazinyl)propyl]amino}-5-pyrimidinyl)-2-furamide Acetic acid Salt i 0 0 ~
I N \ ~N~
CI

Compound B53 was synthesized in a manner analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions.
Example B54: 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N
(2,4,6-trimethoxyphenyl)-2-furamide CH3 Br O O
HaC O O CHs I I NH ~ ~ O
~CH

Compound B54 was synthesized in a mamier analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was prepared according to the following method:
I \ OH Br2, CCI4, 0 °C ~OH
,~ \
I

NMR data consistent with the title product were as follows: 1H NMR (ppm, CDC13): 8 7.20 (bs, 1H), 7.05 (d, 1H, J = 3.40 Hz), 7.00 (s, 1H), 6.18 (s, 2H), 5.04 (d, 1H, J =
3.78 Hz), 3.83 (s, 6H), 3.82 (s, 3H), 2.85 (t, w2H, J = 7.55 Hz), 2.23 (s, 3H), 1.98 (dd, 2H, J = 14.73, 7.55 Hz), 1.42 (s, 6H).
1o Example B55: 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy] N
(4,6-dimethoxy-2- f [3-(4-methylpiperazin-1-yl)propyl]amino~pyrimidin-5-yl)-2-furamide CH3 Br O O _N ~N-CH3 HsC I i O 101 NH I-'N NH,/~N

Compound B55 was synthesized in a manner analogous to that of B1, 1s according to Scheme B, using similar~starting compounds and reaction conditions.
NMR data consistent with the title product were as follows: 1H NMR (ppm, CDC13): 8 7.04 (d, 1H, J = 3.78 Hz), 7.00 (s, 1H), 6.97 (s, 1H), 5.70 (bs, 1H) 5.03 (d, 1H, J = 3.78 Hz), 3.89 (s, 6H), 3.46 (d, 2H, J = 5.29 Hz), 2.85 (dd, 2H, J
=
14.73, 7.18 Hz), 2.56 (dd, 8H, J = 7.55, 6.80 Hz), 2.35 (s, 3H), 2.22 (s, 3H), 1.98 20 (t, 2H, J = 7.55 Hz), 1.79 (d, 2H, J = 6.42 Hz), 1.42 (s, 6H).
Example B56: 5-[(4-bromo-3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N
{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-2-furamide OH3 er ; H3 Hs0 O O O O
NH ~ ~NH
CH3 N/ ~ O
N' B56 H3~- V
Compound B56 was synthesized in a manner analogous to that of B 1, 2s according to Scheme B, using similar starting compounds and reaction conditions.

NMR data consistent with the title product were as follows: 1H NMR (ppm, CDC13): 8 7.13 (s, 1H), 7.08 (d, 1H, J = 3.40 Hz), 7.01 (s, 1H), 5.78 (bs, 1H), 5.05 (d, 1H, J = 3.78 Hz), 3.90 (s, 10H), 3.53 (s, 2H), 3.06 (s, 6H) 2.84 (t, 2H, J
= 7.18 Hz), 2.22 (s, 3H), 1.95 (d, 4H, J = 7.55 Hz), 1.41 (s, 6IT).
Example B57: 5-(2-bromo-5-tent-butylphenoxy)-N (4,6-dimethoxy-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrimidin-5-yl)-2-furamide HsC C p 0 _N
H3C I / I ~NH
N ~~H ~~--------~~
Br ~ N ~N-CH3 '~~JJ/N
B57 H3c--o Compound B57 was synthesized in a manner analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions.
to The requisite phenol was synthesized according to the following method:
Br o' I ~ OH Br _ I ~ OH NaOCHz/MeOH I ~ OH
z / Acetic Acid / CuBr, EtOAc, D /
102 92 k Yleld 89.57 h Yleld 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol: In a 500 mL round bottom flask, 3,5,5,8,8-pentamethyl-5,6;7,8-tetrahydro-2-naphthalenol (10.2 g, 46.72 mmol) was dissolved in 100mL acetic acid. To this solution Bromine 15 (8.2 g, 51.39 mmol) was added. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate.
The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-2o naphthalenol (12.8 g, 92% yield). NMR data consistent with the title product were as follows: 1H NMR (CDC13): 8 1.25 (s, 6H), 1.52 (s, 6H), 1.58-1.63 (m, 2I~, 1.68-1.71 (m, 2H), 2.25 (s, 3H), 5.99 (s, 1H), 7.05 (s, 1H).
1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol: In 1000 mL round-bottom flask, 1-bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-2s naphthalenol (12.8 g, 43.06 mmol) and Sodium methoxide in methanol (5.0 IVIJ were combined. To this solution CuBr (1.24 g, 8.61mmo1) was added followed by ethyl acetate (2.5 mL). The reaction was stirred and heated to reflux for 16 hours.
The reaction mixture was cooled to room temperature then poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated to yield 1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (9.58 g, 90% yield). NMR data consistent with the title product were as follows: IIiNMR (CDC13): 8 1.25 (s, 6H), 1.39 (s, 6H), 1.52-1.61 (m, 4H), 2.21 (s, 3H), 3.81 (s, 3H), 5.08 (s, 1H), 7.01 (s, 1H).
5-[(1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2 naphthalenyl)oxy]-2-furoic acid: 1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8 tetrahydro-2-naphthalenol (2.0 g, 8.05 mmol), methyl 5-bromo-2-furoate (1.65 g, 8.05 mmol), and Cs2C03 were dissolved in DMF (20 mL). The solution was placed under 1o nitrogen, stirred and heated to 70°C overnight. The cooled reaction mixture was poured into water, acidify with 6N HCl (100 mL) and extracted with ethyl acetate.
The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane/ethyl acetate (2:1 v/v) to yield 5-[(1-methoxy-3,5,5,8,8-pentamethyl-1s 5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furoic acid (1.1 g, 37 % yield).
NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR
(CDC13): 8 1.26 (s, 6H), 1.35 (s, 6H), 1.60 (m, 4H), 2.17 (s, 3H), 3.84 (s, 3H), 5.09 (d, ll~, 6.92 (s, 1H), 7.24 (d, 1H), APCI-MS m/z 373.1 (M+H)+. NMR data consistent with the title product were as follows: 1(ppm, CDCl3): S 7.53 (d, 1H, J = 8.31 2o Hz), 7.17 (d, 1H, J =1.89 Hz), 7.13 (d, 2H, J = 5.29 Hz), 6.97 (s, 1H), 5.71 (bs, 1H), 5.44 (d, 1H, J = 3.40 Hz), 3.87 (s, 6H), 2.57 (dd, 8H, J = 13.60, 6.80 Hz), 2.36 (s, 3H), 2.10 (d, 4H, J = 18.89 Hz), 1.78 (d, 2H, J =13.22 Hz), 1.28 (s, 9H).
Example B58: 5-[(1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I
o' o o , o~
I
I w o \o/ H
i ~ o~

Compound B58 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (DMSO-d6): 8 1.29 (s, 6H), 1.39 (s, 6H), 1.68 (m, 4H), 2.22 (s, 30 3H), 3.82 (s, 6H), 3.84 (s, 3H), 3.88 (s, 3H), 5.10 (d, 1H), 6.29 (s, 2H), 7.05 (s, 1H), 7.11 (d, 1H), APCI-MS m/z 524 (M+H)+

1e 859: N-(2,6-dimethoxyphenyl)-5-[(1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-2-furamide o~ o o _ \/
.. _ o 859 ' Compound B59 was synthesized in a manner analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (acetonitrile-d3): 8 1.29 (s, 6H), 1.38 (s, 6H), 1.67 (s. 4H), 2.25 (s, 3H), 3.82 (s, 6H), 3.87 (s, 3H), 5.15 (d, 1H), 6.71 (s, 1H), 6.73 (s, 1H), 7.03 (d, 1H), 7.09 (s, 1H), 7.29 (t, 1H) 7.62 (s, 1H), APCI-MS m/z 494 (M+H)+.
to Example B60: 5-[(1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-N-(2,4,6-trimethoxypyrimidin-5-yl)-2-furamide I I
o~ o o~Yo O O N-~wYN

Compound B60 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.
~s NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (MeOD): 8 1.20 (s, 6H), 1.29 (s, 6H), 1.58 (d, 4H, J = 2.27 Hz), 2.11 (s, 3H), 3.78 (s, 3H), 3.89 (s, 6H), 3.91 (s, 3I~; 5.01 (d, 1H, J = 3.78 Hz), 6.95 (s, 1H), 7.03 (d, 1H, J = 3.40 Hz), API-MS m/z 526 (M+H)+.
Example B61: 5-[5-(tert-butyl)-2-methylphenoxy]-N-(4,6-diemthoxy-2- f [3-(4-20 methyl-1-piperazinyl)propyl]amino]-5-pyrimidinyl)-2-furamide N~
O O N~N~
O O N ~ N

Compound B61 was synthesized in a manner analogous to that of B 1, according to Scheme B (HBTIJ coupling), using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title 2s product were as follows: 1H NMR (CDC13): 8 1.30 (s, 9H), 1.80 (m, 6H), 2.26 (s, 3H), 2.50 (s, 3H), 2.60 (br m, 6H), 3.64 (t, 2H), 3.88 (s, 61H), 5.35 (d, 1H), 5.82 (t, 1H), 6.98 (s, 1H), 7.10 (s and d, 2H), 7.17 (m, 2H), APCI-MS nZ/z 567.2 (M+I~+' Example B62: 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide I
O O NYO\
O O ~N
H
w \
B62 ~
Compound B62 was synthesized in a manner analogous to that of B 1, according to Scheme B (HBTIJ coupling), using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows:1H NMR (d4-CH30H): 81.23 (s, 6H), 1.27 (s, 6H), 1.69 (s, 4H), 2.22 (s, 3H), 3.95 (s, 6H), 3.98 (s, 3H), 5.34 (d, 1H), 7.02 (s, 1H), 7.14 (d, 1H), 7.23 (s, 1H), APCI-MS m/z 496.5 (M+H)+.
1o Example B63: 5-(5-tert-butyl-2-methylphenoxy)-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide O \O/ H \ N

Compound B63 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(CDCl3):
1s 8 1.29 (s, 9H), 2.24 (s, 3H), 3.95 (s, 6H), 3.98 (s, 3H), 5.36 (d, 1H), 7.12 (s, 1H), 7.15 (d, 1H), 7.22 (m, 2H), APCI-MS m/z 442.1 (M+H)+.
Example B64: N (2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide 0 j YG

0 ~ / ~ ~ 0 20 Compound B64 was synthesized according to Scheme B. NMR data consistent with the title product were as follows: 1H NMR (CDC13): 8 1.46 (s, 6H), 2.29 (s, 3H), 4.01 (s, 6H), 5.02 (s, 2H), 5.37 (d, 1H, J = 3.40 Hz), 6.81 (s, 1H), 7.08 (s, 1H), 7.16 (d, 1H, J = 3.59 Hz).
Example B65: N-(2,4,6-trimethoxy-5-pyrimidinyl)-5-[(3,8,8-trimethyl-5,6,7,8-25 tetrahydro-2-naphthalenyl)oxy]-2-furamide I
0 0~~~0 I ~ \ / JT~Io i Compound B65 was synthesized in a manner analogous to that of B 1, according to Scheme B (HBTU coupling), using similar starting compounds and reaction conditions. Yield of purified product was 33%. NMR and mass s spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): 8 1.24 (s, 6H), 1.68 (m, 2H), 1.78 (m, 2H), 2.19 (s, 3H), 2.72 (t, 2H, J =
6.32 Hz), 3.95 (s, 6H), 3.98 (s, 3H), 5.29 (d, 1H, J = 3.59 Hz), 6.96,(d, 1H,), 7.06 (s, 1H), 7.14 (d, 1H, J = 3.59 Hz), Mass APCI 468.5.
Example 866: 5-[(3,6,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide \/
i Compound B66 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized according to the following method:

a.
I~ I~
b d. I ~ OS~ c. I ~ off i O O
O
e.
r \/ f. H
O.
SIB

a. AIC13, AcylChlodde, CH3N02,0°C, 7 hrs.
b. McPBA, NaHC09(aq), CHzCIZ, air 423-120 o. TBDMS, DMF, imldazole d. 1. LDA, -78°C, THF, 30 min 2. Mel, 12h, RT
e, hydrogentation 1$ f. acid NMR and mass spectrometry data consistent with the title product were as follows:
1HNMR (dmso-d6): b 1.00 (d, 3H, J = 6.42 Hz), 1.14 (s, 3H), 1.21 (s, 3H), 1.29 (d, 1H, J =12.65 Hz), 1.57 (d, 1H, J = 13.03 Hz), 1.87 (s, 1H), 2.14 (s, 3H), 2.25 (dd, 1H, J = 12.09,, 8.50 Hz), 2.72 (d, 1H, J = 16.43 Hz), 3.72 (s, 6H), 3.79 (s, 3H), 5.40 (d, 1H, J = 3.40 Hz), 6.26 (s, 2H), 6.97 (s, 1H), 7.11(s, 1H), 7.17 (d, 1H, J = 3.21 Hz), 8.90 (s, 1H), APCI mass 480.2.
Example B67: N-(2-methoxy-3-pyridinyl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furamide ~I I I b 0 Compound B67 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
1o NMR and mass spectrometry data consistent with the title product were as follows:
1I3N1VIR (CD30D): 8 1.23 (s, 6H), 1.66 (m, 2H), 1.81 (m, 2H), 2.19 (s, 3H), 2.72 (t, 2H, J = 6.23 Hz), 4.03(s, 3H), 5.34 (d, 1H, J = 3.59 Hz), 6.96 (m, 2H, J =
5.10, 4.91, 3.02, 1.89 Hz), 7.09 (s, 1H), 7.22 (d, 1H, J = 3.59 Hz), 7.89 (td, 1H, J =
5.10, 1.70 Hz), 8.42 (dd, 1H, J = 7.74, 1.70 Hz), APCI mass 407.2.
15 Example B68: N-(2,4-dimethoxy-3-pyridinyl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furamide I

0 0 ~ \ I
I~ I I o \

Compound B68 was synthesized in a manner analogous to that of B1, according to Scheme B, using similar starting compounds and reaction conditions.
2o NMR and mass spectrometry data consistent with the title product were as follows:
1HNMR (CDC13): 81.44 (s, 6H), 1.85 (m, 2H), 2.00 (m, 2H), 2.43 (s, 3H), 2.92 (t, 2H, J = 6.33 Hz), 4.10 (s, 3H), 4.18 (s, 3H), 5.50 (d, 1H, J = 3.59 Hz), 6.81 (d, 1H, J =
.85 Hz), 7.14 (s, 1H), 7.35 (d, 1H, J = 3.59 Hz), 7.47 (s, 1H), 8.22 (d, 1H, J
= 5.85 Hz), APCI mass 437.2.
25 Example B69: 5-(4-chloro-5-isopropyl-2-methylphenoxy)-N-[2-(2-hydroxyethoxy)-4,6-dimethoxy-5-pyrimidinyl]-2-furamide O N O
O ~ ~ ~OH
O 0 ~ N
I "
o~
ci Compound B69 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
I I
O N\ CI RAH O NYO.R O I NYO.R
O N I N ~ 02N I i NI ~ H2N~N

O~
NMR and mass spectrometry data consistent with the title product were as follows:
1HNMR (CDC13): 8 1.19 (d, 6H, J = 7.18 Hz), 2.24 (s, 3H), 3.33 (dq, 1H, J =
7.18, 6.80 Hz), 3.97 (m, 8H), 4.48 (dd, 2H, J = 4.91, 4.53 Hz), 5.35 (d, 1H, J =
3.40 Hz), 6.97 (s, 1H), 7.02 (s, 1H), 7.14 (d, 1H, J = 3.78 Hz), 7.25 (m, 1H), APCI Mass 492.1.
Example B70: 5-(4-chloro-5-isopropyl-2-methylphenoxy)-N-[4,6-dimethoxy-2-(2-l0 methoxyethoxy)pyrimidin-5-yl]-2-furamide ,o (,0 0 0 ~y ~0 N
CI

Compound B70 was synthesized in a manner analogous to that of B 1, 1s according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows:
IIiNMR (CDC13): 8 1.16 (d, 6H, J = 6.80 Hz), 2.23 (s, 3H), 3.33 (m, 1H, J =
6.80, 6.80, 6.80, 6.80 Hz), 3.42 (s, 3H), 3.76 (t, 2H, J = 4.91 Hz), 3.96 (s, 6H), 4.50 (dd, 2H, J = 5.29, 4.91 Hz), 5.34 (d, 1H, J = 3.40 Hz), 6.99 (s, 2H), 7.14 (d, 1H, J = 3.78 2o Hz), 7.23 (s, 1H), APCI Mass 506.1.
Example B71: 5-(4-chloro-5-isopropyl-2-methylphenoxy)-N-(4,6-dimethoxy-2-phenoxypyrimidin-5-yl)-2-furamide 0 0 / \
N
/ N
CI I \ O \O/ N~ ~ O
O\

2s Compound B71 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.

NMR and mass spectrometry data consistent with the title product were as follows:
1HNMR (CDC13): S 1.19 (d, 6H, J = 7.18 Hz), 2.24 (s, 3H), 3.34 (m, 1H, J =
7.18, 6.80, 6.80, 6.42 Hz), 3.85 (s, 6H), 5.35 (d, 1H, J = 3.40 Hz), 6.98 (s, 1H), 6.99 (s, 1H), 7.02 (s, 1I~, 7.14 (d, 1H, J = 3.40 Hz), 7.21 (d, 2H, J = 8.31 Hz), 7.37 (d, 1H, J = 8.31 Hz), 7.39 (dd, 1H, J = 8.31, 7.18 Hz), APCI Mass 522.2.
Example B72: 5-(5-isopropyl-2-methylphenoxy)-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide I

\ N

Compound B72 was synthesized in a manner analogous to that of B 1, 1o according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDCl3): 8 1.22 (6H, d), 2.27 (3H, s), 2.87 (1H, hep), 3.94 (9H, s), 5.35 (1H, d), 6.93 (1H, s), 7.02 (2H, br s), 7.15 (2H, m), FI-PCI m/z 428.2 (M+H)+.
15 Example B73: 5-(4-chloro-3-isopropyl-2-methoxy-6-methylphenoxy)-N-(4,6-dimethoxy-2-{ [3-(4-methyl-1-piperazinyl)propyl] amino}-5-pyrimidinyl)-2-furamide I H~/\
o. o~ ~YN~
CI I \ \ / N \ \ N
H O
N

Compound B73 was synthesized in a manner analogous to that of B 1, 2o according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (CDC13): 8 1.34 (6H, d), 1.78 (2H, m), 2.19 (3H, s), 2.31 (3H, s), 2.51 (10H, br m), 3.38 (2H, m), 3.55 (1H, hep), 3.83 (3H, s), 3.89 (6H, s), 5.10 (1H, d, J =
4.8 Hz), 5.82 (1H, br t), 6.88 (1H, s, amide NH], 7.01 (1H, s), 7.06 (1H, d, J = 4.8 Hz), FI-PCI
2s m/z 618.4, 619.4 (M+H)+.
Example B74: 5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide Compound B74 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.
The yield of the purified product was 41%. NMR and mass spectrometry data s consistent with the title product were as follows: 1H NMR (300 MHz, CDC13):
8 1.51 (s, 6H), 3.12 (s, 2H), 3.80 (s, 9H), 5.48 (d, 1H), 6.20 (s, 2H), 6.81 (t, 1H), 6.98 (dd, 2H), 7.15 (d, 1H), 7.20 (br s, 1H), APCI-MS m/z 440.1 (M+H)+.
Example B75: 5-(3-chloro-2-isopropyl-5-methylphenoxy)-N-(2,6-dimethoxyphenyl)-2-furamide to B75 Compound B75 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (300 MHz, CDC13): ~ 1.25 (s, 3H), 1.27 (s, 3H), 2.34 (s, 3H), 3.28 (septet, 1H, J
15 = 9Hz), 3.87 (s, 6H), 5.44 (d, 1H, J =~3Hz), 6.62 (s, 1H), 6.65 (s, 1H), 6.95 (s, 1H), 7.17 (d, 1H), 7.23 (t, 1H), 7.31 (s, 1H), 7.37 (s, 1H), APCI-MS mlz 430.1 (M+H)+.
Example B76: 5-(3-chloro-2-isopropyl-5-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide 2o Compound B76 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows:

1HNMR (300 MHz, CDC13): 8 1.24 (s, 3H), 1.26 (s, 3H), 2.34 (s, 3H), 3.27 (septet, 1H, J = 9 Hz, J = 6 Hz), 5.44 (d, 1H, J = 3 Hz), 6.20 (s, 2H), 6.94 (s, 1H), 7.16 (d, 1H, J = 6 Hz), 7.23 (s, 1H), 7.30 (s, 1H), APCI-MS m/z 460.2 (M+H)+.
Example B77: 4-bromo-N-(2,6-dimethoxyphenyl)-5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furamide Compound B77 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H
1o NMR (300 MHz, DMSO-d6): 8 1.16 (s, 6H), 1.24 (s, 6H), 1.61 (s, 4H), 2.26 (s, 3H), 3.72 (s, 6H), 6.70 (d, 2H), 6.81 (s, 1H), 7.21 (t, 1H), 7.26 (s, 1H), 7.46 (s, 1H), 9.25 (s, 1H), APCI-MS m/z 498.3 (M+H)+.
Example B78: N-(4,6-dimethoxy-2- f [3-(4-methyl-1-piperazinyl)propyl]amino)-5-pyrimidinyl)-5-[(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-2-furamide Compound B78 was synthesized in a manner analogous to that of compound B 1, according to scheme B, using similar starting materials and reaction conditions.
2o Example B79: 4-bromo-5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-n-(2,4,6-trimethylphenyl)-2-furamide o-/ \
i H O-O
8r O
(/

Compound B79 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows:
1HIVMR (300 MHz, DMSO-d6): 8 1.15 (s, 6H), 1.22 (s, 6H), 1.60 (s, 4H), 2.25 (s, 3H), 3.69 (s, 6H), 3.78 (s, 3H), 6.28 (s, 2H), 6.82 (s, 1H), 7.24 (s, 1H), 7.43 (s, 1H), 9.08 (s, 1H), APCI-MS m/z 572.4 (M+H)+.
Example B80: N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl~-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide acetate O N~/ N~
\ O O N
/
~ /° ~O

Compound B78 was synthesized in a manner analogous to that of compound B 1, according to scheme B, using similar starting materials and reaction conditions.
Example B81: 5-[(3-chloro-8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I~ \/ H ~ ~ °v ci o Compound B81 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized according to the following method:
$6 O CI / OH MeOH CI OMe CI~ _ ~ ~ I O
, HO ~ HO ~ I O TsOH HO
AICI3, nitrobenzene Et3SiH TFA
OMe OH 01 / OH MeMgCI (3.5 eq.) 01 AICI3,~ CH3N02 I ~ I O
HO
I HO THF
123 >95% 88%
NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (DMSO-d6): b 1.21 (s, 6H), 1.61 (m, 2H), 1.73 (m, 2H), 2.71 (t, 2H), 3.71 (s, 6H), 3.78 (s, 3H), 5.51 (d, 1H), 6.26 (s, 2H), 7.18 (s, 1H), 7.29 (s, 1H), 7.37 (s, 1H), 5 8.92 (s, 1H), APCI-MS m/z 486.3 (M+H)+.
Example B82: 5-[(3-methoxy-1,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I
0 0 ~ o~
I
I ~ o \ / H
q ,0 Compound B82 was synthesized in a manner analogous to that of B1, Io according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized according to the following method:
c1 OH OMe O
I ~ OH Mel (1 eq.) ~:z_ I w OH 01 I
_~zC M / AICI3 OMe 48% 26 NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (DMSO-d6): ~ 1.24 (s, 6H), 1.39 (s, 6H), 1.66 (s, 3H), 3.76 (s, 9H), 3.82 (s, 15 3H), 5.10 (d, 1H), 6.37 (s, 2H), 7.14 (s, 1H), 7.48 (d, 1H), 8.94 (s, 1H), APCI-MS m/z 524.3 (M+H)+.
Example B83: 5-[(3-methoxy-1,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide I
0 0 ~~o~
O \O/ H~N
i _ ~ ,O
B83 v q Compound B83 was synthesized in a manner analogous to that of Bl, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (DMSO-d6): ~ 1.27 (s, 6H), 1.34 (s, 6H), 1.61 (s, 4H), 2.30 (s, 3H), 3.71 (s, 3H), 3.86 (s, 6H), 3.90 (s, 3H), 5.08 (d, 1H), 6.94 (s, 1H), 7.09 (d, 1H), 9.14 (s, 1H), APCI-MS m/z 526.3 (M+H)+.
Example B84: 5-[(7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide \ / H \ /
,c1 o 1o Compound B84 was synthesized in a manner analogous to that of B 1, according to Scheme B, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDCl3): 8 1.25 (s, 6H), 1.71 (t, 2H), 3.31 (t, 2H), 3.81 (s, 9H), 5.22 (d, 1H), 6.18 (s, 2H), 6.50 (s, 1H), 7.06 (s, 1H), 7.08 (d, 1H), 7.19 (s, 1H), 15 APCI-MS m/z 487.2 (M+H)+.
Example B85: 5-[(1-acetyl-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide o /o\ r"v \ /
NCI C
B85 ~O
Compound B85 was synthesized in a manner analogous to that of B1, 2o according to Scheme B, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized as follows:
OMe II CI / I CMe ~B , I OMe C
HZN ~ I CI ESN, CHZCIz ~HN~CI LDA, THF N CI
100 rt, Sh 92~
AIC13 I ~ Dli NaOH I ~ OH
130°C ~ ~ CI H ~ CI

NMR and mass spectrometry data consistent with the title product were as follows:1H
NMR (CDC13): 8 1.26 (s, 6H), 1.78 (t, 2H, J = 6.318 Hz), 2.28 (s, 3H), 3.76(t, 2H), 3.78 (s, 9H), 5.48 (d, 1H, J = 3.546 Hz), 6.17 (s, 2H), 7.13 (s, 2H), 7.15 (s, 1H), APCI-MS rnlz 529 (M+H)+.
Example B86: 5-[(1-acetyl-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide \ O O O O N~
/ HN ~ // O
N CI N
B86 ~o -O
Compound B 86 was synthesized in a manner analogous to that of B l, according to Scheme B, using similar starting compounds and reaction conditions.
1o NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (DMSO-d6): ~ 1.15 (s, 6H), 1.67 (t, 2H, J = 6.04 Hz), 2.17 (s, 3H), 3.66 (t, 2H, J = 6.14 Hz), 3.81 (s, 6H), 3.85 (s, 3H), 5.55 (d, 1H, J = 3.59 Hz), 7.15 (d, 1H, J =
3.40 Hz), 7.36 (s, 1H), 7.81(s, 1H), 9.16 (s, 1H), APCI-MS m/z 532 (M+H)+.
Example B87: 5-[(4,6-dibromo-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-15 N-(4,6-dimethoxy-2-~[3-(4-methylpiperazin-1-yl)propyl]amino]pyrimidin-5-yl)-furamide j ~NH~\~N~
O ~ ~IO
N~
\ O N

er er 2o Compound B87 was synthesized according to Scheme B.

