WO2012074980A2 - Methods of treating or preventing autoimmune disorders and liver disorders using indane acetic acid derivatives - Google Patents

Abstract

The present invention provides indane acetic acids and their derivatives and methods for the treatment and/or prevention of autoimmune disorders and liver disorders using the same.

Description

METHODS OF TREATING OR PREVENTING AUTOIMMUNE DISORDERS AND

LIVER DISORDERS USING INDANE ACETIC ACID DERIVATIVES

Related Application Data

This application claims the benefit of U.S. Provisional Patent Application Serial No. 61/418,712, filed December 1, 2010 and U.S. Provisional Patent Application Serial No. 61/418,700, filed December 1 , 2010, the disclosures of which are incorporated herein by reference in their entirety.

Field of the Invention

The present invention generally relates to the use of indane acetic acids and their derivatives to treat autoimmune disorders and liver disorders.

Background of the Invention

Autoimmune disorders are typically caused by an overactive immune response of the body against normally present substances and tissues. For example, multiple sclerosis (MS) is a disorder of the central nervous system (CNS) that affects the brain and spinal cord. Common signs and symptoms of MS include paresthesias in one or more extremities, in the trunk, or on one side of the face; weakness or clumsiness of a leg or hand; or visual disturbances (such as partial blindness and pain in one eye), dimness of vision, or scotomas. Current treatments for MS include corticosteroids, beta interferons (Betaferon, Avonex, Rebif), glatiramer acetate (Copaxone), methotrexate, azathioprine, cyclophosphamide, cladribine, baclofen, tizanidine, amitriptyline, carbamazepine (Berkow et al. (ed.), 1999, Merck Manual of Diagnosis and Therapy: 17^th Ed). Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized generally by synovitis of joints that typically affects small and large joints, leading to their progressive destruction (Berkow et al. (ed,), 1999, supra). Symptoms of RA can include stiffness, tenderness, synovial thickening, flexion contractures, visceral nodules, vasculitis causing leg ulcers or mononeuritis multiplex, pleural or pericardia] effusions, and fever (Berkow et al. (ed.), 1999, supra). Current treatments for RA include nonsteroidal anti-inflammatory drugs (including salicylates), gold compounds, methotrexate, hydroxychloroquine, sulfasalazine, penicillamine, corticosteroids, and cytotoxic or immunosuppressive drugs. (Berkow et al. (ed.), 1999, supra.). None of the existing therapies for autoimmune disorders have proven to be satisfactory at least because of limited efficacy and/or significant toxicity.

Liver disorders such as fatty liver, i.e., steatosis, are diseases in which excessive amounts of lipids accumulate in the liver. Fatty liver may develop due to many possible factors such as medicine, alcohol use, viral or bacterial infections or obesity. Steatohepatitis is inflammation of the liver related generally to fat accumulation. Heavy alcohol use may lead to fatty liver and inflammation and is usually referred to as alcoholic hepatitis. Steatohepatitis resembles alcoholic hepatitis, but may occur in people who seldom or never drink alcohol. It is often called nonalcoholic steatohepatitis or NASH. Both alcoholic hepatitis and steatohepatitis can lead to scarring, e.g., cirrhosis, and hardening of the liver resulting in serious liver damage. In addition, there are more than 1,000 reported drugs that may cause injury to the liver. Drug- induced liver injury may account for as many as 10 percent of hepatitis cases in adults overall, 40 percent of hepatitis cases in adults over fifty years old, and 25 percent of cases of fulminant liver failure. Certain active agents, such as glucocorticoids, synthetic estrogens, amiodarone, acetaminophen, tamoxifen and valproic acid, for example, have been associated with fatty liver.

Accordingly, there is an ongoing need for an effective treatment for these diseases.

Summary of the Invention

The present invention provides methods of treating or preventing autoimmune disorders and/or liver disorders. The methods include administering to a subject in need thereof an effective amount of a compound of Formula I:

Formula I

wherein in Formula I

R is H or C_rC₆ alkyl;

R¹ is H, COOR, C₃-C₃ cycloalkyl, or

Ci-C₆ alkyl, C₂-C₆ alkenyl, or Ci-Q alkoxy, each of which may be unsubstituted or substituted with fluoro, methylenedioxyphenyl, or phenyl which may be unsubstituted or substituted with R⁶;

R² is H, halo, or C C₆ alkyl which may be unsubstituted or substituted with C C₆ alkoxy, oxo, fluoro, or

R² is phenyl, fur l, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidmyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl, each of which may be unsubstituted or substituted with R⁶;

R³ is H, C_rC₆ alkyl, or phenyl, which may be unsubstituted or substituted with R⁶;

X is O or S;

R⁴ is C C₆ alkyl or C. C₈ cycloalkyl, either of which may be unsubstituted or substituted with fluoro, oxo, or Q-Cg alkoxy which may be unsubstituted or substituted with Ci-C₆ alkoxy, or phenyl optionally substituted with R⁶, or

each of which may be substituted with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or further substituted with R⁶, or

Ci-Ce alkyl may also be substituted with C₃-Q cycloalkyl or with phenoxy which may be unsubstituted or substituted with R⁶ or with phenyl, naphthyl, furyl, thienyl, pyrroiyl, tetrahydrofuryl, pyrrol idinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl,benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or

R⁴ is phenyl, naphthyl, furyl, thienyl, pyrroiyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or with phenyl, furyl, thienyl, pyrroiyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isotliiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, benzodioxolyl, dihydrobenzofuranyl, indolyl, pyrimidinyl or phenoxy, each of which may be unsubstituted or substituted with R⁶;

R⁵ is H, halo or C C₆ alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, Ci-C₆ alkyl optionally substituted with oxo or hydroxy, or

Ci-C_fi alkoxy optionally substituted with fluoro;

or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

In one embodiment, the compound of Formula I is a meglumine, potassium or sodium salt thereof. In some embodiments, the compound of Formula I has the following structure:

A further aspect of the present invention provides methods of treating and/or preventing autoimmune and/or liver disorders. The methods comprise administering a compound of Formula IB,

Formula IB wherein

R is H or C C₆ alkyl;

R^! is H, COOH, -C(=0)-OR', C₃-C₈ cycloalkyl, d-C₆ alkyl, C₂-Q alkenyl, or C,-C₆ alkoxy, wherein R is C]-C₆alky], and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally and independently substituted with R⁶;

R² is H, halo, or C,-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting of C C₆ alkoxy, oxo and fluoro, or

R² is C5.1 aryl, C_Mi heterocycle or C₅-u heteroaryl, wherein said aryl, heterocycle or heteroaryl may be optionally substituted with one or more R⁶;

R³ is H, Ci-C_fi alkyl, or phenyl, wherein said alkyl or phenyl may be optionally substituted with one or more R⁶;

X is O or S;

R⁴ is C5.14 aryl, C₃.₁₄ heterocycle or C₅._u heteroaryl, wherein said aryl, heterocycle or heteroaryl is substituted with one or more R⁷,

R⁵ is H, halo or C C₆ alkyl wherein said alkyl may be optionally substituted with oxo;

R⁶ is halo, CF₃, C,-C₆ alkyl wherein said alkyl may be optionally substituted with oxo or hydroxy, or C1-C6 alkoxy optionally substituted with fluoro;

R⁷ is selected from the group consisting of

(a) hydroxyl,

(b) C]-C6 alkoxy 1, wherein one or more H of the alkoxyl is ²H (D), and

(c) -O-protecting group;

(d) -0-C(=0)-R^!1 wherein R¹¹ is C_rC₆ alkyl or C_5-i₄ aryl wherein said alkyl or aryl may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -SH, amide, carboxylic acid, CN, CpQ alkyl, C C₆ thioalkyl, C₆ ^ aryl and C₅ heteroaryl and -N _cR_d> and wherein R_c and R_d are independently hydrogen, or Ci-Ce alkyl;

(e) -0-C(=0)-R^m, wherein R^m is -NR-R_f and wherein R» and R_f are independently hydrogen, or C

Q alkyl;

or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer or racemate thereof.

In some embodiments, the compound of Formula IB is a meglumine, potassium or sodium salt thereof.

In one embodiment, for the compound of Formula IB, R is H, R¹ is H, R² is H, R³ is Q-C₆ alkyl, X is O, and R⁴ is a phenyl substituted with one or more R⁷, wherein R⁷ is selected from the group consisting of (a) hydroxyl, (b) C_rC₆ alkoxyl, and one or more H of the alkoxyl is ²H (D), and (c) -0-CH₂-Ph, wherein said phenyl may be optionally substituted with C_rC₆ alkoxyl; and R⁵ is H, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula IB has the following structure:

A further aspect of the present invention provides a compound of Formula IB or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a composition comprising a compound of Formula ΓΒ or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides different methods of treating or preventing autoimmune and/or liver disorders. The methods include administering to a subject in need thereof an effective amount of a compound of Formula VI:

Formula VI

wherein

R¹ andR² are independently H, C]-C₆ alkyl, or C Ce cycloalkyl;

L is a linker and selected from the group consisting of -(CH₂)_m-X-, -Y-(CH₂)j,-X-,and

wherein

X is selected from the group O, S, S(=0), and S(=0)₂,

Y is selected from the group O, NR.⁵, S, S(=0), and S(=0)₂,

m is 1, 2, or 3,

n is 2, 3, or 4,

t is 0 or 1,

p is 0,1, 2, or 3,

q is 1, 2, 3, or 4,

wherein the sum of p and q is 1, 2, 3, or 4;

Ar is phenyl or a 6-membered heteroaryl containing up to three N atoms,

wherein said Ar is optionally substituted at any available position by 1 to 5 independently selected R³ groups, and

optionally fused to a 5- or 6-membered saturated carbocyclic ring,

a 5- or 6-membered unsaturated carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing up to 3 additional eteroatoms selected from

N, O, and S,

wherein said fused ring may be optionally substituted at any available position by 1 to 4 independently selected R⁴ groups;

R³ is selected from the group consisting of hydroxy, SH, halo, CN, N0₂, C(=0)OH, C(=0)-OC C₆ alkyl, C(=0)-OC₃-C₆ cycloalkyl, NR⁶R⁷, C(=0)NR⁶R⁷, C(=S)NR⁶R⁷, C C₆ alkyl optionally substituted with halo, OH, NR⁶R⁷, or C C₆ alkoxy, C C₆ haloalkyl, C C₆ alkoxy, C C₆ thioalkyl, C₂-C₆ alkenyl, C C₆ haloa!koxy, C₃-Cg cycloalkyl, C₃-C₈ cycloalkoxy, phenoxy optionally substituted on the phenyl ring with halo, Ci-Cs alkyl, or C1-C6 alkoxy, and

a mono or bicyclic ring radical selected from the group consisting of

a) phenyl optionally fused to

a 5- or 6-membered saturated .or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S, and

b) a 5- or 6-membered heterocyclic ring radical containing up to 4

heteroatoms selected from N, O, or S, optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S,

said mono or bicyclic ring radical being optionally substituted with up to 5 groups independently selected from the group consisting of halo, hydroxy, oxo, CN, C,-C<; alkyl optionally substituted with halo, OH, NR⁶R⁷, C_rC₆ alkoxy, C_rC₆ haloalkyl, C_rC₆ alkoxy, C C₆ thioalkyl, Ci- C₆ haloalkoxy, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C C₆ acyl, C(=0)OH, CH₂C(=0)OH, NR⁶R⁷, C(=0)NR⁶R⁷, C(=0)OCi-C₆ alkyl, and C(=0)OC₃-Q cycloalkyl;

R⁴ is selected from the group consisting of oxo, hydroxy, halo, CN, NR R⁷, Ci-C₆ alkyl optionally substituted with OH, NR⁶R⁷, or Ci-C₆ alkoxy, C_rC₆ haloalkyl, C_rC₆ alkoxy, Q-Q thioalkyl, C C₆ haloalkoxy, C₃-C₃ cycloalkyl, and C₃-C₃ cycloalkoxy;

R⁵ is selected from the group consisting of H, Q-Q, alkyl optionally substituted with C₃-C₆ cycloalkyl, C_rQ acyl, benzyl optionally substituted with halo, Ci-C₆ alkoxy, (C_rC6)alkyl, CN, NH₂, N[(C C₃)alkyl]₂, N0₂, or CF₃, C₃-C₆ cycloalkyl, and C(=0)OC C₆ alkyl;

R⁶ and R⁷ are independently selected from the group consisting of H, C C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl, Ci-C₆ acyl, benzyl optionally substituted with halo, C C₆ alkoxy, (C]- C₆)alkyl, CN, NH₂, N[(C_rC₃)alkyl]₂, N0₂, or CF₃, C₃-C₆ cycloalkyl, and phenyl optionally substituted with halo, C C₆ alkoxy, (C,-C₆)a]kyl, CN, N[(C_rC₃)alkyl]₂, N0₂, or CF₃, or

R⁶ and R⁷ may be taken together with the nitrogen atom to which they are attached to form a 5- or 6- membered heterocyclic ring optionally interrupted by NR⁵ or O; and

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof. In some embodiments, the compounds of formula (VI) is alkali metal salt, basic nitrogen containing group.

In some embodiments, the compounds of formula (VI) is a meglumine, caclsium, magnesium, ammonium salts, potassium or sodium salt thereof.

In one embodiment, the compound of formula (VI) has the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the methods described herein may further include administration of at least one additional therapeutic agent.

Aspects of the present invention will be appreciated by those of ordinary skill in the art from a reading of the Examples and the detailed description of the embodiments, which follow, such description being merely illustrative of the present invention.

Detailed Description

The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, the absence of articles "a", "an" are intended to include both the singular forms and plural forms. Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1 % of the specified amount. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there is a plurality of definitions for a term used herein, those in this section prevail unless stated otherwise.

All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling.

A. Definitions

The term "halo" means F, CI, Br, or I.

The term "C_rC₆ alkyl" means a straight or branched saturated hydrocarbon carbon chain of from 1 to about 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl, n-hexyl, and the like.

The term "C2-Q alkenyl" means a straight or branched unsaturated hydrocarbon carbon chain of from 2 to about 6 carbon atoms. Examples of such groups include vinyl, allyl, isopropenyl, 2-butenyl, 3- ethyl-2-butenyl, 4-hexenyl, and the like.

The term "Ci-C₆ haloalkyl" means a C C₆ alkyl group substituted by 1 to 3 halogen atoms or fluorine up to the perfluoro level. Examples of such groups include trifluoromethyl, tetrafluoroethyl, 1,2- dichloropropyl, 5-bromopentyl, 6-iodohexyl, and the like.

The terms "C₃-C₆ cycloalkyl" and "0₃-¾ cycloalkyl" mean a saturated carbocyclic ring system of from 3 to about 6 carbon atoms or from 3 to about 8 carbon atoms, respectively. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "Ci-Q acyl" means a Cj-Ce alkyl group attached at the carbonyl carbon atom. The radical is attached to the rest of the molecule at the carbonyl bearing carbon atom. Examples of such groups include acetyl, propionyl, n- butanoyl, 2-methylpentantoyl, and the like.

The term "CpQ alkoxy" means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an O atom. The O atom is the point of attachment of the alkoxy substituent to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "C C6 thioalkyl" means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an S atom. The S atom is the point of attachment of the thioalkyl substituent to the rest of the molecule. Such groups include, for example, methylthio, propylthio, hexylthio, and the like. The term "Ci-C₆ haloalkoxy" means a Ci-G₆ alkoxy group further substituted on C with 1 to 3 halogen atoms or fluorine up to the perfluoro level.

The term "C₃-Cg cycloalkoxy" means a C₃-C₈ cycloalkyl group attached to an O atom. The O atom is the point of attachment of the cycloalkoxy group with the rest of the molecule.

The term "phenoxy" means a phenyl group attached to an O atom. The O atom is the point of attachment of the phenoxy group to the rest of the molecule.

The term "6-membered heteroaryi ring" means a 6-membered monocyclic heteroaromatic ring radical containing 1-5 carbon atoms and up to the indicated number of N atoms. Examples of 6-membered heteroaryi rings are pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, and the like.

The term "5- or 6-membered heterocyclic ring" means a 5 or 6-membered ring containing 1-5 C atoms and up to the indicated number of N, O, and S atoms, and may be aromatic, partially saturated, or fully saturated.

The term "optionally substituted" means that, unless indicated otherwise, the moiety so modified may have from one to up to the number of the substituents indicated, provided the resulting substitution is chemically feasible as recognized in the art. Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. For example, a chemically unstable compound would be one where each of two substituents is bonded to a single C atom through each substituents heteroatom. Another example of a chemically unstable compound would be one where an alkoxy group is bonded to the unsaturated carbon of an alkene to form an enol ether. When there are two or more substituents on any moiety, each substituent is chosen independently of the other substituent so that, accordingly, the substituents can be the same or different.

When the 5-or 6-membered heterocyclic ring is attached to the rest of the molecule as a substituent, it becomes a radical. Examples of 5- or 6-membered heteroaryi ring radicals are furyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, imidazolyl, oxazolyl, thiazolyi, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, and the like. Examples of partially unsaturated 5- or 6- membered heterocyclic ring radicals include dihydropyrano, pyrrolinyl, pyrazolinyl, imidazolinyl, dihydrofuryl, and the like. Examples of saturated 5- or 6-membered heterocyclic ring radicals include pyrrolidinyl, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuryl, tetrahydrothienyl, piperazinyl, and the like. The point of attachment of the radical may be from any available C or N atom of the ring to the rest of the molecule. When the 5- or 6-membered heterocyclic ring is fused to another ring contained in the rest of the molecule, it forms a bicyclic ring. Examples of such 5-and 6-heterocyclic fused rings include pyrrolo, furo, pyrido, piperido, thieno, and the like. The point of fusion is at any available face of the heterocyclic ring and parent molecule.

As used herein, "subject", as used herein, means a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and particularly human subjects (including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects, and further including various races and ethnicities including, but not limited to, white, black, Asian, American Indian and Hispanic). As used herein, "treatment", "treat", and "treating" refer to reversing, alleviating, mitigating or slowing the progression of or inhibiting the progress of a disorder or disease as described herein.

As used herein, "prevention", "prevent", and "preventing" refer to eliminating or reducing the incidence or onset of a disorder or disease as described herein, as compared to that which would occur in the absence of the measures taken.

As used herein, "an effective amount" refers to an amount that causes relief of symptoms of a disorder or disease as noted through clinical testing and evaluation, patient observation, and/or the like. An "effective amount" can further designate a dose that causes a detectable change in physical, biological, or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process. Moreover, an "effective amount" can designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition of interest. An "effective amount" can further refer to a therapeutically effective amount.

The compounds described herein may optionally be administered in combination (or in conjunction) with other medications useful in the treatment of autoimmune disorders. The administration of two or more compounds "in combination" or "in conjunction" means that the two compounds are administered closely enough in time to have a combined effect, for example an additive and/or synergistic effect. The two compounds may be administered simultaneously (concurrently) or sequentially or it may be two or more events occurring within a short time period before or after each other. Simultaneous administration may be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration. In some embodiments, the other medication for treating autoimmune disorder may optionally be administered concurrently.