I \ OH grz I ~ OH
Br ~ Br r.t. 126 To a solution of phenol (3.28 g, 20 mmol) in carbon tetrachloride (50 mL) was added bromine (2.06 mL, 40 mmol) dropwise. The reaction mixture was stirred at r.t.
overnight. It was washed with water, saturated sodium bicarbonate, brine, dried 2s (sodium sulfate) and evaporated to a dark oil. The dibrominated product was purified by flash chromatography (eluting solvent: lethyl acetate/10 hexanes to lethyl acetate/Shexanes): 4.5 g (70%). NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDCl3): 8 1.55 (6H, d), 1.90 (2H, sextet), 2.28 (3H,,s), 2.46 - 2.51 (lOH,m), 3.10 (2H, s), 3.44 (2H, m), 3.87 (6H, s), 5.52(1H, d, J = 3.78 Hz), 5.82 (1H, t), 6.93 (1H, s), 7.14 (1H, d, J = 3.78 Hz), 7.26 (1H, s), FI-PCI
mlz 725.1 and 727.1 (M+I~+.
Example B88: N-(2-anilino-4,6-dimethoxypyrimidin-5-yl)-5-(4-chloro-5-isopropyl-2-methylphenoxy)-2-furamide O r~ N~N
I / H~N
CI

Compound B88 was synthesized according to Scheme B. NMR and mass 1o spectrometry data consistent with the title product were as follows: IIiNMR
(CDC13):
8 1.19 (d, 6H, J = 6.80 Hz), 2.24 (s, 3H), 3.33 (dd, 1H, J = 7.18, 6.42 Hz), 3.98 (s, 6H), 5.35 (d, 1H, J = 3.78 Hz), 6.98 (s, 2H,) 7.04 (t, 1H, J = 7.55 Hz), 7.14 (d, 1H, J =
3.40 Hz), 7.32 (dd, 2H, J = 8.31, 7.55 Hz), 7.62 (d, 2H, J = 8.31 Hz), Mass (M-H)' _ 521.3.
is Example B89: N-(4,6-dimethoxy-2- f [3-(4-methylpiperazin-1-yl)propyl] amino~pyrimidin-5-yl)-5-[(3.3.6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide ~ O ~ -N N -HN~ ~~--NH
~~-N
O
B89 - \
Compound B89 was synthesized in manner analogous to that of B52. NMR
2o and mass spectrometry data consistent with the title product were as follows: 1H NMR
(300 MHz, CDCl3): 1H NMR (300 MHz, CDC13): 8 1.21 (s, 6H), 1.76 (dd, 2H, J =
12.84, 6.42 Hz), 1.92 (t, 2H, J = 7.18 Hz), 2.24 (s, 3H), 2.34 (s, 3H), 2.54 (dd, l OH, J
= 7.18, 6.42 Hz), 2.84 (d, 2H, J = 7.18 Hz), 3.45 (dd, 2H, J = 12.09, 6.04 Hz), 3.87 (s, 6H), 5.29 (d, 1H, J = 6.80 Hz), 5.78 (bs, 1H), 6.82 (s, 1H), 6:94 (s, 1H), 7.05 (s, 1H), 25 7.09 (m, 1H), APCI-MS m/z 579.7 (M+H)+.
Example B90: N-(2-{[2-(dimethylamino)ethyl]amino-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide HN \ N>--NH
N
O N-Compound B90 was synthesized in manner analogous to that of B52. NMR
and mass spectrometry data consistent with the title product were as follows:

(300 MHz, CDC13): 8 1.21 (s, 6H), 1.92 (dd, 2H, J = 14.73, 7.18 Hz), 2.23 (s, 3H), s 2.28 (s, 6H), 2.51 (t, 2H, J = 6.04 Hz), 2.84 (dd, 2H, J =14.35, 7.18 Hz), 3.48 (ddd, 2H, J = 11.71, 11.33, 5.67 Hz), 3.87 (s, 6H), 5.28 (m, 1H), 5.42 (t, 1H, J =
10.20 Hz), 6.82 (s, 1H), 6.97 (s, 1H), 7.05 (s, 1H), 7.10 (d, 1H, J = 3.40 Hz), APCI-MS
rn/z 579.7 (M+H)+.
Example B91: 5-[(3,5,5,7,8,8-hexamethyl-5,6,7,8- tetrahydro-2-1o naphthalenyl]oxy~-N-(2,4,6-triethyl-5-pyrimidinyl)-2-furamide ~ / ~ N
~N
'-N

Compound B91 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, 1s MeOH-d4): 8 0.90 (d, 3H, J = 6.6 Hz), 0.96, 1.12, 1.14, 1.23 (4s, 3H each), 1.29 (dd, 1H, J = 2.4, 13.5 Hz), 1.55 (dd, 1H, J =12.8, 13.4 Hz), 1.72-1.84 (m, 1H), 2.13 (s, 3H), 3.85 (s, 6H), 3.88 (s, 3H), 5.25 (d, 1H, J = 3.59 Hz), 6.91 (s, 1H), 7.05 (d, 1H, J
= 3.59 Hz), 7.18 (s, 1H), 7.20-7.31 (m, 2H), APCI-MS nalz 510.4 (M+H)+.
Example B92: N-(2,6-dimethoxyphenyl)-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-2o tetrahydro-2-naphthalenyl]oxy}-2-furamide I w o /o \ r"~ w i o I i B92 \ I
Compound B92 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, MeOH-d4): 8 0.99 (d, 3H, J = 6.8 Hz), 1.03, 1.22, 1.23, 1.32 (4s, 3H each), 1.38 (dd, 2s 1H, J = 2.4,13.4 Hz), 1.64 (dd, 1H, J = 13.0, 13.2 Hz), 1.80-1.95 (m, 1H), 2.23 (s, 3H), 3.80 (s, 6H), 5.34 (d, 1H, J = 3.59 Hz), 6.68 (d, 1H, J = 8.3 Hz), 7.01 (s, 1H), 7.14 (d, 1H, J = 3.59 Hz), 7.22 (d, 1H, J = 8.5 Hz), 7.27 (s, 1H), APCI-MS m/z 478.2 (~'I+~+.
Example B93: 5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl] oxy~-N-(1H-indol-5-yl)-2-furamide I ~ o / \

i o I i i NH
s B93 Compound B93 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, MeOH-d4): S 0.90 (d, 3H, J = 6.8 Hz), 0.96, 1.11, 1.13, 1.23 (4s, 3H each), 1.28 (dd, 1H, J = 2.6, 13.6 Hz), 1.54 (dd, 1H, J = 13.0, 13.2 Hz), 1.70-1.85 (m, 1H), 2.13 (s, 3H), 5.26 (d, 1H, J = 3.39 Hz), 6.32 (d, 1H, J = 3.59 Hz), 6.92 (s, 1H), 7.08 (s, 1H, J =
3.59 Hz), 7.12 (d, 1H, J = 3.0 Hz), 7.15-7.25 (m, 2H), 7.25-7.30 (m, 1H) 7.70-7.75 (m, 1H), APCI-MS m/z 457.4 (M+H)+.
a Example B94: 5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl] oxy}-N-(6-quinolinyl)-2-furamide i O / N
O O
I / \ /
1s B94 ~' Compound B94 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, DMSO-d6): 8 0.93 (d, 3H, J = 6.61 Hz), 1.00, 1.15, 1.18, 1.30 (4s, 3H each), 1.32 (dd, 1H, J = 2.2, 13.6 Hz), 1.54 (dd, 1H, J =13.0, 13.2 Hz), 1.72-1.85 (m, 1H), 2.19 (s, 3H), 5.53 (d, 1H, J = 3.59 Hz), 7.05 (s, 1H), 7.32 (s, 1H), 7.38 (d, 1H, J =
3.58 Hz), 7.42-7.52 (m, 2H), 7.92-8.06 (m, 2H), 8.27 (d, 1H, J = 7.55 Hz), 8.43 (d, 1H, J = 1.8 Hz), 8.77 (dd, 1H, J = 1.7, 4.3 Hz), 10.32 (br s, 1H, NI-~, APCI-MS m/z 469.4 (M+H)+.
Example B95: N-(1H-benzimidazol-2-ylmethyl)-5-[(4,4,8-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide HI
N L N
B95 l OO

Compound B95 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, MeOH-d4): S 1.32 (s, 6H), 1.85 (dd, 2H, J = 5.29, 5.48 Hz), 2.15 (s, 3H), 4.22 (dd, 2H, J = 4.34, 5.28 Hz), 4.98 (s, 2H), 5.52 (d, 1H, J = 3.78 Hz), 6.79 (d, 1H, J = 2.2 s Hz), 6.99 (d, 1H, J = 2.8 Hz), 7.21 (d, 1H, J = 3.59 Hz), 7.6-7.69 (m, 2H), 7.78 -7.89(m, 2H), APCI-MS m/z 432.4 (M+H)+.
Example B96: N-(1H-benzimidazol-2-ylmethyl)-5-[(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide H

1o Compound B96 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, MeOH-d4): 8 1.31 (s, 6H), 1.84 (dd, 2H, J = 5.29, 5.48 Hz), 2.16 (s, 3H), 4.18 (dd, 2H, J = 4.15, 5.29 Hz), 5.0 (s, 2H), 5.28 (d, 1H, J = 3.59 Hz), 6.69 (s, 1H), 7.08 (s, 1H), 7.19 (d, 1H, J = 3.59 Hz), 7.55 - 7.65 (m, 2H), 7.70-7.85(m, 2H), APCI-MS
m/z 1s 432.3 (M+H)+.
Example 97: 5-[(3-methyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I

w o 0 0~ v I.% I/ N wI
H
B97 Ow Compound B97 was synthesized according to Scheme B.
o I~ I
i i OH O AICI3, CH3CN / OH (CH3CH~3SiH / OH
rt, overnight W I TFA, rt, 8h w I

4B ° 4D 98%

A solution of 4A (3g), 4B (4.5g) and A1C13 (5.6g) was stirred at room temperature overnight. The solution was extracted with EtOAc. Compound 4C
(1.5g) was purified by column (hexane: EtOAC 2:1). To a solution of compound (1.3g) in TFA (5 ml) was added (CH3CH2)3SiH at 0°C. The solution was stirred for 2 2s hours. The solution was warmed up to room temperature and stirred overnight. The solution was extracted with EtOAC, concentrated to give compound 4D (1.2g).
NMR
and mass spectrometry data consistent with the title product were as follows:

(DMSO-d6): 8 1.55 - 1.75 (m, 3H), 1.92-2.05 (m, 1H), 2.03(s, 3H), 2.7-2.85 (m, 2H), 3.65 (s, 6H), 3.72 (s, 3H), 4.02 (t, 1H), 5.6 (d, 1H), 6.20 (s, 2H), 6.6 (s, 1H), 6.8 (s, 1H), 7.02 (d, 2H), 7.1 - 7.2 (m, 2H), 7.25-7.3 (t, 2H), 8.85 (s, 1H), APCI-MS
m/z 514.3 (M+H)+.
Example 898: 5-[(7-chloro-4,4-trimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)ogy]-N-(2,4,6-trimethoxyphenyl)-2-furamide j \ / H \ / °\

1o B98 Compound B98 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as fellows: 1H NMR
(DMSO): 8 1.21 (s, 6H), 2.38 (s, 2H), 3.71 (s, 6H), 3.78 (s, 3H), 5.52 (d, 1H), 6.26 (s, 2H), 7.05 (s, 1H), 7.18 (d, 1H), 7.35 (s, 1H), 8.92 (s, 1H), 10.31 (s, 1H), APCI-MS
1s tnlz 501.2 (M+I~~.
Example B99: 5-[2,4-dimethyl-5-(1,I,3,3-tetramethylbutyl)phenoxy]-N (2,4,6-trimethoxylphenyl)-2-furamide / NN \ /

\

2o Compound B99 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(MeOD):
8 0.97 (s, 9H), 1.64 (s, 6H), 2.15 (s, 2H), 2.35 (s, 3H), 2.56 (s, 3H), 4.05 (s, 6H), 4.06 (s. 3H), 5.32 (d, J = 6 Hz, 1H), 6.51 (s, 2H), 7.22 (s, 1H), 7.36 - 7 .40 (br, 2H), LC/
MS (M+H)+: 510.
25 Example 8100: N-(1H-benzimidazol-2-ylmethyl)-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl]oxy~-2-furamide H

Compound B 100 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, CDCl3): 8 0.99 (d, 3H, J = 6.8 Hz), 1.06, 1.18, 1.20, 1.33 (4s, 3H each), 1.30 - 1.45 s (m, 1H), 1.62 (dd, 1H, J = 12.8, 13.4 Hz), 1,.75 - 1.95 (m, 1H), 2.20 (s, 3H), 5.25-5.32 (m, 1H, NH), 5.32 (d, 1H, J = 3.58 Hz), 6.97 (s, 1H), 7.20 (s, 1H), 7.41 - 7.5 (m, 3H), 7.80 - 7.90 (m, 2H), 10.05 (br s, 1H, NH), APCI-MS m/z 472.3 (M+H)+.
Example B101: N-(2,4,6-trimethoxy-5-pyrimidinyl)-5-[(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide Fi to Compound B 101 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, MeOH-d4): 8 1.29 (s, 6H), 1.80 (dd, 2H, J = 5.2, 5.4 Hz), 2.15 (s, 3H), 3.95 (s, 6H), 15 3.9.7 (s, 3H), 4.15 (dd, 2H, J = 5.2, 5.4 Hz), 5.22 (d, 1H, J = 3.59 Hz), 6.65 (s, 1H), 7.07 (s, 1H), 7.12 (d, 1H, J = 3.59 Hz), APCI-MS m/z 470.1 (M+H)+.
Example B102: N-(2,4,6-trimethoxy-5-pyrimidinyl)-5-[(4,4,8-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide /

o I ~ -p Fi O' Y
O\
2o B102 Compound B 102 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, CDC13): 8 1.31 (s, 6H), 1.82 (dd, 2H, J = 5.2, 5.4 Hz), 2.16 (s, 3H), 3.97 (s, 9H), 4.20 (d, 2H, J = 5.0, 5.4 Hz), 5.39 (d, 1H, J = 3.59 Hz), 6.74 (d, 1H, J = 3.0 Hz), 6.90 (d, 25 1H, J = 3.0 Hz), 6.99 (s, 1H), 7.12 (d, 1H, J = 3.59 Hz), APCI-MS m/z 470.2 (M+H)+.
Example B103: N-~4,6-dimethoxy-2-[methyl(pyridin-2-ylmethyl)amino]pyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide N' N ~I
O O N~N
\ / O~

Compound B 103 was synthesized in a manner analogous to that of compound B 1, according to scheme B, using similar starting materials and reaction conditions.
Example B104: 5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N-(2,4,6-trimethoxy-5-pyrimidinyl)-2-furamide I
o ~~'°' N
H
O

Compound B 104 was synthesized according to Scheme B.
OH O PPA, 100-110 °C ~ I OH pd~C / I OH
O cat HzS04 ~ O

1o NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (d4-CH30H): ~ 1.15 (s, 6H), 1.87 (t, 2H), 2.81 (t, 2H), 3.71 (s, 3H), 3.87 (s, 6H), 3.90 (s, 3H), 5.14 (d, 1H), 6.89 (s, 2H), 7.02 (d, 1H), APCI-MS m/z 470.2 (M+H)+.
Example B105: 5-[(2,5-dimethyl-1,3-benzothiazol-6-yl)oxy]-N-(2,6-15 dimethoxyphenyl)-2-furamide ° O O
s O
HN
N
O

Compound B105 was synthesized according to Scheme B. NMRand mass spectrometry data consistent with the title product were as follows: 1H NMR
(DMSO-d6): ~ 2.38 (s, 3H), 2.76 (s, 3H), 3.72 (s, 6H), 5.71 (d, J = 6 Hz, 1H), 6.69(d, J = 9 Hz, 20 2H), 7.21 - 7.26 (m, 2H), 7.86 (s, 1H), 8.87 (s, 1H), 9.10 (s, 1H), LC/ MS
(M+H)+:
425.
Example B106: 5-[(4,4,7,8-tetra-mehtyl-1,2,3,4-tetrahydroquinolin-6y1)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide \ I r, \ /

Compound B106 was synthesized according to Scheme B.
OMe OMe / AICI3 ~ OH
Et3N, THF ~HN \ I 130°C O N I /
H2N~ J~ /~/~ H
49%

LAH I ~ OH
THF

NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (DMSO-d6): 8 1.20 (s, 6H), 1.61 (t, J = 6 Hz, 2H), 1.97 (s, 3H), 2.06 (s, 3H), 3.25 (br. 2H), 3.72 (s, 6H), 3.79 (s, 3H), 5.14 (d, J = 3 Hz, 1H), 6.27 (s, 2H), 6.89 (s, 1H), 7.10 (d, J = 3 Hz, 1H), 8.81 (s, 1H), LC/ MS (M+H)+: 4.81.
Example 8107: 5-[5-(1-cyano-1-methylethyl)-2-methylphenoxy]-N-(2,4,6-l0 trimethoxyphenyl)-2-furamide NC ~ ~ _ / HN ~ / o O

Compound B 107 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(DMSO-d6): 8 1.58 (s, 6H), 2.18 (s, 3H), 3.63 (s, 6H), 3.70 (s, 3H), 5.53 (d, J = 3 Hz, 1H), 6.18 (s, 2H), 7.11 (br. 1H), 7.20 (d, J = 1.8 Hz, 1H), 7.26 (dd, J = 1.8 Hz, J
= 9 Hz, 1H), 7.34 (d, J = 9 Hz, 1H), 8.84 (s, 1H), LC/ MS (M+H)+: 451.
Example B108: 4-~5-[acetyl(methyl)amino]2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide / HN
O, Compound B 108 was synthesized according to Scheme B.

H
O2N ~ O\ H2, Pd/C HzN ~ \ O\ MeCOCI O~N ~ ~ O\
NEt3 1. MeI, NaH O ~ OH
2. BBr3 NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (MeOD): S 1.87 (s, 3H), 2.36 (s, 3H), 3.22 (s, 3H), 3.81 (s, 6H), 5.62 (d, J = 3.3 Hz, IH), 6.69 (d, J = 8.4 Hz, 2H), 7.08-7.13 (br. d, 2H), 7.18(d, J = 3.3 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, IH), LC/MS (M+H)+: 425.
Example B109: 5-[(2,5-dimethyl-1,3-benzothiazol-6-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I ~ I / "~ ~-\ /

1o Compound B 109 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(DMSO-d6): 8 2.38 (s, 3H), 2.76 (s, 3H), 3.71 (s, 6H), 3.78 (s, 3H), 5.70 (d, J =
3.3 Hz, 1H), 6.26 (s, 2H), 7.22 (d, J = 3.3 Hz, 1H), 7.85 (s, 1H), 7.87 (s, 1H), 8.96 (s, 1H), LC/ MS
(M+I~~: 455. .~._ Example B110: 4-[(7-clrloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]-N-(2,4,6-trimethoxypyrimidin-5-yl)-2-furamide \ O O 0 O N
N ~ / CI ~ ~ HN ~ ~O
H
-~O

Compound B 110 was synthesized according to Scheme B. NMR and mass 2o spectrometry data consistent with the title product were as follows: 1H NMR
(CD3CI~: 8 1.24 (s, 6H), 1.67 (t, 2H,), 3.2 (t, 2H), 3.92 (s, 6H), 3.96 (s, 3H), 4.81 (s, 1H), 5.28 (d, 1H), 6.59 (s, 1H), 7.03 (d, 1H), 7.186 (s, 1H), 7.57 (s, 1H), APCI-MS
m/z 489.2 (M+H)+.

Example 8111: 5-{5-[isopropyl(methyl)amino]-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide 'N
HN
O

Compound B 111 was synthesized according to Scheme B.
OzN ~ ~ O~ ~ PAC H2N ~ ~ O~ Aceton _ \ 'N ~ \ O~

1. MeI, KZC03 ~ \ OH
2. HBr NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (MeOD): 8 1.28 (s, 3H), 1.30 (s, 3H), 2.38 (s, 3H), 3.17 (s, 3H), 3.81 (s, 6H), 3.84 (s, 3H), 3.9-4.0 (m, 1H), 5.75 (d, J = 3.4 Hz, 1H), 6.29 (s, 2H), 7.11-7.30 (m, 3H), 7.49 (d, J = 9 Hz, 1H), LC/ MS (M+H)+: 455.
to Example B112: 5-~5-(diethylamino)-2-methylphenoxy]-N-(4,6-dimethoxy-2-{[3-(4-methylpiperazin-1-yl)-propyl]amino) pyrimidin-5-yl)-2-furamide HN

Compound B 112 was synthesized according to Scheme B.
H2N ~ O~ 1. EtI, KZC03 ~ OH
-~ ~ \
z. HBr is NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (MeOD): 8 1.10 (dd, J = 7.18, 6.80 Hz, 6H), 1.86 (m, 2H), 2.13 (s, 3H), 2.53 (s, 3H), 2.58 - 2.95 (m, l OH), 3.45 (dd, J = 6.80, 6.42 Hz, 2H), 3.88 (s, 6H), 5.37 (d, J =
3.78 Hz, 1H), 6.40 (d, J = 2.27 Hz, 1H), 6.53 (dd, J = 8.31, 2.27 Hz, 1H), 7.06 (d, J =
8.31 Hz, 1H), 7.13 (d, J = 3.40 Hz, 1H), LC/ MS (M+H)+: 582.

Example B113: 5-[5-(isopropylamino)-2-methylphenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide ~ l HN ~ /

Compound B 113 was synthesized according to Scheme B.
02N \ O\ g2, Pd/C HEN ~ \ O\ Aceton ' \ 'N ~ \ O\
BH ~I'3 H$r N \ OH

NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (MeOD): ~ 1.49 (d, J = 9 Hz, 6H), 2.55 (s, 3H), 3.90 (m, 1H), 4.01 (s, 6H), 4.04 (s, 3H), 5.94 (d, J = 3 Hz, 1H), 6.49 (s, 2H), 7.14 (s, 1H), 7.22 (d, J = 6 Hz, 1H), 7.42 (s, 1H), 7.62 (d, J = 6 Hz, 1H), LC/ MS (M+H)+: 441.
to Example B114: 5-(2-methyl-5-tert-pentylphenoxy)-N-(2,4,6-trimethoxylphenyl)-2-furamide / HN

Compound B 114 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(MeOD):
1s ~ 0.67 (t, J = 9 Hz, 3H), 1.25 (s, 6H), 1.63 (q, J = 9 Hz, 2H), 2.25 (s, 3H), 3.79 (3, 6H), 3.81 (s, 3H), 5.32 (d, J = 3 Hz, 1H), 6.26 (s, 6H), 7.06 (s, 1H), 7.12-7.17 (br.d, 2H), 7.23 (d, J = 9 Hz, 1H), LC/ MS (M+H)+: 454.
Example B115: N-(4,6-dimethoxy-2-}[3-(4-methylpiperazin-1-yl)propyl] amino } pyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-20 yl)oxy]-2-furamide acetic acid salt Compound B 115 was synthesized in a manner analogous to that of compound B l, according to scheme B, using similar starting materials and reaction conditions.
Example B116: N-(4,6-dimethoxy-2- f [3-(4-moprpholinyl)propyl]amino}-5-pyrimidinyl)-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furamide o l Vo -N
I H ~ /~NH
N

1o Compound B I 16 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, CDC13): ~ 0.99 (d, 3H, J = 6.79 Hz), 1.05, 1.20, 1.24, 1.31 (4s, 3H each), 1.36 (dd, 1H, J = 2.2, 13.4 Hz), 1.62 (dd, 1H, J =13.0, 13.2 Hz), 1.75-1.95 (m, 3H), 2.24 (s, 3H), 2.40-2.60 (m, 6H), 3.48 (dd, 2H, J = 6.0, 6.2 Hz), 3.70-3.81 (m, 4H), 3.87 (s, 1s 6H), 5.32 (d, 1H, J = 3.59 Hz), 5.73 ~t, 1H, J = 5.4, NH), 6.95 (s, 2H), 7.10 (d, 1H, J =
3.4 Hz), 7.19 (s, 1H), APCI-MS m/z 622.3 (M+H)+.
Example B117: N-(4,6-dimethoxy-2-}[3-(4-morpholinyl)propyl]amino}-5-pyrimidinyl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide / n ~N~O
.N
I H ~ N~NH
2o B117 Compound B 117 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the desired product were as follows: 1H (300 MHz, CDC13): 8 1.45 (s, 6H), 1.72-1.82 (m, 2H), 2.23 (s, 3H), 2.45-2.55 (m, 6H), 3.47 (dd, 2H, J = 6.0, 6.23 Hz), 3.74 (t, 4H, J = 4.54 Hz), 3.86 (s, 6H), 5.01 (s, 2H), 5.36 (d, 1H, J= 3.59 Hz), 5.77(t, 1H, J= 5.48 Hz, NH), 6.79 (s, 1H), 6.90(d, 1H), 7.06 (s, 1H), 7.10 (d, 1H, J = 3.59 Hz), APCI-MS m/z 568.3 (M+H)+.
Example B118: N-(4,6-dimethoxy-2-{[3-(4-morpholinyl)propyl]amino}-5-pyrimidinyl)-S-[(1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-2-furamide O O /-N

H ~ N~NH
..

Compound B 118 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CDC13):
l0 8 1.26 (s, 6H), 1.35 (s, 6H), 1.60-1.67 (m, 4H), 2.12-2.16 (m, 2H), 2.19 (s, 3H), 2.85 -2.94 (m, 2H), 3.16 - 3.21 (m, 2H), 3.49-3.57 (m, 4H), 3.86 (s, 3H), 3.94 (s, 6H), 3.98 -4.01 (m, 4H), 5.10 (d, 1H, J = 3.78 Hz), 6.93 (s, 1H), 6.98 (s, 1H), 7.10 (d, 1H, J =
3.40 Hz), MS (APCI): 638.4 (M+H)+.
Example B119: 4-[(5-{[5-(5-tert-butyl-2-methylphenoxy)-2-furoyl]amino}-4,6-1s dimethoxypyrimidin-2-yl)amino]piperidine-1-carboxylate Compound B 119 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the desired product were as follows: IH NMR
(d4-2o CH30H): 8 1.29 (s, 9H), 1.45 (s, 9H), 1.95 (dd, 2H), 2.24 (s, 3H), 2.97 (t, 4H), 3.30 (s, 3H), 3.93 - 4.03 (m, SH), 5.35 (d, 2H), 7.11 (s, 1H), 7.12 (d, 1H), 7.21 (dd, 2H), APCI-MS f~z/z 610.1 (M+H)+.
Example B120: 5-[(7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyI)oxy]-N-{2,6-dimethoxy-4-[3-(4-morpholinyl)propoxy] pyrimidinyl}-2-furamide i <-o O O N H
~NwN~
~ N
O
25 H ~ ci Compound B 120 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(CDC13):
8 1.24 (s, 6H), 1.61-1.9 (m, 4H), 2.45-2.49 (m, 6H), 3.30 (t, 2H), 3.47 (m, 2H), 3.74 (t, 4H), 3.87 (s, 6H), 5.21 (d, 1H), 5.72 (t, 1H), 6.49 (s, 1H), 6.96 (s, 1H), 7.03 (d, 1H), APCI-MS m/z 601.1 (M+H)+.
Example B121: 5-(2-bromo-5-tert-butylphenoxy)-N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-2-furamide N
H

1o B121 Compound B 121 was synthesized according to Scheme B. NMR data consistent with the title product were as follows: 1HNMR (~00 MHz,.CD30D): S
1.30 (s, 9H), 2.10 (m, 2H), 3.18 (m, 26H), 3.24 (m, 2H), 3.48 (m, 4H), 3.72 (m, 2H), 4.03 (s, 6H), 4.07 (m, 2H), 5.48 (d, 1H, J = 3 Hz), 7.15 (d, 3H, J = 3 Hz), 7.27 (m, 2H), 1s 7:59 (d, 1H, J = 6 Hz).
Example B122: N- f 4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino] pyrimidin-5-yl)-5-[(4,4,7-trimethyl-3,4-dihydro-2H-chromen-6-yl)oxy]-2-furamide o ~ N~o -N
I H ~ N~NH

2o Compound B 122 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1H (300 MHz, DMSO-d6): ~ 1.22 (s, 6H), 1.73 (dd, 2H, J = 4.91, 5.28 Hz), 2.10 (s, 3H), 2.25 - 2.45 (m, 4H), 3.20 - 3.35 (m, 4H), 4.10 (t, 2H, J = 4.91 Hz), 5.30 (d, 1H, J = 3.4 Hz), 6.66 (s, 1H), 7.11 (d, 1H, J = 3.4 Hz), 7.13 (s, 1H), 8.82 (s, 1H, NH), APCI-MS m/z 582.3 2s (M+H)+.
Example B123: ethyl 4-[(5-{[5-(5-tert-butyl-2-methoxyphenoxy)-2-furoyl]amino)-4,6-dimethoxy-2-pyrimidinyl)amino]butanoate H \ N NH O

Compound B 123 was synthesized according to Scheme B, using HBTU as the coupling agent.
/ OH
OFi Br2/CC14 / I OFi CuBr, NaOMe 0 °C to rt ' ~ gr cat. EtOAc, MeOH ~ O
reflux NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (CDC13): b 1.26 (t, 3H), 1.28 (s, 9H), 1.90 (quint, 2H), 2.45 (t, 2H), 3.40 (q, 3H), 3.85 (s, 3H), 3.87 (s, 6H), 5.00 (t, 1H), 5.32 (d, 1H), 6.92 (d, 1H), 6.94 (d, 1H), 7.08 (d, 1H), 7.19(s, 1H), 7.21 (s, 1H), APCI-MS m/z 557.3 (M+H)+.
1o Example B124: 5-(5-tert-butyl-2-methoxyphenoxy)-N-(2-~[3-(dimethylamino)propyl]amino)-4,6-dimethoxy-5-pyrimidinyl)-2-furamide /

-N
I H \ N~NH
O
/ ~ \ \

Compound B 124 _was synthesized according to Scheme B, using HBTU as the ~s coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: IH NMR (d4_CH30H): 8 1.20 (s, 9H), 1.70 (quint, 2H), 2.17 (s, 6H), 2.30 (t, 2H), 3.24 (t, 2H), 3.71 (s, 3H), 3.77 (s, 6H), 5.10 (d, 1H), 6.94 (d, 1H), 6.98 (d, 1H), 7.12 (s, 1H), 7.14 (d, 1H), APCI-MS m/z 528.3 (M+H)+.
Example B125: [5-(tert-butyl)-2-methoxyphenoxy]-N-(4,6-dimethoxy]-2-f [3-(4-20 morpholinyl)propyl]amino)-5-pyrimidinyl)-2-furamide -N
H ~ /~NH
O N ~ /-\
O\ N~

Compound B 125 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (d4_CH30H): S 1.48 (s, 9H), 2.02 (t, 2H), 2.67 (m, 6H), 3.49 (t, 2H), 3.89 (t, 4H), 4.00 (s, 3H), 4.06 (s, 6H), 5.45 (d, 1H), 7.20 (d, 1H), 7.24 (d, 1H), 7.12 (s, 1H), 7.46 (s, 1H), 7.48 (s, 1H), APCI-MS m/z 570.3 (M+H)~.
Example B126: N-(4,6-dimethoxy-2-~[3-(4-methyl-1-piperazinyl)propyl]amino}-5-pyrimidinyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy-2-furamide to Compound B126 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (d4_CH30H): 8 1.21 (s, 6H), 1.76 (quintet, 2H), 1.94 (t, ~s 2H), 2.30 (s, 3H), 2.47 - 2.54 (m, 10H), 2.87 (t, 2H), 3.43 (m, 2H), 3.81 (s, 3H), 3.86 (s, 6H), 5.26 (d, 1H), 5.72 (br s, 1H), 6.84 (s, 1H), 6.90 (s, 1H), 6.96 (s, 1H), 7.08 (d, 1H), APCI-MS m/z 595.3 (M+H)+.
Example B127: N-(4,6-dimethoxy-2-~[3-(4-methyl-1-piperazinyl)propyl]amino}-5-pyrimidinyl-5-[(5-methoxy-1,1-dimethyl-1H-inden-6-yl)oxy]-2-furamide N N~
O
H O
~~O

Compound B 127 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): b 1.29 (s, 6H), 1.92 (quintet, 2H), 2.34 (s, 3H), 2.52 - 2.59 (m, 6H), 2.87 (t, 2H), 3.87 (s, 3H), 3.88 (s, 6H), 5.30 (d, 1H), 5.70 (br s, 25 1H), 6.43 (s, 1H), 6.57 (d, 1H), 6.97 (s, 1H), 7.11 (d, 1H), 7.11 (s, 1H), APCI-MS m/z 593.3 (M+H)+.

Example B128: N-(4,6-dimethoxy-2-{[3-(4-morpholinyl)propyl]amino)-5-pyrimidinyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide N

Compound B128 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): 8 1.23 (s, 6H), 1.95 (quintet, 2H), 1.98 (t, 2H), 2.51 (m, 6H), 2.88 (t, 2H), 3.40 (t, 2H), 3.74 (t, 4H), 3.83 (s, 3H), 3.88 (s, 6H), 5.28 to (d, 1H), 5.72 (br s, 1H), 6.86 (s, 1H), 6.91 (s, 1H), 6.98 (s, 1H), 7.10 (d, 1H), A.PCI-MS m/z 582.3 (M+H)+.
Example B129: N-(4,6-dimethoxy-2-{[3-(4-morpholinyl)propyl]amino)-5-pyrimidinyl)-5-[(5-methoxy-1,1-dimethyl-1H-inden-6-yl)oxy]-2-furamide N~
O ~~

15 Compound B129 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): 8 1.29 (s, 6H), 1.86 (quintet, 2H), 2.53 (m, 6H), 2.88 (t, 2H), 3.40 (t, 2H), 3.78 (t, 4H), 3.87 (s, 3H), 3.88 (s, 6H), 5.30 (d, 1H), 5.74 (br s, 1H), 6.43 (d, 1H), 6.57 (d, 1H), 6.97 (s, 1H), 6.97 (s, 1H) 7.11 (d, 1H)~ 7.11 (d, 20 1H), APCI-MS m/z 580.3 (M+H)+.
Example B130: N-(2,6-dimethoxy-4-{[3-(4-methyl-1-piperazinyl)propyl] amino) phenyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide Compound B 130 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDCl3): 8 1.24 (s, 6H), 1.81 (quintet, 2H), 1.96 (t, 2H), 2.52 (m, 10H), 2.88 (t, 2H), 3.19 (t, 2H), 3.78 (s, 6H), 3.78 (s, 3H), 3.83 (s, 6H), 5.29 (d, 1H), 5.84 (s, 2H), 6.85 (s, 1H), 6.92 (s, 1H), 6.92 (s, 1H), 7.04 (d, 1H), 7.12 (d, 1H), APCI-MS m/z 593.3 (M+H)+.
Example 8131: N-(2-{[3-dimethylamino)propyl]amino}-4,6-dimethoxy-5-to pyrimidinyl)-5-[(5-methoxy-1,1-dimethyl-1H-inden-6-yl)oxy]-2-furamide y \/ o I

Compound B 131 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product 1s were as follows: 1H NMR (CDCl3): 8 1.29 (s, 6H), 1.96 (quintet, 2H), 2.51 (s, 6H)~
2.88 (t, 2H), 3.40 (t, 2H), 3.87 (s, 3H), 3.88 (s, 6H), 5.30 (d, 1H), 5.40 (br s, 1H), 6.43 (d, 1H), 6.57 (d, 1H), 6.97 (s, 1H), 6.99 (s, 1H), 7.11 (d, 1H), 7.11 (s, 1H), APCI-MS m/z 538.2 (M+H)+.
Example B132: N-(2-~[3-(dimethylamino)propyl]amino,-4,6-dimethoxy-5-2o pyrimidinyl)-5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide o ° ,~W
I
\/
o~
I

Compound B 132 was synthesized according to Scheme B, using HBTU as the coupling agent. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): S 1.23 (s, 6H), 1.82 (quintet, 2H), 1.95 (t, 2H), s 2.36 (s, 6H), 2.48 (t, 2H), 2.88 (t, 2H), 3.44 (t, 2H), 3.83 (s, 3H), 3.88 (s, 6H), 5.27 (d, 1H), 5.31 (br s, 1H), 6.85 (s, 1H), 6.91 (s, 1H), 6.98 (s, 1H), 7.11 (d, 1H), APCI-MS tnlz 540.3 (M+H)+.
Example B133: 5-(2-bromo-5-tert-butylphenoxy)-N-(2- f [3-(1H-imidazol-1-yl)propyl]amino}-4.6-dimethoxypyrimidin-5-yl)-2-furamide o ~~
\ 0 0 ~~N

l0 Br Compound B133 was synthesized according to Scheme B. NMRand mass spectrometry data consistent with the title product were as follows: 1HNMR
(300 MHz, CDC13): 8 1.28 (s, 9H), 2.12 (m, 2H), 3.43 (m, 2H), 3:86 (s, 6H), 4.10 (m, 2H), 15 4.98 (m, 1H), 5.45 (d, 1H, J = 3 Hz), 6.97 (s, 1H), 7.15 (m, 3H), 7.55(d, 2H, J = 9 Hz), 7.71 (s, 1H), APCI (M+H)~: 599.
Example B134: 5-(2-bromo-5-tertbutylphenoxy)-N-X4,6-dimethoxy-2-[(2-pyrrolidin-1-ylethyl)amino]pyrimidin-5-yl}-2-furamide I H
\ \ IN
H

Compound B 134 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: ~HNMR
(300 MHz, CDC13): 8 1.28 (s, 9H), 1.90 (m, 4H), 2.85 (m, 4H), 3.64 (m, 2H), 3.87 (s, 6H), 5.45 (d, 1H, J = 3 Hz), 5.63 (m, 1H), 6.97 (s, 1H), 7,15 (m, 3H), 7.53(d, 1H, J = 9 25 Hz), APCI (M+H)+: 588.
Example B135: S-(2-bromo-5-tert-butylphenoxy)-N-(2-~[3-(dimethylamino)propyl]amino}-4,6-dimethoxypyrimidin-5-yl)-2-furamide O j ~b~N\
\ 0 0 ~~~N
/ Br O\

Compound B135 was synthesized according to Scheme B. NMRand mass spectrometry data consistent with the title product were as follows: IIINMR
(300 s MHz, CDCl3): 8 1.16(s, 3H), 1.26 (s, 3H), 1.31 (s, 3H), 2.12 (dd, 2H, J
=18.51, 7.18 Hz), 2.79 (s, 6H), 3.09 (dd, 2H, J = 7.18, 6.80 Hz), 3.56 (dd, 2H, J = 16.24, 6.04 Hz), 5.39 (s, 1H), 5.47 (d, 1H, J = 3.40 Hz), 6.97 (s, 1H), 7.11 (m, 1H), 7.13 (m, 1H), 7.18 (m, 1H), 7.55 (d, 1H, J = 8.31 Hz), APCI (M+H)+: 577.
Example B136: 5-(2-bromo-5-tert-butylphenoxy)-N-(4,6-dimethoxy-2- f [2-l0 (propylamino)ethyl]amino~pyrimidin-5-yl)-2-furamide o ~~b~p~
H IN V
/ ~\
9r 1s Compound B136 was synthesized according to Scheme B. NMRand mass spectrometry data consistent with the title product were as follows: 1HNMR
(300 MHz, CDCl3): ~ 0.96 (dt, 3H, J = 7.66, 7.18 Hz), 1.29 (s, 9H), 1.66 (dd, 2H, J
= 7.55, 7.18 Hz), 2.75 (d, 2H, J = 7.93 Hz), 3.02 (dd, 2H, J = 6.57, 5.29 Hz), 3.65 {m, 2H), 3.87 (s, 6H), 5.43 (d, 1H, J = 3.78 Hz), 5.75 (s, 1H), 6.98 (s, 1H), 7,12 (tt, 2H, J =
20 3.78, 3.40 Hz), 7.17(m, 1H), 7.53 (d, 1H, J = 8.31 Hz), APCI (M+H)+: 577.
Example B137: 5-[(6-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N-(4,6-dimethoxy-2-{[3-(4-methyl-1-piperazinyl)propyl]amino~-5-pyrimidinyl)-2-furamide o ~ ~p~N~
Y N\
\ O O ~~N
H. YO
~CI \
2s B137 Compound B 137 was synthesized according to Scheme B.

I OH + ~ H3 I / I OH + HO / I OH
\ \
CI HO rt, overnight CI CI

AIC13/CHpCl2 ~'~OH
5E (from 5A 48%) Compound 5A (30g) was dissolved in H2P03 (100 ml). To the solution was added compound 5B (26g). The mixture was stirred at room temperature overnight.
The solution was extracted with EtOAC, washed with water, dried (Mg2S04) and s concentrated to give a crude mixture of 5C and SD (50g). The mixture was dissolved in 300 ml of CH2C12 and AlCl3 (31g) was added into. After being stirred at room temperature fox 1.5 hour the solution was poured into ice water and extracted with EtOAC. Column chromatography (hexane:EtOAC 18:1) gave compound 5E (22g).
NMR and mass spectrometry data consistent with the title product were as follows:
IIiNMR (CDC13): 8 1.19 (s, 6H), 1.89 (d, 2H, J = 7.18 Hz), 1.94 (d, 2H, J
=14.73 Hz), 2.82 (s, 3H), 2.86 -2.88 (m, 2H), 3.08-3.18 (m, 4H), 3.3-3.37 (m, 4H), 3.5 - 3.65 (m, 3H), 3.79 (s, 6H), 5.50 (d, 1H, J = 3.78 Hz), 7.18 (d, 1H, J = 3.40 Hz), 7.21 (s, 1H), 7.26-7.32 (m, 1H), 7.44 (s, 1H), 8.98 (s, 1H), MS (APCI): 599.3 (M+IT)+.
Example B138: N-f2-[(2-aminoethyl)(propyl)amino]-4,6-dimethoxypyrimidin-5-yl}-5-(2-bromo-5-tert-butylphenoxy)-2-furamide ~d N
0 0 ~~N Hz N
Br Compound B138 was synthesized according to Scheme B. NMRand mass spectrometry data consistent with the title product were as follows: IIiNMR
(300 2o MHz, CDC13): 8 0.88 (dt, 3H, J = 7.66, 7.18 Hz), 1.28 (s, 9H), 1.66 (dd, 2H, J = 7.55, 7.18 Hz), 3.23 (m, 2H), 3.48 (m, 2H), 3.86 (m, 8H), 5.43 (d, 1H, J = 3 Hz), 7.15(m, 4H), 7.53 (d, 1H, J = 8.31 Hz), APCI (M+H)+: 577.
Example B139: 5-(2-bromo-5-tert-butylphenoxy)-N-(2-chloro-4,6-dimethoxypyrimidin-5-yl)-2-furamide O ,N' /CI
~'O
O O ~ N

Br Compound B I39 was synthesized according to Scheme B. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(300 s MHz, CDC13): 8 1.29 (s, 9H), 3.99 (s, 6H), 4.01 (s, 6H), 5.43 (d, 1H, J =
3.40 Hz), 7.14 (dd, 3H, J = 3.78, 2.27 Hz), 7.15 (s, 3H), 7.53 (d, 1H, J = 8.31 Hz).
APCI
(M+I~+: 510.
Example B140: N (2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide OH,OO
~~OCHy ~O
N ~ N
HacO

Compound B140 was synthesized according to Scheme B. The overall yield was 21%.
1. MCPBA ,NaHC03 H20:DCM reflux \ off \ w / ~/
2. NaOCH3, MeOH

15 NMR data consistent with the title product were as follows: 1H NMR, (DMSO):
b 0.94 (d, 3H, J = 7.37 Hz), 0.99 (s, 3H), 1.01(s, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.79 (q, 1H, J = 7.37 Hz), 2.22 (s, 3H), 3.86 (s, 3H), 3.91 (s, 3H), 5.51 (d, 1H, J =
3.59 Hz), 6.97 (s, 1H), 7.14 (s, 1H), 7.20 (d, 1H, J = 3.59 Hz).
Example B141: N-~4,6-dimethoxy-2-[(3-piperidin-1-ylpropyl)amino]pyrimdine-20 5-yl~-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide N ~

Compound B 141 was synthesized according to scheme B.
Example B142: N [4,6-dimethoxy-2-(2-methoxyethoxy)pyrimidin-5-yl]-S-[(3,3,6-25 trimethyI-1,3-dihydro-Z-benzofuran-5-yl)oxy]-2-furamide CHa CHa HaC O O 0 O N
'\~NH //
O ~ ~ CHa ~ ~ N O
-CHa HaC-O

Compound B 142 was synthesized according to Scheme B. The requisite phenol was prepared according to the following method:
ASH
HO I \ O ~ ~ O ~ ~ ~ ~ ~ OH
s i i i Ha THF NaH
refwxovemi9ht overnight DMF reflux OC to reflux 111 NMR data consistent with the title product were as follows: 1H NMR (MeOD): 8 1.40 (s, 6H), 2.24 (s, 3H), 3.36 (s, 3H), 3.70 (t, 2H, J = 4.53 Hz), 3.90 (s, 6H), 4.45 (dd, 2H, J = 4.91, 4.53 Hz), 4.95 (s, 2H), 5.38 (d, 1H, J = 3.40 Hz), 6.92 (s, 1H), 7.12 (m, 2~.
1o Example B143: N (4,6-dimethoxy-Z-phenoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide HaC Ha OHaCO
o \ N ~
H
CHa Compound B 143 was synthesized according to Scheme B. NMR data consistent with the title product were as follows: 1H NMR, (MeOD): 8 I .40 (s, 6H), 2.24 (s, 3H), 3.78 (s, 6H), 4.95 (s, 2H), 5.38 (d, 1H, J = 3.40 Hz), 6.92 (s, 1H), 7.16 (m, 5H), 7.37 (dd, 2H, J = 7.93, 7.55 Hz).
Example B144: 4-(Methoxymethyl)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl 5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furoate Compound B 144 was synthesized according to Scheme B. NMR data consistent with the title product were as follows:1H NMR, (DMSO): S 1.40 (s, 6H), 2.23 (s, 3H), 2.56 (s, 3H), 3.41 (s, 3H), 3.89 (s, 3H), 4.89 (s, 2H), 4.93 (s, 2H), 5.68 (d, 1H, J = 3.78 Hz), 6.99 (s, 1H), 7.21 (s, 1H), 7.24 (s, 1H), 7.65 (d, 1H, J
= 3.78 Hz).
Example B145: 1-tent-butyl-3,4-dimethyl-1H pyrazolo[3,4-b]pyridin-6-yl 5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furoate N-Compound B 145 was synthesized according to Scheme B. NMR data 1o consistent with the title product were as follows: 1H NMR, (DMSO): S 1.39 (s, 6H), 1.67 (s, 9H), 2.23 (s, 3H), 2.59 (s, 3H), 2.66 (s, 3H), 4.93 (s, 2H), 5.67 (d, 1H, J =
3.78 Hz), 6.82 (s, 1H), 7.21 (s, 1H), 7.24 (s, 1H), 7.65 (d, 1H, J = 3.40 Hz).
Example B146: N-[2-(2-hydroxyethoxy)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide H~CO
H3C Hs 0 \ ~
O ~ ~ O ~ \ ~O~OH

15 v 'CH3 Compound B 146 was synthesized according to Scheme B. NMR data consistent with the title product were as follows: 1H NMR, (MeOD): 8 1.40 (s, 6H), 2.24 (s, 3H), 3.82 (dd, 2H, J = 5.29, 4.53 Hz), 4.39 (t, 2H, J = 4.91 Hz), 4.95 (s, 2H), 20 5.38 (d, 1H, J = 3.40 Hz), 6.92 (s, 1H), 7.11(m, 2H).
Example B147: N (2-anilino-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide o W ~ ~ b y--b I

z5 Compound B 147 was synthesized according to Scheme B. NMR data consistent with the title product were as follows: 1H NMR, (DMSO): 8 1.37 (s, 6I-~, 2.23 (s, 3H), 3.87 (s, 6H), 4.90 (s, 2H), 5.54 (d, 1H, J = 3.40 Hz), 6.94 (dd, 1H, J =

7.55, 7.18 Hz), 7.10 (s, 1H), 7.19 (d, 2H, J = 4.15 Hz), 7.27 (dd, 2H, J =
7.93, 7.55 Hz), 7.76 (d, 2H, J = 7.93 Hz).
Example B148: N-(4,6-dimethoxy-2-}[2-(methyl}5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-S-yl)oxy]-2-furoyl}amino)ethyl]amino}pyrimidin-5-yl)-5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furamide Compound B 148 was synthesized according to acyl chloride coupling method of Scheme B where the amine was:
~O N~ N~Ni H2N I i N
and reacted at both the primary and alkyl-secondary amines to give the dimer B
148.
NMR data consistent with the title product were as follows: 1H NMR, (MeOD): 8 1.35 (s, 6H), 1.39 (s, 6H), 2.19 (s, 3H), 2.23 (s, 3H), 3.14 (s, 3H), 3.55 (t, 2H, J =
6.04, 5.67 Hz), 3.78 (t, 2H, J = 6.80, 6.04 Hz), 3.83 (s, 6H), 4.91 (s, 2H), 4.94 (s, 2H), 5.33 (d, 1H, J = 3.40 Hz), 5.37 (d, 1H, J = 3.40 Hz), 6.82 (s, 1H), 6.90 (s, 1H), 6.96 (d, 1H, J = 3.40 Hz), 7.07 (d, 2H, J = 4.15 Hz), 7.11 (s, 1H).
Example B149: 1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl 5-[(3,3,6-trimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]-2-furoate N-' \
i 0 ~ ~ O N~
O ~ ~ 0 2o B149 Compound B 149 was synthesized according to Scheme B. NMR data consistent with the title product were as follows: 1HNM>ZR, (MeOD): 8 1.40 (s, 6H), 2.22 (s, 3H), 2.59 (s, 3H), 2.66 (s, 3H), 3.87 (s, 3H), 4.95 (s, 2H), 5.44 (d, 1H, J =
3.78 Hz), 6.72 (s, 1H), 6.98 (s, 1H), 7.13 (s, 1H), 7.44 (d, 1H, J = 3.40 Hz).
Example B150: N (2,4,6-trimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-1,3-dihydro-Z-benzofuran-5-yl)oxy]-2-furamide o f ~~o\
O O N
O I \ ~ ~ O

Compound B 150 was synthesized according to Scheme B. Yield of purified product was 36%. NMR data consistent with the title product were as follows:

NMR (CDC13): 8 1.45 (s, 6H), 2.29 (s, 3H), 3.96 (s, 6H), 5.01 (s, 2H), 5.37 (d, 1H, J =
3.59 Hz), 6.80 (s, 1H), 7.07 (s, 1H), 7.14 (d, 1H, J = 3.59 Hz).
Example B151: 5-(2-bromo-5-tert-butyIphenoxy)-N-(4,6-dimethoxy-2-~[3-(4-methylpiperazin-1-yl)propyl]amino)pyrimidin-5-yl)-2-furamide acetate salt \ 0 0 00 0 ~ n Br N~~--N~N~1--N
-O
1o B151 a Compound B 151 was synthesized according to scheme B.
Example B152: 5-[(5-chloro-1,1,7-trimethyl-2,3-dihydro-1H-inden-4-yl)oxy]-N-(2,6-dimethoxyphenyl)-2-furamide I

° o \ / N
ci °\
1s B152 Compound B152 was synthesized according to scheme B wherein the phenol was synthesized according to the following scheme.
O KzC03 I ~ CI CI v \ DMF
r.t., 30 min.
O
A1C13 NaCI (Et)3SiH
\ OH \ OH
210°C 15 min. ' I , TFA I , ' ~ ~CI r.t., overnight CI
Example B153: 5-[(5-chloro-1,1,7-trimethyl-2,3-dihydro-1H-inden-4-y1)oxy]-N-20 f 4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-S-yl)-2-furamide acetate O O NY N~
W O O N

ci Compound B 153 was synthesized in a manner analogous to that of compound B 152, according to scheme B.
Example B154: 5-(2-bromo-5-tert-butylphenoxy)-N-(4,6-dimethoxy-2- f [2-(propylamino)ethyl]amino]pyrimidin-5-yl)-2-furamide acetate salt O IO OO--N
Br N~N N
O~-O N~.