B. Compounds

(1) Formula I

The present invention encompasses the compounds of Formula I,

Formula I

wherein in Formula I

R is H or d - C₆ alkyl; R¹ is H, COOR, C₃-C₈ cycloalkyl, or Q - C₆ alkyl, C C₆ alkenyl, or C,-C₆ alkoxy each of which may be unsubstituted or substituted with fiuoro, methylenedioxyphenyl, or phenyl which may be unsubstituted or substituted with R⁶;

R² is H, halo, or Ci-C₆ alkyl which may be unsubstituted or substituted with C C6 alkoxy, oxo, fiuoro, or

R² is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl,

each of which may be unsubstituted or substituted with R⁶;

R³ is H, C,-C₆ alkyl, or phenyl, which may be unsubstituted or substituted with R⁶;

X is O or S;

R⁴ is Ci-C₆ alkyl or C₃-Cg cycloalkyl, either of which may be unsubstituted or substituted with fluoro, oxo, or C_rC₆ alkoxy which may be unsubstituted or substituted with Q-C₆ alkoxy, or phenyl optionally substituted with R⁶,

each of which may be substituted with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazoly], benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or further substituted with R⁶, or

C]-C₆ alkyl may also be substituted with C₃-C₈ cycloalkyl or with phenoxy which may be unsubstituted or substituted with R⁶ or with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl,benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or

R⁴ is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or with phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, benzodioxolyl, dihydrobenzofuranyl, indolyi, pyrimidinyl or phenoxy,

each of which may be unsubstituted or substituted with R⁶;

R⁵ is H, halo or CrQ alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, C]-C₆ alkyl optionally substituted with oxo or hydroxy, or

C C₆ alkoxy optionally substituted with fluoro; .

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

R³ may be attached to the heterocyclic moiety of the compound of Formula I at either the 4 or 5 position (i.e., at either available carbon atom) and, accordingly, the remaining portion of the molecule will be attached at the remaining available carbon atom.

In some embodiments, the compound of Formula I has the following structure:

In some embodiments, the compound of Formula I is a meglumine, potassium or sodium salt thereof.

In other embodiments, for the compound of Formula I, R is H, R¹ is H, R² is H, R³ is C₆ alkyl, X is O, and R⁴ is a phenyl substituted with R⁶, wherein R⁶ is Ci-C₆ alkoxyl or C C₆ alkyl, or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound has the following structure:

In other embodiment, the compound of Formula I is a meglumine, potassium or sodium salt of the structure

Exemplary compounds of Formula I are listed in Table 1. Table 1. Illustrative Examples of Com ounds of Formula I

Formula I

Entry No. R¹ R² R³ R⁴ R⁵ X

55 H CH₃ Et 4-CH₃0 Ph H s

56 H CH₃ Et 4-CH₃O Ph CH₃ 0

57 H CH₃ Et 3,4-di-CH₃0 Ph CH₃ 0

58 H CH₃ Et 4-Ph Ph CH₃ 0

59 H CH₃ Et 4-Ph Ph CH₃ s

60 H CH₃ Et CH₃ 0

61 H CH₃ Ph cyclopropyl H 0

62 H CH₃ Ph cyclohexyl H 0

63 H CH₃ Ph cyclohexyl H s

64 H CH₃ p-F Ph ^■ cyclohexyl H 0

65 H CI i-Pr Ph H 0

66 H CI i-Pr Ph H s

67 H CI i-Pr Ph CI 0

68 H CI i-Pr 4-C¾ Ph CI 0

69 H Br C¾ Ph Br 0

70 H Br CH₃ 3-F h Br 0

71 H Br CH₃ 3-F Ph Br s

72 H CH₃CO CH₃ n-propyl CH₃CO 0

73 H CH₂OCH₃ Et 2-thienyl H 0

74 H Ph H 2,4-di-Cl Ph H 0

75 H Ph H 2,4-di-Cl Ph H s

76 H Ph CH₃ 2,4-di-Cl Ph H 0

77 H Ph Et 2,4-di-Cl Ph H 0

78 H Ph Ph 2,4-di-Cl Ph H 0

79 H Ph Ph 2,4-di-Cl Ph H s

80 H Ph 4-CH₃0- 2,4-di-Cl Ph H 0

Ph

81 H 4-F Ph CH₃ 4-F Ph H 0

82 H 4-F Ph CH₃ 2,4-di-Cl Ph H 0

83 H 3-pyridyl CH₃ 2,4-di-Cl Ph H 0

84 H 3-pyridyl CH₃ 2,4-di-Cl Ph H s

85 H 2-thienyl CH₃ Ph H 0

86 H 2-thienyl CH₃ 2,4-di-Cl Ph H 0

87 H 2-thienyl CH₃ 2,4-di-Cl Ph H s

88 H 2-thienyl CH₃ 3-pyridyl H 0

Entry No. R¹ R² R³ R⁴ R⁵ X

195 CH₃ n-propyl CH₃ PhOCH₂ H 0

196 CH₃ n-propyl C¾ PhOCH₂ n-propyl 0

197 CH₃ n-butyl CH₃ PhOCH₂ H 0

198 CH₃ n-hexyl CH₃ PhOCH₂ H 0

199 CH₃ n-hexyl CH₃ PhOCH₂ H s

200 CH₃ n-hexyl isopropyl 3-Cl Ph H 0

201 c¾ n-hexyl Ph 3-Cl Ph H 0

202 c¾ C¾OCH₂ CH₃ PhOCH₂ H 0

203 c¾ Ph n-butyl 3,4-di-F Ph H 0

204 c¾ 3-F Ph CH₃ 1-napthyl H 0

205 CH₃ 4-pyridyl H 4-CF₃ Ph H 0

206 CH₃ 4-pyridyl H 4-CF₃ Ph H s

207 CH₃ CI CH₃ 3,5-di-F-Ph H 0

208 CH₃ Br CH₃ CF₃CF₂ H 0

209 CH₃ Br n-butyl CF₃CF₂ H 0

210 CH₃ Br n-butyl CF₃CF₂ Br 0

211 CH₃ Br Ph CF₃CF₂ Br 0

212 CH₃ 2-furyl C¾ isobutyl H 0

213 CH₃ 2-furyl CH₃ isobutyl H s

214 CH, 2-furyl CH₃ 2-F-4-CF₃ Ph H 0

215 CH₃ 2-furyl CH₃ 2-napthyl H 0

216 CH₃ 2-furyl i-Pr isobutyl H 0

217 CH₃ EtCO n-propyl 3-CH₃O Ph EtCO 0

218 Et H H cyclopropyl H 0

219 Et H H 4-F Ph H 0

220 Et H H 3,5-di-F-Ph H 0

221 Et H H 4-Cl PhCH₂ H 0

222 Et H H 2-quinolinyl H 0

223 Et H CH₃ PhCH₂ H 0

224 Et H CH₃ 4-F PhCH₂ H 0

225 Et H CH₃ 3,4-di-F-PhOCH₂ H 0

226 Et H CH₃ H 0

227 Et H CH₃ H s

~^L

380 n-butyl H CH₃ (4-CH₃O) PhCH₂CH₂ H 0 Entry No. R¹ R¹ R³ R⁴ R⁵ X

381 n-butyl H CH₃ H 0

F F

382 n-butyl H CH₃ H s

383 n-butyl H Et H 0

F F

384 n-butyl H n-propyl cyclobutyl H 0

385 n-butyl H n-propyl H 0

F F

386 n-butyl H isopropyl H 0

F

387 n-butyl H Ph n-propyl H 0

388 n-butyl H Ph H 0

F F

389 n-butyl H Ph Ph H 0

390 n-butyl H Ph Ph H s

391 n-butyl c¾ CH₃ 4-CH₃ Ph H 0

392 n-butyl CH₃ CH₃ 4-CH₃ Ph CH₃ 0

393 n-butyl CH₃ Et 4-CH₃ Ph H 0

394 n-butyl CH₃ Ph 4-CH₃ Ph H 0

395 n-butyl CH₃OCH₂ CH₃ 2,4-di-CH₃ Ph H 0

396 n-butyl CI CH₃ H 0

397 n-butyl CI CH₃ H 0

398 n-butyl CI Ph H 0

399 n-pentyl H H CH₃ H 0

400 n-pentyl H H CH₃ H s

401 n-pentyl H H Et H 0

402 n-pentyl H H cyclopentyl H 0 Entry No. R¹ R² R³ R⁴ R⁵ X

403 n-pentyl H H cyclopentyl H s

404 n-pentyl H H cycloheptyl H 0

405 n-pentyl H H Ph H 0

406 n-pentyl H H Ph H s

407 n-pentyl H H 2-furyl H 0

408 n-pentyl H H 2-(5-CF₃) fuiyl H 0

409 n-pentyl H H 2-thienyl H 0

410 n-pentyl H H ^■.3,4-di-Cl Ph H 0

411 n-pentyl H CH₃ n-butyl H 0

412 n-pentyl H CH₃ n-butyl H s

413 n-pentyl H CH₃ H 0

414 n-pentyl H CH₃ PhOCH₂ H 0

415 n-pentyl H CH₃ PhCH₂OCH₂ H 0

416 n-pentyl H Et 2-F Ph H 0

417 n-pentyl H Et 2-F Ph H s

418 n-pentyl H 4-CH₃ Ph 2-F Ph H 0

419 n-pentyl c¾ Et 4-CH₃ Ph H 0

420 n-pentyl CI CH₃ n-butyl H 0

421 n-pentyl CI CH₃ Ph H 0

422 n-pentyi CI CH₃ Ph H s

423 n-pentyl CI CH₃ 4-Ph Ph H 0

424 n-pentyl CI CH₃ H 0

425 n-pentyl CI CH₃ CI 0

426 n-pentyl PrCO CH₃ 4-CH₃ Ph PrCO 0

427 n-pentyl Ph CH₃ 3-Br Ph H 0

428 n-pentyl 2-thienyl CH₃ 3 -Br Ph 2-thienyl 0

429 n-hexyl H H 2-F Ph H 0

430 n-bexyl H c¾ cyclopentyl H 0

431 n-hexyl H CH₃ cycloheptyl H 0

432 n-hexyl H CH₃ 2-F Ph H 0

433 n-hexyl H CH₃ 2-F Ph H s

Entry No. R² R³ R⁴ R⁵ X

462 cyclobutyl H Et H O

463 cyclobutyl H Et H O

464 cyclobutyl H Et H O

465 cyclobutyl H 4-F Ph H 0

466 cyclobutyl CI CH₃ 3-Cl Ph CI 0

467 cyclobutyl CI CH₃ 3 -CI Ph CI s

468 cyclopentyl H H 3-CF₃ Ph H 0

469 cyclopentyl CH₃ 2,4-di-CF₃ Ph H 0

470 cyclopentyl H CH₃ 2,4-di-CF₃ Ph H s

471 cyclopentyl H n-butyl H 0

472 cyclopentyl H 3-F Ph 4-CH₃ Ph H 0

473 cyclopentyl CH₃ CH₃ Ph H 0

474 cyclopentyl CH₃ CH₃ 3, 5-di-Cl Ph H 0

475 cyclopentyl c¾ CH₃ Ph H s

476 cyclopentyl Et CH₃ Ph H 0

477 cyclopentyl CI CH₃ Ph CI 0

478 cyclopentyl CI CH₃ Ph CI s

479 cyclohexyl H H 3-F Ph H 0

480 cyclohexyl H H 2, 4-di-CH₃ Ph H 0

481 cyclohexyl H H H 0

482 cyclohexyl H CH₃ n-propyl H 0

483 cyclohexyl H CH₃ n-propyl H s

484 cyclohexyl H CH₃ H 0

F F

485 cyclohexyl H CH₃ 3-Cl Ph H 0

486 cyclohexyl H CH₃ 3-Cl Ph H s

Entry No. R¹ R² R* R⁴ R⁵ X

515 2-propenyl H Et 2-napthyl H O

516 2-propenyl H Et 2-napthyl H s

517 2-propenyl H Et H 0

518 2-propenyl H Et cx- H 0

519 2-propenyl H n-propyl 2-F-4-CF3 Ph H 0

520 2-propenyl H Ph 2,4-di-CF₃ Ph H 0

521 2-propenyl H 4-F Ph 2-F-4-CF3 Ph H 0

522 2-propenyl C¾ Et H 0

523 2-propenyl Ci CH₃ 3-CF₃ Ph CI 0

524 2-propenyl CI CH₃ 3-CF₃ Ph CI s

525 2-propenyl Br Et 3-CF₃ Ph Br 0

526 2-isobuteny] H H 3-pyridyl H 0

527 2-isobutenyl H H H 0

528 2-isobutenyl H CH₃ 4-(CF_aO)Ph H 0

529 2-isobutenyl H CH₃ 4-(CF₃0)Ph H 0

530 2-isobutenyl H CH₃ 4-(CF₃0)Ph H s

531 2-isobutenyl H n-butyl 4-(CH₃0)Ph H 0

532 2-isobutenyl H n-butyl (4-F Ph)OCH₂ H 0

533 2-isobutenyl H n-butyl (4-CH₃O) PhCH₂CH₂ H 0

534 2-isobutenyl H Ph 2-thienyl H 0

535 2-isobutenyl H 4-F Ph Ph H 0

536 2-isobutenyl CH₃CO Ph cyclohexyl H 0

537 2-isobutenyl CH₃CO Ph 3-F Ph H 0

538 4-pentenyl H CH₃ Ph H 0

539 4-pentenyl H CH₃ Ph H • S

540 5-hexenyl H H Ph H 0

541 5-hexenyl H CH₃ 2-F Ph H 0

542 5-hexenyl H CH₃ 2-F Ph H s Entry No. R¹ R² R³ R⁴ R⁵ X

543 5-hexenyl H CH₃ N— 0 H O

544 5-hexenyl H isopropyl 4-(CF₃0)Ph H O

545 5-hexenyl H Ph 4-(CF₃0)Ph H O

546 5-hexenyl CH₃CO CH₃ 2-CH₃ Ph CH₃CO O

547 CH₃0 H H cyclobutyl H O

548 CH₃O H H 2,4-di-F Ph H O

549 CH₃0 H H (4-CH₃) PhCH₂ H O

550 CH₃O H H 2-quinoHnyl H 0

551 CH₃O H CH₃ CH₃ H O

552 CH₃O H CH₃ CH₃ H s

553 CH₃O H CH₃ 3-CF₃ Ph H O

554 CH₃0 H CH₃ 2-furyl H 0

555 CH₃O H CH3 2-furyl H s

556 CH₃0 H CH₃ 2- thienyl H O

557 c¾o H CH₃ 3-(4-(OCH₃)thienyl) H O

558 CH₃O H CH₃ H O

559 CH3O H n-propyl 4-(CF₃0)Ph H O

560 CH₃O H 4-F Ph 4-(CF₃0)Ph H 0

561 CH₃O Br isobutyl 3-CF₃ Ph Br O

562 CH₃O H CH₃ H O

563 EtO 3-F Ph Et cyclopentyl H O

564 EtO H H CH₃ H 0

565 EtO H H CH₃ H s

566 EtO H H 3,4-di-CH₃ Ph H 0

567 EtO H CH₃ n-propyl H 0

568 EtO H CH₃ cyclobutyl H 0

569 EtO H CH₃ cycloheptyl H 0

570 EtO H CH₃ cycloheptyl H s

639 C0₂H n-pentylCO Ph 3-Cl Ph H o

The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific X moiety, and the specific substituents possible at various locations on the molecule, all play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.

In general, the compounds of this invention may be prepared by standard techniques known in the art and by known processes analogous thereto. For example, the compounds may be prepared according to methods described in U.S. Patent No. 6,828,335, which is incorporated by reference in its entirety.

For example, the compounds of Formula I may generally be synthesized according to Reaction Schemes 1, 2, and 3, Reaction Schemes 1 and 2 demonstrate how to make intermediates that are coupled in Reaction Scheme 3 to provide the compounds of Formula I.

Route (A) of Reaction Scheme 1 provides a method to prepare compounds 4 and 5 where R" is Ci- C lower alkyl or benzyl, R³ is not hydrogen, and X is O. The first step shows protection of the acid group of a commercially available aspartate derivative compound 1 by means well known in the art such as, for example, by forming a silyl ester, followed by N-acylation with the appropriate R⁴-acid derivative, R⁴COY, where Y is a leaving group such as halo. Finally, the compound is deprotected by means well known in the art such as, for example, in the case of a silyl ester, an aqueous work up, to give compound 2. Alternatively, condensation of the protected form of compound 1 with a free carboxylic acid such as R⁴COOH in the presence of a dehydrating reagent, such as DCC or EDC1, also provides compound 2. Compound 2 may then be converted to compound 3, where R³ is as defined for Formula I compounds by several methods. For example, one such method, when R³ = Me, is the well known Dakin-West reaction which is typically performed using acetic anhydride and pyridine. When R³ is other than hydrogen, compound 2 may be converted to an acid chloride with a reagent such as thionyl chloride and reacted with a Grignard reagent such as R³Mg-halo, to provide compound 3, Other methods for the formation of ketones of compound 3 from acids and acid derivatives may also be employed, for example, by using Weinreb amides, which are known to those skilled in the art. Compound 3 is then cyclized under acid dehydrative conditions using, for example, phosphorus oxychloride, or a mixture of sulfuric acid and acetic anhydride, generally with heating, to provide compound 4 where X is O and the R³ group is attached at the 5 position.

It will be recognized by those skilled in the art that compound 4 and thus, compound 5, may exist in two regioisomeric forms with respect to the attachment point of the R³, CH₂C0₂R , and CH₂CH₂OH groups. Using Route (B), one can prepare compound 4 in which the R³ is attached at the 4-position and carboxymethyl side chain is attached at the 5-position, that is, the groups are reversed from that of Route (A). In Route (B), a commercially available amino acid, compound 6, may be acylated under basic conditions, for example, with aqueous sodium hydroxide, with an appropriate R⁴-acid derivative, (e.g., R⁴COY), where Y is a leaving group such as chloro, to provide the N-acylated product 7. Compound 7 may be then coupled with an acetic acid ester in the presence of a strong non-nucleophilic base to make the keto ester 8, where R" is C C₆ alkyl or benzyl. Cyclization of compound 8 using a dehydrating reagent such as POCl₃ provides compound 4 where X = O and R³ is attached at the 4 position. Reaction of compound 8 with a nucleophilic S reagent such as P₂S₅ in solvents such as pyridine or acetonitrile/triethylamine, with heating as necessary, gives compound 4 where X = S and R³ is attached at the 4 position.

Route (C) of Reaction Scheme 1 depicts the preparation of compound 4 from ketoesters 9 or 10, where Y is a leaving group such as halo and R" is CpQ alkyl or benzyl. Either compound 9 or 10 may be chosen as the starting material depending on whether the R³ group in the desired end product is hydrogen or is attached at the 4 or 5 position. Accordingly, compound 9 or 10 may be reacted with an amide or thioamide where X is either O or S to yield compound 4. Ketoesters 9 or 10 are commercially available, or may be prepared by methods well known in the art such as by bromination of commercially available ketoesters 9 and 10 where Y is hydrogen. Amides (R⁴C(=X)NH₂) where X is O may be commercially available carboxylic amides, or may be prepared from the corresponding available acids or acid chlorides by well known methods. Thioamides (R C(=X)NH₂) where X is S may be commercially available thioamides, or may be prepared from the corresponding available amides by known methods such as through the use of Lawesson's reagent. Reaction of ketoester 9 with an amide or thioamide in the presence of a base provides compound 4 as an oxazole or a thiazole, respectively, where R³ is other than hydrogen and located at the 4- position. Reaction of ketoester 10 with an amide or thioamide in the presence of base provides compound 4 as an oxazole or thiazole, where R³ is located at the 5-position.