Compound B 154 was synthesized in a manner analogous to that of compound to B1, according to scheme B, using similar starting materials and reaction conditions.
Example B155: N-(2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-2-furamide ~ O O O ~ -N
t , t / N,..r N CI
.«- OO

is Compound B 155 was synthesized in a manner analogous to that of compound B l, according to scheme B, using similar starting materials and reaction conditions:
The following compounds were prepared according to Scheme C set forth below:
Scheme C

O ~ ~ NH2 (HCI) B ' ~ H SOCIZ, cat. DMF B , ~ I
a benzene, refiux (Et)3N, CHZCI2, rt 31 98%

OO p~ ~~ O~ / O
R
Br O N ~ 35 ' ~ O O N
H O- Cs2C03 (1.3 equiv.) R'~ ~ / H
34 600 DMF, 145 °C 60-65%
15-24 h 36 5-bromo-2-furoyl chloride 32: A suspension of 5-bromo-2-furoic acid (31, 57.3 g, 300 mmol) in anhydrous benzene (100 mL) containing few drops of anhydrous DMF' was heated to reflux under nitrogen as thionyl chloride (1.1 equiv., s 24.6 mL) in benzene (35 mL) was added dropwise. The resulting pale brown solution was further reflux for an additional 10 hours. The solution was cooled to room temperature and concentrated under vacuum to give 61.5 g (98%) of crude acid chloride. The 1HNMR of the crude showed >95% purity. The crude acid chloride thus obtained was used in the next step without further purification. NMR data 1o consistent with the title product were as follows: 1HNMR (CDCl3): 8 6.74 (d, 1H), 7.38 (d, 1H).
5-bromo-N-(2,4,6-trimethoxyphenyl)-2-furamide 34: A mixture of trimethoxyaniline hydrochloride (33 1.2 equiv., 21.1 g, 96 mmol) and triethyl amine (2.5 equiv., 27.9 mL, 200 mmol) in dichloromethane (200 mL) was stirred at 0°C
15 under nitrogen as a solution of 5-bromo-2-furoyl chloride (I6.8 g, 80 mmol) in dichloromethane (120 mL) was added dropwise. The solution was allowed to warm to room temperature and further stirred for 12 hours. The resulting suspension was washed several times with 2N hydrochloric acid, saturated sodium bicarbonate, brine and water successively. The organic layer was dried over anhydrous sodium sulfate, 2o concentrated under vacuum to give about 25 g of brown colored crude material. The crude material (in two equal batches) was subjected to silica gel chromatography using ethyl acetate/hexane 3:2 as the eluant to give 17.1 g (60%) of the desired bromofuranamide 34. NMR data consistent with the title product were as follows: 1H
NMR (CDC13): 8 3.82 (s, 9H), 6.18 (s, 2H), 6.47 (d, 1H), 7.19 (d, 1H), 7.29 (br s, 1H).
25 5-aryloxy-2-furamide 36: A suspension of a phenol (35, 2.85 g, 13 mmol) and cesium carbonate (1.3 equiv., 4.24 g, 13 mmol) in anhydrous DMF (20 mL) was stirred at room temperature under nitrogen for 15 minutes before adding 5-bromo-N-(2,4,6-trimethoxyphenyl)-2-furamide (34, 3.57 g, 10 mmol) at once. The resulting suspension was stirred at 145 °C (bath temperature) for 18 hours. The progress of the reaction was monitored by TLC and FIMS. The suspension was quenched with cold water and extracted several times with chloroform. The organic layer was washed with brine and water, dried (anhydrous sodium sulfate) and concentrated. The crude brown oil was further dried under high vacuum to remove last traces of solvents. The residue thus obtained was either recrystallized from ether or subjected to chromatography and dried overnight at 45 °C under vacuum to give title compound (60-65%) as a white solid which showed >95% purity by I~PLC analysis.
Example Cl: 5-[(6-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide o i °
o °
d o o~

Compound Cl was synthesized according to Scheme C, using similar starting ci~mpounds and reaction conditions, with the exception that the residue obtained from the reaction between 5-bromo-N-(2,4,6-trimethoxyphenyl)-2-furamide and 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol was subjected to chromatography to give Compound C 1 and dried overnight at 45 °C under vacuum to give title compound (60-65%) as a white solid, which showed >95% purity by HPLC analysis.
2o The requisite phenol, 6-methoxy-3,3-dimethyl-5-indanol, was prepared starting from 2-methoxyphenol via Fries rearrangement as described below:
OH + ~O PPA _ / I OH Pd/C _ / I OH
0 0H 45 to 110 °C ~ O conc. H S04 ~ O
I 2 h O I CH301-~ I
iii iv 5-hydroxy-6-methoxy-3,3-dimethyl-1-indanone iii : A mixture of 3,3-dimethylacrylic acid, 2-methoxyphenol (1.25 equiv.), and polyphosphoric acid (3 g/mmol) was heated to 45 °C for 0.5 hours. The reaction temperature was gradually increased to 110 °C and kept at that temperature for 2 hours. The viscous oil was cooled to 55-60 °C and extracted extensively with ethyl acetate. The organic layer was washed with saturated NaHC~3, dried over Na2S04 and concentrated. The crude residue was recrystallized from ether to afford 5-hydroxy-6-methoxy-3,3-dimethyl-1-indanonesin 30-35% isolated yield. NMR data consistent with the title product were as follows: 1H NMR (CDC13): S 1.48 (s, 6H), 2.51 (s, 2H), 3.91 (s, 3H), 6.35 (s, 1H), 6.98 (s, 1H), 7.16 (s, 1H).
s 6-methoxy-3,3-dimethyl-5-indanol iv : 5-hydroxy-6-methoxy-3,3-dimethyl-1-indanone was hydrogenated with 10% Pd on carbon (25 mg/mmol), in the presence of catalytic amount of concentrated H2SO4 ( 25 mg/mmol) in methanol (2 mL/mmol) for 15 hours. The resulting suspension was filtered through Celite and washed the precipitate with ethyl acetate. The filtrate was dried over Na2S04 and concentrated to 1o give 6-methoxy-3,3-dimethyl-5-indanol in 90% yield. NMR data consistent with the title product were as follows: ~H NMR (CDC13): ~ 1.10 (s, 6H), 1.78 (t, 2H), 2.70 (t, 2H), 3.74 (s, 3H), 5.41 (br s, 1H), 6.58 (s, 2H). NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): 8 1.25 (d, 6H), 2.36 (s, 3H), 3.85 (s, 9H), 4.25 (m, 1H), 5.44 (d, IH), 5.9I (br d, 1H), 6.17 (s, 2H), ~s 7.11 (d, 1H), 7.I8 (s, 1H), 7.32 (d, 1H), 7.48 (d, 1H), 7.51 (s, 1H), MS
(APCI+):
469.1 (M+ H)+.
Example C2: 5-(5-tert-butyl-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
° °
° °
I ~ I I " ~
C2 °
2o Compound C2 was synthesized in a manner analogous to that of C1, according to Scheme C.
The requisite phenol for the synthesis of Compound C2, 5-tert-butyl-2-methyl-phenol, was prepared as follows:
(OHa)aNN03_ / I Pd/C i I - NaN02_ N02 NH~NH2 ~ NH2 H2S04 ~ OH
warm 25 5-tert-butyl-2-vitro-toluene was synthesized from 4-tert-butyltoluene in 90%
yield using tetramethylammonium nitrate according to the nitration procedure discussed in detail above. The regiochemistry of the nitration product was confirmed by NOE studies. NMR data consistent with the title product were as follows: 1H
NMR (CDC13): 8 1.21 (s, 9H), 2.42 (s, 3H), 7.12 (d, 1H), 7.40 (d, 1H), 7.84 (s, 1H).

The reduction of nitro compound to corresponding aniline was accomplished by hydrogenation with excess hydrazine (N50 equiv.) in the presence of Pd/C (10 mol %) in ethanol (2.5 mL/mmol) at room temperature for 15 hours. The aniline derivative was isolated as its HCl salt in 85-90% yield.
NMR data consistent with the title product were as follows: 1H NMR (CDC13): 8 1.15 (s, 9H), 2.00 (s, 3H), 6.50 (s, 1H), 6.56 (d, 1H), 6.82 (d, 1H).
5-tert-butyl-2-methylaniline was diazotized under standard conditions (NaN02, l .I equiv.. concentrated HZS04 0.25 mL/mmol; H2O, 1.7 mL/mmol, 0 °C) which upon heating at 50 °C for 2 hours afforded the requisite phenol in 30-35%
yield. NMR data consistent with the title product were as follows: 1H NMR
(CDC13):
~ 1.38 (s, 9H), 2.43 (s, 3H), 4.82 (br s, 1H), 6.54 (d, 1H), 6.83 (s, 1H), 7.00 (d, 1H).
NMR and mass spectrometry data consistent with the title product were as follows:1H
NMR (d6-DMSO): ~ 1.23 (s, 9H), 2.20 (s, 3H), 3.70 (s, 3H), 3.77 (s, 6H), 5.50 (d, 1H), 6.25 (s, 2H), 7.I I (s, 1H), 7.32-7.50 (m, 3H), 8.88 (s, 1H). The overall yield was is 15%, APCI-MS m/z 440.1 (M+H)+.
Example C3: 5-(5-amino-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
HaN
I / ~ ~ H

Compound C3 was synthesized in a manner analogous to that of C1, according 2o to Scheme C. The overall yield was 60%. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (d4-CH30H): 8 2.16 (s, 3H), 3.78 (s, 3H), 3.82 (s, 6H), 5.46 (d, 1H), 6.28 (s, 2H), 6.50 (d, 1H), 6.52-6.56 (dd, 1H), 7.01 (d, 1H), 7.15 (d, 1H), APCI-MS m/z 399.2 (M+H)+.
Example C4: 5-[2,4-dibromo-5(tert-butyl)phenoxy]-N-(2,6-dimethoxyphenyl)-2-25 furamide \ /
B .. _Br O

Compound C4 was synthesized in a manner analogous to that of C1, according to Scheme C. Compound C4 was obtained as white solid (23 mg, 6.5 %). The requisite phenol was prepared as follows:

OH Br~/FIOAC \ OH
\ _ Br ~ ~ Br To a solution of 3-tert-butylphenol (1.5 g, 10 mmol) in HOAc (4 mL) was added Br2 (2 mL, 15 mmol). The reaction mixture was stirred at room temperature ..
over night. It was quenched with ascorbic acid. The crude product was extracted with EtOAc, washed with brine, dried over Na2S0ø and taken to dryness. Column chromatography with EtOAc and hexane (1:10) offered white solid product (0.42 g, 14%). NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (300 MHz, CDC13): 8 1.46 (9H, s), 5.34 (1H, s), 7.11 (1H, s), 7.65 (1H, s), APCI-MS m/z 305 (M-H)-.
5-bromo-N-(2,6-dimthyloxyphenyl)-2-furamide (0.2 g, 0.49 mmol) and cesium carbonate (0.21 g, 0.63 mmol) were added in the flask containing DMF (2 mL). The reaction mixture was gently heated at 130°C overnight. It was quenched with water, extracted with EtOAc and washed with water and brine. Organic layer was dried over Na2S04 and taken to dryness. Crude product was purified by HPLC.
is NMR and mass spectrometry data consistent with the title product were as follows:
1HNMR (300 MHz, DMSO): ~ 1.48 (9H, s), 3.78 (6H, s), 5.86 (1H, d, J = 3 Hz), 6.75 (2H, d, J = 9 Hz), 7.26 - 7.28 (2H, m), 7.39 (1H, s), 8.07 (1H, s), 9.20 (1H, s), APCI-MS m/z 552 (M+H)+.
Example C5: 5-[2,4-dibromo-5(tert-butyl)phenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide i I ~ ~ \ / ~
~r ~ Br CS
Compound CS was synthesized in a manner analogous to that of C1, according to Scheme C. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (300 MHz, DMSO): ~ 1.48 (s, 9H), 3.76-3.84 (m, 9H), 5.84 (d, 2s 1H, J = 3 Hz), 6.32 (s, 2H), 7.27 (brs, 1H), 7.38 (s, 1H), 8.07 (s, 1H), 9.03 (s, 1H), APCI-MS m/z 584 (M+H)+.
Example C7: N-(2,6-dimethoxyphenyl)-5-[2-methyl-4-(1,1,3,3-tetramethylbutyl)phenoxy]-2-furamide I ~ \ / \ /
- - o Compound C7 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): b 0.73 (9H, s), 1.36 (6H, s), 1.72 (2H, s), 2.30 (3H, s), 3.85 (6H, s), 5.27-5.28 (1H, d, J = 3.59 Hz), 6.59-6.62 (2H, d, J = 8.31 Hz), 6.97-7.00 (1H, d, J = 8.50 Hz), 7.14-7.15 (1H, d, J = 3.59 Hz), 7.18-7.21 (1H, d, J
=
8.31 Hz), 7.19-7.21 (1H, d, J = 8.50 Hz), 7.24 (1H, s); m/z 466.
Example C8: 5-[2-Methyl-4-(1,1,3,3-tetramethylbutyl)phenoxy]-N-(2,4,6-1o trimethoxyphenyl)-2-furamide o \o/ ~ \ /
- o Compound C8 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR
~s (CDCl3): 8 0.72 (9H,s), 1.35 (6H, s)~1.71(2H, s), 2.28 (3H, s), 3.81(9H, s), 5.25-5.26 (1H, d, J = 3.59 Hz), 6.16 (2H, s), 6.96-6.99 (1H, d, J = 8.49 Hz)~ 7.13-7.14 (1H, d, J
= 3.02 Hz), 7.18-7.21 (1H, d, J = 8.31 Hz), 7.23 (1H, s); m/z 496.
Example C9: 5-(3-hydroxy-2-mehtylphenoxy)-N-(2,4,6-trimethyoxyphenyl)-2-furamide /

I ~ \o/ \ / °

2o Cg o" \
Compound C9 was synthesized in a manner analogous to that of C 1, according to Scheme C, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR, (MeOD): 8 2.14 (3H, s), 3.81 (6H, s), 3.82 (3H, s), 5.41-5.42 (IH, d, J = 3.59 Hz), 6.27 (2H, s), 6.58-6.61 (1H, d, J = 4.91 Hz), 6.67-6.69 (1H, d, J = 8.31 Hz), 7.01-7.06 (1H, t, J = 5.85 Hz), 7.13 (1H, d, J = 3.02 Hz);
m/z 400.
Example C10: 5-[(1,1,3,3,6-pentamethyl-2,3-dihydro-1H-inden-5-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide \ /
i v _ y Compound C10 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
Yield of purified product was 4%. NMR data consistent with the title product were as follows: 1H NMR, (CDCl3): 8 1.27 (6H,s), 1.30 (6H, s), 1.92 (2H, s), 2.27 (3H, s), 3.81 (9H, s), 5.33-5.35 (1H, d, J= 3.40 Hz), 6.17 (2H, s), 6.18 (1H, s), 6.69 (1H, s), 7.15-7.16 (1H, d, J = 3.40 Hz); m/z 480.
Example Cll: 5-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide /
o ° i o.
~ o o N ~ I
~ \/ H

~s Compound C11 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
Yield of purified product was 4%. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (d6-DMSO): ~ 1.30 (s, 12H), 1.70 (s, 4H), 3.78 (s, 6H), 3.85 (s, 3H), 5.85 (d, 1H), 6.33 (s, 2H), 6.95-6.99 (dd, 1H), 7.19 (d, 1H), 7.43 (d, 1H), 8.98 (s, 1H), APCI-MS m/z 480.1 (M+H)+.
Example C12: 5-[(5-methoxy-1,1-dimethyl-1H-inden-6-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I ~ o \ / ~ of C12 °
Compound C12 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as follows:1H
NMR (d4-CH30H): 8 I.28 (s, 6H), 3.80 (s, 3H), 3.8I (s, 3H), 3.84 (s, 6H), 5.24 (d, 1H), 6.26 (s, 2H), 6.44 (d, 1H), 6.62 (d, 1H), 7.10 (d, 1H), 7.10 (s, 1H), 7.20 (s, 1H), APCI-MS m/z 466.2 (M+H)+.
Example CI3: 5-[(3-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I
o°
I ~ o o ~ I
\ / H

Compound C13 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
00 ~ o. oo ~ o~
\O/ N ~ I tBuLi, DMF I ~ O ~ / N
O~ i O~
II
O
NMR and mass spectrometry data consistent with the title product were as follows: 1H
1o NMR (CDC13): 8 1.18 (s, 6H), 1.23 (s, 6H), 1.62 (s, 4H), 3.73 (s, 9H), 5.55 (d, 1H), 6.08 (s, 2H), 6.89 (d, 1H), 7.08 (d, 1H), 7.09 (s, 1H), 7.82 (s, 1H), 10.32 (s, 1H), APCI-MS m/z 508.2 (M+H)+.
)Jxample C14: 5-{4-[2-(dimethylamino)ethoxy]-5-isopropyl-2-methylphenoxy}-N-(2,4,6-trimethoxyphenyl)-2-furamide I
_ o o ~ o~
I
I ~ ~ ° \o/
1s C14'N'~o Compound C14 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
NaOH \ \ I OH
/N ~°

NMR and mass spectrometry data consistent with the title product were as 2o follows: 1H NMR (CDC13): 8 1.16 (s, 3H), 1.18 (s, 3H), 2.24 (s, 3H), 2.44 (s, 6H), 2.90 (t, 2H), 3.29-3.35 (s, m), 3.79 (s, 6H), 3.81 (s, 3H), 4.14 (t, 2H), 5.21 (d, 1H), 6.26 (s, 2H), 6.87 (s, 1H), 6.99 (s, 1H), 7.11 (d, 1H), APCI-MS rnlz 513.4 (M+H)+.

Example C15: 5-(3-tert-butyl-5-methoxyphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
o°
I~ o o ~I
\ / H o Compound C15 was synthesized in a manner analogous to that of Cl, according to Scheme C, using similar starting compounds and reaction conditions.
/ OH
/ I OH Br2/CC14 ~ I OH CuBr, NaOMe I
0 0~ ~ Br cat. EtOAc, MeOH
reflux NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (d6-DMSO): ~ 1.26 (s, 9H), 3.72 (s, 6H), 3.79 (s, 6H), 5.35 (d, 1H), 6.27 (s, 2H), 7.14 (d, 1H), 7.14 (d, 1H), 7.2 (d, 1H), 7.25 (s, 1H), 8.86 (s, 1H), APCI-MS m/z 456.1 (M+H)+.
Example C16: 5-[5-(dimethylamino)-2-methylphenoxy]-N-(2,4,6-trimethoxyphenoxy)-2-furamide I
o°, o iN ~ O O N
\ / H

Compound C16 was synthesized in a manner analogous to that of Cl, according to Scheme C, using similar starting compounds and reaction conditions.
I
H2N~OH aq, HCHO iN / I OH
Pd/C (10 mold) NMR and mass spectrometry data consistent with the title product were as follows: IH NMR (d4-CH30H): 8 2.26 (s, 3H), 3.05 (s, 6H), 3.79 (s, 6H), 3.82 (s, 3H), 5.50 (d, 1H), 6.27 (s, 2H), 6.80 (d, 1H), 6.90 (d, 1H), 7.25 (s, 1H), 7.35 (d, 1H), APCI-MS m/z 427.2 (M+H)+.
Example C17: 5-(5-tert-butyl-2,4-dimethylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
I
I w o \o/ H
o~

Compound C17 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
I
I OH Br2, CCI4 / I OH K2C03, CH31 ~ I O tBuLi, CH31 heat gr ~ Br acetone Br ~ Br BBr3 , I OH

NMR and mass spectrometry data consistent with the title product were as s ~ follows: 1H NMR (CDCl3): 8 1.36 (s, 9H), 2.21 (s, 3H), 2.49 (s, 3H), 3.81 (s, 9H), 5.25 (d, 1H), 6.18 (s, 2H), 6.99 (s, 1H), 7.09 (d, 1H), 7.09 (s, 1H), 7.17 (s, 1H), APCI-MS r~alz 454.3 (M+H)+.
Example C18: 5-[(3-Chloro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide \/ H
~cl o 1o C18 Compound C18 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized according to the following scheme:
OFi CI CI AICI3 I ~ OH
I ~ CI ~ ~~~ GH3N02 ~ CI
rt 38% yield 15 NMR and mass spectrometry data consistent with the title product were as follows:1H NMR (CDC13): S 1.22 (s, 6H), 1.27 (s, 6H), 1.67 (s, 4H), 3.81 (s, 9H), 5.43 (d, 1H), 6.17 (s, 2H), 7.11 (d, 1H), 7.1~ (s, 1H), 7.34 (s, 1H), APCI-MS
m/z 514.4 (M+H)+.
Example C19: 5-[(6-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)oxy]-N-20 (2,4,6-trimethoxyphenyl)-2-furamide(8783) i \/ H
C~ 0 Compound C19 was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
The requisite phenol was synthesized according to the following scheme:

OMe ~ D ~ I OMe i I Me0 CI
H2N ~ CI Et3N, CHZCIz Me0 HN CI LDA, THF
45~ rt, 5h OMe ' 'N ~ I CI AIC13 I ~ OH
130°C H ~ CI
96~

NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (DMSO-d6): S 1.23 (s, 6H), 2.60 (s, 1H) 3.33 (s, 2H), 3.39 (s, 2H), 3.75 (s, 9H), 5.27 (d, 1H, J = 3.59 Hz), 6.10 (s, 2H), 6.70 (s, 1H), 6.84(s, 1H), 7.06 (d, 1H, J = 3.40 Hz), 7.19 (s, 1H), 7.22 (s, 1H), APCI-MS m/z 473 (M+H)+.
Example C20: 5-[(7-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]-N-1o (2,6-dimethoxyphenyl)-2-furamide w o o N w I
I~ \/
C20 H c1 Compound C20 was synthesized in a manner analogous to that of Cl, according to Scheme C, using similar starting compounds and reaction conditions.
NMR and mass spectrometry data consistent with the title product were as ~s follows: 1H NMR (DMSO-d6): 8 1.11 (s, 6H), 1.53 (t, 2H, J = 5.67 Hz), 3.10 (t, 2H, J = 5.67 Hz), 3.68 (s, 6H), 5.23 (d, 1H, J = 3.59 Hz), 6.52 (s, 1H), 6.63 (m, 2H), 7.07 (d, 1H, J = 3.40 Hz) 7.12 (s, 1H), 7.19 (d, 1H, J = 4.15 Hz), 8.96 (s, 1H), Al'CI-MS m/z 456 (M+H)+.
Example C21: N-(2,4,6-trimethoxyphenyl)-5-[(4,4,7-trimethyl-1,2,3,4-tetrahydro-20 6-quinolinyl)oxy]-2-furamide I
D °

\ / H
~o Compound C2I was synthesized in a manner analogous to that of C1, according to Scheme C, using similar starting compounds and reaction conditions.
The particular procedure utilized is shown below:

OII Br Br \ I Br ~CI ~HN / I \ Br ~N
HzN Et3N, CHzCl2 LDA, THF
45% rt, overnight 83%~
O
AICI3 ~ Br NaOMe ~~~OMe ~CI ~ OMe - o ' N ~ / ~ < ~~/ ~ N I
130 C CuBr, DMF N Et3N, CH2CI2 ~0 H ~O
7go~ 55%
O O / O\
BBrs/CH2CIz I ~ OH general scheme 2A ~ O ~O~ H \ I
/
O O
70% 71 00 / ~ O\
NaOH/EtOH
reflux I / O~
N
H

NMR and mass spectrometry data consistent with the title product were as follows:
1HNMR (DMSO-d6): 8 1.24 (s, 6H), 1.70 (t, 2H, J = 5.76 Hz), 2.15 (s, 3H), 3.29 (t, 2H, J = 5.76 Hz), 3.83 (s, 9H), 5.15 (d, 1H, J = 3.59 Hz), 6.20 (s, 2H), 6.32 (s, 1H), 6.95 (s, 1H), 7.07 (d, 1H, J = 3.59 Hz), 7.18 (s, 1H), APCI-MS m/z 467 (M+I~+.
Example C22: [3,S-dimethoxy-2-(]S-[(3,S,S,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]-2-furoyl}amino)phenoxy]acetic acid z.._ p HO~
OO
p O
/ H O

Compound C22 was synthesized in a manner analogous to that of C1, to according to Scheme C, using similar starting compounds and reaction conditions.
The particular procedure utilized is shown below:
OH
O
O / O\ ~ / O\
O O I 1. BBr3 O O
~ I N~ 2. ~ ~ I H
~H O O ~ / p / w gr~
OMe 3, NaOH

NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR (CH30D): 8 1.13(s, 6H), 1.19 (s, 6H), 1.59 (s, 4H), 2.13 (s, 3H), 3.68 (s, 3H), 3.72 (s, 3H), 4.57 (s, 2H), 5.21 (d, 1H, J = 3.78 Hz), 6.01 (d, 1H, J = 2.64 Hz), 6.12 (d, 1H, J = 2.64 Hz), 6.94 (s, 1H), 7.09 (d, 1H, J = 3.40 Hz), 7.15 (s, 1H), APCI-MS
m/~ 538 (M+H)+.
Example C23: [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]-N(2,4,6-trimethoxyphenyl)-2-furamide °
I pil Compound C23 was synthesized according to Scheme C. The requisite phenol 1o was synthesized according the following method:
OH 1 DCIv~I' ~ OH
Cl /

3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol 36: A solution of o-cresol (17.3 g, 160 mmol), 2,5-dichloro-2,5-dimethylhexane (32.1 g, 175 mmol) in dichloromethane (80 mL) was stirred at 0°C under nitrogen as anhydrous AlCl3 (2.34 1s g, 17.5 mmol) was added portionwise while keeping the temperature below 5°C. The suspension was allowed to warm to room temperature and further stirred for about 15 hours. The resulting white suspension was poured into ice water (50 mL) and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na2S04 and 2o concentrated. The white solid thus obtained was recrystallized from toluene to give 28 g (80%) of the desired phenol. NMR data consistent with the title product were as follows: 1HNMR (CDCl3): 8 1.25 (s, 12H), 1.60 (s, 4H), 2.25 (s, 3H), 4.73 (s, 1H), 6.69 (s, 1H), 7.03 (s, 1H).
Compound C23: A suspension of phenol 3f (2.85 g, 13 mmol) and cesium 2s carbonate (1.3 equiv., 4.24 g, 13 mmol) in anhydrous DMF (20 mL) was stirred at room temperature under nitrogen for 15 minutes before adding 5-Bromo-N-(2,4,6-trimethoxyphenyl)-2-furamide (3.57 g, 10 mmol) at once. The resulting suspension was stirred at 145 °C (bath temperature) for 18 hours. The progress of the reaction was monitored by TLC and FIMS. The suspension was quenched with cold water and extracted several times with chloroform. The organic layer was washed with brine and water, dried (anhydrous sodium sulfate) and concentrated. The crude brown oil was further dried under high vacuum to remove last traces of solvents. The residue thus obtained was either recrystallized (Compound C23) from ether and dried s overnight at 45 °C under vacuum to give title compound (60-65%) as a white solid which showed >95% purity by HPLC analysis. NMR and mass spectrometry data consistent with the title product were as follows: IIINMR (300 MHz, CDC13): 8 1.16 (s, 6H), 1.20 (s, 6H), 1.60 (s, 4H), 2.18 (s, 3H), 3.75 (s, 9H), 5.25 (d, 1H), 6.11 (s, 2H), 6.92 (s, 1H), 7.04 (d, 1H), 7.08 (s, 1H), 7.13 (br s, 1H), APCI-MS rralz 494.2 io (M+H)+.
The following compounds were prepared according to Scheme D set forth below:
Scheme D
/ /
H ~ - CszC03 DMF
+B ~ \ / ~(OT~2> Cat ~ I / ~ \

NaOH _ H I ~ I / - R~1F-I2(excess) MeOH ~ ~ \ / HATU,DMF

RH I j I ~ /
20 O~
is Condensation 18: A DMF solution (10 mL) containing 16 (0.365 g, 2.2 mmol), 17 (0.712 g, 2.0 mmol), cesium carbonate (0.716 g, 2.2 mmol), and copper triflate (0.036 g, 5 mol%), was heated at 100°C for 16 hours. DMF was then removed under reduced pressure. The crude was redissolved in ethylacetate and washed with 20 10%HCI, brine, dried (magnesium sulfate) and evaporated. The product 18 was purified by flash chromatography (1:1 EtOAc/Hexanes to EtOAc): 0.13 g.
Saponification 19: Compound 18 (0.126 g, .28 mmol) was saponified in methanolic NaOH. The reaction was monitored by TLC (1:1 EtOAc/Hexanes) and NaOH was added as needed. The reaction mixture was then concentrated. The crude 2s was redissolved in water and extracted with diethyl ether. The aqueous layer was acidified to pH 2-3 with concentrated HCl and extracted with methylene chloride.
The methylene chloride extract was dried (magnesium sulfate) and evaporated to give the desired acid 19: 0.10 g.
HATU coupling 20: To a DMF solution (1 mL) containing 19 (0.056 g, .12 mmol) was added HATU (0.046 g, 0.121 mmol), and isopropylamine (9 molar excess). The reaction mixture was stirred at room temperature overnight. It was then diluted with ethyl acetate, washed with 10%HCl, saturated sodium bicarbonate, brine, dried (magnesium sulfate), and concentrated. The product 20 (Compound Dl) was purified by prep TLC (5% MeOH m CH2C12): 0.019 g.
to Example D1: 5-~5-[(isopropylamino)carbonyl]-2-methylphenoxy}-N-(2,4,6-trimethoxyphenyI)-2-furamide I
0.
~H ' i ~ ~ H
D1 °' Compound D1 was synthesized according to Scheme D above. NMR and mass spectrometry data consistent with the title product were as follows: 1H
NMR
1s (CDCl3): 8 1.25 (d, 6H), 2.36 (s, 3H), 3.85 (s, 9H), 4.25 (m, 1H), 5.44 (d, 1H), 5.91 (br d, 1H), 6.17 (s, 2H), 7.11 (d, 1H), 7.18 (s, 1H), 7.32 (d, 1H), 7.48 (d, 1H), 7.51 (s, 1H), MS (APCI ~: 469.1 (M+IT)+.
Example D2: 5-carboxy-(2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide FI° / ~ ° I
2o D2 Compound D2 was synthesized in a manner analogous to that of D1, according to Scheme D. The yield of the purified product was 11 %. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(CDCl3): 8 2.39 (3H, s), 3.82 (9H, s), 5.48 (1H, d), 6.16 (2H, s), 7.14 (1H, d), 7.20 25 (1H, s), 7.35 (1H, d), 7.76 (1H, s), 7.85 (1H, d), FI-NCI m/z 426.1 (M-H).
Example D3: 5-~5-[(diethylamino)carbonyl]-2-methylphenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide 0 0 ° ~

H
/ ,o J

Compound D3 was synthesized in a manner analogous to that of D1, according to Scheme D, with the exception that compound 18 was coupled with diethylamine to give Compound D3, 5-~5-[(diethylamino)carbonyl]-2-s methylphenoxy}-N-(2,4,6-trimethoxyphenyl)-2-furamide. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR
(300 MHz, CDC13): 8 1.15 (br, 6H), 2.38 (s, 3H), 3.28 (br, 2H), 3.50 (br, 2H), 3.82 (s, 9H), 5.51 (d, 1H), 6.18 (s, 2H), 7.05 (s, 1H), 7.15 (m, 3H), 7.28 (s, 1H), APCI-MS
m/z 483.1 (M+H)+.
to Diarylthio ether analogs of the present invention, such as Compound F1, can be synthesized according to Scheme F shown and described below:
Scheme F
'/\~ 0 0 R-SH + B~~O~ NaH S O ~ NaOH S O
~J ---RB \I o ~R' \/ OH

O
_HATU S O
R- H R~ \ / NHR

OR
° SOC12 ° R-NHZ O
S ° ~ S O ~ S O
R \ I OH R~ \ I C~ ~ R' \ I NHR

1s Methyl 5-thioaryl-2-furoate 41: A suspension of thiol 40 (1 mmol), NaH
(60% dispersion in mineral oil, 1.1 mmol) in anhydrous N,N-dimethylacetamide (DMA, 3 mL/mmol) was heated under nitrogen at 60-70 °C with stirring for 30 minutes. A solution of methyl 5-bromo-2-furoate 11 (1 mmol) in anhydrous DMA
(1 mL/mmol) was added dropwise to the hot solution. The temperature of the reaction 20 mixture was gradually increased to 145°C. The reaction mixture was stirred at this temperature for an additional I S hours. The solution was cooled and concentrated to about one quarter of its original volume in vacuo before adding to cold water (10 mL).
The solution was extracted with ether (3 X 10 mL). The combined ether layer was washed with saturated NaHCO3 (2 X 5 mL) and brine (2 X 5 mL), dried (Na2S04) and concentrated in vacuo to give pure methyl 5-thioaryl-2-furoate 41.
Acidification of the aqueous layer resulted a mixture consisted of small amounts of 5-thioaryl-2-furoic acid and 5-bromo-2-furoic acid. Yield of 41: 40-75%.
Saponification 42: Compound 41 was saponified to the acid in ethanolic s NaOH solution under similar reaction conditions as described above.
HATU coupling 45: The acid 42 was dissolved with DMF and coupled with the amine 44 under similar reaction conditions as described above to produce the Compound 45.
Acylhalide route 45: The acylhalide route via 43 can also be used to produce 1o Compound 45.
Example Fl: 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)sulfanyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide o \ / ~ \ /
- - o F1 \
Compound Fl was synthesized according to Scheme F. The overall yield was 1s 2,0%. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (300 MHz, CDCl3): 8 1.18 (s, 6H), 1.25 (s, 6H), 1.63 (s, 4H), 2.93 (s, 3H), 3.78 (s, 6H), 3.80 (s, 3H), 5.17 (br s, 2H, hydrated water), 6.14 (s, 2H), 6.58 (d, 1H), 7.12-7.13 (d, 2H), 7.24 (d, 1H), 7.46 (s, 1H), MS (APCI) m/z 510.1 (M+H)+.
Example F2: 5-[(2,5-dimethoxyphenyl)sulfanyl]-N-(2,4,6-trimethoxyphenyl)-2-2o furamide Compound F2 was synthesized in a manner analogous to that of F 1, according to Scheme F. NMR and mass spectrometry data consistent with the title product were as follows: 1F~MR (300 MHz, CDCl3): 8 3.72 (s, 3H), 3.82 (s, 6H), 3.83 (s, 3H), 2s 3.89 (s, 3H), 6.18 (s, 2H), 6.54 (d, 1H), 6.75 (dd, 1H), 6.84 (d, 1H), 6.85 (d.lH), 7.28 (s, 1H), 7.49 (s, 1H), APCI-MS mlz 446.0 (M+IT)+. The overall yield was 45%.

Example F3: 5- f [5-(tert-butyl)-2-methylphenyl]sulfanyl,~-N-(2,4,6-trimethoxyphenyl)-2-furamide Compound F3 was synthesized in a manner analogous to that of F1, according s to Scheme F. The overall yield was 45%. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (300 MHz, CDC13): 8 1.26 (s, 9H), 2.35 (s, 3H), 1.70 (s, 6H), 1.72 (s, 3H), 6.10 (s, 2H), 6.60 (d, 1H), 7.04 - 7.10 (m, 3H), 7.13 (d, 1H), 7.21 (s, 1H), APCI-MS m/z 456.1(M+H)+.
1o The following compounds were prepared according to Scheme H set forth below:
Scheme H
\ off /
s +
H \ ~ ° / \ /

1-methyl-2-pyn'olidinone / /, /
Microwave - HO
~ ~ / \
P
Synthesis of Compound 55: Phenol, bromide, and Cs2C03 were semi-15 dissolved in minimum I-methyl-2-pyrrolidinone. Mixture was placed in microwave for 2 minutes at 1100 W then allowed to cool for 1 minute before placing the mixture in microwave for an additional 2 minutes. Reaction was quenched with water/HCl and extracted with ethyl acetate.
Example Hl: N-(2,6-dimethoxyphenyl)-5-[(6'-hydroxy-4,4,4',4',7,7'-hexamethyl-20 2,2'-spirochromen-6-yl)oxy]-2-furamide O I / O ~O/
'~I \y/~O~/
Hl ° /
Compound H1 was synthesized according to Scheme H. Purification was done by HPLC to give a 26% overall yield. NMR and mass spectrometry data consistent with the title product were as follows: IHhIM>ZR, (MEOD): 8 1.30 (6H, s), 1.31 (6H, s), 1.56 (6H, s), 1.58 (6H, s), 1.92 - 1.98 (2H, dd, J = 4.35 Hz, 14.14 Hz), 2.03 (3H, s), 2.04 - 2.11 (2H, dd, J = 6.04 Hz, 14.14 Hz), 2.13 (3H, s), 3.82 (6H, s), 5.29 (1H, d, J = 3.77 Hz), 6.29 (1H, s), 6.52 (1H, s), 6.68 - 6.71 (2H, d, J =
8.69 Hz), 6.72(lH,s),7.13(lH,s),7.13-7.14(lH,d,J=2.61Hz),7.22-7.28(lH,t,J=8.50 Hz); m/z 614.
to Example H2: 5-~[7-( f 5-[(2,6-dimethoxy anilino)carbonyl]-2-furyl~oxy)-4,4,4',4',7,7'-hexamethylbis-2,2'-spirochromen] oxy}-N-(2,6-dimethoxyphenyl)-2-furamide p ° 00 O I I I HN
~~ /O\ O ~ I O~ ~'0 O

Compound H2 was synthesized in a manner analogous to that of Hl, 1s according to Scheme H, using similar starting compounds and reaction conditions.
The yield of the title product was 31 %. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR, (MEOD): 8 1.34 (6H, s), 1.61 (6H, s), 1.99 - 2.04 (2H, d, J = 14.16 Hz), 2.14 (6H, s), 2.15 - 2.17 (2H, d, J =
14.16 Hz), 3.82 (12H, s), 5.31 (2H, d, J = 3.58 Hz), 6.55 (2H, s), 6.67-6.72 (4H, d, J =
8.49 Hz), 20 7.12-7.15 (2H, d, J = 3.58 Hz), 7.16 (2H, s), 7.22-7.28 (2H, t, J = 8.40 Hz); m/z 859.
The following compounds were synthesized via the phenol coupling procedure set forth below in Scheme I:
Scheme I

R X Br ' ' a. R~ \ O O O O -I / + ~ O/ H ~ / O\ ~ I / ~ / ~ ~ / O\
O
\ O\
X is SH or OH
25 a. CsC03, DMF, microwave 220°C, iminute; 180°C, l0minutes To an empty glass tube (specifically manufactured for the Smith synthesizer), phenol (77.6 mgs, 0.421 mmol, 1.5 ec~, 5-bromo-N (2,4,6-trimethoxyphenyl)-2-furamide (100 mgs, 0.28 mmol, l.Oec~, and Cesium carbonate (183 mgs, 0.56 mmol, 2.0 e~ were suspended in 2.25 mL of anhydrous DMF. A Teflon coated stir bar was added. The tube was crimp-sealed and placed in the Smith Synthesizer microwave then heated for 1 minute at 220°C, and 10 minutes further at 180°C.
Example Tl: 5-(1,3-benzodioxol-5-yloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide !~

o i I o\
\/

Compound I1 was synthesized by Scheme I. Product was purified by HPLC
to to yield compound in 10-50% yield. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR (CD30D): 8 3.79 (s, 9H), 3.81 (s, 3H), 5.57 (d, 1H, J = 3.59 Hz), 5.99 (s, 2H), 6.26 (s, 2H), 6.67 (dd, 1H, J = 8.50, 2.27 Hz), 6.76 (dd, 1H, J = 2.27 Hz), 6.82 (d, 1H, J = 8.50 Hz), 7.13 (d, 1H, J = 2.64 Hz), Mass APCI 414.1.
15 Example I2: 5-(3-morpholin-4-ylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I w r~ /o\
\ I N 1 ~IO
Compound I2 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 2o spectrometry data consistent with the title product were as follows: 1HNMR
(CD3OD): 8 3.17 (t, 4H, J = 4.82 Hz), 3.79 (s, 9H), 3.81 (t, 4H), 5.66 (d, 1H, J = 3.59 Hz), 6.26 (s, 2H), 6.63 (dd, 1H, J = 7.93, 1.89 Hz), 6.78 (t, 1H, J = 2.17 Hz), 6.84 (d, 1H, J = 7.93 Hz), 7.15 (d, 1H, J = 2.64 Hz), 7.27 (t, 1H, J = 8.22 Hz), Mass APCI
455.2.
25 Example I3: 5-(4-isopropyl-3-methylphenogy)-N-(2,4,6-trimethylphenyl)-2-furamide I
o ~ o~

\ / b o Compound I3 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
s (CD30D): 8 1.18 (m, 3H), 1.23 (s, 3H), 2.32 (s, 3H), 3.16 (t, 1H, J = 6.80 Hz), 3.79 (s, 6H), 3.81 (s, 3H), 5.59 (d, 1H, J = 3.40 Hz), 6.24 (s, 2H), 6.96 (m, 2H), 7.14 (s, 1H), 7.28 (d, 1H, J = 9.44 Hz), APCI 426.2.
Example I4: 5-(4-chloro-5-isopropyl-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I

p \/ o a w l0 I4 Compound I4 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1 (CD30D): b 1.20 (d, 6H, J = 6.99 Hz), 2.25 (s, 3H), 3.37 (m, 1H, J = 6.89 Hz), 3.78 15 (s, 6H), 3.83 (s, 3H), 5.46 (d, 1H, J = 3.59 Hz), 6.26 (s, 2H), 7.06 (s, 1H), 7.15 (d, 1H, J = 2.83 Hz), 7.31 (s, 1H), Mass APCI 460.1.
Example I5: 5-(3-isopropylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide b / \ ~ I

IS I
Compound IS was made in a manner analogous to Il, according to Scheme I, 2o using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: lI3NMR
(CD30D): 8 1.23 (d, 6H, J = 6.99 Hz), 2.91 (q, 1H, J = 6.92 Hz), 3.77 (s, 6H), 3.80 (s, 3H), 5.64 (d, 1H, J = 3.59 Hz), 6.25 (s, 2H), 6.95 (d, 1H, J = 8.12 Hz), 7.04 (s, 1H), 7.10 (d, 1H, J = 7.74 Hz), 7.16 (s, 1H), 7.31 (t, 1H, J = 7.93 Hz), APCI mass 412.1.

Example I6: 5-[4-(cyanomethyl)phenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide b w o I~
~I
N
I6 '' Compound I6 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): 8 3.78 (s, 6H), 3.81 (s, 3H), 3.90 (s, 2H), 5.74 (d, IH, J = 3.59 Hz), 6.26 (s, 2H), 7.19 (t, 3H, J = 8.50 Hz), 7.42 (d, 2H, J = 8.69 Hz), APCI 409.1.
Example I7: 5-(4-benzylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide to I7 Compound I7 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: IIINMR
(CD3OD): b 3.76 (s, 6H), 3.79 (s, 3H), 3.94 (s, 2H), 5.58 (d, 1H, J = 3.40 Hz), 6.24 (s, 1s 2H), 7.14 (m, IOH), Mass APCI 460.1.
Example I8: 5-(1,1'-biphenyl-4-yloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide Compound I8 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 2o spectrometry data consistent with the title product were as follows: 1HNMR
(DMSO-d6): 8 3.71 (s, 6H), 3.78 (s, 3H), 5.94 (d, 1H, J = 3.59 Hz), 6.27 (s, 2H), 7.26 (d, 3H, J
= 8.69 Hz), 7.36 (t, 1H, J = 7.27 Hz), 7.46 (dd, 2H, J = 7.74, 7.18 Hz), 7.65 (d, 2H, J =
7.37 Hz), 7.73 (d, 2H, J = 8.88 Hz), 8.97 (s, 1H), APCI mass 446.4.

Example I9: 5-(3,4-dimethoxyphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide /\

of , I9 ~
Compound I9 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): b 3.79 (s, 6H), 3.81 (s, 3H), 3.83 (s, 6H), 5.57 (d, 1H, J = 3.59 Hz), 6.26 (s, 2H), 6.74 (dd, 1H, J = 8.69, 2.64 Hz), 6.87 (d, 1H, J = 2.64 Hz), 6.96 (d, 1H, J = 8.88 Hz), 7.14 (d, 1H, J = 2.64 Hz), APCI mass 430.2.
Example I10: S-~3-[(1S)-1-hydroxy-2-(methylamino)ethyl]phenoxy}-N-(2,4,6-1o trimethoxyphenyl)-2-furamide Chirel /

o I i b I10 0"
Compound I10 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
15 (CD30D): 8 2.73 (s, 3H), 3.11 (dt, 1H, J =12.46, 9.82 Hz), 3.23 (m, 1H, J
=12.65, 9.25, 3.40, 3.40 Hz), 3.78 (s, 6H), 3.82 (s, 3H), 4.97 (dt, 1H, J = 9.63, 3.21 Hz), 5.76 (d, 1H, J = 3.59 Hz), 6.26 (s, 2H), 7.17 (s, 2H), 7.29 (s, 2H), 7.45 (s, 1H), APCI mass 443.3.
Example Ill: S-(dibenzo[b,d]furan-2-yIoxy)-N-(2,4,6-trimethoxyphenyl)-2-2o furamide o , / \ ~ I o /o\ b ~
I

Compound I11 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR

(CD30D): 8 3.76 (s, 6H), 3.78 (s,, 3H), 5.62 (d, 1H, J = 3.40 Hz), 6.23 (s, 2H), 7.16 (d, 1H, J = 2e 83 Hz), 7.30 (d, 1H, J = 5.29), 7.34 (d, 1H, J = 7.74 Hz), 7.48 (dd, 1H, J =
8.12, 7.18 Hz), 7.57 (dd, 2H, J = 8.50, 6.61 Hz), 7.83 (s, 1H), 7.97 (d, 1H, J
= 7.74 Hz), Mass APCI 460.4.
Example I12: 5-(4-amino-3-chlorophenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide /\ p I
~I o I12 N"
Compound I12 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 1o spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): 8 3.79 (s, 6H), 3.81 (s, 3H), 5.52 (d, 1H, J = 3.59 Hz), 6.26 (s, 2H), 6.89 (d, 1H, J = 8.88 Hz), 6.98 (d, 1H, J = 8.88 Hz), 7.13 (s, 1H), 7.15 (d, 1H, J =
2.64 Hz), Mass APCI 419.4.
Example I13: 5-(quinolin-6-yloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide /\ p i o I i ~I
,J
I13 ~~
Compound I13 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD3OD): 8 3.78 (s, 6H), 3.79 (s, 3H), 6.04 (d, 1H, J = 3.59 Hz), 6.24 (s, 2H), 7.28 (d, 1H, J = 3.02 Hz), 7.86 (m, 3H), 8.22 (d, 1H, J = 9.06 Hz), 8.81 (d, 1H, J =
8.31 Hz), 9.02 (d, 1H, J = 6.42 Hz), Mass APCI 422.1.
Example I14: Ethyl 7-[(5-~[(2,4,6-trimethoxyphenyl)amino]carbonyl-2-furyl)oxy]-1H-indole-2-carboxylate Compound I14 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNNIR
(CD30D): ~ 1.40 (t, 3H, J = 7 Hz), 3.79 (s, 3H), 3.81 (s, 6H), 4.37 (q, 2H, J
= 6.99 Hz), 5.49 (d, 1H, J = 3.4 Hz), 6.26 (s, 2H), 7.17 (m.3H), 7.48 (m, 2H), APCI
mass 481.6.
Example I15: 5-(1-Naphthyloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide o \o/ ~ / \ o I15 ~
Compound I15 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): 8 3.80 (s, 6H), 3.81 (s, 3H), 5.66 (d, 1H, J = 3.59 Hz), 7.17 (d, 1H, J = 3.59 Hz), 7.23 (d, 1H, J = 7.74 Hz), 7.47 (t, 1H, J = 8.12 Hz), 7.57 (m, 2H), 7.75 (d, 1H, J
1s = 8.12 Hz), 7.93 (m, 1H), 8.18 (m, 1H), APCI mass 421Ø
Example I16: 5-(4-phenoxyphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide i I I ~ o \o/ (~ / \ o I16 \
Compound I16 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 2o spectrometry data consistent with the title product were as follows: iHNMR
(CD30D): 8 3.78 (s, 6H), 3.81 (s, 3H), 5.65 (d, 1H, J = 3.59 Hz), 6.26 (s, 2H), 7.00 (m, 4), 7.10 (t, 1H, J = 7.37 Hz), 7.19 (m, 2H), 7.34 (dd, 2H, J = 8.50, 7.37 Hz), APCI
mass 463.1.
Example I17: 5-(quinolin-8-yloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide ° ~ / \ o I
I wN

Compound I17 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): 6 3.79 (s, 6H), 3.81 (s, 3H), 5.91 (d, 1H, J = 3.59 Hz), 6.25 (s, 2H), 7.23 (d, 1H, J = 3.02 Hz), 7.69 (d, 1H, J = 7.74 Hz), 7.78 (t, 1H, J = 8.03 Hz), 7.88 (t, 1H, J =
4.82 Hz), 7.99 (d, 1H, J = 8.31 Hz), 8.82 (d, 1H, J = 8.50 Hz), 9.04 (d, 1H, J
= 4.72 Hz), APCI mass 421.8.
Example I18: 5-(3-{[(4-chlorophenyl)sulfonyl]amino~phenoxy)-N-(2,4,6-to trimethoxyphenyl)-2-furamide Compound I18 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HIVMRR
1s (CD30D): ~ 3.79 (s, 6H), 3.81 (s, 3H), 5.68 (d, 1H, J = 3.21 Hz), 6.26 (d, 1H, J = 3.21 Hz), 6.91 (m, 3H), 7.18 (d, 1H, J = 1.89 Hz), 7.26 (t, 1H, J = 8.40 Hz), 7.51 (d, 2H, J
= 8.50 Hz), 7.74 (d, 2H, J = 8.31 Hz), APCI mass 559.5.
Example I19: 5-(2-naphthyloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide o °

\ / (~ \ / °\

I19 \
2o Compound I19 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD3OD): 8 3.78 (s, 3H), 3.83 (s, 6H), 5.77 (d, 1H, J = 3.59 Hz), 6.25 (s, 2H), 7.21 (s, 1H), 7.36 (dd, 1H, J = 9.06, 2.27 Hz), 7.48 (m, 2H), 7.58 (s, 1H), 7.83 (d, 1H, J = 7.74 Hz), 7.88 (d, 1H, J = 7.74 Hz), 7.95 (d, 1H, J = 8.88 Hz), APCI mass 420.9.
Example I20: 5-{4-[(2-chlorobenzoyl)amino]phenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide G

s I20 °\
Compound I20 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: IHNMR
(DMSO-d6): 8 3.71 (s, 6H), 3.78 (s, 3H), 5.79 (d, 1H, J = 3.40 Hz), 6.27 (s, 2H), 7.23 (m, 3H), 7.52 (m, 3H), 7.78 (m, 2H), 8.93 (s, 1H), 10.59 (s, 1H), APCI mass 523.6.
Example T21: 5- f (6-amino-1-naphthyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide /

\ / b \ / °\
I~
NHs Compound I21 was made in a manner analogous to I1, according to Scheme I, 1s using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with therytitle product were as follows: 1HNMR
(CD30D): 8 4.52 (s, 6H), 4.59 (s, 3H), 6.61 (d, 1H, J = 3.40 Hz), 7.08 (s, 2H), 7.67 (d, 1H, J = 7.55 Hz), 7.85 (s, 1H), 7.91 (dd, 1H, J = 9.07, 2.27 Hz), 8.04 (s, 1H), 8.12 (t, 1H, J = 7.93 Hz), 8.27 (d, 1H, J = 8.31 Hz), 8.72 (d, 1H, J = 9.07 Hz), 9.77 (s, 1H), 2o APCI mass 435.1.
Example I22: 5-][3-(2-hydroxyethyl)-1H-indol-7-yl]oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide ° \°/ <i \ / °~
H
~2 off Compound I22 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: IIfNMR
(DMSO-d6): 8 2.80 (d, 2H, J = 6.99 Hz), 3.61 (t, 2H, J = 7.18 Hz), 3.72 (s, 6H), 3.79 (s, 3H), 5.53 (d, 1H, J = 3.59 Hz), 6.27 (s, 2H), 6.96 (d, 1H, J = 8.69 Hz), 7.16 (s, 1H), 7.23 (s, 1H), 7.35 (s, 1H), 7.37 (d, 1H, J = 9.06 Hz), 8.87 (s, 1H), 10.94 (s, 1H), APCI mass 453.1.
Example I23: 5-[(6-benzoyl-1-naphthyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide 1o I23 Compound I23 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNM1ZR
(dmso-d6): 8 3.71 (s, 6H), 3.79 (s, 3H), 6.07 (d, 1H, J = 3.40 Hz), 6.27 (s, 1H), 7.52 (d, 1H, J
1s = 9.07 Hz), 7.59 (dd, 2H, J = 7.55, 7.18 Hz), 7.70 (dd, 1H, J = 7.55, 7.18 Hz), 7.76 (m, IH), 7.81 (d, 2H, J = 7.18 Hz), 7.89 (d, 1H, J = 8.31 Hz), 8.10 (d, 1H, J
= 8.69 Hz), 8.24 (d, 1H, J = 9.07 Hz), 8.36 (s, 1H), 9.01 (s, 1H), APCI mass 524.2.
Example I24: 5-[3-(diethylamino)phenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I
~N ~ 0 O I
O
2o I24 Compound I24 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): S 1.15 (t, 6H, J = 7.18 Hz), 3.50 (t, 4H, J = 7.18 Hz), 3.78 (s, 6H), 3.82 (s, 2s 3H), 5.77 (d, 1H, J = 3.02 Hz), 6.26 (s, 2H), 6.84 (s, 3H), 7.19 (s, 1H), 7.38(t, 1H, J =
8.31 Hz), APCI mass 441.1.

Example I25: 5-(2-iodophenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
~ o \/
,o IZS ~' Compound I25 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): ~ 3.79 (s, 6H), 3.82 (s, 3H), 5.57 (d, 1H, J = 3.40 Hz), 6.26 (s, 2H), 7.02 (t, 1H, J = 7.55 Hz), 7.16 (s, 1H), 7.20 (d, 1H, J = 8.69 Hz), 7.43 (dd, 1H, J =
6.80, 1.51 Hz), 7.91 (dd, 1H, J = 7.93, 1.51 Hz), APCI mass 496.1.
Example I26: 5-[(2-methyl-1-naphthyl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-to furamide I
w o o b w I
I \/
,o Compound I26 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNIVIR
(dmso-1s d6): 8 2.38 (s, 3H), 3.70 (s, 6H), 3.81 (s, 3H), 5.06 (d, 1H, J = 3.40 Hz), 6.28 (s, 2H), 7.10 (s, 1H), 7.54 (m, 3H), 7.87 (d, 2H, J = 8.31 Hz), 7.99 (d, 1H, J = 8.31 Hz), 8.91 (s, 1H), APCI mass 434.1.
Example I28: 5-(2,3-dihydro-1H-inden-5-yloxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide HN
20 I28 H3co Compound I28 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CD30D): 8 2.10 (m, 2H, J = 7.37, 7.55, 7.37, 7.37 Hz), 2.89 (q, 4H, J = 7.49 Hz), 25 3.78 (s, 6H), 3.82 (s, 3H), 5.56 (d, 1H, J = 3.40 Hz), 6.26 (s, 2H), 6.92 (d, 1H, J = 8.12 Hz), 7.02 (s, 1H), 7.13 (s, 1H), 7.22 (d, 1H, J = 8.12 Hz), APCI mass 410.1.