Routes (A), (B), and (C) each provide compound 4 where R³ and R⁴ are each as described for a compound of Formula I and where R" is a lower alkyl or benzyl. Compound 4 may then be reduced to compound 5 using reducing agents such as lithium aluminum hydride, lithium borohydride, or other suitable hydride donors under conditions well known in the art. Reaction Scheme 1 Route (A) Route (B)

1. protection

R COY

2. R⁴COY, base or

base

R⁴COOH, DCC

3. deprotection

l .

2. e;

Reaction Scheme 2 depicts the conversion of commercially available hydroxy ketone 11 to a protected derivative 12, by reaction with R⁷-Y in the presence of a base, where R⁷ is C -Ce alkyl optionally substituted with phenyl or oxo, Ci-Cg trialkylsilyl, arylalkylsilyl, or COR⁸; and R⁸ is C_rC₆ alkyl or phenyl optionally substituted with Q-Ce alkyl, halo, or nitro; and Y is a leaving group. "C Q trialkylsilyl" means three independently selected straight or branched chain alkyl groups having from one to about six carbon atoms, each of which are bound to silicon and includes such groups as trimethylsilyl, teri-butyldimethyl silyl, and the like. "Arylalkylsilyl" means at least one phenyl or substituted phenyl group bound to silicon, with an appropriate number of independently selected straight or branched chain alkyl groups having from one to about six carbon atoms, each of which are also bound to silicon, and includes such groups as t- butyldiphenylsilyl methyldiphenylsilyl, dimethylpentafluorophenylsilyl, and the like. "Leaving group" includes halides such as I, Br, and CI; carboxylates such as acetates, and trifluoroacetates; and aryl and alkyl sulfonates such as methanesulfonates (mesylates) and p-toluene sulfonates (tosylates), and the like.

Compound 12 is substituted with R² (as described in Formula I) by means of, for example, reaction with a source of electrophilic halogen, or a Friedel -Crafts reaction in the presence of a Lewis acid and R²-Y where Y is as described above, to form a substituted ketone 13. Alternatively, a halogenated compound formed in this manner (for example, substituted with bromine or iodine) may be reacted with a range of coupling partners under metal catalysis, using complexes and compounds of elements such as palladium and nickel well known to those skilled in the art, to form further substituted ketone 13. Examples of such catalysts include tetrakis(triphenylphosphine)palladium(0) and [ '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), and similar nickel(O) and nickel(H) compounds; and examples of coupling partners include boronic acids and esters (the well known Suzuki coupling, carried out in solvents such as toluene in the presence of a base such as potassium carbonate), and organometallics such as Grignard reagents, organozincs (Negishi coupling), and organotin derivatives (Stille coupling), reaction conditions for which are widely known. Furthermore, such halogenated compounds may be coupled with secondary amines such as piperidine using similar palladium or nickel catalysts (Hartwig or Buchwald coupling) to provide further substituted ketones 13.

Further reaction of compound 13 with a halogen source or R⁵-Y, (where R⁵ is as described in Formula I), under similar conditions gives disubstituted compound 14. A Wittig reaction, or the Horner- Emmons-Wadsworth variation, each well known in the art, may be used to convert 14 to compound 15. For example, reaction of compound 14 with a trialkylphosphonoacetate, where R" is lower alkyl and R is as described in Formula I, in the presence of a strong base such as sodium hydride, provides compound 15. In like manner, compound 13 may be converted to compound 1 where R⁵ is H.

Regardless of the isomeric mixture of isomers of 15 produced in the reaction, either isomer (E or Z) or a mixture of both, may be converted to the corresponding compound 17 by catalytic hydrogenation or reduction with a hydride reagent capable of 1,4 (conjugate) addition, which are known to those skilled in the art. This route is particularly advantageous for preparing compound 17 where R¹ is hydrogen.

Compound 17 where R¹ is COOR, may be prepared through standard condensation reactions, for example, the well known Knoevenagel reaction. In such cases, the ketone 13 or 14 may be reacted with a suitable active-hydrogen coupling partner, under the influence of acidic reagents such as titanium tetrachloride, or basic reagents such as piperidine, in appropriate solvents. The product 15b (compound 15 where R¹ is COOR), may be reduced to 17b (compound 17 where R¹ is COOR), which may be further alkylated with another R¹ group in the presence of base, hydrolyzed and decarboxylated to give 17d (compound 17 where R¹ is other than COOH and R is H). Reesterification of 17d and removal of the protecting group R⁷ would afford 17c. Reesterification may be performed using standard conditions using the well-known Fischer esterification by treatment with an acid and an alcohol or by reaction with diazoalkyl reagents or with an electrophilic species such as, for example, methyl iodide or dimethyl sulfate. Compound 17 where R¹ is alkoxy may be prepared by a similar condensation reaction of ketone 13 or 14 with a silylated enol ester of Formula R¹CH=C(OR")0-alkylsilyl, where R¹ is alkoxy, under the influence of acidic reagents such as titanium tetrachloride, and reducing the intermediate compound 15, where R^! is alkoxy, in the presence of hydrogen and a catalyst as described above.

A general coupling reaction of compound 13 or 14 via the Reformatsky reaction produces compound 16 (Formula II), when R¹ is alkyl, or compound 15a when R¹ is H. The ketone is condensed with an appropriate organozinc reagent prepared in situ from Zn and R'CHYC0₂R, where Y is halo. The alpha- halo ester compounds of formula R'CHYC0₂R, are , either commercial reagents or are prepared by halogenation of commercially available R¹CH₂C0₂R compounds by methods well known to those skilled in the art.

The conversion of 16 to 17 may be accomplished by standard hydrogenation conditions, for example, Pd/C and hydrogen; and deprotection of compound 17, where R⁷ is a protecting group, to compound 17c, where R⁷ is hydrogen, may be accomplished by standard means. For example, when the R⁷ group is alkyl (e.g., methyl), the compound 17a may be generated by nucleophilic cleavage with a reagent such as an alkali metal thiolate. Alternatively, compound 17 when R⁷ is methyl, may be converted to compound 7c by reaction with a Lewis acid such as a bromoborane. When R⁷ is benzyl, the compound 17 may be converted to 17c under hydrogenation conditions, typically carried out using a catalyst such as palladium. Other conditions for the removal of the protecting group R⁷ from compound 17, where R⁷ is other than hydrogen which produces the hydroxy compound 17c, are dependent on the specific protecting group chosen from among those which are well known by those skilled in the art.

Reaction Scheme 2

Notes:

a. (R"0)₂P(=0)CHR¹COOR, where R¹ = H, strong base

b. R^!CH₂COOR, where R¹ = COOR, acid or base catalyst

c. R'CHBrC0₂R₅ Zn

The final step in the preparation of Formula I compounds is shown in Reaction Scheme 3. The alcohol 5 (from Reaction Scheme 1) is coupled with the hydroxy indane 17c (from Reaction Scheme 2) via a Mitsunobu coupling, facilitated by an azodicarboxylate reagent such as DEAD, and a phosphine such as triphenylphosphine to make the compounds of Formula I. Alternatively, the hydroxy group of alcohol 5 is converted to a leaving group such as halo, tosylate (OTs), or mesylate (OMs), by reaction with a halogenating agent such as thionyl chloride or CCl₄/triphenylphosphine; or by reaction with a Y-halo compound, where Y is tosyl (Ts) or mesyl (Ms), in the presence of a base, providing compound 18. Compound 18 may be reacted with compound 17c in the presence of a base, providing the compounds of Formula I.

Compounds of Formula I in which R is alkyl, may be converted to compounds of Formula I in which R is H by treatment with a base (e.g., KOH) in a suitable solvent (e.g., methanol, THF, or water, or mixtures thereof) with heating. Alternatively, this conversion may be accomplished by reaction with a nucleophile such as iodide or cyanide, in a suitable solvent, such as pyridine. In addition, when R is benzyl, the cleavage to compounds of Formula I in which R is H may be affected through hydrogenolysis by means well known in the art.

Reaction Scheme 3

'

(I)

An alternative route to Formula I compounds, useful when X = S and the R⁴ group contains one or R⁶ substituents labile to the reaction conditions of Scheme 1 or 2. is shown in Reaction Scheme 3a. Reaction Scheme 3a

17

(I, X = S)

In Scheme 3a, a 2-aminothiazole 4 may be prepared using thiourea (similar to Route C, Reaction Scheme 1) and converted to a 2-halo thiazole 5a as shown above (Erlenmeyer et al., Helv. Chim. Acta 28:362-363, 1945). Mitsunobu coupling of 5a by a method analogous to Reaction Scheme 3 is then accomplished, and product 19 is further elaborated by a Palladium-catalyzed cross-coupling reaction to introduce the R⁴ substituent. Hydrolysis as described in Reaction Scheme 3 gives Formula I compounds where R = H.

The foregoing reaction schemes are further illustrated by the specific Examples described herein.

The salts and esters of this invention may be readily prepared by conventional chemical processes as described previously herein.

The invention is further directed to novel Formula II compounds (compound 16) and Formula III (compounds 17, including compounds 17a-d) compounds shown in Reaction Scheme 2. These compounds are useful in the preparation of the compounds of Formula I, and are further described as follows. The present invention encompasses the compounds of Formula II and Formula ΠΙ,

(II) (III)

wherein

R, R¹, R², R³, R⁴, R⁵, R⁶, and X are as defined for Formula I above; and

R⁷ is H, C_rC₆ alkyl optionally substituted with phenyl or oxo, CpQ trialkylsilyl, arylalkylsilyl, COR⁸, COOR⁸, or

R is Ci-Ce alkyl, or phenyl optionally substituted with C -Ce alkyl, halo, or nitro; and

the salts thereof.

Ci-Ce trialkylsilyl means three independently selected straight or branched chain alkyl groups having from one to about six carbon atoms, each of which are bound to silicon and includes such groups as trimethylsilyl, ieri-butyldimethyl silyl, and the like,

Arylalkylsilyl means at least one phenyl or substituted phenyl group bound to silicon, with an appropriate number of independently selected straight or branched chain alkyl groups having from one to about six carbon atoms, each of which are also bound to silicon, and includes such groups as t- butyldiphenylsilyl methyldiphenylsilyl, dimethylpentafluorophenylsilyl, and the like.

The salts of this invention may be readily prepared by conventional chemical processes as described previously herein.

The compounds of Formula II and Formula III may each contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration. Preferred isomers are those with the absolute configuration, which produces the compound of Formula II or Formula III that will be useful in producing the compounds of Formula I having a more desirable biological activity, hi certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two aromatic rings of the specified compounds.

Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form.

It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art, as well as by the novel means described herein.

For example, Formula II compounds may contain an asymmetric center (labeled C-2) and Formula III compounds may contain two asymmetric centers (labeled C-2 and C-1') which give rise to enantiomers and diastereomers. Examples of these and other compounds of Formula II and Formula III, which are illustrative of the present invention, are shown in Table 2.

Table 2

Illustrative Exam les of Compounds II and HI

(Π) (Hi)

absolute

Entry No. Formula configuration R' R² R⁵ R⁷

C-2 c-r

20 II S — CH₃ H H t-BuCO

21 ΠΙ s s CH₃ H H t-BuCO

22 Π R — CH₃ CH₃ H PhCH₂

23 II R — CH₃ CH₃CO H PhCH₂

24 II S — CH₃ 2-thienyl H t-Bu(CH₃)₂Si

25 III S R c¾ 2-thienyl H t-Bu(CH₃)₂Si

26 II s — c¾ Ph H CH₃

27 II R — CH₃ CI H CH₃

28 II S — c¾ CI H CH₃

29 III s S c¾ CI H CH₃

30 II R — c¾ Br H Ph(CH₃)₂Si

31 III R R CH₃ Br H Ph(CH₃)₂Si

32 II S — CH₃ Br H Ph(CH₃)₂Si

33 III S R CH₃ Br H Ph(C¾)₂Si

34 Π s — CH₃ CI CI CH₃

35 II R — Et H H CH₃

36 ΠΙ R R Et H H C¾

37 Π S — Et H H PhCH₂

38 ΠΙ s S Et H H PhCH₂

39 u R — Et H H t-Bu

40 II S — Et H H t-Bu

41 Π s — Et CH₃ H Ph(CH₃)₂Si

42 ΠΙ s s Et CH₃ H Ph(CH₃)₂Si

43 II R — Et n-propyl H CH₃

44 Π S — Et Ph H CH₃

45 II s — Et 3-Cl Ph H t-Bu(CH₃)₂Si

46 III s R Et 3-Cl Ph H t-Bu(CH₃)₂Si

47 n s — Et 4-pyridyl H t-Bu(CH₃)₂Si

48 ΠΙ s S Et 4-pyridyl H t-Bu(CH₃)₂Si

49 II s — Et CH₃ H Ph(CH₃)₂Si

50 II R — Et n-propyl CI CH₃

51 II R — Et Br Br t-Bu(CH₃)₂Si

52 III R R Et Br Br t-Bu(CH₃)₂Si

53 II S — CF₃CH₂ H H CH₃ absolute

Entry No. Formula configuration R¹ R¹ R⁵ R⁷

C-2 c-r

54 Π S — CF₃CH₂ CH₃ CH₃ (4-CH₃0)PhCH₂

55 III s s CF₃CH₂ CH₃ CH₃ (4-CH₃0)PhCH₂

56 II s — n-propyl H H (i-Pr)₃Si

57 II R — n-propyl PrCO PrCO t-Bu

58 Π R — n-propyl CI CI (i-Pr)₃Si

59 III R R n-propyl CI CI (i-Pr)₃Si

60 II S — isopropyl CH₃ H CH₃

61 III S R isopropyl CH₃ H CH₃

62 II R — isopropyl ^■ n-hexyl H (4-CH₃0)PhCH₂

63 III R S isopropyl n-hexyl H (4-CH₃0)PhCH₂

64 II S — n-butyl H H PhCH₂

65 II s — n-butyl CH₃OC¾ H t-Bu(CH₃)₂Si

66 III s s n-butyl C¾OCH₂ H t-Bu(CH₃)₂Si

67 II R — n-butyl CI H CH₃

68 II R — n-pentyl CI CI (4-CH₃0)PhCH₂

69 II S — n-pentyl 2-thienyl 2-thienyl CH₃

70 III s s n-pentyl 2-thienyl 2-thienyl CH₃

71 II R — n-hexyl CH₃CO H t-Bu(CH₃)₂Si

72 III R s n-hexyl C¾CO H t-Bu(CH₃)₂Si

73 Π R — n-hexyl Ph H Ph(CH₃)₂Si

74 ΠΙ R R n-hexyl Ph H Ph(CH₃)₂Si

75 II R — cyclopropyl H H t-BuCO

76 II S — cyclopropyl CH₃ H (i-Pr)₃Si

77 Π s — cyclobutyl H H CH₃

78 m s s cyclobutyl H H CH₃

79 II s — cyclobutyl CI CI (4-CH₃0)PhCH₂

80 II R — cyclopentyl CH₃ H t-Bu(CH₃)₂Si

81 ΠΙ R s cyclopentyl CH₃ H t-Bu(CH₃)₂Si

82 II S — cyclohexyl Et Et CH₃

83 Π R — cyclohexyl 2-thienyl H CH₃CO

84 II R — cyclohexyl CI H CH₃

85 III R R cyclohexyl CI H CH₃

86 II S — 2-propenyl H H t-Bu(CH₃)₂Si

87 II R — 2-propenyl CH₃ H C¾CO absolute

Entry No. Formula configuration R¹ R² R^s R⁷

C-2 c-r

88 II S — 2-isobutenyl CH₃CO H CH₃

89 Π s — 5-hexenyl CH3CO CH₃CO c¾

90 II s — CH₃0 H H PhCH₂

91 III s R CH₃O H H PhCH₂

92 II R — CH₃O 3-F Ph H (4-CH₃0)P CH₂

93 II S — EtO CI CI PhCH₂

94 III S R EtO CI CI PhCH₂

95 II R — (i-Pr)O H H PhCH₂

96 III R R (i-Pr)0 H H PhCH₂

97 Π S — (n-pentyl)O c¾ H t-Bu(CH₃)₂Si

98 ΠΙ s S (n-pentyl)O CH₃ H t-Bu(CH₃)₂Si

99 Π s — C0₂H H H (4-CH₃0)PhCH₂

Another embodiment of the present invention is an improved process for the preparation of compounds having a specific isomeric configuration when that specific configuration is desired for the ultimate desired end product of Formula I. The improved process yields these intermediate compounds in significantly greater diastereomeric excess than was heretofore possible.

Previously, for example, in the absence of stereocontrol during the hydrogenation step of Reaction Scheme 2, hydrogenation of a Formula II compound, where R¹ is alkyl may produce an unequal mixture of diastereomeric products of Formula III, in which one pair of enantiomers is favored because of the asymmetric nature of the starting material. Separation of such compounds may be accomplished by stepwise separation of the enantiomeric pairs, then by resolution of each enantiomer by crystallization or by chiral HPLC. Prior resolution of the starting material into a single enantiomer produces mixtures with enrichment of a single enantiomer that may likewise be separated.

However, when a compound of a specific relative configuration, namely a syn form (defined below) is desired, the yield is low when R¹ is alkyl, because the conditions of the hydrogenation step described in the art may favor the other (i.e., anti) diastereomers.

The desired isomeric configurations realized from this improved process are in the syn form where, for example, in compounds of Formula Va and Vb (depicted in Reaction Schemes 4 and 5), the R⁹ group and the 2' methylene carbon of the cyclopentane ring are both below the plane or are both above the plane. Anti diastereomers are those compounds where, for example, R⁹ is above the plane and methylene is below the plane. This is further exemplified in Figures 1 and 2 below, in which solid wedge bonds are used to indicate projection of the bond above the plane and dashed wedge bonds are used to indicate projection of the bond below the plane. Figure 1. syn diastereomers of Formula V

(Va) (Vb)

Figure 2. anti diastereomers of Formula V

(Ve) (Vf)

The improved process of this invention yields compounds in the syn form (Formulas Va and Vb, as drawn in Figure 1 and Reaction Schemes 4 and 5) in significantly higher diastereomeric excess than was generally possible.

The intermediate compounds used as starting materials for this process (compound IV of Reaction Schemes 4 and 5) are related to the compounds of Formula II (compound 16) in Reaction Scheme 2, and may be prepared by the same or analogous methods. These intermediates may be reacted under certain conditions to yield Formula V compounds that are related to compounds of Formula III (compounds 17 and 17a of Reaction Scheme 2), or to directly yield compounds of Formula I. However, due to the constraints of the improved process, only certain substituents are appropriate for completing this process.

Accordingly, the present invention relates to an improved process for the preparation of a substantially enriched syn form of a com ound of Formula V,

wherein

R⁹ is methoxy optionally substituted by fluoro,

C₂-C₆ alkoxy, C,-C<5 alk l, or C₄-Cg cycloalkyl each optionally substituted by fluoro,

methylenedioxyphenyl or phenyl optionally substituted with R¹³;

R¹⁰ is hydrogen, fluoro, methyl optionally substituted with fluoro, oxo, or C₂-C₆ alkyl which may be unsubstituted or substituted with C_rC₆ alkoxy, oxo,

fluoro, or with phenyl, furyl, thienyl, pyiTolyl, oxazolyl, thiazolyl, imidazolyl,

pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,

pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,

piperazinyl, or morpholinyl,

each of which may be unsubstituted or substituted with R¹³,

or

R¹⁰ is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,

isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl,

each of which may be unsubstituted or substituted with R¹³;

R¹¹ is halo or Ci-C₆ alkyl optionally substituted with oxo;

R¹² is hydrogen, methyl optionally substituted with fluoro or oxo,

C₂-C₆ alkyl optionally substituted with phenyl, fluoro, or oxo,

C,-C₆ trialkylsilyl, arylalkylsilyl, COR¹⁴, COOR¹⁴, or

R¹³ is fluoro, CF₃, Ci-C₆ alkyl optionally substituted with oxo, or C C₆ alkoxy optionally

substituted with fluoro;

R¹⁴ is Ci-C₆ alkyl, or phenyl optionally substituted with Ci-C₆ alkyl or fluoro;

R¹⁵ is hydrogen, C C₆ alkyl or phenyl substituted with R¹³;

R¹⁶ is methyl optionally substituted with fluoro, oxo or

with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazoiyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1 ,4- benzodioxanyl,

each of which may be unsubstituted or substituted with R¹³, or

C₄-Cg cycloalkyl or C₂-C₆ alkyl, either of which may be unsubstituted or substituted

with fluoro, methoxy, C₂-C₆ alkoxy optionally substituted with phenyl or

C_rC₆ alkoxy, oxo or with, phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl,

pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,

isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,

piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl,

dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1 ,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R , or

C₂-Q alkyl which may also be substituted with C₄-C₈ cycloalkyl or with phenoxy which

may be unsubstituted or substituted with R⁶ or with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, moφholin l, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, . benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R ^" ,

or

R¹⁶ is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,

tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,

triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, diliydrobenzothiopyranyl, or 1,4- benzodioxanyl,

each of which may be unsubstituted or substituted with R , or with

phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,

pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, pyrimidinyl or phenoxy

each of which may be unsubstituted or substituted with R¹³, and

X is O or S;

comprising hydrogenation of a racemic mixture or isolated o tical isomer of a compound of Formula IV,

(IV) wherein the substituents are as defined above, in the presence of hydrogen source, a catalyst, optionally in the presence of a base.

Substantially enriched syn form means at least about seventy percent (70%) or greater of one or both of the compounds of the configuration of Va or Vb. This is equivalent to at least about 40% de (diastereomeric excess) of the syn diastereomer. Diastereomeric excess of the syn diastereomer is calculated from the following formula:

[syn] - [anti]

% de (syn) = x 100 = % syn diastereomer - % ant diastereomer

[syn] + [anti]

in which

% de (syn) represents the diastereomeric excess of the syn diastereomer

[syn] represents the concentration of the syn diastereomer

[anti] represents the concentration of the anti diastereomer,

and where

% syn + % anti = 100%.

Thus, a 40% de of the syn diastereomer is calculated from a mixture of 70% syn diastereomer and 30% anti diastereomer:

40% de (syn) = 70 % syn diastereomer - 30% anti diastereomer

Catalyst means any of the transition metal catalysts well known in the art to effect hydrogenation reactions (P.A. Chaloner, Handbook of Co-ordination Catalysis in Organic Chemistry, Butterworth, 1986), and includes homogeneous hydrogenation catalysts. A homogeneous catalyst is a catalyst which is at least partially soluble in the reaction medium and which effects the reduction of a double bond in the presence of hydrogen. Such catalysts include, for example, ClRh[P(Ph)₃]₃ (Wilkinson's catalyst), (1,5- cyclooctadiene)tricyclohexylphosphinepyridinoiridium(I) hexafluorophosphate, (1,5- cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate (Crabtree's catalysts), and the like.

Base means a substance with a p _¾ sufficient to form a salt in situ with a carboxylic acid {see, e.g., Advanced Organic Chemistry, 3rd Ed., Jerry March, pp 220-222). The base which is used in this reaction may be any inorganic or organic base, and may be soluble in the reaction medium. Such bases include, for example, mono, di, and tri(Ci-C<j alkyl)amines such as isopropyl amine, diisopropyl amine, triethylamine, and the like; additional primary amines such as, for example, cyclohexane methylamine and ethanolamine; additional secondary amines such as, for example, morpholine and piperidine; and additional tertiary amines such as, for example, l,8-diazaobicyclo[5.4.0]undec-7-ene and l,5-diazabicyclo[4.3.0]non-5-ene as well as inorganic bases such as alkali metal and alkaline earth hydroxides, carbonates, bicarbonates, and optically active bases such as quinine, cinchonine or (+)- or (-)-alpha-methylbenzylamine.

Such bases also include, for example, the chiral bases named below that are useful for resolution.

Hydrogen source refers to any means of delivering hydrogen to the reaction medium and includes the use of hydrogen gas. Hydrogenation may by performed under a broad range of hydrogen pressures, that is, from about atmospheric pressure to about 1000 psi, preferably from about 20 to about 100 psi. Suitable hydrogenation solvents include, but are not limited to, protic solvents such as ethanol, methanol, water, 2- proponal, ieri-butanol, methyl cellosolve and the like, and mixtures thereof, or optionally mixtures thereof with a miscible aprotic solvent such as THF, such that the hydrogenation catalyst, the base, and the starting material are each at least partially soluble.

The resolution of the starting indene acetic acid derivatives of Formula IV or of the indane acetic acid derivatives of Formula V may be accomplished by means well known in the art, for example, by using optically active bases as resolving agents such as, for example, a readily available base such as quinine, cinchonine or (+)- or (-)-alpha-methylbenzylamine. Choice of the base will depend on the solubility properties of the salt formed, so that resolution by differential recrystallization may be readily accomplished. By selecting bases with opposite absolute configuration, separation of the salt of each enantiomer may be accomplished. For example, for the embodiment illustrated in Reaction Scheme 4, the desired enantiomer rVc or IVd may be separated, and the undesired isomer may be recycled by racemization under basic conditions to the starting material of Formula IV.

Suitable crystallization solvents refer to those solvents in which one diastereomeric salt of a mixture is more soluble than the other, enabling them to be separated by recrystallization. Such solvents include, for example, acetonitrile, acetone, i-butanol, 2-propanol, ethanol, methanol, and the like, and mixtures thereof.

Aqueous mineral acids include, for example, the commonly used inorganic acids such as hydrochloric or sulfuric acid, and the like.

The process may be carried out starting with a racemate of Formula IV (see Reaction Scheme 4), or with a Formula V compound with the configuration at one asymmetric carbon which corresponds to that desired for the end product (see Reaction Scheme 5). Starting with the generally pure configuration is preferred, although either process will yield the desired configuration of the end product (V) in substantially enriched syn form.

One embodiment of this process is shown in the example of Reaction Scheme 4 and includes the steps of

(1 ) formation of diastereomeric salts of IVc and IVd by treatment of IV with a suitable basic resolving agent,

(2) separation of the diastereomeric salts IVc and IVd by crystallization in a suitable crystallization solvent,

(3) optionally liberating the individual antipodes IVa and Vb from the separated salts by treatment with aqueous mineral acid, and

(4) reduction of either the separated diastereomeric salts IVc and Vd or the individual antipodes IVa and IVb by hydrogenation in the presence of a homogeneous hydrogenation catalyst, a suitable solvent and a base, wherein M+ is a cation selected from an alkali metal, alkaline earth metal, ammonium, and mono-, di-, tri- or quaternary alkylammonium or aralkylammonium, and R⁹-R¹² are as defined above. The enantiomeric purity of the product Va and Vb will correspond to the enantiomeric purity of the isomer IVa or IVb used, respectively, but will not include any substantial amount of the other (anti) diastereoisomer.

Reaction Scheme 4

A second embodiment of this process is shown in Reaction Scheme 5 and includes the steps of (1) reduction of the indene carboxylic acid of Formula IV by hydrogenation in the presence of a homogeneous hydrogenation catalyst, a suitable solvent, and a base,

(2) formation of diastereomeric salts of Vc and Vd by treatment of V with a suitable basic resolving agent,

(3) separation of the diastereomeric salts Vc and Vd by crystallization in a suitable crystallization solvent, and

(4) liberating the individual antipodes Va and Vb from the separated salts by treatment with aqueous mineral acid.

Reaction Scheme 5

The resolution of the racemate of either Formula IV or Formula V compounds may be accomplished by means well known in the art, such as by chiral HPLC, crystallization of chiral salt derivatives, chiral ester derivatives, and the like.

The determination of absolute chirality of rVa, IVb, IVc, IVd, Va, and Vb may be accomplished by several means known to those skilled in the art. X-ray crystallographic methods may provide such information under certain well-established conditions. For example, the presence in the crystallographic unit cell of another component of known chirality, such as a chiral resolving agent or auxiliary in the form of a salt, complex, or covalently attached group, may allow such determination. Another method known in the art, heavy atom scattering technique may be utilized when the compound to be assayed contains an atom of sufficient mass (for example, bromine or iodine). Other methods involving optical properties and the use of plane-polarized light may also be employed. For example, one skilled in the art would recognize that such techniques as circular dichroism may be applicable to a given structure or structural class.

Specific examples of the intermediates that may be made with the process of the present invention are shown below by way of example, and not by way of limitation, and may be used for the preparation of compounds of Formula I of the same absolute configuration.

Compounds of Formula HI in which R¹ = H may also be prepared in an optically active fashion by the methods summarized in Reaction Scheme 6. Resolution of racemic ester 17a (Formula III, where R¹ is H) may be accomplished by selective enzymatic hydrolysis using Amano Lipase PS to yield 17f. Alternatively, 17e, which may be prepared by hydrolysis of 17a, may be resolved by crystallization of the diastereomeric salts formed with an optically active amine, for example, (S)-(-)-a-methyl-benzylamine, followed by regeneration of the carboxylic acid by treating the salt with mineral acid. Further conversion of 17f to the intermediates 17g and 17h may be accomplished by means analogous to that described for the preparation of 17c in Reaction Scheme 2: reesterification and removal of the R⁷ protecting group. Reaction Scheme 6

= H) zation

17h (Formula III, R¹, R⁷ = H)

(2) Formula IB

The present invention also encompasses a compound of Formula IB,

Formula IB wherein

R is H or Ci-C₆ alkyl;

R¹ is H, COOH, -C(=0)-O C₃-C₈ cycloalkyl, C C₆ alkyl, C₂-C₆ alkenyl, or C C₆ alkoxy, wherein R¹ is C]-C₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally and independently substituted with R⁶;

R² is H, halo, or Ci-Q alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting of Ci-Q alkoxy, oxo and fluoro, or

R² is C5.1 aryl, C₃.₁₄ heterocycle or C_5-i₄ heteroaryl, wherein said aryl, heterocycle or heteroaryl may be optionally substituted with one or more R⁶;

R³ is H, Ci-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally substituted with one or more R⁶;

X is O or S;

R⁴ is C_5-H aryl, C_3-i₄ heterocycle or C5.14 heteroaryl, wherein said aryl, heterocycle or heteroaryl is substituted with one or more R⁷,

R⁵ is H, halo or C C₆ alkyl wherein said alkyl may be optionally substituted with oxo;

R⁶ is halo, CF₃, Ci-C₆ alkyl wherein said alkyl may be optionally substituted with oxo or hydroxy, or Ci-C₆ alkoxy optionally substituted with fluoro;

R⁷ is selected from the group consisting of

(a) hydroxyl,

(b) Ci-C₆ alkoxyl, wherein one or more H of the alkoxyl is ²H (D), and

(c) -Oprotecting group;

(d) -0-C(=0)-R" wherein R" is Q-Q alkyl or C_5-i₄ aryl wherein said alkyl or aryl may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -SH, amide, carboxylic acid, CN, C C₆ alkyl, Ci-C₆ thioalkyl, C₆ aryl and C₅ heteroaryl and -NR.R4 and wherein R_c and j are independently hydrogen, or C,-C₆ alkyl;

(e) -0-C(=0)-R"', wherein R¹¹¹ is -NR-R_f and wherein R_e and R_f are independently hydrogen, or C

C₆ alkyl;

or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer or racemate thereof.

In some embodiments, the compounds of Formula IB is alkali metal salt, basic nitrogen containing group.

In some embodiments, the compounds of Formula IB is a meglumine, calcium, magnesium, ammonium salts, potassium or sodium salt thereof.

In another embodiment, the compound of Formula IB has the following structure:

As used herein in Formula IB, the term "O-protecting group" refers to oxygen containing functional groups such as hydroxyl that are temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. Protecting groups may be introduced and removed at appropriate stages during the synthesis of a compound using methods that are known to those of ordinary skill in the art. The protecting groups are applied according to standard methods of organic synthesis as described in the literature (Theodora W. Green and Peter G.M. Wuts (2007) Protecting Groups in Organic Synthesis, 4^th edition, John Wiley and Sons, incorporated by reference with respect to protecting groups).

Exemplary oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p-methoxybenzyloxymethyl ether), optionally substituted ethyl ethers, optionally substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilyiether), TIPS (triisopropyisilyl ether), TBDMS (t-but ldimethylsilyl ether), tribenzyl silyl ether, TBDPS t- butyldiphenyl siJyl ether), esters (e.g. formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate) carbonates, cyclic acetals and ketals.

In some embodiments, the -O-protecting group is -O-CH2-PI1, wherein said phenyl may be optionally substituted with Ci-C₆ alkoxyl, (e.g. -4 methox benzyl).

In another embodiment, for the compound of Formula IB, R₇ is an ester having the structure of -O- C(=0)-R", wherein R" is defined as in Formula IB. The ester of "-0-0(=0)^^ϋ" may be a product of compound of Formula IB, wherein R₇ is -OH, reacting with an appropriate carboxylic acid. Any applicable carboxylic acid may be used. In some embodiments, the carboxylic acid may be an amino acid. In another embodiment, the carboxylic acid may be a natural a amino acid.

As used herein, the term "amino acid" refers to a compound comprising a primary amino (-NH₂) group and a carboxylic acid (-COOH) group. The amino acids used in the present invention include naturally occurring and synthetic α, β, γ or δ amino acids, and include, but are not limited to, amino acids found in proteins. Exemplary amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. hi some embodiments, the amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyros inyl, asparaginy], glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β- tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β- glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. Additionally, as used herein, "amino acids" also include derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmaco-properties upon metabolism to an active form.

As used herein, the term "natural a amino acid" refers to a naturally occurring a-amino acid comprising a carbon atom bonded to a primary amino (-NH₂) group, a carboxylic acid (-COOH) group, a side chain, and a hydrogen atom. Exemplary natural a amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophane, proline, serine, threonine, cysteine, tyrosine, asparaginate, glutaminate, aspartate, glutamate, lysine, arginine and histidine.

In one embodiment, for the compound of Formula IB, R is H, R¹ is H, R² is H, R³ is Ci-C₆ alkyl, X is O, and R⁴ is a phenyl substituted with one or more R⁷, wherein R⁷ is selected from the group consisting of (a) hydroxyl, (b) Cj-C₆ alkoxyl, and one or more H of the alkoxyl is ²H (D), and (c) -0-CH₂-Ph, wherein said phenyl may be optionally substituted with Ci-Ce alkoxyl; and R⁵ is H, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula IB has the following structure:

In another embodiment, the compound of Formula IB has the following structure:

or

Further, in one embodiment, the compound of Formula IB is a meglumine (N-Methyl-d-glucamine), potassium or sodium salt of the following structure

In one embodiment, for compounds of Formula IB, R² is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, tnazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one or more R⁶ as defined herein.

In one embodiment, for compounds of Formula IB, R⁴ is selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrotliienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indo!yl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, and 1 ,4-benzodioxanyl, each of which may be substituted with one or more R⁷ as defined herein.

hi one embodiment, for compounds of Formula IB, R⁷ is CpCe alkoxyl, wherein one or more H of the alkoxyl is ²H (D). The deuterated substituted compounds may be used as medical treatment as described below. In addition, the deuterated substituted compounds may also be used as a biomarker for pharmacological study of the compounds. For example, the deuterated compounds may be used to determine the bioavailability and quantification of the compounds by measuring the amount of compounds in serum using, for example, mass spectroscopy.

When an alkyl, cycloalkyl, alkenyl, or alkoxy group is described as being substituted with fluoro, it may be substituted with one or more fluorine atoms at any available carbon atom up to the perfluoro level.

When an alkyl substituent is described as being substituted by oxo, it means substitution by a doubly bonded oxygen atom, which forms together with the carbon to which it is attached, a carbonyl group - (C=0)-.

When any moiety is described as being substituted, it can have one or more of the indicated substituents that may be located at any available position on the moiety. When there are two or more substituents on any moiety, each substituent may be defined independently of any other substituent and may, accordingly, be the same or different.

The term "optionally substituted" means that the moiety so modified may be unsubstituted or substituted with the identified substituent(s).

R³ may be attached to the heterocyclic moiety of the compound of Formula IB at either the 4 or 5 position (i.e., at either available carbon atom) and, accordingly, the remaining portion of the molecule will be attached at the remaining available carbon atom.

Examples of the compounds of Formula IB, which are illustrative of the present invention, but not limiting in any way, include the following:

or a pharmaceutically acceptable salt thereof.

Embodiments of the present invention can comprise a compound of Formula IB or a pharmaceutically acceptable salt thereof, in some embodiments of the presention, a composition is provided that comprises, consists essentially of, or consists of a compound of Formula IB or a pharmaceutically acceptable salt thereof. In particular embodiments of the present invention, a pharmaceutical composition is provided that comprises a compound of Formula IB or a pharmaceutically acceptable salt thereof.

The process to be utilized in the preparation of the compounds of Formula IB depends upon the specific compound desired. Such factors as the selection of the specific X moiety, and the specific substituents possible at various sites on the molecule, all play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.

In general, the compounds of the present invention may be prepared by standard techniques known in the art and by known processes analogous thereto. Exemplary synthetic methods are shown in the General Reaction Scheme. The compounds of Formula A (Formula IB, wherein R ^a is C5.14 aryl, and said aryl is substituted with C_1-6 alkoxyl or -O-protecting group) may be prepared according to methods described in the literature with modifications known to those skilled in the art. For example, the compound of Formula A may be prepared according to methods described in U.S. Patent No. 6,828,335 with modifications known to those skilled in the art.

The compounds of Formula A may first undergo dealkylation or deprotection to provide the compound of Formula B. Subsequently, the compound of Formula B may react with an appropriate acid to provide an ester of Formula C. The compound of Formula B may also react with an appropriate reagent to provide compounds of Formula D, wherein R ^d is an -O-protecting group. For example, Formula B may undergo an alkylation to provide a compound of Formula D, wherein R^4d is C C₆ alkoxyl optionally with one or more H of the alkoxyl is D. Alternatively, the compound of Formula B may be subjected to other appropriate reaction conditions to provide other analogues. For example, the compound of Formula B may react with a compound containing an isocyanate group to provide a carbamate analogue of a compound of Formula B, as shown in General Reaction Scheme.