Example I29: 5-[3-(dimethylamino)phenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide N

HN
I29 H,oo Compound I29 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: IIiNMR
(CD30D): 8 2.99 (s, 6H), 3.77 (s, 6H), 3.82 (s, 3H), 5.69 (d, 1H, J = 3.59 Hz), 6.26 (s, 1H), 6.60 (d, 1H, J = 8.12 Hz), 6.69 (s, 1H), 6.76 (d, 1H, J = 8.31 Hz), 7.16 (d, 1H, J =
2.83 Hz), 7.28 (t, 1H, J = 8.22 Hz), APCI mass 413.1.
to Example I30: 5-(3-piperidin-4-ylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide HN
H~CO
/ / ~ ~ OCH3 HN
I30 H3~o Compound I30 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 1s spectrometry data consistent with the title product were as follows: IIiNMR
(CD30D): 8 1.87 (t, 2H, J = 12.84 Hz), 2.09 (d, 2H, J =13.98 Hz), 2.95 (m, 1H, J =
12.09, 11.33, 3.78, 3.40 Hz), 3.12 (dd; 2H, J = 12.84, 12.09 Hz), 3.49 (d, 2H, J =
10.95 Hz), 3.77 (s, 6H) 3.82 (s, 3H), 5.70 (d, 1H, J = 3.02 Hz), 6.25 (s, 2H), 7.12 (M, 3H), 7.39 (M, 1H), APCI mass 453.2.
2o Example I31: 5- f 4-[(lE)-3-oxobut-1-enyl]phenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide / ~ / ~ ~ HN ~ ~ CHa I31 H3oo Compound I31 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 25 spectrometry data consistent with the title product were as follows: 1HNMR
(CD3OD): ~ 2.37 (s, 3H), 3.77 (s, 6H), 3.83 (s, 3H), 5.85 (d, 1H, J = 3.40 Hz), 6.27 (s, 2H), 6.76 (d, 1H, J = 16.24 Hz), 7.13 (bs, 1H), 7.21 (d, 2H, J = 6.23 Hz), 7.62 (d, 1H, J = 16.24 Hz), 7.74 (s, 2H), APCI mass 438.1.
Exmple I32: 5-(4-Ethyl-phenylsulfanyl)-furan-2-carboxylic acid (2,4,6-trimethoxy-phenyl)-amide I
o , o~
\I
\/ H
~ io Example I33: 5-[(4-methylpyridin-2-yl)oxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide 0 HsC
SN ~ ~ ~ HN ~ ~ OCHy I33 H3~o 1o Compound I33 was made in a manner analogous to I1, according to.Scheme h using similar starting compounds and reaction conditions. NMR and mass spectrometry data consistent with the title product were as follows: 1HNMR
(CDC13):
8 2.27 (s, 3H), 3.77 (s, 6H), 3.84 (s, 3H), 6.27 (s, 2H), 6.38 (d, 1H, J =
7.18 Hz), 6.46 (s, 1H), 6.92 (s, 1H), 7.29 (s, 1H), 8.02 (d, 1H, J = 6.80 Hz), APCI mass 385.1.
Example I34: 5-(4-amino-5-isopropyl-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
O O O \.I Ow O
H

Compound I34 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. NMR and mass 2o spectrometry data consistent with the title product were as follows: 1H NMR
(CDCl3):
8 1.22 (6H, d), 2.17 (3H, s), 2.86 (1H, hep), 3.60 (2H, br s), 3.82 (9H, s), 5.15 (1H, d), 6.18 (2H, s), 6.54 (1H, s), 6.90 (1H, s), 7.07 (1H, d), 7.18 (1H, s), FI-PCI
m/z 441.2 (M+H)+.

Br H pd/C
Br OH N02+'OTf ~ OH z~
OH NBS/iPr2NH ~
-" ~x CH C1 I ~ CHZC12 02N' v ' 9515:EtOH/

aq.l0%HC1 OH
.HC1 HzN

Example I35: 5-(5-isopropyl-4-methoxy-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I

I \/ o i Compound I35 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions. i NaOCH3 OH Brz I ~ OH CuBr I ~ OH
CC14 Br ~ CH30H O
0°C - r.t. reflex 156 OH

O
I
NaOCH3 I ~ OH Br2 I ~ OH CuBr f ~ OH

CC14 Br ~ CH30H O

0C reflex -r.t.

to To a carbon tetrachloride solution (25 mL) containing 5-isopropyl-2-methylphenol (1.5 g, 10 mmol) was added bromine (.550 mL, 10 mmol) dropwise at 0°C.
The mixture was allowed to warm to r.t. and was stirred overnight. It was diluted with dichloromethane, washed with aq. Sodium bicarbonate, brine, dried (magnesium sulfate) and evaporated to a liquid: 2.41 g (94%). 1H NMR (CDCl3) 8 1.21 (6H, d), 2.18 (3H, s), 3.22 (1H, hep), 4.66 (1H, s), 6.69 (1H, s), 7.25 (1H, s). To a RB flask was charged with 4-bromo-5-isopropyl-2-methylphenol (1.82 g, 8 mmol), ethylacetate (.7 mL), cuprous bromide (.23 g, 1.6 mmol), and 25 wt% (~SlVn sodium methoxide in methanol (16 mL). The mixture was heated gradually in an oil bath to reflex (oil bath temperature 90-95oC) under argon atmosphere for 16 h. After cooling to r.t., the reaction mixture was acidified with conc. HCl to pH 2. The acidified mixture was concentrated on a rotovap. The aqueous solution was extracted with diethyl ether 3 times. The combined ether extracts were washed with brine, dried over magnesium sulfate, and evaporated to an orange-colored liquid. The desired product was purified by flash chromatography (eluting solvents: hexanes to 10% ethylacetate in hexanes):
1.05 g (73%). 1H NMR (CDC13) 8 1.35 (6H, d), 2.42 (3H, s), 3.42 (1H, hep), 3.95 (3H, s), 4.80 (1H, s), 6.83 (1H, s), 6.84 (1H, s). NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDC13): S 1.16 (6H, d), 2.25 (3H, s), 3.52 (1H, hep), 3.82 (12H, s), 5.21 (1H, d), 6.18 (2H, s), 6.71 (1H, s), 7.0 (1H, s), 7.12 (1H, d), 7.19 (1H, s), FI-PCI mlz 456.2 (M+H)+.
Example I36: 5-[4-(dimethylamino)-5-isopropyl-2-methylphenoxy]-N-(2,4,6-trimethoxyphenyl)-2-furamide I
0 0 00 ~ I o~
N ~
N

Compound I36 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. The specific method utilized for the synthesis of I36 is depicted as follows:
Br Br OH NOz+-OTf ~OH HzCO
OH NBSIiPrzNH ~ ~ I
O N ~ Ha Pd/C
CHZCIz a MeOH
I
8r O O N W I O o , Ow ~ a H ,0 0 0 ~~ I~ W
N i0 N
CszC03, DMF I
microwave, 200°C, 2x10 min. >36 (Scheme 7) Bromination: A solution of 5-isopropyl-2-methylphenol (3.0 g, 20 mmol) in methylene chloride (5 mL) was mixed with diisopropylamine (.280 mL, 2 rnmol) in a 500 mL 1tB flask. To this mixture was added dropwise a solution of N-bromosuccinimide (3.56 g, 20 mmol) in methylene chloride (120 mL). The reaction mixture was stirred at room temperature overnight. It was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and the solvent was then evaporated to give the product 6-bromo-5-isopropyl-2-methylphenol: liquid, 4.22 g (92.6%). NMR data consistent with the title product were as follows: 1H NMR
(CDC13): eS 1.22 (6H, d), 2.26 (3H, s), 3.27 (1H, hep), 5.73 (1H, s), 6.75 (1H, d), 7.02 (1H, d).
Nitration: Into a RB flask containing a stirred suspension of tetramethylammonium nitrate (96%, Aldrich) (1.288 g, 9.07 mmol) in anhydrous methylene chloride (25 mL) was added trifluoromethane sulfonic anhydride (1.58 mL/2.65 g, 9.31 mmol) dropwise at room temperature, under argon. The suspension was stirred at room temperature for 1.5 hours. The flask was then placed in a dry ice/acetone cold bath. A methylene chloride solution (10 mL) of 6-bromo-5-isopropyl-2-methylphenol (1.96 g, 8.63 mmol) was added via a syringe. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. It was diluted with methylene chloride, washed with water until neutral pH
was reached, followed by brine, dried (magnesium sulfate) and evaporated. The product 6-bromo-4-vitro-5-isopropyl-2-methylphenol was purified by flash.
chromatography on silica gel (eluting solvent: 1 ethyl acetate/5 hexanes):
0.60 g, (25.4%). NMR data consistent with the title product were as follows: 1H NMR
(CDCl3): 8 1.40 (6H, d), 2.30 (3H, s), 3.50 (1H, hep), 6.21 (1H, s), 7.36 (1H, s).
Hydrogenation: A mixture of 6-bromo-4-vitro-5-isopropyl-2-methylphenol (0.60 g, 2.19 mmol), formaldeyde solution (40% aqueous solution, 700 mL, 8.80 2o mmol), 10% palladium on carbon (0.2 g), in methanol (20 mL) was hydrogenated in a Parr apparatus at 45 psi for 16 hours. The mixture was then filtered through a pad of Celite. The filtrate was concentrated on a rotovap to give the product 4-N,N-dimethylamino-5-isopropyl-2methylphenol. HBr as a dark solid residue: 0.522 g (87%). NMR and mass spectrometry data consistent with the desired title product is 2s as follows: 1H NMR (CDCl3): 8 1.28 (6H, d), 2.25 (3H, s), 3.22 (6H, s), 3.80 (1H, hep), 5.85 (1H, br s), 6.92 (1H, s), 7.18 (1H, s).
Phenol coupling: The microwave protocol of Scheme I was followed.
Condition: DMF, 200°C, 2x10 minutes. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (CDCl3): 8 1.16 (6H, d), 2.25 (3H, s), 30 2.66 (6H, s), 3.52 (1H, hep), 3.82 (9H, s), 5.30 (1H, d), 6.18 (2H, s), 6.96 (2H, s), 7.12 (1H, d), 7.21 (1H, s), FI-PCI m/z 469.2 (M+H)+.
Example I37: 5-(4-bromo-5-isopropyl-2-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
00 , B o lo/ H ~I

I37 Br w Compound I37 was made in a manner analogous to Il, according to Scheme I, using similar starting compounds and reaction conditions.
OH gr2 ~ OH
CC14 gr 0°C - r.t. 157 s To a carbon tetrachloride solution (25 mL) containing 5-isopropyl-2-methylphenol (1.5 g, 10 mmol) was added bromine (.550 mL, 10 mmol) dropwise at 0°C.
The mixture was allowed to warm to r.t. and was stirred overnight. It was diluted with dichloromethane, washed with aq. Sodium bicarbonate, brine, dried (magnesium sulfate) and evaporated to a liquid: 2.41 g (94%). 1H NMR (CDC13) b 1.21 (6H, d), 2.18 (3H, s), 3.22 (1H, hep), 4.66 (1H, s), 6.69 (1H, s), 7.25 (1H, s). NMR
and mass spectrometry data consistent with the title product were as follows: 1H NMR
(DMSO-d6): 8 1.09 (6H, d), 2.15 (3H, s), 3.13 (1H, hep), 3.65 (6H, s), 3.7 (3H, s), 5.54 (1H, d), 6.20 (2H, s), 7.07 (1H, s), 7.12 (1H, br d), 7.53 (1H, s), 8.85 (1H, br s). FI-PCI m/z 504.1, 506.0 (M+H)+.
i5 Example I38: 5-(4-chloro-3-isopropyl-2-methoxy-6-methylphenoxy)-N-(2,4,6-trimethoxyphenyl)-2-furamide I
0 0 , o~
\ / H w I38 c~
Compound I38 was made in a manner analogous to I1, according to Scheme I, using similar starting compounds and reaction conditions. The specific method 2o utilized for the synthesis of I38 is depicted as follows:
gr o. o OH NaOMe ~ OH SOZC12 ~ OH
I, CuBr MeOH

Br 'O/ O N o I O\ of O O ~ I O
O
I~
CI
CszCOs, DMF
microwave, 200°C, 2x10 min. 13g Displacement of bromine by methogide: A mixture consisting of 6-bromo-5-isopro~yl-2-methylphenol (2.28 g, 10 mmol), ethyl acetate (0.8 mL), cuprous bromide (0.286 g, 2 mmol), and a 25wt% solution of sodium methoxide (20 mL) was heated at reflux (oil bath 90 - 95°C) under argon for 16 hours. The reaction mixture was cooled to room temperature, and was acidified with concentrated HCl to pH
2-3.
The mixture was then diluted with methanol and filtered through Celite. The filtrate was concentrated. The concentrate was redissolved in diethyl ether, washed with aqueous 10% HCI, brine, dried (magnesium sulfate), and evaporated to a solid residue 6-methoxy-5-isopropyl-2-methylphenol: 1.5 g (83%). NMR data consistent with the to desired title product is as follows:1H NMR (CDCl3): 8 1.22 (6H, d), 2.22 (3H, s), 3.23 (1H, hep), 3.78 (3H, s), 5.64 (1H, s), 6.68 (1H, d), 6.85 (1H, d).
Chlorination: Sulfuryl chloride (.442 mL, 5.5 mmol) was added to a chloroforni solution (25 mL) of 6-methoxy-5-isopropyl-2-methylphenol (1.05 g, mmol). The reaction mixture was heated at 60°C for 2 hours, then was stirred at room 1s temperature for 16 hours. The reaction mixture was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated to an oil (1.33 g).
The product 6-methoxy-4-chloro-5-isopropyl-2-methylphenol was purified by flash chromatography on silica gel: 1.03 g (96%). NMR data consistent with the title product were as follows: 1H NMR (CDC13) 0 1.41 (6H, d), 2.19 (3H, s), 3.51 (1H, 2o hep), 3.76 (3H, s), 5.53 (1H, s), 6.88 (1H, s).
Phenol coupling: The microwave protocol of Scheme I was followed.
Condition: DMF, 200°C, 2x10 minutes. NMR and mass spectrometry data consistent with the title product were as follows: 1H NMR (MeOD-d4): 8 1.35 (6H, d), 2.21 (3H, s), 3.61 (1H, hep), 3.80 (6H, s), 3.81 (3H, s), 3.85 (3H, s), 5.16 (1H, d), 6.26 (2H, s), 2s 7.10 (2H, s), FI-PCI mlz 490.1, 492.1 (M+H)+.
Example I39: 5-o-Tolylogy-furan-2-carboxylic acid (2,4,6-trimethogy-phenyl)-amide \ / ~ \ / o\
o\

so Compound I39 was synthesized in a manner analogous to compound Il, according to scheme I, using similar starting materials and reaction conditions.

Example I40: 5-(1-Methyl-1H-indazol-6-yloxy)-furan-2-carboxylic acid (2,4,6-trimethoxy-phenyl)-amide H

Compound I40 was synthesized in a manner analogous to compound I1, according to scheme I, using similar starting materials and reaction conditions.
Example I41: 5-(3-text-Butyl-phenoxy)-furan-2-carboxylic acid (2,4,6-trimethoxy-phenyl)-amide to Compound I41 was synthesized in a manner analogous to compound I1, according to scheme I, using similar starting materials and reaction conditions.
Example I42: 5-(3-Trifluoromethyl-phenylsulfanyl)-furan-2-carboxylic acid (2,4,6 trimethoxy-phenyl) -amide F
F /
O

H
1s I42 Compound I42 was synthesized in a manner analogous to compound I1, according to scheme I, using similar starting materials and reaction conditions.
Example I43: 5-(4-Isopropyl-phenylsulfanyl)-furan-2-carboxylic acid (2,4,6-trimethoxy-phenyl)-amide I
o / o S O
I
/O

Compound I43 was synthesized in a manner analogous to compound I1, according to scheme I, using similar starting materials and reaction conditions.
Example I44: 5-(3,4-Dimethoxy-phenylsulfanyl)-furan-2-carboxylic acid (2,4,6-trimethoxy-phenyl)-amide I

\ S O N \ I
l H
O /O
~o Compound I44 was synthesized in a manner analogous to compound Il, according to.scheme I, using similar starting materials and reaction conditions.
to Scheme J
CI N N~ NaOH
CI N\ CI O O CsZCO3 ~ i _ 1// o N~ + HZN ~ / o DMF N / ~ CH30H
110°C, 20 h.

rO~Ow H O INI~ IN H 00Y N~NHR
CIYN\ N \O/ OH NHR OI\'N\ N 'O/ H~N
- N~ TNI O~w HA'I'IT
Example Jl: 5-[(2-chloro-5-methylpyrimidin-4-yl)amino]-N-(4,6-dimethoxy-2-~[3-(4-methylpiperazin-1-yl)propyl]amino~pyrimidin-5-yl)-2-furamide acetate N
O N~
CI !~ N O N
1i~ v / o 1s Jl Compound JI was synthesized according to scheme J, using similar starting materials and reaction conditions.
Exmaple J2: 5-[(2-chloro-5-methylpyrimidin-4-yl)amino]-N-(2-([3-(dimethylamino)propyl]amino-4,6-dimethogypyrimidin-5-yl)-2-furamide 20 acetate p ~1~N~N~
O ~
CI~N~ N O N~N
O
N / \ / O~
O

Compound J2 was synthesized according to scheme J, using similar starting materials and reaction conditions.
s Example J3: 5-((2-chloro-5-methylpyrimidin-4-yl)amino]-N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl)-2-furamide acetate o ,J'1 N~
CI N N O N
\/
N~ O~
O

Compound J3was synthesized according to scheme J, using similar starting 1o materials and reaction conditions.
Exmaple J4: 5-[(2-chloro-5-methylpyrimidin-4-yl)amino]-N-(2,6-dimethoxyphenyl)-2-furamide I
o /
CI N~ N 0 N
N~ O~
"J4 1s Compound J4 was synthesized according to scheme J, using similar starting materials and reaction conditions.
Scheme I~
O ~OH SOCl2 0 Br O CI N~ -~ Br \O/ N
CHZC12 0°C -~ r.t.
2 h. 62% (2 steps) OH
O I
O
W O~ ~N
CszC03, DMF O I i 120°C, 16 h.

Example Kl: 4,4-Dimethyl-2-[5-(3,3,6-trimethyl-1,3-dihydro-isobenzofuran-5-yloxy)-faran-2-yl]-4,5-dihydro-oxazole o I i \ / N

Compound I~1 was synthesized according to scheme K.
Biological Testing And Enzvme Assays Ih Vitro Assays:
Assessment of GnRU Receptor Activation Using Microphysiometrv 1o By performing exemplary assays described below, the functionality of the compounds of the invention as GnRH antagonists may be confirmed.
Materials and Methods.
GnRH, Ac-D-2-Nal-p-chloro-D-Phe-(3-(3-pyridyl)-D-Ala-Ser-Lys(nicotinoyl)-D-Lys(nicotinoyl)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2 (amide), the superagonist peptide [D-Ala6, des-Gly1°]proethylamide9-LHRH (GnRH-A), and TRH may be purchased from Bachem (Torrance, CA). Cell Culture media and forskolin may be purchased from Sigma (St. Louis, MO). Fetal bovine serum (FBS) and penicillin/streptomycin are available from Omega Scientific, Inc. (Tarzana, CA).
6418 may be obtained from Gemini (Calabasas, CA). Staurospoxine, Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-CAMPS), PMA, and 5-(N-methyl-N-isobutyl)-amiloride (MIA) are available from RBI (Natick, MA). 2-[1-(3-Dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide (GF 109203 may be purchased from Tocris (Ballwin, MO).
Cell Culture. GGH3 cells (Dr. William Chin, Harvard Medical School, Boston, MA) are grown in low glucose Dulbecco's modified Eagle's medium (DMEM) containing 100U/mL penicillin/streptomycin, 0.6 g/L G418 and 10% heat-inactivated FBS.
Total Inositol Phosphates Measurement.
The activity of various GnRH peptide agonists is initially assessed utilizing an 3o assay that measures accumulation of total inositol phosphates.
Approximately 200,000 GGH3 cells/well are plated onto 24-well tissue culture plates using DMEM
media. The following day, cells are loaded with [3H]myoinositol (0.5 Ci/ml) for 16-18 hours in inositol-free medium. The medium is aspirated and the cells rinsed with serum-free DMEM. Cells are stimulated with GnR_H_ (0.1 nM-1 p,M) or the superagonist, GnRH-A (0.01 nM-100 nNl) dissolved in DMEM media in a total volume of 1 mL containing 10 mM LiCI at 37°C for 45 minutes. The media is replaced with 1 mL ice-cold 10 mM formic acid, which stops the reaction and also serves to extract cellular lipids. Inositol phosphates are separated by ion-exchange chromatography on Dowex columns, which are washed with 2.5 mL of 10 mM
myoinositol and 10 mM formic acid. The columns are then washed with 5 mL of 60 mM sodium formate and 5 mM borax, and total inositol phosphates are eluted with 5 1o mL 1M ammonium formate, 0.1 M formic acid. The column eluates are added to liquid scintillation vials containing 15 ml of scintillation cocktail and are counted by liquid scintillation counting.
Preparation of l2sl-GnRH-A radioligand.
The radioiodinated agonist analog of GnRH, lzsl-GnRH-A, is used as the 1s radioligand. One ~g of GnRH-A diluted in O.1M acetic acid is added to an Iodogen~-coated borosilicate glass tube (Pierce) containing 35 p1 of 0.05 M phospate buffer (pH
7.4-7.6) and I rnCi of Na[lzsl]. The reaction mixture is vortexed and incubated for I
min at room temperature. 2 ml of 0.5 M acetic acid is added to the reaction tube and the mixture is added to a C18 Sep-Pak cartridge. The cartridge is washed with 2o subsequent washes of 5 ml H20 and 5 ml O.SM acetic acid and then eluted with 5 x 1.
ml of 60% CH3CN/40% O.SM acetic acid. The eluate is diluted with 3x volume of HPLC buffer A (0.1 % TFA in H20)° and loaded onto a C 18 column. The iodinated product is eluted over 20-25 min with a gradient of 25-100% CH3CN containing 0.1%TFA. The radioactive fractions (750 p,l/fraction) are collected into clean 25 polypropylene tubes containing 100 ~1 of 10% BSA. Fractions are assessed for biological activity by radioligand binding.
Competition Radioligand Binding.
Approximately two million GGH3 cells/tube are utilized for radioligand binding. Izsl-GnRH-A (approximately 0.1-0.3 nM) is incubated with cells in the 3o presence or absence of competing agents in a final volume of 300 p,1 binding assay buffer [50 mM HEPES (pH 7.4), 1 mM EDTA, 2.5 mM MgClz, and 0.1% BSA~ to test the ability of compounds to displace agonist binding. Reactions are performed on ice for 2 hr and stopped by the addition of 2 mI of ice-cold PBS wash buffer (SO mM

NaP04, 0.9% NaCI, 2 mM MgCl2, and 0.02% NaN3, pH 7.4) and rapid filtration onto GF/C filters presoaked with 0.05% polyethylenimine utilizing a Brandcl cell harvester. Filters are counted on a gamma counter.
Microphysiometry.
s 'The Cytosensor~ Microphysiometer (Molecular Devices, Sunnyvale, CA) is a real-time, noninvasive, nonradioactive semiconductor-based system for monitoring the cellular responses to various stimuli. It is based on a pH-sensitive silicon sensor, the light-addressable potentiometric sensor which forms part of a microvolume flow chamber in which cultured cells are immobilized (14, 15, I7). GGH3 cells are seeded 1o in low-buffered minimal essential media (MEM, Sigma) containing 25 mM NaC1 and 0.1% BSA at a density of 500,000 cells/capsule onto the polycarbonate membrane (3 pm porosity) of cell capsule cups (Molecular Devices, Sunnyvale, CA). Capsule cups are transferred to sensor chambers where cells are held in close apposition to a silicon sensor within a sensor chamber, which measures small changes in pH in the 15 microvolume of the sensor chamber. Low-buffered medium is pumped continuously across the cells at a rate of approximately 100 ~,1/min from one of two fluid reservoirs.
A selection valve determines which reservoir from which fluid is perfused onto the cells.
The Cytosensor~Microphysiometer generates a voltage signal, which is a 20 linear function of pH, every second. In order to measure acidification rates, flow to the sensor chamber containing the cells is periodically interrupted, allowing excreted acidic metabolites to build up in the extracellular fluid of the cells. Cells are maintained at 37 °C on a two-minute flow cycle with cells being perfused with media for ~0 seconds followed by 40 seconds in which the flow of media is stopped.
During 25 this 40-second interval, acidification rates are measured for a 30 sec interval. In this fashion, a single acidification rate is calculated every two min. The Cytosensor Microphysiometer device contains eight such sensor units, allowing for eight simultaneous experiments to be performed. Each unit is individually programmed utilizing a computer linked to the system.
3o GGH3 cells are initially equilibrated in the low-buffered MEM media for a period of 30-60 min in which basal acidification rates (measured as ~,V/sec), in the absence of any stimuli, are monitored. When the basal rate of acidification changes by less than ten percent over a period of twenty minutes, experiments are initiated.