Compounds of Formula IB, wherein R⁴ is Ci-C₆ alkoxyl and one or more H of the alkoxyl is ²H (D) may be prepared according to methods known to those skilled in the art. For example, they may be prepared by using an appropriate deuterated starting material or deuterated intermediates according to methods described herein, e.g., Example 256.

General Reaction Scheme

R^4a is C₅.₁₄aryl substituted with

C_]_₆ alkoxyl or -O-proiecting group Formula A

Another aspect of the present invention provides processes of preparing a compound of Formula IB' including dealkylation of a compound of Formula B to give a compound of Formula IB'

Formula IB¹

wherein for Formula B and Formula IB'

R is H or C]-C₆ alkyl;

R^l is H, COOH, -C(=0)-OR', C₃-C₈ cycloalkyl, C C₆ alkyl, C₂-C₆ alkenyl, or C,-C₆ alkoxy, wherein R' is Ci-Ce alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fiuoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally substituted with R⁶;

R² is H, halo, or Ci-Ce alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting of Ci-C₆ alkoxy, oxo and fiuoro, or

R² is Cj-C aryl, C3-C14 heterocycle or C5-C14 heteroaryl, wherein said aryl, heterocycle and heteroaiyl may be optionally and independently substituted with one or more R⁶:

R³ is H, i-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally and independently substituted with one ore more R⁶:

X is O or S;

R^a Ci-C₆ alkoxyl,

R⁵ is H, halo or Ci-Cg alkyl wherein said alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, C C₆ alkyl optionally substituted with oxo or hydroxy, or C]-C₆ alkoxy optionally substituted with fiuoro.

According to another aspect of the present invention, processes of making compound B are provided. The processes include dealkylation of compound A

A to give compound B

B wherein said R^c is hydrogen or C,-C_fe alkyl.

In some embodiments, in the process of preparing compound B, the dealkyiation is carried out by treating compound A with boron tribromide (ΒΒ^) in a solvent such as dichloromethane. Alternatively, the dealkylation may be carried out by treating compound A with aluminum chloride in dodecyl thiol in a solvent.

In one embodiment, when compound A is an ester, R^c is Ci-Cg alkyl. The process further includes hydrolysis of compound B to give a compound of the following structure:

some embodiments, in the process of making compound B, compound A has the structure of COOH

and compound B has the structure of

COOH

In another embodiment, in the process of making compound B, compound A has the structure of

and compound B has the structure of

Further, one aspect of the present invention provides processes of making compound D. The processes include cleaving the ether bond of 0-CH₂Ph of compound C

to provide compound D

D wherein R^c is hydrogen or Ci ^ alkyl.

In some embodiments, the cleaving step is carried out by hydrogenolysis. The hydrogenolysis may be carried out by any known methods that may cleave the ether bond of 0-C¾Ph to provide compound D. For example, hydrogenolysis may be carried out by treating compound C with a catalyst and hydrogen (1¾) gas. Exemplary catalysts include, but are not limited to, palladium (Pd) on carbon, platinum oxide, Raney nickel or a combination thereof.

In one embodiment, the cleaving step is carried out by treating compound C with boron tribromide or boron trichloride.

Further, in one embodiment, the cleaving step is carried out by treating compound C with trimethylsilyl iodide.

In one embodiment, in the process of making compound D, for compound C, when R^c is . s alkyl, the processes further include hydrolysis of compound D to give a compound of the following structure:

In some embodiments, for the process of making compound D, compound C has the following structure:

and compound D has the following structure:

In another embodiment, for the process of making compounds D, compound C has the following structure:

and compound D has the following structure:

(3) Formula VI

The present invention also encom asses compounds of Formula VI:

Formula VI

wherein

R^] and R² are independently H, Ci-Cg alkyl, or C3-C6 cycloalkyl;

L is a linker and selected from the group consisting of -(CH₂)_m-X-, -Y-(CH₂)_n-X-, and

wherein

X is selected from the group O, S, S(=0), and S(=0)₂,

Y is selected from the group O, NR⁵, S, S(=0), and S(=0)₂,

m is 1, 2, or 3,

n is 2, 3, or 4,

t is 0 or 1,

p is 0,1, 2, or 3,

q is 1, 2, 3, or 4,

wherein the sum of p and q is 1, 2, 3, or 4;

Ar is phenyl or a 6-membered heteroaryl containing up to three N atoms,

wherein said Ar is optionally substituted at any available position by 1 to 5 independently selected R³ groups, and

optionally fused to a 5- or 6-membered saturated carbocyclic ring,

a 5- or 6-membered unsaturated carbocyclic ring, or

a 5- or 6-membered heterocyclic ring containing up to 3 additional

heteroatoms selected from N, O, and S,

wherein said fused ring may be optionally substituted at any available position by 1 to 4 independently selected R⁴ groups;

R³ is selected from the group consisting of hydroxy, SH, halo, CN, N0₂, C(=0)OH, C(=0)-OC C₆ alkyl, C(=0)-OC₃-C₆ cycloalkyl, NR⁶R⁷, C(=0)NR⁶R⁷, C(=S)NR R⁷, C C₆ alkyl optionally substituted with halo, OH, NR⁶R⁷, or Q-Q, alkoxy, C,-C₆ haloalkyl, C C₆ alkoxy, Q-Q thioalkyl, C₂-Q alkenyl, C C₆ haloalkoxy, C₃-C₈ cycloalkyl, C₃-Cg cycloalkoxy, phenoxy optionally substituted on the phenyl ring with halo, Ci-Q alkyl, or Q-Q, alkoxy, and

a mono or bicyclic ring radical selected from the group consisting of

c) phenyl optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S,

d) a 5- or 6-membered heterocyclic ring radical containing up to 4

heteroatoms selected froni N, O, or S, optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S,

said mono or bicyclic ring radical being optionally substituted with up to 5 groups independently selected from the group consisting of halo, hydroxy, oxo, CN, C_rQ alkyl optionally substituted with halo, OH, NR⁶R⁷, Q-Q alkoxy, Q-Q haloalkyl, C C₆ alkoxy, C C thioalkyl, Q- C₆ haloalkoxy, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C C₆ acyl, C(=0)OH, CH₂C(=0)OH, NR⁶R⁷, C(=0)NR⁶R⁷, C(=O)0C C₆ alkyl, and C(=0)OC₃-C₆ cycloalkyl; R⁴ is selected from the group consisting of oxo, hydroxy, halo, CN, NR⁶R⁷, Ci- alkyl optionally substituted with OH, NR⁶R⁷, or C,-C₆ alkoxy, C C₆ haloalkyl, C,-C₆ alkoxy, C C₆ thioalkyl, C C₆ haloalkoxy, C₃-Q cycloalkyl, and C3-Q cycloalkoxy;

R⁵ is selected from the group consisting of H, -Ce alkyl optionally substituted with C₃-C₆ cycloalkyl, C_rC₆ acyl, benzyl optionally substituted with halo, C_\-C₆ alkoxy, (Ci-C₆)alkyl, CN, NH₂, N[(C C₃)alky¾ N<¾, or CF₃, C₃-Q cycloalkyl, and C(=0)Od-C₆ alkyl;

R⁶ and R⁷ are independently selected from the group consisting of H, Q-Ce alkyl optionally substituted with C₃-Q, cycloalkyl, Ci-C₆ acyl, benzyl optionally substituted with halo, - alkoxy, (C_r C₆)alkyl, CN, NH₂, N[(C C₃)alkyl]₂₅ N0₂, or CF₃, C₃-C₆ cycloalkyl, and phenyl optionally substituted with halo, C C₆ alkoxy, (C,-C₆)alkyl, CN, N[(Ci-C₃)alkyl]₂, N0₂, or CF₃, or

R⁶ and R⁷ may be taken together with the nitrogen atom to which they are attached to form a 5- or 6- membered heterocyclic ring optionally interrupted by NR⁵ or O; and

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

In some embodiments, the compounds of Formula VI is a meglumine, potassium or sodium salt thereof.

In one embodiment, the compound of Formula VI, R^! and R² are H, L is -0-(CH₂)_n-0, wherein n is 2, 3 or 4, Ar is a phenyl substituted with one to five R³, wherein each occurrence of R³ is independently Cj- C6 alkyl or a 5- or 6-meniber heterocyclic ring containing up to 4 hetero atoms selected from the group consisting of N, O and S, wherein the heterocyclic ring is substituted with C]-C₆ alkyl.

In some embodiments, the com has the structure:

In another embodiment, 11. the compound of Formula VI has the structure:

or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt is a meglumine, potassium or sodium salt of the above two structures. In some embodiments, the linker L is substituted at either the 4- or 5- carbon atom (as shown above) of the indane ring in Formula (VI), replacing H atom.

Exemplary compounds of Formula (VI), wherein R² and R¹ are H, L is -Y-(CH₂)_n-X-, X and Y are O, and n is 2, are shown in Table 3 a below.

Table 3a

Table 3 b

IUPAC Names for Compounds in Table 3a

Examples of compounds of Formula (km) [Formula (II), where R² and R¹ are H, L is -Y-(CH₂)_n- , X and Y are O, and n is 3], as shown in Table 4a below.

Table 4a

Formula Imm

Table 4b

IUPAC Names for Compounds in Tabie 4a

83 (( 1 S)- 5 - {3 -[(3 -methy 1-7-propyl- 1 ,2-benzisoxazol-6-y l)oxy]propoxy } -2,3 -dihydro- lH-inden-l-yl)acetic acid

84 2-[(lS)-5-(3-(5,6,7,8-tetrahydronaphthyloxy)propoxy)indanyl]acetic acid

85 2-{(lS)-5-[3-(5-oxo(6,7,8-trihydronaphthyloxy))propoxy]indanyl}acetic acid

The compounds of Formula (Inn) [Formula (H) where R^! and R² are H, L is -Y-(CH₂)_n-X-, X and Y O, Ar is substituted phenyl, and n is 3] are shown below in Table 5a.

Table 5a

Formula Inn

11 PLC RT

Ex. No R³ ' R^{3 2} LC-MS [M+H]⁺

(min)

59 H 3.57 492.0

H

* These compounds did not ionize under ESI-MS conditions.

Table 5b

IUPAC Names for Compounds in Table 5a

129 2-[( 1 S)-5 -(3 - {4-[4-hydroxy-4-(trifluoromethyl)( 1 ,3-thiazolin-2-yl)] phenoxy} propoxy)indanyl]acetic acid

130 2-{(l S)- -[3 -(4-(3-furyl)phenoxy)propoxy] indanyl} acetic acid

131 2-{(l S)-5-[3-(2-methoxy-4-(2-thienyl)phenoxy)propoxy]indanyl}acetic acid

132 2-((lS)-5-{3-[2-methoxy-4-(4-methyl(2-thienyl))phenoxy]propoxy}indanyI) acetic acid

133 {( 1 S)-5 -[3-( 1 , 1 '-biphenyl-4-yloxy)propoxy]-2,3-dihydro- 1 H-inden- 1 -yl} acetic acid

134 2-(( 1 S)-5 - { 3 -[2-methoxy-4-(4-methoxyphenyl)phenoxy]propoxy} indanyl) acetic acid

135 2-((l S)-5-{3-[4-(4-f!uorophenyl)-2-metlioxyphenoxy]propoxy} indanyl)acetic acid

136 2-{(l S)-5-[3-(4-(3-pyridyl)phenoxy)propoxy]mdanyl}acetic acid

137 2-{(l S)-5-[3-(2-methoxy-4-(3-pyridyl)phenoxy)propoxy]indanyl} acetic acid

138 2-((l S)-5-{3-[4-(4-methoxy-(3-pyridyl))phenoxy]propoxy} indanyl)acetic acid

139 2- [( 1 S)-5 -(3 - {4- [5 -(trifluoromethyl)(2-pyridyl)]phenoxy } propoxy)indanyl] acetic acid

140 2-{(l S)-5-[3-(4-pyrimidin-5-ylphenoxy)propoxy]indanyl} acetic acid

141 2-((l S)-5-{3-[4-(2,4-dimethoxypyrimidin-5-yl)phenoxy]propoxy}indanyl)acetic acid

142 2- { ( 1 S)- 5 - [3 -(4-indol-6-ylphenoxy )propoxy] indanyl} acetic acid

Compounds of Formula (loo) ) [Formula (Π), where R¹ and R² are H, L is -Y-(CH₂)_n-X-, X and Y are O, Ar is heterocyclyl substituted phenyl, and n is 3], and (Ipp) [Formula (II), where R¹ and R² are H, L is -Y-(CH₂)_n-X-, X and Y are O, Ar is substituted phenyl, and n is 3], are listed in Table 6a and Table 7a, respectively, below.

Table 6a

Formula loo

HPLC RT LC-MS

Ex. No w _R3M _R3-2.2 R^{3 1}

(min) IM+H]⁺

99 o C(=0)CH₃ Me n-Pr 3.74 492.1

100 o C(=0)CH₃ Me OMe 3.08 480.3 s C(=0)NMe 3.42

101 Me n-Pr .537.5

2

s C(=0)NMe 2.96

102 Me OMe 525.1

2

103 s C(=0)OH Me H 3.13 468.3

104 s C(=0)OH Me n-Pr 3.58 510.2

Table 6b

ΠΙΡ AC Names for Compounds in Table 6a

Ex. No. H P AC Name

189 2- {( 1 S)-5-[3 -(4-(4,5 ,6-trihydrocyclopenta[ 1 ,2-d] 1 ,3 -thiazol-2-yl)phenoxy)

propoxy]indanyl}acetic acid

190 2-{(l S)-5-[3-(2-propyl-4-(4₅5,6-trihydrocyclopenta[l,2-d] l,3-thiazol-2-yl)

phenoxy )propoxy] indanyl } acetic acid

191 2- {( 1 S)-5 -[3-(2-methoxy-4-(4₅5,6-trihydrocyclopenta[ 1 ,2-d] 1 ,3 -thiazol-2- yl)phenoxy)propoxy]indanyl}acetic acid

192 2-{(l S)-5-[3-(4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy] indanyl}acetic acid

193 2-{(l S)-5-[3-(2-methoxy-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)

propoxy]indanyl}acetic acid

194 2-{(lS)-5-[3-(4-(4,5,6,7-tetrahydrobenzcixazol-2-yl)phenoxy)propoxy]indanyl} acetic acid

195 2- {( 1 S)-5 -[3 -(2-propyl-4-(4,5 ,6,7-tetrahydrobenzoxazol-2-yl)phenoxy)propoxy]

indanyl} acetic acid

196 2-{(lS)-5-[3-(2-ethoxy-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)

propoxy]indanyl}acetic acid

197 2-{(l S)-5-[3-(2-propoxy-4-(4,5,6,7 etrahydrobenzothiazol-2-yl)phenoxy)

propoxyjiiidanyl) acetic acid

198 2-{(l S)-5-[3-(2-methoxy-4-(4,5,6,7-tetrahydrobenzoxazol-2-yl)phenoxy)

propoxy]indanyl}acetic acid

199 2-{(l S)-5-[3-(2-methoxy-4-(5,6,7-trihydro-2H-pyrano[2,3-d] l,3-thiazol-2- yl)phenoxy )propoxy] indanyl } acetic acid

200 2-((l S)-5-{3-[4-(5,5-dimethyl-7-oxo(4,5,6-trihydrobenzothiazol-2-yl))-2- propylphenoxy]propoxy } indany l)acetic acid

201 2-((lS)-5-{3-[4-(4-methoxy(l ,3-thiazol-2-yl))phenoxy]propoxy}indanyl)acetic acid

202 2-((l S)-5- {3-[2-methoxy-4-(4-methoxy(l ,3-thiazol-2-yl))phenoxy]propoxy}

indanyl)acetic acid

203 2-(( 1 S)-5- {3 -[4-(4-ethoxy( 1 ,3 -thiazol-2-yl))phenoxy]propoxy} indanyl)acetic acid

204 2-((l S)-5-{3^:[4-(4-ethoxy(l,3-thiazol-2-yl))-2-propylphenoxy]propoxy} indanyl) acetic acid

205 2-(( 1 S)-5 - { 3 -[4-(4-ethoxy( 1 ,3 -thiazol-2-yl))-2-methoxyphenoxy]propox }

indanyl)acetic acid

206 2-[(l S)-5-(3- {4-[4-(methylethoxy)(l ,3-thiazol-2-yl)]-2-propylphenoxy}propoxy) indanyl] acetic acid

207 2-((lS)-5-{3-[4-(4-ethoxy-5-metliyl(l,3-thiazol-2-yl))-2-propylphenoxy]propoxy} indany l)acetic acid Ex. No. lUPAC Name

208 2-(( 1 S)-5- { 3 -[4-(4-ethoxy-5-methyl(l ,3-thiazol-2-yl))-2-methoxyphenoxy]

propoxy}indanyl)acetic acid

209 2-((lS)-5-{3-[4-(4-ethoxy-5-et yl(l,3-thiazol-2-yl))-2-methoxyphenoxy]

propoxy}indanyi)acetic acid

210 2-((l S)-5- {3-[4~(5-acetyl-4-methyl(l ,3-thiazol-2-yl))phenoxy]propoxy}indanyl) acetic acid

211 2-((l S)-5-{3-[4-(5-acetyl-4-methyI(l_;3"tliiazol-2-yl))-2-propylphenoxy]propoxy} indanyl)acetic acid

212 2-(( 1 S)- 5 - {3 - [4-(5 -acetyl-4-m et yl( 1 ,3 -thiazol-2-yl))-2-methoxyphenoxy]

propoxy}indanyl)acetic acid

213 2-((l S)-5-{3-[4-(5-acetyl-4-methyl(l,3-oxazol-2-yl))p enoxy]propoxy}indanyl) acetic acid

214 2-((lS)-5-{3-[4-(5-acetyl-4-methyl(l,3-oxazol-2-yl))-2-propylphenoxy]propoxy} indanyl)acetic acid

215 2-(( 1 S)-5 - {3 - [4-(5 -acetyl-4-methy 1( 1 ,3 -oxazol-2-yl))-2-methoxyphenoxy]

propoxy}indanyl)acetic acid

216 2-[(l S)-5-(3-{4-[5-(N,N-dimethylcarbamoyl)-4-methyl(l,3-thiazol-2-yl)]-2- propylphenoxy } propoxy)indany 1] acetic acid

217 2-[(l S)-5-(3-{4-[5-(N,N-dimethylcarbamoyl)-4-methyl(l ,3-tliiazol-2-yl)]-2- methoxyphenoxy}propoxy)indanyl]acetic acid

218 2-(4- {3 -[( 1S)-1 -(carboxymet yl)indan-5-yloxy]propoxy }phenyl)-4-m ethyl- 1 ,3 - thiazoIe-5-carboxylic acid

219 2-(4- {3 -[(1 S)- 1 -(carboxy methyl)indan-5-yIoxy]propoxy } -3 -propylphenyl)-4-methyl- l,3-thiazole-5-carboxylic acid

Table 7a

Elimination of water did not occur in this case.

Table 7b

TUPAC Names for Compounds in Tab.e 7a

Compounds of Formula (Iqq) [Formula (II), where R¹ and R² are H, L is -Y-(C¾)_D-X-, X and Y O, Ar is substituted phenyl, and n is 3], appear in Table 8a below.

Table 8a

Formula Iqq

IIPLC

LC-MS

Ex. No R^{3 1} R^{3 2} R" R^{3 4} RT

[M+H]⁺

(min)

112 OMe OMe H H 3.07 387.0

113 H H NHC(=0)CH₃ OMe 3.38 414.1

114 H H Me Me 4.24 *

115 H OMe OMe OMe 3.73 417.2

*These compounds did not ionize under ESI-MS conditions.

Table 8b

IUPAC Names for Compounds in Table 8a

Exemplary compounds of Formula (Irr) ) [Formula (II), where R¹ is H, R² is methyl, L is (CH₂)_n-X-, X and Y are O, and n is 3] is shown in Table 9a below.

Table 9a

Formula Irr

Table 9b

IUPAC Names for Compounds in Table 9a

Table 10a

Table 10b

IUPAC Names for Compounds in Table 10a

Tabie 11a

Formula Iss

Table lib

IUPAC Names for Compounds in Table 11a

Table 12a

Formula Itt

Table 12b

IUPAC Names for Compounds in Table 12a

278 2-[(l S)-5-(3- {[5-(4,5-dimethyl(l ,3 hiazol-2-yl))(2-pyridyl)]methylamino}

propoxy)indanyl] acetic acid

279 2-[(l S)-5-(3- {[5-(4-ethyl(l ,3-thiazol-2-yl))(2-pyridyl)]propylamino}propoxy) mdanyl]acetic acid

280 2-[(lS)-5-(3-{[5-(5-acetyl-4-methyl(l,3-thiazol-2-yl))(2-pyridyl)]propylamino}

propoxy)indanyI]acetic acid

Table 13a

Formula Iuu

Table 13b

IUPAC Names for Compounds in Table 13a

Table 14a

Table 14b

IUPAC Names for Compounds in Table 14a

Table 15a

Exemplary Compounds of Formula (Iww)

Table 15b

IUPAC Names for Compounds in Table 15a

amino }propoxy)indanyl]acetic acid

Exemplary compounds of Formula (Ixx) and (lyy) were listed in Table 16a and Table 17a below.

Table 16a

Formu a Ixx

Ex. RT

R² R^{3 1} R^{3 2} R^{3 3 1} R^{3 3 2} _R3 3-3 LCMS

No. (M+H) (min)

193 H Me H H CI H 466.4 3.18

194 H Me H H H CI 466.3 2.43

195 Me Me H H H Et 474.5 2.59

196 Me Me H H H MeO 476.5 2.44

197 Me Me H H H CI 480.4 2.55

198 Me Me H H -O-Cl ¾-o- 490.5 2.40

199 H F H H H MeO 466.4 2.57

200 H F H H H CF₃ 504.4 3.58

201 H F H H H i-Pr 478.4 3.01

202 H . F H H H Ac 478.4 3.00

203 H F H H H CI 470.3 3.28

204 H F H H H H 436.2 2.88

205 H F H H H CF₃0 520.2 3.64

206 H F H H H EtO 480.3 2.83

207 H F H H H Me 450.2 2.93

208 H F H H H F 454.2 3.20

209 H F H H H Et 464.3 3.06

210 H F H H -O-Cl ¾-0- 480.4 2.66

211 H Et H H H F 464.3 2.49

212 H Et H H H Et 474.5 2.61

213 H Et H H -O-Cl ¾-o- 490.4 2.43

214 H H Me H H Et 460.3 2.56

215 H H Me H H i-Pr 474.3 2.62

216 H H Me H H EtO 476.3 2.53

217 H H Me H H Cyclohexyl 514.4 2.97

218 H H Me H H n-butyl 488.6 2.69

219 H H Me H H Me 448.3 2.46

220 H H Me H H t-Bu 448.3 2.30

221 H H Me H H Ac 474.3 2.30

222 H H Me H -O-C] ¾-0- 476.3 2.36

223 H H Me H H F 450.4 2.29

224 H H Me F H H 450.4 2.22 Table 16b

IUPAC Names for Compounds in Table 16a

Ex. No. IUPAC Name

364 2-{(l S)-5-[3-(methyl{5-met yl-2-[4-(methylethyl)phenyl]pyrimidin-4-yl}amino) propoxyjindanyl} acetic acid

365 2-[( 1 S)-5 -(3 - { [2-(4-ethoxyphenyl)-5 -methylpyrimidin-4-yl]methylamino }

propoxy)indanyl]acetic acid

366 2-[( 1 S)-5-(3-{ [2-(4-acetylphenyl)-5-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl]acetic acid

367 2-((lS)-5-{3-[methyl(5-methyl-2-phenylpyrimidin-4-yl)amino]propoxy}indanyI) acetic acid

368 2-[(l S)-5-(3-{methy][5-methyl-2-(3-methylphenyl)pyrimidin-4-yl]amino}

propoxy)indanyl]acetic acid

369 2-[(lS)-5-(3-{[2-(3-chlorophenyl)-5-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl]acetic acid

370 2-[(l S)-5-(3-{[2-(4-chlorophenyl)-5-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl] acetic acid

371 (2S)-2-[(] S)-5-(3-{[2-(4-ethylpheny])-5-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl]propanoic acid

372 (2S)-2 (lS)-5 3-{[2 4-methoxyphenyl)-5-methylpyrimidin-4-yl]methylamino} propoxy)indanyl]propanoic acid

373 (2S)-2-[(lS)-5-(3-{[2-(4-cMorophenyl)-5-methylpyrimidin-4-yl]methylamino} propoxy)indanyl]propanoic acid

374 (2S)-2-((l S)-5-{3-[{2-(2H-benzo[3,4-d] 1 ,3-dioxolan-5-yl)-5-metliylpyrimidin-4- yl)methylamino]propoxy}indanyl)propanoic acid

375 2-[(lS)-5-(3-{[5-fluoro-2-(4-methoxyphenyl)pyrimidin-4-yl]methylamu o}

propoxy)indanyl]acetic acid

376 2-{(l S)-5-[3 {5-fluoro-2 4-(trifluororaediyl)phenyl]pyrimidin-4-yl}methyl

amino)propoxy]indanyl} acetic acid

377 2-{( 1 S)-5-[3-({5-fluoro-2-[4-(methyIethyl)phenyl]pyrim.idin-4-yl} methylamino) propoxyjindanyl} acetic acid

378 2-[(lS)-5-(3-{ [2-(4-acety lphenyl)- 5 -fl uoropyrimid in-4-yl]methy lamin o} propoxy) indanyljacetic acid

379 2-[( 1 S)-5-(3 - { [2-(4-chlorophenyl)-5 -fluoropyrimidin-4-y 1] methylamino }

propoxy)indanyl] acetic acid

380 ((l S)-5-{3-[(5-fluoro-2-phenyl-4-pyrimidinyi)(methyl)amino]propoxy}-2,3-dihydro- l H-inden-l-yl)acetic acid

381 2-{(l S)-5-[3-({5-fluoro-2-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}methyl amino)propoxy] indanyl } acetic acid Ex. No. IUPAC Name

382 2-[(lS)-5-(3-{.[2-(4-ethoxyphenyl)-5-fluoropyrimidiii-4-yI]methylamino}

propoxy)indanyl]acetic acid

383 2-[(l S)-5-(3-{[5-fluoro-2-f4-methylphenyl)pyrimidin-4-yl]methylamino}

propoxy)indanyl]acetic acid

384 2-[(l S)-5-(3-{[5-fluoro-2-(4-fluorophenyl)pyrimidin-4-yl]methylamino}

propoxy)indanyl]acetic acid

385 2-[(lS)-5-(3-{[2-(4-ethylphenyl)-5-fliioropyrimidin-4-yl]methylamino}

propoxy)indanyl]acetic acid

386 2-((l S)-5-{3-[(2-{2H-benzo[3,4-d] l,3-dioxolan-5-yl)-5-fluoropyrimidin-4-yl)

methylaminojpropoxy} indanyl)acetic acid

387 ((l S)-5-{3-[[5-ethyl-2-(4-fluorophenyl)-4-pyrimidinyI](methyl)amino]propoxy}-2,3- dihydro- 1 H-inden- 1 -y l)acetic acid

388 2- [( 1 S)-5 -(3 - { [5-ethyl-2-(4-ethylpheny l)pyrimidin-4-y l]methylamino} propoxy ) indanyl] acetic acid

389 2-((l S)-5-{3-[(2-(2H-benzo[3,4-d] l,3-dioxolan-5-yl)-5-ethylpyrimidin-4-yl)

methylaminojpropoxy } indanyl)acetic acid

390 (( 1 S)-5 - {3 - [ [2-(4-ethylphenyl)-6-methyl-4-pyrim i d inyl](methyl)amino] propoxy } -2,3 - dihydro- 1 H-inden- 1 -yl)acetic acid

391 2-{(l S)-5-[3-(methyl{6-methyl-2-[4-(methylethyl)phenyl]pyrimidin-4-yl}amino) propoxy]indanyl}acetic acid

392 2-[(l S)-5-(3-{[2-(4-ethoxyphenyl)-6-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl] acetic acid

393 2-[(lS)-5-(3-{[2-(4-cyclohexylphenyl)-6-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl]acetic acid

394 2- [( 1 S)- 5 -(3 - { [2-(4-buty lphenyl)-6-methy lpyrimidin-4-yl] methylamino }

propoxy)indanyl]acetic acid

395 2-[(l S)-5-(3-{methyl[6-methyl-2-(4-methyIphenyl)pyrimidin-4-yl]amino}

propoxy )indanyl]acetic acid

396 2-{(lS)-5-[3 {2-[4-(tert-butyl)phenyl]-6-methylpyrimidin-4-yl}methylamino)

propoxy]indanyl}acetic acid

397 2-[( 1 S)-5 -(3 - { [2-(4-acetylpheny l)-6-methylpy ri m i din-4-y IJmethy lam ino }

propoxy)indanyl]acetic acid

398 2-(( 1 S)-5- { 3 -[(2-(2H-benzo[3 ,4-d] 1 ,3 -dioxolan-5 -yl)-6-methylpyrimidin-4-yl)

methylaminojpropoxy} indanyl)acetic acid

399 2-[(l S)-5-(3-{[2-(4-fluorophenyl)-6-methylpyrimidin-4-yl]methylamino}

propoxy)indanyl] acetic acid Ex. No. IUPAC Name

400 2-[( 1 S)-5-(3 - { [2-(2-fluorophenyl)-6-methylpyrimidin-4-yl]methylamino}propoxy) indanyl] acetic acid

Table 17a

Formula Iyy

Table 17b

IUPAC Names for Com ounds in Table 17a

Exemplary compounds of Formula (Izz) is listed in Table 18a.

Table 18a

LCMS RT

Ex. R⁵ R^{3 1} R^{3 2} R^{3 3}

(M+H) (min) No.

254 Et Me H 4-Et-Ph 474.5 2.61

255 Et Me H 4-Me-Ph 460.4 2.52

256 Et Me H 3,4-dioxolane-Ph 490.4 2.42

257 Ac Me H 4-Et-Ph 488.1 3.35

258 Ac Me H 3,4-dioxolane-Ph 504.2 2.92

Table 18b

IUPAC Names for Compounds in Table 18a

Ex. No. IUPAG Name

424 2-((l S)-5 - {3 - [(2-(2H-benzo [3 ,4-d] 1 ,3 -dioxolan-5 -yl)-5 -methy Ipyrimidin-4- yl)propylamino]propox } indanyl)acetic acid

425 2-((lS)-5-{3-[(5-methyl-2-(3-thienyl)pyrimidin-4-yl)propylamino]propoxy}

indanyl)acetic acid

426 2-[(l S)-5-(3- { [2-(4-fluorophenyl)-5-methylpyrimidin-4-yl]propylamino}

propoxy) indanyl]acetic acid

427 2-[(lS)-5-(3-{[5-methyl-2-(3-methylphenyl)pyrimidin-4-y]]propylamino}

propoxy)indanyl]acetic acid

428 2-[( 1 S)-5-(3 - { [2-(4-methylphenyl)pyrimidin-4-yl]propylainino} propoxy)

indaivyl] acetic acid

429 2-[(lS)-5-(3- { [2-(4-ethylphenyl)pyrimidin-4-yI]propylamino}propoxy) indanyl]acetic acid

430 2-(( 1 S)-5-{3-[(2-(2H-benzo[3,4-d] l,3-dioxolan-5-yl)pyrimidin-4-yl)propylamino] propoxy} indanyl)acetic acid

431 2-[{ 1 S)-5-(3 - { [2-(4-methoxypheny])pyrimidin-4-yl]propylamino} propoxy)

indanyl]acetic acid

432 2-[(l S)-5-(3-{(cyclopropylmethyl)[2-(4-ethylphenyl)-5-methylpyrimidin-4- yI]amino}propoxy)indanyl]acetic acid

433 2-[(l S)-5-(3-{ethyl[2-(4-ethylphenyl)-5-methylpyrimidin-4-yl]amino}propoxy)

indanyl]acetic acid

434 [(l S)-5-(3-{ethyl[5-methyl-2-(4-methylphenyl)-4-pyrimidinyl]amino}propoxy)-2,3- dihydro- 1 H-inden-l-yl]acetic acid

435 2-(( 1 S)-5 - { 3 -[(2-(2H-benzo[3 , 4-d] 1 ,3 -d ioxoian-5 -y l)-5 -methylpyr imidin-4- yl)ethylamino]propoxy}indanyl)acetic acid

436 2-[(l S)-5-(3-{N-[2-(4-ethylphenyl)-5-methylpyrimidin-4-yl]acetylamino}

propoxy)indanyl]acetic acid

437 [( 1 S)-5 -(3 - {acetyI[2-( 1 ,3 -benzod ioxol-5-yl)-5-methyl-4-pyrimidinyl] amino}

propoxy)-2,3 -dihydro- 1 H-inden- 1 -yl]acetic acid

Exemplary compounds of Formula (Iaaa) are listed in Table 19a below.

Formula laaa

Table 19b

IUPAC Names for Compounds in Table 19a

453 2-{(lS)-5-[3-({2-chloro-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}methyl amino)propoxy]indanyl} acetic acid

454 2-(( 1 S 5 - {3 - [(5-(2H-benzo[3 ,4-d] 1 ,3 -dioxolan-5 -y l)-2 -chloropyr imidin-4-yl)

methylamino]propoxy} indanyl)acetic acid

455 2-[( 1 S)-5-(3 - { [2-chloro-5-(4-fluorophenyl)pyrimidin-4-yl]methylamino }

propoxy)indanyl]acetic acid

456 ((l S)-5-{3-[[2-chJoro-5-(4-methyIphenyl)-4-pyriraidinyl](methyl)amino] propoxy}- 2,3-dihydro-lH-inden-l-yl)acetic acid

457 ((l S)-5-{3-[[2-chloro-5-(3,4-difluorophenyl)-4-pyrimidinyl](methyl)ainino]

propoxy } -2,3 -dihydro- 1 H- inden- 1 -y l)acetic acid

Exemplary compounds of Formula (I bb) are shown in Table 20a below.

Table 20a

¹ The absolute configuration at carbon * is S.

Table 20b

IUPAC Names for Compounds in Table 20a

463 [(1 S)-5-({ 1 -[2-(4-i-propylphenyl)-5-methyi-4-pyrimidinyl]-4-piperidinyl} oxy)-2,3-dihydro-lH-inden-l-yl] acetic acid

464 [(lS)-5-({ l-[2-(4-methoxyphenyl)-5-methyl-4-pyrimidinyl]-4-piperidinyl} oxy)-2,3 -dihydro- lH-inden- 1 -yl] acetic acid

465 [(lS)-5-({ l-[2-(4-chlorophenyl)-5-methyl-4-pyrimidinyl]-4-piperidinyl} oxy)-2,3-dihydro-lH-inden-l-yl]acetic acid

466 [(1 S)-5-({ 1 -[2-(l ,3-benzodioxol-5-yl)-5-methyl~4-pyrimidinyI]-4- piperidinyl}oxy)-2,3-dihydro-lH-inden-l-yl]acetic acid exemplary compounds of Formula (Iccc), is listed in Table 21 a below.

Table 21a

Formula Iccc

289 H H 396.3 1.91

290 Et H 446.3 3.74

291 Et H 4-Et-Ph 430.4 3.74

292 Et H 4-CF₃-Ph 470.4 4.35

293 H Me 4-Et-Ph 416.2 2.85

294 H Me 4-CF₃-Ph 456.2 3.57

295 Me H Et 340.2 2.07

296 H H Et . 326.2 1.94

Table 21b

IUPAC Names for Compounds in Table 21a

499 (2S)-2-[(lS)-5-(2-{6-[4-(trifluoromethyI)phenyl](2-pyridyl)}ethoxy) indanyl]butanoic acid

500 2-((lS)-5-{2-[6-(4-ethylphenyl)-3-methyl(2-pyridyl)]ethoxy}indanyl)acetic acid, chloride

501 2-[(l S)-5-(2- {3-methyl-6-[4-(trifluoromethyl)phenyi](2-pyridyl)} ethoxy)

indanyl] acetic acid

502 (2S)-2- {( 1 S)-5-[2-(5 -ethyl(2-pyridyl))ethoxy] indanyl } propanoic acid

5Θ3 2-{(l S)-5-[2-(5-ethyl(2-pyridyl))ethoxy]indanyl}acetic acid

In general, the compounds of Formula VI of this invention may be prepared by standard techniques known in the ait and by known processes analogous thereto. For example, the compounds may be prepared according to methods described in U.S. Patent Application Publication No. 2006/0084680, which is incorporated by reference in its entirety.

The present invention also encompasses indane acetic acid compounds and derivatives described in U.S. Patent Nos, 7,476,742 and 7,592,361, which are incorporated by references in their entirety.

The compounds described in Tables 1 -20 are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

(4) Salts, esters, and/or isomers of a compound of the present invention

A salt of a compound described in the present invention may be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Likewise, when a compound described in the present invention contains a carboxylic acid moiety, (e.g., R = H), a salt of said compound may be prepared by separately reacting it with a suitable inorganic or organic base and isolating the salt thus formed. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention (see, e.g., Berge et al., J. Pharm. Sci. 66: 1-19, 1977).

Representative salts of the compounds described in the present invention include the conventional non-toxic salts and the quaternary ammonium salts, which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesuIfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and the like.

Base salts include, for example, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups in the conjugate base may be quaternized with alkyl halides, e.g., alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and diburyl sulfate; and diamyl sulfates, Cio- 0 alkyl halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides; or aralkyl halides like benzyl and phenethyl bromides. In some embodiments, the salts are alkali salt such as sodium or potassium salt or an adduct with an acceptable nitrogen base such as meglumine (N- Methyl-d-glucamine) salt.

The esters of the compounds described in the, present invention are non-toxic, pharmaceutically acceptable esters, for example, alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters. Additional esters such as, for example, methyl ester or phenyl-CpCs alkyl may be used. The compound described in the present invention may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the compounds described in the present invention compound. The appropriate anhydride may be reacted with the alcohol in the presence of a base to facilitate acylation such as l,8-bis[dimethylamino]naphthalene or Ν,Ν-dimethylaminopyridine. An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, l-[3-dimethylaminopropyl]-3- ethylcarbodiimide, or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be effected using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N, N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-D AP or pyridine.