Time course experiments are performed to determine the optimal time for agonist exposure prior'to acidification rate measurement and the duration of exposure needed to obtain peak acidification responses to various agonists. From these time course experiments, it has been determined that cells should be exposed to GnRH
peptide agonists at least one minute prior to collection of acidification rate data.
Peak acidification rates usually occur in the first two-rnin exposure cycle. When the effects of various inhibitors are measured, cells are pretreated for 20 min with test compound diluted in low-buffered MEM containing 1% DMSO final concentration prior to exposure of the cells for 4 min to a solution containing GnR_H_ or PMA at appropriate concentration in the presence of inhibitor.
Cyclic AMP Measurement.
The ability of various compounds to increase basal CAMP formation in GGH3 cells is assessed utilizing 96-well adenylyl cyclase flashplates purchased from New England Nuclear (NEN, Boston, MA). Cells (approximately 50,000 cells/well) are incubated with either forskolin (10 nM-10 ~, GnIZ_H_ (1 nM-1 pM) or GnRH-A
(0.1 nM-100 nM) in a total volume of 100 p1 on flashplates for 20 minutes at room temperature to assess for agonist activity. 100 p,1 of detection mix containing 125I-cAMP is added to quench reactions according to the manufacturer's instructions.
Plates are counted on a Packard TopCount after approximately two hours. Cyclic 2o AMP levels are determined from standard curves generated to non-radioactive cAMP
standards (10 nM-1 ~.
Data Analysis.
Cytosensor ° Microphysiometer data are normalized utilizing Cytosoft~
software (Molecular Devices, Sunnyvale, CA). ECSO values for agonists and TCSo values for inhibitors are generated utilizing PrismTM (version 2.01, GraphPad Software, San Diego, CA), a computer graphics and statistics program. Values for multiple experiments are presented as means ~ SE of at least three replicate experiments.
Effect of Compounds on lzSI-GnRH-A Binding to GGH~ Cells.
3o In order to assess the specific functionality, compounds were assessed for their ability to inhibit lzSZ-GnRH-A binding to GGH3 cells. The peptide ligands GnRH, GnRH-A, and Antide, but none of the tested compounds of the invention, blocked iasl-GnRH-A binding to these cells. Thus, the compounds of the invention are GnRH
antagonists.
Determination of Binding Inhibition Constants Using the assay described below, Ki values for compounds of the invention were determined.
Chemicals and Reagents.
GnRH (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), was purchased from Sachem (Torrance, CA). Cell Culture media was purchased from Sigma (St.
Louis, MO). Fetal bovine serum (FBS) was from Omega Scientific, Inc. (Tarzana, 1o CA). 6418 and penicillin/streptomycin were from Gemini (Calabasas, CA).
Newborn calf serum was from Summit Biotech (Fort Collins, CO). All other reagents were of the highest quality from standard sources.
Cell Culture.
HEK 293 cells stably transfected with mouse or human GnRH receptors as 1s described above were grown in Dulbecco's high-glucose, modified Eagle's medium (DMEM) supplemented with 0.2% 6418, 10% fetal bovine serum (FBS) and 100U1mL penicillin/streptomycin. GH3 cells stably transfected with the rat GnR_H_ receptor (GGH3) were provided by Dr. William Chin (Harvard Medical School, Boston, MA). These cells have been extensively characterized previously (Kaiser et 2o al., 1997). The cells were grown in low glucose DMEM containing: 100U/mL
penicillin/streptomycin, 0.6% 6418 and 10% heat-inactivated FBS.
Cell Membrane Preparation.
HEK 293 cells containing mouse or human receptors, or rat pituitaries (Pel Freez Biologicals, Rogers, AR) were homogenized in buffer A containing: 50 mM
2s Tris (pH 7.4), 0.32 M sucrose, 2 mM EGTA, 1 mM PMSF, 5 wg/ml aprotinen, 5 p,g/ml Pepstatin A, and 1 pg/ml leupeptin. Homogenized cells were centrifuged at 4°C at 20,000 x g for 25 minutes, re-suspended in buffer A and re-centrifuged at 4°C
at 20,000 x g for an additional 25 minutes. Total membrane protein was determined with a BCA kit (Pierce, Rockford, IL). Membranes were stored at -70°C
at a final 3o membrane protein concentration of approximately 5 mg/ml.
Radioli and d Preparation.
The radioiodinated agonist analog of GnRH, [des-Glyl°,D-Ala6)GnRH
ethylamide (l2sI-GnRH-A), was used as the radioligand. One ~g of GnRH-A
diluted in 0.5 M phosphate buffer (pH 7.4) was added to an Iodogen~-coated borosilicate glass tube (Pierce, Rockford, IL) containing 35 p1 of 0.05 M phosphate buffer (pH
7.4-7.6) and 1 mCi of Na[lasl]. The reaction mixture was vortexed and incubated for 1 minute at room temperature. After one minute, the mixture was vortexed and allowed to incubate for an additional minute. 2 ml of 0.5 M acetic acid/1% BSA
was added to the reaction tube and the mixture was added to a C18 Sep-Pak cartridge.
The cartridge was washed with subsequent washes of 5 ml H20 and 5 ml 0.5 M
acetic acid and then eluted with 5 x 1 ml of 60%CH3CN/40% 0.5 M acetic acid. The eluate was diluted with 3x volume of HPLC buffer A (0.1% TFA in H20) and loaded onto a 1o C18 column. The iodinated product was eluted over 20-25 min with a gradient of 25-100% CH3CN containing 0.1% TFA. The radioactive fractions (750 p,l/fraction) were collected into clean polypropylene tubes containing 100 ~,1 of 10% BSA.
Fractions were assessed for biological activity by radiolig and binding. Specific activity of the radioligand was approximately 2200 Ci/mmol.
Radioli~and Binding_Assays.
Membranes were diluted to 0.01-0.5 mg/ml (depending upon the species of receptor) with assay buffer containing 50 mM HEPES (pH 7.4), 1 mM EDTA, 2.5 mM MgCl2, and 0.1% BSA. Membranes (diluted to utilize similar receptor numbers between assays) were incubated with approximately 0.04-0.06 nM lasl-GnRH-A in 2o the presence or absence of competing agents (0.1- 10,000 nM) in a total volume of 200 ~,1 in 96-well polypropylene.plales for 1 hour at room temperature. Assays were stopped by rapid filtration onto 96-well GF/C filters soaked in 0.1 %
polyethylenimine (PEI) utilizing a Packard 96-well cell harvester. Filters were washed three times with ice-cold PBS (50 mM NaP04, 0.9% NaCI, 2 mM MgCl2, and 0.02% NaN3, pH 7.4).
2s 35 ~,1 of scintillation cocktail was added to each filter well and filters were counted on a Packard Topcount. Control dose-response curves were generated to GnRH (0.1 nM-100 nM] in each competition binding experiment. Binding inhibition constants (K;) for the GnRH agents were calculated and are provided in Table 2 below. Ki values were calculated from IC50 values according to Cheng et al., Biochemical Pharmacol.
so 22: 3099-3108, 1973.
IC~n K; = ~1 + [ligand]
Kd of ligand Table 2 K; for GnRH Agents:
Tnhibition Binding of lzsI-GnRH-A to GnRH Receptors of Various Species Example GnRH ReceptorK; (nNn No.

A1 Human >10000 Mouse ND

Rat ND

A2 Human 180 Mouse 87 Rat 69 A3 Human 42 Mouse 16 Rat 14 A4 Human 189 Mouse 101 Rat 84 AS ~ Human 42 Mouse 134 Rat 46 A6 Human 455 Mouse ND

Rat ND

A7 Human 244 Mouse 435 Rat 191 A8 Human 3 Mouse 2 Rat 4 A9 Human 2 Mouse 3 Rat 11 A10 Human 649 Example GnRH ReceptorK; (n1V>) No.

Mouse ND

Rat ND

All Human 460 Mouse ND

Rat ND

A12 Human 2716 Mouse ND

Rat ND

A13 Human 78 Mouse 2S

Rat 80 A14 Hurnan 844 Mouse ND , Rat ND

A15 Human 2 Mouse 2 Rat 2 A16 Human 47S

Mouse ND

Rat ND

A17 Human 1S3 Mouse 74 Rat 126 Bl Human 0.42 Mouse 1 Rat 4 B2 Human >1000 Mouse ND

Rat ND

B3 Human 3 Mouse 2 Example GnRH ReceptorK; (nlVn No.

Rat 7 B4 Human 103 Mouse 157 Rat 563 BS Human 14 Mouse ND

Rat 14 B6 Human 999 Mouse ND

Rat ND

B7 Human 561 Mouse ND

Rat ND

B8 Human >10000 Mouse ND

Rat ND

B9 Human ~0 Mouse 69 Rat 203 B10 I4uman 4 Mouse 6 Rat 5 Bll Human 403 Mouse ND

Rat ND

B12 Human 520 Mouse ND

Rat ND

B13 Human >10000 Mouse ND

Rat ND

Example GnRH ReceptorK; (nlV~
No.

B14 Human 5 Mouse 29 Rat 32 B15 Human 11 Mouse 7 Rat 10 B16 Human 2 Mouse 2 Rat 4 B17 Human 251 Mouse ND

Rat ND

B18 Human 6 Mouse 3 Rat 4 B19 Human 138 Mouse 84 Rat 72 B20 Human 4906 Mouse ND

Rat ND

B21 Human 14 Mouse 11 Rat 24 B22 Human 16 Mouse 20 Rat 42 B23 Human 5 Mouse 6 Rat 13 B24 Human 457 Example GnRH ReceptorK; (nlVn No.

Mouse ND

Rat ND

B25 Human 1180 Mouse ND

Rat ND

B26 Human 1.4 Mouse 1.1 Rat 1.7 B27 Human 0.9 Mouse ND

Rat 0.7 B28 Human 4 Mouse ND ~

Rat 1 B29 Human 1 Mouse ND

Rat 0.69 B30 Human 2 Mouse 1.2 Rat 1 B31 Human 2 Mouse 0.74 Rat 1 B32 Human 2 Mouse 2 Rat 5 B33 Human 6 Mouse 7 Rat 9 B34 Human 0.2 Mouse ND

Example GnRH ReceptorK; (nlV~
No.

Rat 0.3 B35 Human 3 Mouse 6 Rat 3 B36 Human 0.18 Mouse 0.26 Rat 0.43 B37 Human 5 Mouse 4 Rat 4 B38 Human 7 Mouse 6 Rat 9 B39 Human 2 Mouse 2 Rat 3 B40 Human 0.2 Mouse ND

Rat 0.4 B41 I~uman ND

Mouse ND

Rat ND

B42 Human 31 Mouse 21 Rat 96 B43 Human 63 Mouse 411 Rat 711 B44 Human 1362 Mouse ND

Rat ND

Example GnRH ReceptorK; (nlVn No.

B45 Human 1 Mouse 0.96 Rat Z

B46 Human 0.5 Mouse ND

Rat 0.6 B47 Human 1402 Mouse ND

Rat ND

B48 Human 11 Mouse ND

Rat 15 B49 Human 4 Mouse 4 Rat 16 B50 Human I

Mouse 3 Rat 2 B51 Human 3 Mouse 0.13 Rat 6 B52 Human 0.1 Mouse 0.18 Rat 0.13 B53 Human 10 Mouse ND

Rat 8 B54 Human 13 Mouse ND

Rat 7 B55 Human 2 Example GnRH ReceptorK; (nM~
No.

Mouse ND

Rat 3 B56 Human 2 Mouse ND

Rat 3 B57 Human 0.96 Mouse ND

Rat 0.24 BS8 Human 2 Mouse 0.93 Rat 2 B59 Human 3 Mouse . 6.4 $

. Rat 2 B60 Human 0.67 Mouse 2 Rat 0.8 B61 Human 3 Mouse ND

Rat 0.34 B62 Human 0.58 Mouse 0.8 Rat 0.7 B63 Human 3 Mouse 2 Rat 3 B64 Human 25 Mouse 21 Rat 29 B65 Human 0.41 Mouse 0.4 Example GnRH ReceptorK; (nN~
No.

Rat 0.33 B66 Human 3 Mouse 2 Rat 5 B67 Human 350 Mouse ND

Rat ND

B68 Human 0.86 Mouse 1 Rat 1 B69 Human 5 Mouse 3 Rat 7 B70 Human 1I

Mouse ND

Rat 13 B71 Human 11 Mouse ND

Rat 38 B72 vIuman 5 Mouse 3 Rat 5 B73 Human 2 Mouse ND

Rat 1 B74 Human 2117 Mouse ND

Rat ND

B75 Human 3096 Mouse ND

Rat ND

Example GnRH ReceptorK; (nlVn No.

B76 Human 1909 Mouse ND

Rat ND

B77 Human 16 Mouse 30 Rat 34 B78 Human 1010 Mouse ND

Rat ND

B79 Human 29 Mouse 7 Rat 33 B80 Human ND

Mouse ND

Rat ND

B81 Human 9 Mouse 2 Rat 4 B82 Human 29 Mouse 25 Rat 34 B83 Human 5 Mouse 10 Rat 13 B84 Human 10 Mouse 6 Rat 5 B85 Human 1401 Mouse ND

Rat ND

B86 Human 196 E$ample GnRH ReceptorK; (nlV~
No.

Mouse ND

Rat ND

B87 Human 580 Mouse ND

Rat ND

B88 Human 4 Mouse ND

Rat 6 B89 Human 0.24 Mouse 0.22 Rat 0.14 B90 Human 0.42 Mouse ND d Rat 0.52 B91 Human 0.42 Mouse 0.97 Rat 0.71 B92 Human 0.96 Mouse 2 Rat 3 B93 Human 24 Mouse 51 Rat 39 B94 Human 102 Mouse 75 Rat 154 B95 Human >10000 Mouse ND

Rat ND

B96 Human 987 Mouse ND

Example GnRH ReceptorK; (nlVn No.

Rat ND

B97 Human 53 Mouse 18 Rat 65 B98 Human 2751 Mouse ND

Rat ND

B99 Human 1268 Mouse ND

Rat ND

B100 Human 261 Mouse 22 Rat 26 B101 Human 11 Mouse 4 Rat 3 8102 Human 372 Mouse ND

Rat ND

B103 I4uman ND

Mouse ND

Rat ND

B104 Human 2 Mouse 3 Rat 4 B10S Human 1533 Mouse ND

Rat ND

B106 Human 478 Mouse ND

Rat ND

Example GnRli ReceptorK; (nlVn No.

B107 Human 94 Mouse 43 Rat 41 B108 Human >10000 Mouse ND

Rat ND

B109 Human 2804 Mouse ND

Rat ND

B110 Human 1 Mouse 0.8 Rat 1 Blll Human 55 Mouse 13 Rat 16 B112 Human 5 Mouse ND

Rat 3 B113 Human 703 Mouse ND

Rat ND

B114 Human 7 Mouse ND

Rat 5 B115 ~ Human ND

Mouse ND

Rat ND

B116 Human 0.84 Mouse ND

Rat 0.67 B117 Human 6 Example GnRH ReceptorK; (nlV~
No.

Mouse ND

Rat 2 B118 Human 0.57 Mouse ND

Rat 1.1 8119 Human 3 Mouse ND

Rat 3 B120 Human 0.5 Mouse ND

Rat 1 B121 Human 2 Mouse ND ~

Rat 0.73 B122 Human 1 Mouse ND

Rat 0.57 B123 Human 6.6 Mouse ND

Rat 4 B124 Human 1 Mouse ND

Rat 0.57 B125 Human 1 Mouse ND

Rat 0.49 8126 Human 0.72 Mouse ND

Rat 0.53 B127 Human 0.92 Mouse ND

Example GnRH ReceptorK; (nlVn No.

Rat 0.47 8128 Human 0.56 Mouse ND

Rat 0.23 B129 Human 0.70 Mouse ND

Rat 0.62 B130 Human 5 Mouse ND

Rat 4 8131 Human 1 Mouse ND

Rat 2 8132 Human 0.3 7 Mouse ND

Rat 0.47 8133 Human 4 Mouse ND

Rat 4 B134 ~I4uman 0.79 Mouse ND

Rat 0.5 B135 Human 1 Mouse ND

Rat 1 B136 Human 0.21 Mouse 0.35 Rat 0.6 B137 Human 0.7 Mouse ND

Rat 0.22 Example GnRH ReceptorK; (nNn No.

B138 Human 4.7 Mouse ND

Rat 3.7 B139 Human 9.2 Mouse ND

Rat ND

B140 Human 0.66 Mouse 0.35 Rat 0.25 B141 Human >1000 Mouse ND

Rat ND

B142 Human 73 Mouse ND

Rat 32 B143 Human 10 Mouse ND

Rat 21 8144 Human 3093 Mouse ND

Rat ND

B145 Human 650 Mouse ND

Rat ND

B146 Human 28 Mouse ND

Rat 18 B147 Human 3 Mouse ND

Rat 3 B148 Human 27 EaampIe GnRH ReceptorK; (nll~
No.

Mouse ND

Rat ND~

B149 Human 198 Mouse ND

Rat ND

B150 Human 13 Mouse 14 Rat 11 B151 Human ND

Mouse ND

Rat ND

B152 Human 21 Mouse ND , Rat 170 B153 Human 4.9 Mouse ND

Rat 2 B154 Human ND

Mouse ND

Rat ND

B155 Human ND

Mouse ND

Rat ND

C1 Human 2 Mouse 1 Rat 4 C2 Human 7 Mouse 4 Rat 4 C3 Human 3669 Mouse ND

Example GnRH ReceptorK; (nlV~
No.

Rat ND

C4 Human 25 Mouse 51 Rat 76 CS Human 17 Mouse 11 Rat 27 C6 Human >10000 Mouse ND

Rat ND

C7 Human 12 Mouse 26 Rat 51 C8 Human 51 Mouse 31 Rat 3 8 C9 Human > 10000 Mouse ND

Rat ND

C10 -Human 1 Mouse 1 Rat 2 C1I Human 220 Mouse 154 Rat 198 C12 Human 12 Mouse 3 Rat 11 C13 Human 15 Mouse 5 Rat 17 Example GnRH ReceptorK; (nlVn No.

C14 Human 693 Mouse ND

Rat ND

C15 Human 11 Mouse 5 Rat 15 CI6 Human 450 Mouse ND

Rat ND

C17 Human 14 Mouse 75 Rat 154 C18 Human 5 Mouse S

Rat 7 C19 Human 59 Mouse 36 Rat 16 C20 Human 10 Mouse 29 Rat 15 C21 Human 29 Mouse 13 Rat 11 C22 Human 74 Mouse 97 Rat 142 C23 Human 4 Mouse 3 Rat 0.34 Dl Human >10000 Example GnRH ReceptorK; (nlV1) No.

Mouse ND

Rat ND

D2 Human 841 Mouse ND

Rat ND

D3 Human 3747 Mouse ND

Rat ND

Fl Human 31 Mouse 36 Rat 65 F2 Human 6430 Mouse ND , Rat ND

F3 Human 380 Mouse ND

Rat ND

Hl Human 27 Mouse 14 Rat 115 H2 Human 7 Mouse 20 Rat 207 Il Human >10000 Mouse ND

Rat ND

I2 Human 6540 Mouse ND

Rat ND

I3 Human 4910 Mouse ND

E$ample GnRH ReceptorI~; (nlV1) No.

Rat ND

I4 Human 8 Mouse 8 Rat 6 IS Human 455 Mouse ND

Rat ND

I6 Human >10000 Mouse ND

Rat ND

I7 Human 3654 Mouse ND

Rat ND

I8 Human 7379 Mouse ND

Rat ND

I9 Human >10000 Mouse ND

Rat ND

I10 ~~uman >10000 Mouse ND

Rat ND

Ill Human 3226 Mouse ND

Rat ND

I12 Human >10000 Mouse ND

Rat ND

I13 Human >10000 Mouse ND

Rat ND

Ezample GnRH ReceptorK; (nlV1) No.

I14 Human 2474 Mouse ND

Rat ND

I15 Human 2740 Mouse ND

Rat ND

I16 Human 2204 Mouse ND

Rat ND

I17 Human >10000 Mouse ND

Rat ND

I18 Human >10000 Mouse ND

Rat ND

I19 ~ Human 8006 Mouse ND

Rat ND

IZO Human >10000 Mouse ND

Rat ND

I21 Human >10000 Mouse ND

Rat ND

I22 Human >10000 Mouse ND

Rat ND

I23 Human 1313 Mouse ND

Rat ND

I24 Human 88 Example GnRH ReceptorK; (nlV1) No.

Mouse 64 Rat 76 I25 Human 992 Mouse ND

Rat ND

I26 Human 113 Mouse 67 Rat 93 I28 Human 12361 Mouse ND

Rat ND

I29 Human 3201 Mouse ND ~

Rat ND

I30 Human >10000 Mouse ND

Rat ND

I31 Human >10000 Mouse ND

Rat ND

I32 Human 3700 Mouse ND

Rat ND

I33 Human 8400 Mouse ND

Rat ND

I34 Human 99 Mouse 24 Rat 61 I35 Human 44 Mouse 16 Example GnRH ReceptorK; (nlV1) No.

Rat 29 I36 Human 6 Mouse 9 Rat 9 I37 Human 13 Mouse 6 Rat 10 I38 Human 6 Mouse 4 Rat 9 I39 Human ND

Mouse ND

Rat ND

I40 Human ND

Mouse ND

Rat ND

I41 Human ND

Mouse ND

Rat ND

I42 Human 6870 Mouse ND

Rat ND

I43 Human >1000 Mouse ND

Rat ND

I44 Human >1000 Mouse ND

Rat ND

Jl Human > 1000 Mouse ND

Rat ND

Example GnRH ReceptorK; (nIV~
No.

J2 Human >1000 Mouse ND

Rat ND

J3 Human >1000 Mouse ND

Rat ND

J4 Human > 1000 Mouse ND

Rat ND

K1 Human 1620 Mouse ND

Rat ND

ND = not determined Micr~hysiometry.
GGH3 cells were seeded~in low-buffered minimal essential media (MEM, Sigma) containing 25 mM NaCI and 0.1°1o BSA at a density of 500,000 cellslcapsule onto the polycarbonate membrane (3 pxn porosity) of cell capsule cups (Molecular Devices, Sunnyvale, CA). Capsule cups were transferred to sensor chambers where cells were held in close apposition to a silicon sensor within a sensor chamber, which measures small changes in pH in the microvolume of the sensor chamber. Low-no buffered medium was pumped continuously across the cells at a rate of approximately 100 ul/min from one of two fluid reservoirs. A selection valve determined which reservoir from which fluid was perifused onto the cells.
The Cytosensor~Microphysiometer generates a voltage signal, which is a linear function of pH, every second. In order to measure acidification rates, flow to 1s the sensor chamber containing the cells was periodically interrupted, allowing for excreted acidic metabolites to build up in the extracellular fluid of the cells. In these experiments, cells were maintained at 37 °C on a two-minute flow cycle with cells being perfused with media for 80 seconds followed by 40 seconds in which the flow of media was stopped. During this 40-second interval, acidification rates were 2o measured for a 30-second interval. In this fashion, a single acidification rate was calculated every two minutes. The Cytosensor~ Microphysiometer unit contains eight such sensor units, allowing for eight simultaneous experiments to be performed. Each unit was individually programmed utilizing a computer linked to the system.
GGH3 cells were initially equilibrated in the low-buffered MEM media for a period of 30-60 minutes in which basal acidification rates (measured as uV/sec), in the absence of any stimuli, were monitored. When the basal rate of acidification changed by less than ten percent over a period of twenty minutes, experiments were initiated. Cells were pretreated for 20 minutes with cell media containing vehicle (1%
DMSO) or test compounds at various concentrations (in 1% DMSO final 1o concentration) prior to stimulation with CmRH at various concentrations.
Total Inositol Phosphates Measurement.
Approximately 200,000 GGH3 cells or 293 cells containing human GnRH
receptors were plated onto 24-well tissue culture plates using DMEM media. The following day, cells were loaded with [3H] myoinositol (0.5 Ci/ml) for 16-1 ~
hours in 15 inositol-free medium. The medium was aspirated and the cells rinsed with serum-free DMEM. Cells were pretreated with various compounds (dissolved in I% DMSO
final concentration) for 30 minutes and were then stimulated for 45 minutes with (inRH (0.1 nM-1 ~M) dissolved in DMEM media in a total volume of 1 mL
containing IO mM LiCI at 37°C. The media was replaced with 1 mL ice-cold 10 mM
2o formic acid, which stopped the reaction and also served to extract cellular lipids.
Inositol phosphates were separated by ion-exchange chromatography on Dowex columns, which were washed with 2.5 mL of 10 mM myoinositol and 10 mM formic acid. The columns were then washed with 5 mL of 60 mM sodium formate and 5 mM
borax, and total inositol phosphates were eluted with 5 mL of 1 M ammonium 2s formate, 0.1 M formic acid. The column eluates were added to liquid scintillation vials containing 15 ml of scintillation cocktail and were counted by liquid scintillation counting.
Pharmacokinetics and Metabolism:
Pharmacokinetics.
3o Rats (male or female, 200-225 g) were prepared with indwelling jugular vein cannula as described by Harms et al., Applied Playsiol. 36:391-398 (1974), and allowed to recover overnight with free access to the standard vivarium chow and water. The compounds were administered to female rats at 5 mg/lcg i.v. and 10 mg/kg p.o. as solutions in 10% DMSO+10% cremophor+80% saline or 10%
cremophor+90% saline. The male rats were dosed orally at 50 mg/kg in the vehicles specified in Table 3. The blood samples were withdrawn at specific times, plasma was immediately separated and compound extracted with ethyl acetate. The samples were analyzed by LC-MS using 30-90% gradient of ACN in 50 mM ammonium acetate.
The pharmacokinetic parameters were calculated using WinNonlin software (Scientific Consulting Inc.). The bioavailability was calculated as AUCp.o./AUCi.v., where AUCp.o. and AUC i.v. are areas under the plasma concentration-time curve 1o after oral and i.v. administration, respectively.
In vitro metabolism.
Human, rat, dog, and monkey liver microsomes were isolated by differential centrifugation. Specimens of human liver were obtained from the International Institute for the Advancement of Medicine (Scranton, PA). The disappearance of the 1s parent compound was studied in a mixture containing 5 uM compound, 0.5 mg/ml microsomal protein, and 2 mM NADPH in 50 mM I~ Phosphate buffer, pH 7.4.
Samples were incubated for 30 minutes at 37°C. The reaction was terminated by the addition of acetonitrile and compounds analyzed by LC-MS as described above.

Table 3 Compound No. Human M F Rat Dog MonkeyH Solubility a a S
I m A
a a a a t R
a t rem. % TvzCm~T~ Faa% TvzCm~ Tm~FØplasma% % columnug/ml 5' rem. hrpM hr rem. hrwM hr % rem.rem. a pH2 30' ' 5' remain30' 30' pH6.5 30' 30' A2 ND 40 NDNDND ND ND ND 280.63.340.523%'ND ND ND ND NDND

A8 ND 30 NDNDND ND ND ND 682.11 1 7/z 76 0 ND >30 ND0.3 , A9 ND 36 NDNDND ND ND ND 862 0.2 0.54%' 9 ND ND 18 ND0.7 Bl ND 5070 16ND0.31 ND ND 893.21.7 1 41%'79 8 1 12 NDQ.9 B10 ND 23 NDNDND ND ND ND 78NDND NDND 100 0 ND 3 ND1.9 Bll ND 24 NDNDND ND ND ND NDNDND NDND ND ND ND ND NDND

B14 ND 30 NDNDND ND ND ND 574 ND ND** 1 1 ND 2 ND3.5 B3 ND 24 1 2.81 1 15%'ND 382.94 3 74%'100 1 0 11 ND0.8 B7 ND 60 NDNDND ND ND ND NDNDND NDND ND ND Nb ND NDND

B75 ND 80 NDNDND ND ND ND NDNbND NDND ND ND ND ND NDND

B79 ND 57 NDNDND ND ND ND 742 1 1 10%zND ND ND ND NDND

C10 ND 32 NDNDND ND ND ND 74NDND NDND 92 ND ND 15 ND0.7 C18 ND 5763 7 ND1.51 ND ND 881.71 1 21%z82 4 ND >30 ND0.5 C23 88 4255 152.50.41 17%z95 871.61.5 1 33%z76 0 ND 26 ND5.9 C7 ND 16 NDNDND ND ND ND 34NDND NDND 100 5 ND ND ND0.4 CS ND 25 NDNDND ND ND ND ND~NDND NDND ND ND ND ND NDND

D3 ND 49 NDNDND ND ND Nb NDNDND NDND ND ND ND ND NDND

H2 ND 100 NDNDND ND ND ND ND1.50.1 1 0.1%'100 ND ND ND ND0.4 Compound No. HumanM F Rat Dog MonkeyH Solubility a a S
I m A
a a a a t R
a t rem. % Tz,z FRa% Tl,zCm~ Tm~ plasma% % columnlZg/ml rem. Cm~ rem. FP,, rem.rem.
Tm~

5' 30'' 30'hrIcMhr 5' 30'hr~M hr % 30' 30' a pH2pH6.5 remain B101 ND 39ND 3 NDND ND ND ND 601.81.2 0.529%'100 1 1 2 NDND

B104 ND 37ND 11NDND ND ND ND 69NDND NDND ND 45 1 3 5.84.4 B140 ND 49ND 1 NDND ND ND ND 871.10.4 1 7%'zND 2 1 22 0.70.7 B16 ND 6080 7 NDND ND ND ND 862.52.3 2 37%'z84 10 3 >30 1.20.4 B18 ND 7272 13NDND ND ND ND 862.62 2 17%'388 11 1 >30 ND0.8 B21 ND 93ND 31NDND ND ND ND 842.52.4 I 8/' 100 25 7 >30 NDND

B22 ND 58ND 11NDND ND ND ND 941.7L8 1 19%'15 32 1 >30 NDND

B30 ND 75ND NDNDND ND ND ND 953.20.5 0.535/'100 45 0 6 ND1.4 B31 ND 8573 18ND0.51 ND ND 923.40.9 1 34%'100 36 2 5 ND0.7 B32 ND 31ND 0 NDND ND ND ND 741.60.3 0.258/' 7 1 1 15 0.91.4 B33 ND 73ND 1 NDND ND ND ND 82NDND NDND 42 3 1 23 ND0.8 B35 ND 6764 32ND1.12 ND ND 875.30.9 3 31 100 63 2 7 ND1 %"

B36 ND 6766 191.10.2I 8%$ND 762.21.4 0.527%'100 43 1 6 ND1 B37 ND 6560 12ND1.22 ND ND 872.51.8 2 52%'3100 17 0 37 ND0.5 B38 ND 51ND 31ND4.52 ND ND 743.83.7 2 46/'I00 45 3 26 ND0.9 B39 ND 60ND 1 ND1.33 ND ND 1002.50.8 2 17%'z100 14 1 >30 ND0.7 B62 ND 28ND 8 1.3<0.03ND <I%'ND 831.71.4 1 24%'100 2 2 14 ND0.4 B63 ND 7661 13NDND ND ND ND 852.80.7 1 32%';100 74 11 4 ND2.8 B65 ND 62 NDNDND ND ND ND 892.40.351 50%'100 6 1 10 ND0.9 B66 ND 7080 21NDND ND ND ND 802.80.8 2 35%'"100 18 3 25 ND0.8 B68 ND 41ND 4 NDND ND ND ND 702.30.6 2 15%z'1 10 0 6 7.22.2 B72 "ND83ND 0 NDND ND ND ND 493.4LI 2 65%z'100 43 0 3 ND1.8 B81 ND 90ND 12NDND ND ND ND 812.72.7 1 57/'100 20 1 14 ND0.8 B83 ND 37ND 1 NDND ND ND ND 823.60.3 1 5%' 100 4 I 13 ND0.8 B84 ND 60ND 13ND0.11 ND ND 861.70.6 1 47%'''100 18 2 5 ND2.1 B91 ND 62ND 11NDND ND ND ND 791.90.9 1 14%'100 2 5 8 0.30.4 B92 ND 58ND 3 NDND ND ND ND 681.10.7 1 10%z21 18 1 >30 NDND

C12 ND 55ND 13NDND ND ND ND 593.54.6 0.534%'ND 20 0 3 7 ND

C13 ND 63ND 3 NDND ND ND ND 50NDND NDND 46 ND ND 8 0.3ND

C17 ND 6479 214.10.41 15%'ND 772.94.4 1 75%'80 47 1 2 0.9LS

C2 ND 8077 30ND3.22 ND ND 852.91.7 1 57%'24 65 2 5 ND0.7 C5 ND 86 NDNDND ND ND ND NDNDND NDND ND ND 25 ~ ND
ND

Table 3 (cont'd.) Compound No. Human M F Rat Dog MonkeyH Solubility . a a S
I m A
a a a a t R
a t rem. % TvzCm~T~ Fa0.% TvzCm~Tm~Fp,0.plasma% % columnpglml rem. rem. rem.rem. ' 5' 30'' 30'hr1tMhr S' 30'hr plvlhr % 30' 30' a pH2pH6.5 remain B53 ND 81 13NDND ND ND ND 50ND ND ND ND ND 8 26 Nb NDND

A15 ND 52 3 NDND ND ND ND 82ND ND ND ND ND 1 0 12 ND0.6 B114 ND 51 25NDND ND ND ND 82ND ND ND ND ND 22 0 ND ND1.5 B143 ND 69 17NDND ND ND ND 70ND ND ND ND ND 11 4 4 ND0.3 B147 ND 57 19NDND ND ND ND 89ND ND ND ND ND 35 11 ND ND0.4 B41 ND 57 29ND3.61 ND ND 793.64 2 64%'ND 58 1 8 NDI

B45 ND ND NDNDND ND ND ND NDND ND ND ND ND ND ND ND ND1.5 B49 ND 59 61NDND ND ND ND 952.62.31 17%'83 63 0 >30 ND0.5 BSO ND 50 70NDND ND ND ND 822.25 2 15%'100 77 0 >30 ND0.5 B51 ND 86 2 NDND ND ND ND SO2.30.21 4%'94 27 1 7 ND0.6 BS2 ND 57 43ND0.93 ND ND 906.60.42 27%'100 33 0 4 ND8 B54 ND 38 1 NDND ND ND ND 77ND ND ND ND ND 25 2 ND ND0.5 B55 ND 75 20NDND ND ND ND 60ND ND ND ND ND 12 30 >10 ND4.2 B56 ND 57 54NDND ND ND ND 88ND ND ND ND ND 31 0 >20 ND2.8 B57 ND 76 24ND4.87 ND ND 61>101.25 46%'100 33 48 >20 ND>I5 B61 ND 86 15ND2.37 ND ND 436.20.75 34/100 13 54 5 ND12 B64 ND 69 0 NDND ND ND ND 71ND ND ND ND ND 0 0 0.9 ND7 B69 ND 80 6 NDND ND ND ND 1002.45.21 53%'ND 75 1 4 ND2.5 B71 ND 72 23NDND ND ND ND 76ND ND ND ND ND 25 7 >10 ND0.4 B88 ND 74 46NDND ND ND ND 8IND ND ND ND ND 54 20 14 ND0.4 C15 ND 59 16ND3.23 ND ND 892 1.70.531/'ND 52 0 2 NDND

C20 ND 28 0 NDND ND ND ND 171 <0.1ND <1/'0 1 1 5 ND4,5 136 ND 26 0 NDND ND ND ND 823.20.40.520/'100 0 0 3 ND4 I37 ND 66 NDNDND ND ND ND 893.40.71 25/'ND ND ND 21 ND0.8 I38 ND 82 17NDND ND ND ND 822.10.92 20%'24 7 2 8 ND1 T4 ND 68 31NDND ND ND ND 893.10.72 21%'81 30 1 10 ND0.2 Table 3 (cont'd.) Compound No. Human M F Rat Dog MonkeyH Solubility a a S
1 m A
a a a a t R
a t rem. % T1,2Cm~Tm~FP.,% TvaCm~ Tm~Fp,,plasma% % columnpg/ml rem. rem. rem.rem.

5' 30'' 30'hrpM hr 5' 30'hr~M hr % 30' 30' a pH2pH6.5 remain Bil2 ND 73 11 NDND ND ND ND 51NDND ND ND ND 15 18 ND NDND

B116 ND 78 63 NDND ND ND ND 100NDND ND ND 100 33 0 >30 ND1.6 BII7 ND 56 9 NDND ND ND ND 59NDND ND ND ND 5 0 2 ND>15 B118 ND 60 31 NDND ND ND ND 845.90.3 3 8/'100 15 1 >4 ND3.8 BI19 ND 72 80 NDND ND ND ND 962.91.2 1 11/'95 82 ND >30 ND0.5 B120 ND 51 13 NDND ND ND ND 571.81 1 23%'100 12' 1 >4 ND10 BI21 ND 71 29 NDND ND ND ND 645.20.9 7 45%'86 36 1 >30 ND9 B123' ND 12 0 NDND ND ND ND 0 NDND ND ND ND 4 0 ND NDND

B124 ND 95 76 NDND ND ND ND 774.60.9 3 35%1ND 65 59 5 NDND

BI32 ND 86 83 NDND ND ND ND 867.90.6 3 31%'ND 58 51 7 NDND

B89 ND 99 40 ND2.65 ND ND 788.90.7 7 31%'100 44 55 >10 ND50 B90 ND 91 65 NDND ND ND ND 80NDI ND ND ~ I ~ I ~ ~

Table 3 Notes:
' 10 mg/kg as 5 mg/ml solution in 10% DMSO 10% cremophor 80% saline 2 IO mg/kg as 5 mg/ml solution in 10% cremophor 90% saline ' SOmg/kg as 25mg/ml solution in 50%Labraso150%H20(Cmax-l.4uM,Tmax-lhras100mg/ml inLabrasol;Cmax<O.OSuMas25mg/ml in0.5%CMC) 4 50 mg/kg as 25 mg/ml solution in 50%Labrasol 50%H20 (Cmax - 0.04uM, Tmax -2hr as 25 mg/ml in 0.5%CMC) s 50 mg/kg as 50 mg~ml solution in 50%Labrasol 50%H20 (Cmax - 0.6uM, Tmax -lbr as 100 mg/ml in PEG400;
Cmax - 0.6uM, Tmax - Shr as 100mg/ml in PG; Cmax - 0.3uM Tmax - 3hr as 25 mg/ml in 0.5%CMC) 6 50 mg/kg as 25 mgJml solution in 50%Labrasol 50%H20 (Cmax - O.IuM, Tmax -lhr as 100mg/ml in Labrasol;
Cmax<O,luM as 100mg/ml in PEG400 or 25 mg/ml in 0.5%CMC) ' S0 mg/kg as 25 mg/ml solution in 50%Labrasol 50%H20 (Cmax - 0.2uM, Tmax -Shr as 100 mg/ml in PEG400;
Cmax - 0.4uM, Tmax - Shr as 25 mg/ml solution in 0.5%CMC) $ 20 mg/kg as 10 mg/ml solution in 50% Labrasol 50% H20 (at SOmg/kg dose: Cmax -O.luM Tmax - 2hr as 25 mg/ml in 50%Labrasol 50%H20; Cmax<O.OSuM as 100mgJm1 in PEG400 or 25 mg/ml in 0.5%CMC) 0 20 mg/kg as 10 mg/ml solution in 10% DMSO 10% cremophor 80% saline (when given as 40 mg/ml in PEG400 or PG, FP,°_ was 0%) '° 10 mg/lcg as 5 mg/ml solution in 10% DMSO 20% cremophor 70% saline " 6 mg/kg as 3 mg/ml solution in 10% DMSO 10% cremophor 80% saline 'z 10 mg/kg as 5 mg/ml solution in 30% Labrasol 70% saline "10 mg/kg as 5 mg/ml solution in 50% Labrasol 50% H20 '45 mg/kg as 2.5 mg/ml solution in 10% DMSO 10% cremophor 80% saline 's 50 mg/kg as 50 mg/ml solution in 50%Labrasol 50%H20 (Cmax - 3.4uM, Tmax -lhr as 25 mg/ml in 0.5% CMC;
Cmax - 0.4uM, Tmax - 2hr as 100 mgJml in PEG400) '620 mg/kg as 10 mg/ml solution in 10% DMSO 10% cremophor 80% saline (could not dissolve it in PEG, Labrasol or PG at 50 mg/ml) "50 mg/kg as 25 mg/ml solution in 50%Labrasol 50%H20 (Cmax - 0.07uM, Tmax -3hr as 25 mg/ml in 0.5% CMC) 'B 50 mg/lcg as 100 mg/ml in PEG400 or as 25 mg/ml in 0.5% CMC (Cmax - 0.2uM, Tmax - 0.25 hr as 50 mg/ml solution in 50%Labrasol 50%H20) '9 50 mg/kg as 50 mg/ml solution in 50%habrasol 50%H20 (Cmax - 0.9uM Tmax -lhr as 100 mg/ml in PEG400;
Cmax - 0.9uM Tmax - O.Shr as 100 mg/ml in PG; Cmax - 0.4uM Tmax- lhr as 25 mg/ml in 0.5%CMC) zo 50 mg/Icg as 50 mg/ml solution in 50%Labrasol 50%H20 (Cmax - O.SuM; Tmax -3hr as 25 mg/ml in 0.5%CMC) z' S0 mg/kg as 50 mg/ml solution in Labrasol/H201/1 (Cmax - I .2uM, Tmax - 7hr as 100 mg/ml in PEG400;
Cmax - 0.7uM, Tmax - 3hr as 25 mg/ml in 0.5% CMC; Cmax -1 uM, Tmax - 7hr as I
OOmg/ml in PG) zz 50 mg/kg as 25 mg/mI suspention in 0.5%CMC (Cmax - 3.3uM, Tmax - Shr as 50 mg/ml in Labrasol/H201/1) z' S0 mg/kg as 25mg/ml solution in Labrasol/H201/1 (Cmax-2.SuM, Tmax-7hr as 100 mg/ml in PG;
Cmax-3.6uM, Tmax-7hr as 25 mg/ml in 0.5%CMC) z° 50 mp~kg as 50 mg/ml in 50%Labrasol 50%H20 (Cmax -l.9uM, Tmax - Shr as 25 mg/ml in 1%CMC) In Tlivo Tests Materials and Methods:
Adult male Sprague-Dawley rats were purchased from Harlan Sprague Dawley (San Diego). Animals were housed two per cage and maintained in a temperature- controlled room (22 ~ 2°C) with a photoperiod of 12 hours light/12 hours dark (lights on at 0600 hours). Rat chow (Teklad LM-485 rat diet, Madison, WI) and tap water were provided ad libitum.
Animal models to assess activity of GnR_u_ anta onists:
Model # 1: Castrated Male Rat Model 1o Surgical removal of the gonads removes circulating testosterone and eliminates the negative feedback of testosterone on the hypothalamus. As a result, GnRH is elevated and consequently elevates LH. A GnRH antagonist would be expected to reduce GnR_H_ mediated elevations of LH levels. Amide, a GnR_H_ peptide antagonist, reduces LH levels in castrated rats. The model seems suitable for is evaluating small molecule GnRH antagonists.
Male Sprague-Dawley (200-225 g) rats were castrated via the scrotal approach under halothane anesthesia. Animals were allowed 14 days post operative recovery prior to study. Thirteen days following castration, animals were anesthetized with halothane and instrumented with indwelling jugular vein cannula. Details ofthe 2o cannulation procedure have been described previously (Harms et al., Applied Physiol.
36:391-398 (1974)).
On study day, animals were .allowed to acclimate to the procedure room while residing in their home cage. Basal blood samples were drawn from all animals.
Immediately following basal sampling, vehicle or test compounds were administered 25 by intravenous (iv), intraperitoneal (ip), intramuscular (im) or oral (po) routes. Test compounds were formulated in vehicles specified in Table 3. Blood samples were drawn into heparin containing tubes at multiple time points post treatment.
Blood was centrifuged immediately, plasma collected and stored in -20° freezer until assayed.
Plasma samples were analyzed using DSL-4600 ACTIVE LH coated-tube 3o immunoradiometric assay kit from Diagnostic Systems Laboratories, Inc.
Webster, Texas. Cremophor EL obtained from Sigma, St. Louis, MO.

The results of the GnRH antagonist experiments with various concentrations (1.0-100 mg/kg) in different administration routes (iv, im, and po) of GnRH
agents, Compounds C23, and B52 in the above castrated rat model are shown in Figures 1-4.
Model #2: Intact Male Rat Testosterone is a hormone regulated by the hypothalamic-pituitary-gonadal axis. GnRH is secreted in pulses from the hypothalamus and stimulates the anterior pituitary gland to release gonadotropic hormones LH and FSH. Testosterone is produced when the testes are stimulated by LH. A GnRH antagonist is expected to reduce testosterone levels by inhibiting GnRH stimulation of LH release.
' Male Sprague-Dawley (250-275 g) rats were single-housed and allowed to acclimate for 1 week prior to study. On study day animals were treated with vehicles specified in Table 3) or test compound. Blood samples were obtained via indwelling jugular vein cannulae implanted 5 days prior to study (Harms et al., Applied Physiol.
36:391-398 (1974)). Blood samples were drawn into heparin containing tubes at multiple time points post treatment. Blood was centrifuged immediately, plasma collected and stored in -20° freezer until assayed. Plasma samples were analyzed using DSL-4000 ACTIVE Testosterone coated-tube radioimmunoassay kit from Diagnostic Systems Laboratories, Inc. Webster, TX.
The results of the GnRH antagonist experiments with various concentrations (1.0 -100 mg/lcg) in administration routes (iv, im, and po) of GnR_H_ agents, Compounds C23, B3, C2, B52, and B89 in the above intact rat model are shown in Figures 5-10.
Pharmaceutical Compositions The exemplary compounds described above may be formulated into 2s pharmaceutical compositions according to the following general examples.
Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of the Formula I, II, or III is dissolved in DMSO and then mixed with 10 mL of 0.9%
sterile 3o saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
Oral Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula I, II or III is mixed with 750 mg of lactose. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
Intxaocular Composition To prepare a sustained release pharmaceutical composition for intraocular delivery, a compound of Formula I, II or III is suspended in a neutral, isotonic solution of hyaluronic acid (1.5% cone) in a phosphate buffer (pH 7.4) to form a 1%
suspension, which is suitable for intraocular administration.
It is to be understood that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Thus, scope of the invention should be understood to be defined not by the foregoing description, but by the following claims and their equivalents.
1s h

Claims (38)

WHAT IS CLAIMED IS:
1. A compound represented by Formula I:
wherein:
Ar1 is a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2 CN where 2 is an integer from 0 to 4, NH, NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where 2 is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)2-CN where z is an integer from 0 to 4, -OR c, -NR c OR c, -NR c R c, -C(O)NR c, -C(O)OR c, -C(O)R c, -NR c C(O)NR c R c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR c R c, -SR c, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
Z is O, S, SO, SO2, or N(R f) where R f is hydrogen or an alkyl or -O-alkyl group;
V is SO, S, or C;
X is O, N or S, Y is O or N(R f) where R f is hydrogen or an alkyl or -O-alkyl group; and R1 is an unsubstituted aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, or an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -N-alkyl, or -O-alkyl group substituted with one or more substituent groups independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 4, =NH, NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said substituent group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O;
=S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)2-CN where z is an integer from 0 to 4, -OR c, -NR c OR c, -NR c R c, -C(O)NR c, -C(O)OR c, -C(O)R c, NR c C(O)NR c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR c R c, -SR c, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -N-alkyl, or -O-alkyl; where at least one of the substituent groups on said alkyl, alkenyl, or alkynyl group is said unsubstituted or substituted aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group.
2. A compound, salt, prodrug, or metabolite according to claim 1, wherein: Z is O.
3. A compound, salt, prodrug, or metabolite according to claim 1, wherein: V is C; and X is O.
4. A compound, salt, prodrug, or metabolite according to claim 1, wherein: Y is NH.
5. A compound or salt according to claim 1, wherein: R1 is an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group unsubstituted or substituted with one or more substituent groups independently selected from the group consisting of: halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where 2 is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(Q)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(02)NH2, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2CN where z is an integer from to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(02)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(S02)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(02)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -N02, -CN, -(CH2)2 CN where z is an integer from 0 to 4, -ORc, -NRcORc, -NRcRc, -C(O)NRc, -C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRS, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
6. A compound or salt according to claim 5, wherein: Z is O; V is C;
Y is NH;and X is O.
7. A compound or salt according to claim 6, wherein Arl is a group unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, alkyl, =O, -O-alkyl, -C(O)-alkyl, -N(alkyl)(alkyl), -NH(alkyl), -OH, -NH2, -C(O)-N(alkyl)(alkyl), -C(O)-N(H(alkyl), and -C(O)-H.
8. A compound or salt according to claim 7, wherein: Rl is a heteroaryl group unsubstituted or substituted with one or more substituent groups independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2CN where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(S02)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(02)H, -S(O)H, -NHa, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(Oz)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -N02, -CN, -(CH2)2 CN where z is an integer from 0 to 4, -ORc, -NRcORc, -NRc, -C(O)NRc, -C(O)ORc, -C(O)c, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRS, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
9. A compound represented by Formula (II):
wherein:
Ar2 is a six-membered heteroaryl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogens; =O;
=S;
-CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2CN where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NFI)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(Oz)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH, -NHCS(O)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2CN where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC2NHz, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(Oz)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)2- CN where z is an integer from 0 to 4, -ORc, -NRcORc, -NRc, -C(O)NRc, -C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRS, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R~
is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
Z is O, S, SO, SO2, or N(Rf) where Rf is hydrogen or an alkyl or -O-alkyl group;
V is S or C;
X is S, O, or N;
Y is O or N(Rf) where Rf is hydrogen or an alkyl or -O-alkyl group; and R2 is an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; =O; =S; -CN;
and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(02)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(S02)OH, -NHC(S)II, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(02)NH2, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -N02; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)zCN where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(02)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(S02)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(02)NH2, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -N02, -CN, -(CH2)2 CN where z is an integer from 0 to 4, -ORc, -NRcORc, -NRcRc, -C(O)NR2, -C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R~
is hydrogen, unsubstituted alkyl, unsubstituted allcenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
10. A compound, salt, prodrug, or metabolite according to claim 9, wherein: Z is O.
11. A compound, salt, prodrug, or metabolite according to claim 9, wherein: V is C; and X is O.
12. A compound, salt, prodrug, or metabolite according to claim 9, wherein: Y is NH.
13. A compound, salt, prodrug, or metabolite according to claim 9, wherein: R2 is an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)zCN
where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)nNHz, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(02)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(02)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO2)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -N02; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)zCN
where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(02)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(02)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(02)NHz, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -N02, -CN, -(CH2)z CN where z is an integer from 0 to 4, -ORc, -NRcORc, NRcRc, -C(O)NRc, -C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more ubstituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc gxoups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
14. A compound, salt, prodrug, or metabolite according to claim 13, wherein: Z is O; V is C; Y is NH; and X is O.
15. A compound or salt according to claim 9, wherein: Ar2 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -N02; and alkyl, allcenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN
where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, =NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)zCN
where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(02)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(02)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)z CN where z is an integer from 0 to 4, -ORc, -NRcORc-NRcRc-C(O)ORc,-NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
16. A compound or salt according to claim 15, wherein: Z is O; V is C; X is O; and Y is NH.
17. A compound or salt according to claim 16, wherein: R2 is a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens; =O; =S; -CN; and N02; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)zCN where z is an integer from to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(02)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHS02H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(02)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, arid -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; =O; =S; -CN; and -N02; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)zCN
where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(02)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(02)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(S02)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(S02)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)z CN where z is an integer from 0 to 4, -ORc, -NRcORc, -NRc, -C(O)NRc, -C(O)ORc, -C(O)Rc, -NRcC(O)NRcRc, -NRcC(O)Rc, -OC(O)ORc, -OC(O)NRcRc, -SRc, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where Rc is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more Rc groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
18. A compound represented by Formula (III):
wherein:
R4, R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen; halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2CN
where z is an integer from 0 to 4, NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)z-CN where z is an integer from 0 to 4, -OR c, -NR c OR c, -NR c R c, -C(O)NR c, -C(O)OR c, -C(O)R c, -NR
c(O)NR c,R c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR c R c, -SR c, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
or any two of R4, R5, R6, R7 and R8 together with the phenyl ring to which they are attached form a fused polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN
where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN
where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)z-CN where z is an integer from 0 to 4, -OR c, NR c OR c, -NRc R c, -C(O)NR c, -C(O)OR c, -C(O)R c, -NR c C(O)NR c R c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR cR c, -SR c, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
Z is S, SO, SO2, O, or N(R f) where R f is hydrogen or an alkyl or -O-alkyl group;
each W is independently N or C; and R3 is hydrogen; halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; =O; =S; -CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN
where z is an integer from 0 to 4, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH]NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with halogens, =O, -NO2, -CN, -(CH2)z-CN where z is an integer from 0 to 4, -OR c, -NR c OR c, -NR c R c, -C(O)NR c -C(O)OR c, -C(O)R c, -NR c C(O)NR c R c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR c R c, -SR c, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
19. A compound, salt, prodrug, or metabolite according to claim 18, wherein: Z is O.
20. A compound, salt, prodrug, or metabolite according to claim 18, wherein: each W is N.
21. A compound or salt according to claim 18, wherein: Z is O; and each W is N.
22. A compound or salt according to claim 21, wherein: R6 and R7 together with the phenyl to which they are attached form a fused polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, =O, -O-alkyl, -CO-alkyl, -N(alkyl)(alkyl), -NH(alkyl), -OH, -NH2, and -CO-H groups.
23. A compound or salt according to claim 22, wherein: R3 is -NH-alkyl-N(R d)(R e) or -N(alkyl)-alkyl-N(R d)(R e) where R d and R e are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, -COR c, -COOR c, -O-CO-O-R c, -O-CO-R c, -OH, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or R d and R e together cyclize to form part of a heteroaryl or heterocycloalkyl group, where R c is as previously defined.
24. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising: a therapeutically effective amount of an agent selected from the group consisting of compounds and salts as defined in claim 25; and a pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising: a therapeutically effective amount of an agent selected from the group consisting of compounds, salts, prodrugs, and metabolites as defined in claim 1; and a pharmaceutically acceptable carrier.
27. A pharmaceutical composition comprising: a therapeutically effective amount of an agent selected from the group consisting of compounds, salts, prodrugs, and metabolites as defined in claim 9; and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising: a therapeutically effective amount of an agent selected from the group consisting of compounds, salts, prodrugs, and metabolite as defined in claim 18; and a pharmaceutically acceptable carrier.
29. A method for regulating the secretion of gonadotropins in a mammal, comprising administering a therapeutically effective amount of a compound, salt, prodrug, or metabolite as defined in claim 1.
30. A method for regulating the secretion of gonadotropins in a mammal, comprising administering a therapeutically effective amount of a compound, salt, prodrug, or metabolite as defined in claim 9.
31. A method for regulating the secretion of gonadotropins in a mammal, comprising administering a therapeutically effective amount of a compound, salt, prodrug, or metabolite as defined in claim 18.
32. A process of making a compound of Formula IVa:
wherein: Het is a 5- or 6-membered heteroaryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
halogens;
-CN; and -NO2; and alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2) Z CN where z is an integer from 0 to 4, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2, -NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups, each said group being unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, =O, -NO2, -CN, -(CH2)2 CN where z is an integer from 0 to 4, -NR c OR c, -NR c R c, -C(O)NR c, -C(O)OR c, -C(O)R c, -NR c C(O)NR c R c, -NR c C(O)R c , -OC(O)OR c , -OC(O)NR c R c, -SR c, unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or two or more substituents may cyclize to form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, where R c is hydrogen, unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R
c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;
comprising the steps of:
(a) preparing a nitrating reagent by adding trifluoromethanesulfonic anhydride to 2-tetramethylammonium nitrate in a polar solvent; and (b) conducting a reaction of said nitrating reagent with a compound of Formula IV:
wherein Het is as previously defined;
to form said compound of the formula IVa.
33. A process according to claim 32, wherein Het is a heteroaryl selected from the group consisting of furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, and 1,3,5-triazine.
34. A process according to claim 32, wherein said solvent is dichloromethane, chloroform, dichloroethane, or nitromethane.
35. A process according to claim 32, wherein said forming step (a) further comprises adding the 2-tetramethylammonium nitrate to the polar solvent prior to the adding of said trifluoromethanesulfonic anhydride.
36. A process according to claim 32, further comprising cooling said nitrating reagent to a temperature of from 0°C to -80°C and then adding said compound of Formula IV to the cooled nitrating reagent.
37. A process according to claim 32, further comprising:
(c) quenching the reaction and then separating out and purifying the compound of Formula IV.
38. A process according to claim 32, wherein steps (a) and (b) are performed under an inert atmosphere.
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