One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols.

Additionally, sensitive or reactive groups on the compound described in the present invention may need to be protected and deprotected during any of the above methods for forming esters. Protecting groups in general may be added and removed by conventional methods well known in the art (see, e.g., T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).

The compounds described in the present invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration. Preferred isomers are those with the absolute configuration, which produces the compound of described in the present invention with the more desirable biological activity. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form.

It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the scope of the instant invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. In general, the term "substituted" refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.

C. Evaluation of biological activity of compounds

Demonstration of the activity of the compounds of the present invention may be accomplished through in vilro, ex vivo, and in vivo assays that are well known in the art. Some recent studies indicate that agonists of peroxisome proliferator-activated receptor (PPAR) may also be used as a potential treatment for autoimmune disorders (See Racke, et al., Nuclear Receptors and Autoimmune Disease: the potential of PPAR agonists to treat multiple sclerosis, The Journal of Nutrition, 700-703, March, 2010). It is also indicated that PPAR agonists may be used to treat liver disorders. (See Seo et al., PPAR agonists treatment is effective in a nonalclholic fatty liver disease animal model by modulating fatty-acid metabolic enzymes, Journal of Gastroenterology and Hepatology, 23, 102-109 (2008)).

PPAR receptor agonist activity may be determined by conventional screening methods known to those skilled in the art. For example, methods described in U.S. Patent Application Publication No. 2007/0054907, 2008/0262047 and U.S. Patent No. 7,314,879, which are incorporated by reference in their entireties. Exemplary screening tests are described below:

(1) Binding Assays

Compounds may be tested for their ability to bind to hPPAR gamma, hPPAR alpha or hPPAR delta using a Scintillation Proximity Assay (SPA). The PPAR Iigand binding domain (LBD) may be expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD may then be labelled with biotin and immobilized on streptavidin-modified scintillation proximity beads. The beads may then be incubated with a constant amount of the appropriate radioligand (5-{4-[2-(Methyl-pyridin-2-yl-amino)-ethoxy]-benzyl}- thiazolidine-2,4-dio-ne (J. Med. Chem. 1994, 37(23), 3977), for PPAR gamma), and labelled GW 2433 (see Brown, P. J et al. Chem. Biol. 1997 4: 909-918), for the structure and synthesis of this ligand) for PPAR alpha and PPAR delta) and variable concentrations of test compound, and after equilibration the radioactivity bound to the beads may be measured by a scintillation counter. The amount of nonspecific binding, as assessed by control wells containing 50 uM of the corresponding unlabeled ligand, is subtracted from each data point. For each compound tested, plots of ligand concentration vs, CPM of radioligand bound may be constructed and apparent Ki values are estimated from nonlinear least squares fit of the data assuming simple competitive binding. The details of this assay have been reported elsewhere (see, Blanchard, S. G. et. al. Anal. Biochem, 257 112-1 19 (1998)).

(2). Functional Assays

(a) Functional cell based assays are developed to discriminate agonists and antagonists.

Agonist Assay: HEK 293 cells stably expressing a human melanocortin receptor (see e.g., Yang, et al., Mol-Endocrinol., 11(3): 274-80, 1997) are dissociated from tissue culture flasks using a trypsin/EDTA solution (0.25%; Life Technologies, Rockville, Md.). Cells are collected by centrifugation and resuspended in DMEM (Life Technologies, Rockville, Md.) supplemented with 1% L-glutamine and 0.5% fetal bovine serum. Cells are counted and diluted to 4.5 xl0⁵/ml.

A compound of the present invention is diluted in dimethylsulfoxide (DMSO) (3*10^"5 to 3 lO^"10 M final concentrations) and 0.05 volume of compound solution is added to 0.95 volumes of cell suspension; the final DMSO concentration is 0.5%. After incubation at 37°C /5% C0₂ for 5 hours, cells are lysed by addition of luciferin solution (50 mM Tris, 1 mM MgCl₂, 0.2% Triton-X l OO, 5 mM DTT, 500 micromolar Coenzyme A, 150 micromolar ATP, and 440 micromolar luciferin) to quantify the activity of the reporter gene luciferase, an indirect measurement of intracellular cAMP production,

Luciferase activity is measured from the cell lysate using a Wallac Victor 2 luminometer. The amount of lumen production which results from a compound of present invention is compared to that amount of lumens produced in response to NDP-alpha-MSH, defined as a 100% agonist, to obtain the relative efficacy of a compound. The EC5₀ is defined as the compound concentration that results in half maximal stimulation, when compared to its own maximal level of stimulation.

(b) Melanocortin Receptor Whole Cell cAMP Accumulation Assay Compound preparation:

In the agonist assay, compounds are prepared as 10 mM and NDP-aMSH (control) as 33.3 μΜ stock solutions in 100% DMSO. These are serially diluted in 100% DMSO. The compound plate is further diluted 1:200 in compound dilution buffer (HBSS-092, 1 mM Ascorbic Acid, 1 mM IBMX, 0.6% DMSO, 0.1% BSA). The final concentration range being 10 μΜ-100 pM for compound and 33.33 nM-0.3 pM for control in 0.5% DMSO. Transfer 20 μΐ from this plate into four PET 96-welI plates (all assays are performed in duplicate for each receptor).

I l l (c) Cell Culture and Cell Stimulation:

HEK 293 cells stably transfected with the MC3R and MC4R are grown in DMEM containing 10% FBS and 1% Antibiotic/Antimycotic Solution. On the day of the assay the cells are dislodged with enzyme free cell dissociation solution and resuspended in cell buffer (HBSS-092, 0.1 % BSA, 10 mM HEPES) at l x e6 cells/ml. Add 40 μΐ of cells/well to the PET 96-well plates containing 20 ul diluted compound and control. Incubate @ 37 °C. in a water bath for 20 minutes. Stop the assay by adding 50 μΐ Quench Buffer (50 mM Na Acetate, 0.25% Triton X-100).

(3) Radioligand Binding Assays

Radioligand binding assays are run in SPA buffer (50 mM Sodium Acetate, 0.1% BSA). The beads, antibody and radioligand are diluted in SPA buffer to provide sufficient volume for each 96-well plate. To each quenched assay well is added 100 ul cocktail containing 33.33 μΐ of beads, 33.33 μΐ antibody and 33.33 μΐ ¹²⁵ I-cAMP. This is based on a final concentration of 6.3 mg/mf beads, 0.65% anti-goat antibody and 61 pM of ¹²⁵ I-cAMP (containing 25000-30000 CPM) in a final assay volume of 210 μΐ. The plates are counted in a Wallac MicroBeta counter after a 12-hour incubation.

The data is converted to pmoles cAMP using a standard curve assayed under the same conditions. The data is analyzed using Activity Base software to generate agonist potencies (EC₅₀) and percent relative efficacy data to NDP-aMSH.

(4) Transfection Assays

Compounds may be screened for functional potency in transient transfection assays in CV-1 cells for their ability to activate the PPAR subtypes (transactivation assay). A previously established chimeric receptor system may be utilized to allow comparison of the relative transcriptional activity of the receptor subtypes on the same target gene and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example, Lehmann, J. M et al J. Biol. Chem., 1995 270: 12953-6. The ligand binding domains for murine and human PPAR alpha, PPAR gamma and PPAR delta are each fused to the yeast transcription factor GAL4 DNA binding domain. CV-1 cells are transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placental alkaline phosphatase (SPAP) and beta- galactosidase. After 16 h, the medium are exchanged to DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration. After an additional 24 h, cell extracts are prepared and assayed for alkaline phosphatase and beta-galactosidase activity. Alkaline phosphatase activity is corrected for transfection efficiency using the beta-galactosidase activity as an internal standard (see, for example, Kliewer, S. A., et. al. Cell 1995 83: 813-819). Rosiglitazone (BRL 49653) may be used as a positive control in the hPPAR gamma assay. The positive control in the hPPAR alpha assays may be 2-4-[2-(3-[4-fluorophenyl]-l -heptylureido)ethyl]-phenoxy-(2-methyl propionic acid (WO 97/36579). The positive control for PPAR delta assays may be 2-{2-methyl-4-[({4-methyl-2- {trifluoromethyl)phenyl]-l,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid (WO 01/00603). An EC50 may be determined as the concentration at which a compound achieves 50% activation relative to the appropriate positive control.

An "agonist" will typically have a p i of at least 6.0 preferably at least 7.0 to the relevant PPAR in the Binding Assay described above, and achieves at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the Transfection Assay described above at concentrations of 10^{"5 M} or less.

(5) Cross Curve PPAR Transactivation tests

The activation of receptors with an agonist (activator) in HeLN cells leads to the expression of a reporter gene, luciferase, which, in the presence of a substrate, generates light. The modulation of the receptors is measured as quantity of luminescence produced after incubating the cells in the presence of a reference agonist. The ligands will displace the agonist from its site. The measurement of the activity is performed by quantification of the light produced. This measurement makes it possible to determine the modulatory activity of the compounds according to the invention by determining the constant, which is the affinity of the molecule for the receptor. Since this value can fluctuate according to the basal activity and the expression of the receptor, it is called apparent Kd (Kd app in nM).

To determine this constant, the cells are in contact with a concentration of the product to be tested and a concentration of the reference agonist, 2-(4-{2-[3-(2,4-difluorophenyl)-l- heptylureido]ethyl}pheny]sulfanyl)-2-methylpropionic acid for PPARa, {2-methyl-4-[4-methyl-2-(4- trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]phenoxy}acetic acid for PPAR5 and 5-{4-[2- (methylpyridin-2-ylamino)ethoxy]benzyl}thiazoHdine-2,4-dione for PPARy. Measurements are also carried out for the controls total agonist with the same products.

The HeLN cell lines used are stable transfectants containing the plasmids ERE-PGlob-Luc-SV-Neo (reporter gene) and PPAR (α, δ, γ) Gal-hPPAR. These cells are inoculated into 96-well plates in an amount of 10 000 cells per well in 100 μΐ of DMEM medium free of phenol red and supplemented with 10% lipid- free calf serum. The plates are then incubated at 37 ⁰ C, 7% C⁽¾ for 16 hours.

The various dilutions of the test products and of the reference ligand are added in an amount of 5 μΐ per well. The plates are then incubated for 18 hours at 37 ^DC, 7% C0₂. The culture medium is removed by turning over and 100 μΐ of a 1 : 1 PBS/Luciferin mixture are added to each well. After 5 minutes, the plates are read by the luminescence reader.

These cross curves make it possible to determine the AC₅₀ values (concentrations at which 50% activation is observed) for the reference ligand at various concentrations of test product. These AC₅o values are used to calculate the Schild regression by plotting a straight line corresponding to the Schild equation (^'Quantitation in Receptor Pharmacology" Terry P. Kenakin, Receptors and Channels, 2001, 7, 371-385) which leads to Kd app values being obtained (in nM). (6) Animal Models

(a) Autoimmune disorders, for example multiple sclerosis

Any animal model known to those skilled in the art may be used in connection with the present invention. For example, the representative animal models for multiple sclerosis include Experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) infection. {See Diem et al., Combined therapy with ethylprednisolone and erythropoietin in a model of multiple sclerosis, Brain (2005), 128, 375-385 and Mix et al., Animal models of multiple sclerosis for the development and validation of novel therapies - potential and limitations, Journal of Neurology, 255, 6, 1432-1459 (Online) (Dec, 2008); and Clatch et al., Characterization of Theiler's murine encephalomyelitis virus (TMEV)- specific delayed-type hypersensitivity responses in TMEV-induced demyelinating disease: correlation with clinical signs, The Journal of Immunology, 136, 3, 920-927).

(b) Liver disorders, for example fatty liver

Any animal model known to those skilled in the art may be used in the present invention. An exemplary animal model using intact and castrated male rats is described below:

Male Sprague-Dawley rats weighing are maintained on a 12-h light/dark cycle with food and water available ad libitum. The compound of the present invention is dissolved in 10% DMSO diluted with PEG 300 (Acros Organics, NJ) for preparation of the appropriate dosage concentrations. The animals are housed in groups of 2 to 3 animals per cage. Animals are randomly assigned to one of seven groups consisting of 4 to 5 animals per group. Control groups (intact and ORX) are administered vehicle daily. Compounds of the present invention are administered via oral gavage at doses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg day to both intact and ORX groups. Where appropriate, animals are castrated on day one of the study. Treatment with compounds of the present invention begins nine days post ORX and is administered daily via oral gavage for fourteen days.

The animals are sacrificed under anesthesia (ketamine/xyalzine, 87: 13 mg/kg) and body weights are recorded. In addition, ventral prostate, seminal vesicles, and levator am^' muscle are removed, individually weighed, normalized to body weight, and expressed as a percentage of intact control. Student's T-test is used to compare individual dose groups to the intact control group. Significance is defined a priori as a P-value <0.05. Blood is collected from the abdominal aorta, centrifuged, and sera are frozen at -80 °C prior to determination of serum hormone levels. Serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations are determined.

D. Pharmaceutical Compositions

According to another aspect of the present invention, pharmaceutical compositions of compounds described herein are provided. In some embodiments, the pharmaceutical compositions further include a pharmaceutically acceptable carrier.

In some embodiments of the present invention, the pharmaceutical compositions described herein may further include one or more additional therapeutic agents. Based on the above tests, or other assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and die nature and extent of the condition treated.

The total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.

Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt thereof may be ascertained by those skilled in the art using conventional treatment tests.

The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds described herein may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage, unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.

For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft- shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (3 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-l,l-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, , and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a nonionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,01 1 ,472, incorporated herein by reference.

The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

Commonly used pharmaceutical ingredients which may be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.

Other pharmaceutical ingredients include, for example, but are not limited to, adsorbents (e.g., powdered cellulose and activated charcoal); aerosol propellants (e.g., carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF₃); air displacement agents (e.g., nitrogen and argon); antifungal preservatives (e.g., benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (e.g., ascorbic acid, ascorbyl palmitate, but lated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (e.g., block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (e.g., potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (e.g., edetate disodium and edetic acid); colorants (e.g., FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (e.g., bentonite); emulsifying agents (but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (e.g., gelatin and cellulose acetate phthalate); flavorants (e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (e.g., glycerin, propylene glycol and sorbitol); levigating agents (e.g., mineral oil and glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (e.g., diethyl phthalate and glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (e.g., cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (e.g., cocoa butter and polyethylene glycols (mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10, oxtoxynol 9, poiysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening e.g., aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (e.g., magnesium stearate and talc); tablet binders (e.g., acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (e.g., liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (e.g., dibasic calcium phosphate); tablet disintegrants (e.g., alginic acid, carboxymethylceliulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (e.g., colloidal silica, com starch and talc); tablet lubricants (e.g., calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing agents (e.g., carnuba wax and white wax); thickening agents (e.g., beeswax, cetyl alcohol and paraffin); tonicity agents (e.g., dextrose and sodium chloride); viscosity increasing agents (e.g., alginic acid, bentonite, carbomers, carboxymethylceliulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (e.g., heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, poly oxy ethylene sorbitol monooleate, and polyoxyethylene stearate).

The compounds described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-obesity, or with known antidiabetic or other indication agents, and the like, as well as with admixtures and combinations thereof.

The compounds described herein may also be utilized, in free base form or in compositions, in research and diagnostics, or as analytical reference standards, and the like. Therefore, the present invention includes compositions which include an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

The compounds may be administered to subjects by any suitable route, including orally (inclusive of administration via the oral cavity), parenterally, by inhalation spray, topically, transdermal ly, rectally, nasally, sublingually, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, parenterally, transdermally or by inhalation spray.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, gender, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000). The following examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.

Capsule Formulation

A capsule formula is prepared from:

Compound of this invention 10 mg

Starch 109 mg

Magnesium stearate 1 mg

The components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.

Tablet Formulation

A tablet is prepared from:

Compound of this invention

Cellulose, microcrystalline

Colloidal silicon dioxide

Stearic acid

The ingredients are mixed and compressed to form tablets. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Sterile IV Solution

A mg/mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration with sterile 5% dextrose and is administered as an IV infusion.

Intramuscular suspension

The following intramuscular suspension is prepared:

Compound of this invention 50 μg/mL

Sodium carboxymethylcellulose 5 mg mL

TWEEN 80 4 mg/mL

Sodium chloride 9 mg/mL

Benzyl alcohol 9 mg/mL

The suspension is administered intramuscularly. Hard Shell Capsules

A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate. Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Immediate Release Tablets/Capsules

These are solid oral dosage forms made by conventional and novel processes. These units are taken orally witliout water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

E. Methods of use

(1) Autoimmune disorders

A further aspect of the invention provides methods of treating or preventing an autoimmune disorder. The methods comprise administering to a subject in need thereof an effective amount of a compound of the present invention.

In some embodiments, the autoimmune disorder is selected from acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis ubiterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, fibrosing alveolitis, Juvenile RA, Guillain-Barre syndrome, Hashimoto's thyroiditis, celiac disease, Crohn's disease, ulcerative colitis, primary sclerosing cholangitis, autoimmune hepatitis, temporal Arteritis, and Giant Cell Arteritis.

In another embodiment, the autoimmune disorder is an autoimmune disorder involving a systemic autoimmune disorder. Exemplary systemic autoimmune disorders include, but are not limited to, systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis- dennatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. In particular embodiments of the present invention, the autoimmune disorder is multiple sclerosis. Accordingly, some embodiments of the present invention provide a method of treating and/or preventing multiple sclerosis comprising administering to a subject a compound of the present invention. In some embodiments of the present invention, the subject can be "in need" of the methods of the present invention, e.g., the subject can be diagnosed with, at risk for, and/or suspected to have multiple sclerosis. Diagnosis of a subject with multiple sclerosis can be achieved by one or more methods known in the art, such as, but not limited to neurological examination/testing, magnetic resonance imaging (MRJ), cerebrospinal fluid analysis, chemical and/or biological assays, and electrical tests, such as evoked potential tests. Those skilled in the art will appreciate that the benefit imparted by the treatment according to the methods of the present invention is not necessarily meant to imply cure or complete prevention and/or abolition of the symptom(s) and/or condition(s). In certain embodiments of the present invention, the method comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

As described above, the administering step can be carried out by any means known in the art, such as, but not limited to, oral, intravenous, and/or topical administration. Further, as those skilled in the art will appreciate, the administering step can be carried out when no symptoms of multiple sclerosis are present and/or as symptoms of multiple sclerosis arise {e.g., administered periodically to treat a symptom of multiple sclerosis). In certain embodiments of the present invention, the subject has a repiasing form of multiple sclerosis and the administering step is carred out periodically to alleviate a symptom of multiple scelorsis.

(2) Liver disorders

Another aspect of the invention is related to methods of treating and/or preventing a liver disorder. The methods can comprise administering to a subject in need thereof an effective amount of a compound of the present invention. Those skilled in the art will appreciate that the benefit imparted by the treatment according to the methods of the present invention is not necessarily meant to imply cure or complete prevention and/or abolition of the symptom(s) and/or condition(s).

In some embodiments, the liver disorder is selected from fatty liver disease, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, cholestatic liver disease and/or liver failure. In one embodiment, the iiver disorder is fatty liver disease. Diagnosis of a subject with a liver disorder can be achieved by one or more methods known in the art, such as, but not limited to blood test panels, such as alanine aminotransferase or aspartate aminotransferase; chemical and/or biological assays; liver biopsy; abdominal ultrasound; endoscopic retrograde cholangiopancreatography; X-ray; computed tomography (CT); magnetic resonance imaging ( RT); and magnetic resonance elastography.

F. Combination

In some embodiments, the compounds described herein may be used in combination with other known medications for treating autoimmune disorders to treat or prevent autoimmune disorders. In one embodiment, the other known medication for treating autoimmune disorder is a medication for multiple sclerosis. Exemplary medications for treating multiple sclerosis include, but are not limited to, corticosteroids, beta interferons (Betaferon, Avonex, Rebif), glatiramer acetate (Copaxone), methotrexate, azathioprine, cyclophosphamide, cladribine, baclofen, tizanidine, amitriptyline, and carbamazepme, natalizumab, and mitoxantrone. In another embodiment, the other known medication for treating autoimmune disorder is a known medication for treating rheumatoid arthritis. Exemplary medications for treating rheumatoid arthritis include, but are not limited to, non-steroidal anti-inflammatory drugs, gold compounds, methotrexate, hydroxychloroquine, sulfasalazine, penicillamine, corticosteroids, cytotoxic and immunosuppressive drugs. More exemplary medications for treating rheumatoid arthritis include, but are not limited to, leflunomide (Arava) and the "biologic" medications etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), rituximab (Rituxan), abatacept (Orencia), golimumab (Simponi), certolizumab pegol (Cimzia), and tocilizumab (Actemra). In one embodiment, the other medication for treating autoimmune disorder is administered concurrently.

G. Examples

The present invention will now be described in more detail with reference to the following examples. However, these examples are given for the purpose of illustration and are not to be construed as limiting the scope of Hie invention

Example 1

Preparation of methyl 2-(6-methoxy-lH-inden-3-yl) butanoate

An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under Ar protection, a suspension of 5-methoxy-l-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in 2 L anhydrous THF was stirred at 60°C (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in 400 mL anhydrous THF was added slowly through an addition funnel. After completion of the addition, the reaction mixture was stirred at 60°C (internal temperature) for 1 hour. The reaction was followed by TLC analysis of aliquots following IN aqueous HC1 work-up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of IN HC1 solution. The pot temperature was kept below 20°C. The mixture was then extracted with 1 L EtOAc. The organic layer was washed with water until pH 6.0-7.0, then saturated NaCl solution, and dried over a₂S04. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. Ή NMR (DMSO-<¾) S 7.28(d, 1 H), 7.05(d, 1H), 6.82(dd, 1 H), 6.22(s, 1H), 3.72(s, 3H), 3.60(m, 1H), 3.58(s, 3H), 3.28(s, 2H), 1.95(m, 1H), 1.80(m, 1H), 0.88(t, 3H). Example 2a

Preparation of 2-( -methoxy-lH-3nden-3-yl) butanoic acid

To a solution of the ester prepared in Example 1 (14.0 g, 58.9 mmol) in 140 mL MeOH, was added a solution of KOH (6.4 g, 113.8 mmol) in 5 mL water. The reaction mixture was stirred at 60°C (pot temperature) for 2 hours. TLC showed 70% conversion. A solution of KOH (3.0 g, 53.6 mmol) in 100 mL water was then slowly added to the pot. After 1 hour, the reaction was completed. After cooling to room temperature, the solvents were removed at a reduced pressure. The residue was dissolved in 500 mL water, and then washed with EtOAc. The aqueous layer was cooled in an ice-water bath, and then acidified with cone. HC1 to pH<3.0. The product was extracted into 300 mL (¾(¾, washed with water (2 x 100 mL), then dried over Na₂S0₄. After Na₂S0₄ was filtered off, the€¾⁽¾ solution was stirred with 3.0 g of charcoal for 2 hours. The charcoal was removed by filtration through a pad of Celite^®. The title product (12.5 g, 95%) was obtained as a light brown solid after solvent removal and vacuum drying. *H NMR (DMSO-i¾) 5 12.20(b, lH), 7.30(d, 1H), 7.06(d, 1 H), 6.82(dd, 1H), 6.22(s, 1H), 3.75(s, 3H), 3.45(t, 1H), 3.30(s, 2H), 1.90(m, 1H), 1.78(m, 1H), 0.90(t, 3H).

Example 2b

Preparation of 2-(6-methoxy-lH-inden-3-yl) propanoic acid

This substrate was prepared using the same procedures as described for Examples 1 and 2a, starting with 5-methoxyl-l -mdanone and methyl 2-bromopropionate. Yield: 68%. 'HNMR (CD₂C1₂) δ 7.34 (d, J= 9, 1 H), 7.07 (d, J= 2, 1 H), 6.85 (dd, J= 9, J= 2, 1H), 6.32 (m, 1H), 3.82 (m, 4H), 3.36 (m, 2H), 1.56 (d, J= 7, 3H).

Example 3

Preparation of (2S)-2-(6-methoxy-lH-inden-3-yl)butanoic acid

To a solution of the racemic indene acid prepared in Example 2a (300 g, 1.29 mol) in 4.5 L C1¾CN, was added quinine (324 g, 1.0 mol) at rt. The mixture was stirred for 1 hour, and became a solution. A small amount of insoluble particles was removed by filtration through a microfiber filter under vacuum. The filtrate was then mechanically stirred under Ar over night. After 24 hours, a small sample of solid was taken and analyzed, showing 76.2% ee. The agitation was stopped after two more days. The suspension was filtered. The filter cake was washed with CH₃CN (3 x 200 mL), and then dried under vacuum at 40°C for 3 hours. This solid was stirred with 4.5 L CH₃CN at 70°C until all solids went into solution. The solution was allowed to cool down to rt slowly. The resulting suspension was stirred at rt for 24 hours. The suspension was filtered. The filter cake was washed with CH₃CN (3 x 250 mL), and then dried under vacuum at 40°C for 24 hours. This quinine salt was collected as a white solid (254.6 g, 35.4% yield, 96.8% ee).

The quinine salt (544.3 g, 0.98 mol) was dissolved in 4.0 L CH₂Cl₂ to obtain a clear solution. It was stirred vigorously with 4.0 L of 2N HC1 solution in a 22_rL round-bottomed flask with a bottom valve. After 30 minutes, the mixture was allowed to settle. The bottom layer was separated and top aqueous layer was extracted with 1 L CH₂C1₂. The combined CH₂C1₂ layers were washed with water (3 x 2.0 L) until pH 5.0- 6.0, and then dried over Na₂S0₄. The product (230.8 g, 99%, 96.8% ee) was obtained as an off white solid after solvent removal and vacuum drying. 'H NMR was identical to that of the racemic material described in Example 2a.

Treatment of the mother liquor in similar fashion gave the (R) isomer. Alternatively, the mother liquor may be subjected to aqueous basic conditions in order to effect racemization and recovery of racemic starting material.

Example 4

Preparation of (2₍S)-2-[(15)-5-methoxy-2,3-dihydro-lH-inden-l-yl]butanoic acid

A solution of the product obtained in Example 3 (105 g, 453 mmol), ClRh(PPh₃)₃ (21.0 g, 5% eq.) and triethylamine (68.8 g, 679.5 mmol) in EtOH (945 mL) and THF (105 mL) was shaken in a 2-L pressure bottle under 60 psi H₂ for 16 hours. The solvents were removed at a reduced pressure. The resulting mixture was stirred in 1.5 L of IN HC1 solution and 1.5 L CH₂C1₂. The aqueous layer was extracted with CH₂C1₂ (2 x 250 mL). The combined CH₂C1₂ layers were washed with 1 L of IN HC1 solution and stirred with 1 L of IN NaOH solution. The organic layer was extracted with IN NaOH solution (2 x 0.5 L). The combined aqueous layer was washed with CH₂C1₂ (2 x 250 mL), and acidified (pH 2,0-3.0) by a slow addition of cone. HC1 solution at below 15°C. The acidic mixture was extracted with CH₂C1₂ (2 x 1.5 L), and washed with water (2 x 0.5 L) until pH 5.0-6.0. After washing with brine and drying over anhydrous Na₂S04, solvent was evaporated under a reduced pressure. The product (101.0 g, 95% yield, 96.8% ee) was obtained as a light yellow oil. ^!H NMR (DMSO-i/₆) δ 12.20(s, 1H), 7.04(d, 1H), 6.78(d, 1H), 6.66(dd, 1H), 3.70(s, 3H), 3.28(m, I H), 2.72(m, 2H)₅ 2.32(m, IH), 2.06(m, IH), 1.80(m, I H), 1.50(m, IH), 1.36(m, IH), 0.82(t, 3H).

Example 5a

Preparation of s ra-2-[5-methoxy-2^-dihydro-lH-inden-l-yl]butanoic acid

A suspension of racemic indene acid (Example 2, 980 mg, 4.2 mmol), ClRh(PPh₃)₃ (139 mg, 0.15 mmol), NaHC0₃ (378 mg, 4.5 mmol) in EtOH (20 mL), and H₂0 (10 mL) was shaken in a 500 mL pressure bottle under 60 psi H₂ for 30 hours. Additional ClRh(PPh₃)3 (300 mg, 0.33 mmol) was added to the reaction mixture and hydrogenation was continued for 3 more days. After this time, EtOH was removed at a reduced pressure and the residue was diluted with 200 mL water. The black solid was removed by filtration and the filtrate was washed with EtOAc (2 x 200 mL). The aqueous solution was then acidified with cone. HC1, and extracted with CH₂C1₂ (2 x 100 mL). The combined CH₂C1₂ layer was washed with brine and dried over Na₂S0₄. Removal of the solvent in vacuum afforded the indane acid as light yellow oil (600 mg, 60%). The product mixture resulted a diastereomeric mixture (87: 33) in favor of the syn isomers as determined by SMR analysis, using the ratio of integration of NMR peaks δ 7.11 (d, IH) for the anti, and δ 7.03 (d, IH) for the syn isomers.

Resolution of the product into optical isomers may be accomplished as follows:

to a mechanically stirred solution of the syn indane acetic acid [(2R,1R) and (2S S), 14.69 g, 62.7 mmol] in acetonitrile (290 mL) at rt, was added (R)-(+)-a-methylbenzylamine (8.49 mL, 65.9 mmol) in one portion. The resulting mixture was stirred overnight. Little solid formation was observed. The reaction mixture was concentrated to dryness and the residue was redissolved in acetonitrile (200 mL) with heating. Magnetic stirring was begun to initiate precipitation. The mixture was stirred overnight. The solids were collected by filtration, and washed three times with a small amount of cold acetonitrile. The solids were then dried under vacuum for 1.5 hours (8.1 g, 86% ee). The slightly wet solids were recrystallized in acetonitrile (120 mL) to give 6.03 g of the (2S)-2-[(15)-5-methoxy-2,3-dihydro-lH-inden-l-yl]butanoic acid, (R)-a- methylbenzylamine salt (94.4% ee). A second crop was collected from various filtrates (0.89 g, 97.6% ee). The overall yield of resolution was 31% (62% based on the maximum content of (2S,\S) acid in the racemate). The material was identical to that obtained in Example 4.

Optical purity for this Example and that of Example 4 may also be analyzed by chiral HPLC; Column: Chiracel AD, 4.6 (LD.) x 250 mm; Mobile Phase, A: 0.1% TFA (trifluoroacetic acid) in hexanes, B: 0.1% TFA in IPA (isopropyl alcohol); Method, Isocratic 95%A (5%B), 20 min.; Flow Rate, 1.5 mL/min.; Detector (UV), 284 nm. Retention times for the four possible diastereomers are 5.163 min. (2S R), 6.255 min. (2R, IS), 10.262 min. (2R, 1R) and 14.399 min. (2S, IS). The first locator (2S or 2R) denotes the absolute configuration of the carbon adjacent to the carboxyl group (the 2-positon); the second locator (IS or Hi) denotes the absolute configuration of the indane ring carbon (its 1 -position).

The stereochemical assignment for each peak was determined by chiral HPLC analysis of a non- equal (syn/anti) racemic diastereomeric mixture of compound 5, which provided four baseline-resolved peaks. Peaks 3 and 4, and peaks 1 and 2 represented enantiomer pairs, based on UV integration. The absolute configuration of the compound of peak 4 was determined to be 2S S by X-ray structural analysis. Peak 3, the corresponding enantiomer, was then assigned a 2R R configuration with certainty. Peak 1 was assigned to the (2S, H?)-diastereomer (retention time: 5.363 min., ca. 0.97% area) by comparison to the minor product obtained from the reduction of the chiral acid (Example 3) as described in Example 4. The remaining peak 2, could then be assigned with certainty to the compound with 2R, IS configuration.

Example Sb

Preparation of syn-2-[5-methoxy-2,3-dihydro-lH-inden-l-yl]propanoic acid

The compound was prepared in 71% yield and >99% de using the same procedure as described for Example 4 starting with (racemic) Example 2b: Ή NMR (DMSO-£¾)□ δ 12.18 (s, 1H), 7.03 (d, J= 8, 1H), 6.75 (d, J= 2, 1H), 6.67 (dd, J, = 8, J₂ = 2, 1H), 3.68 (s, 3H), 3.37 (m, 1H), 2.72 (m, 3H), 2.03 (m, 1H), 1.75 (m, 1H), 0.89 (d, J= 7, 3H); ¹³C NMR (CD₂C1₂) δ 12.626, 28.228, 31.950, 43.300, 46.445, 55.607, 110.054, 112.510, 124.552, 136.702, 146.411, 159.464, 182.330.

Example 6

Preparation of methyl (2iS)-2-[(15)-5-methoxy-2,3-dihydro-ljfiT-inden-l-yl] butanoate

A suspension of acid prepared in Example 4 (220.0 g, 0.94 mol), NaHC0₃ (237.0 g, 2.82 mol), CH₃I (200 g, 1.41 mol) in 2.0 L DMF was stirred under Ar at rt for 18 hours. NMR analysis showed 95% reaction. Adding CH₃I (100 g), and stirring for additional 24 hours at rt caused completion of the reaction. The reaction mixture was poured into 4.0 L water, and extracted with EtOAc (2 x 2 L). The organic layer was sequentially washed with water (2 x 1 L), 1 L of IN NaOH solution, water (2 x 1 L), and 500 mL brine, and dried over Na₂S0₄. The product (233 g, 99%) was obtained as a light yellow oil after solvent removal and vacuum drying. ¾ NMR (DMSO-i¾) δ 6.90(d, 1H), 6.78(d, 1H), 6.66(dd, 1H), 3.70(s, 3H), 3.60(s, 3.20(m, 1H), 2.80(m, 2H), 2,40(m, 1H), 2.08(m, 1H), 1 .80(m, 1H), 1.58(m, 1H), 1 .40(m, 1H), 0.80(t,

Example 7

Preparation of methyl (25 -2-[(15)-5-hydroxy-2,3-dihydro-lH-inden-l-yl]butanoate

To a cold solution (ice water bath) of the compound prepared in Example 6 (233 g, 0.94 mol) in 2.5 L CH2CI2, was added AICI₃ (630 g, 4.7 mol) slowly under Ar. The pot temperature was kept below 20°C, and the color of the reaction turned purple. EtSH (345 mL, 4.7 mol) was added slowly via an addition funnel to the reaction mixture, and the inside temperature was kept below 15°C. After 2 hours of stirring at below 20°C, the reaction went to completion by NMR analysis. The pot mixture was slowly poured into 2.5 L ice water with a strong agitation. The organic layer was separated, and the aqueous layer was extracted with 1L CH₂C1₂. The combined CH2CI2 layers were washed with water (4 x 1 L) until pH 6.0-7.0, and then dried over Na₂S04. The product (216 g, 98%) was obtained as a white solid after solvent removal and vacuum drying. Ή NMR (OMSO- ₆) δ 9.10(s, 1 H), 6.78(d, 1H), 6.58(d, 1H), 6.50(dd, 1 H), 3.60(s, 3.20(q, 1H), 2.70(m, 2H), 2.40(m, 1H), 2.08(m, 1H), 1 .80(m, 1H), 1.50(m, 2H), 0.80(t, 3H).

Example 8

Preparation of methy -[(4-methyIbenzoyl)amino]-4-oxopentanoate

To a suspension of L-aspartic acid D-methyl ester hydrochloride (250 g, 1.36 mol) in chilled (<5°C) CH₂ ¾ (4 L) was added Et₃N (440 g, 4.35 mol) in a steady flow followed by a slow addition of Me₃SiCl (324 g, 2.99 mol). The mixture was warmed to 25°C and stirred for one hour, cooled again (< 10°C), and p- toluoyl chloride (205 g, 1.36 mol) was added dropwise. The mixture was allowed to warm to ambient slowly with stirring for 16 hours. The reaction mixture was then diluted with CH₂CI2 (500 mL) and washed with IN HC1 (500 mL), brine (500 mL), and dried over Na₂S0 . The resultant amide product (310 g, 91%), a white solid, was obtained after solvent removal and drying under vacuum. It was then dissolved in pyridine (1.25 L) and DMAP (5 g) was added. Acetic anhydride (840 mL) was added slowly and then the reaction was heated at 90°C for 2 hours. The cooled solution was poured into 7 L ice water and extracted with 6 L EtOAc. The organic layer was washed with 2N HQ (3 x i L) and IN NaOH (1 L), dried over MgS0₄ and concentrated to afford the title compound as a white solid (301 g, 93%). Example 9

Preparation of methyl [5 I)-l,3-oxazol-4-ylj acetate

The intermediate prepared in Example 8 (280 g, 1.06 mol) was dissolved in acetic anhydride (650 mL) followed by slow addition of cone. H₂S0₄ (60 mL). The pot temperature reached 80°C. The reaction was then held at 85°C for 1 hour, cooled, and the acetic anhydride removed in vacuo. The residue was poured into ice water (2 L) and extracted with EtOAc (4 L total). The organic layer was then stirred with 1 N NaOH (500 mL) for 1 hour, separated, then dried with MgS0₄ and concentrated to afford the title ester as a clear oil (223 g, 87%), which slowly solidified to a white solid.

Example 10

Preparation of 2- [5-m ,3-oxazol-4-yl] ethanol

The oxazole ester prepared in Example 9 (300 g, 1.22 mol) was dissolved in THF (2.7 L) and solid L1BH₄ (26.6 g, 1.22 mol) was added in 5-g portions while maintaining temperature below 45°C. Reaction was complete within an hour after addition. Solvent was reduced to half volume and then poured into ice water (3 L). The mixture was then acidified by slowly adding 1 N HCl (1 L). A white precipitate fonned and was collected by filtration and oven dried over P₂0₅ to give the desired oxazole ester (214 g, 83%).

Example 11

Preparation of methyl (25)-2-((15)-5-{2-[5-methyl-2-(4-methylphenyl)-l,3-oxa2;o!-4-yl]ethoxy}-2,3- dihydro-lff-inden-l-yl)butanoate

A suspension of the hydroxyindane carboxylate prepared in Example 7 (208 g, 889 mmol), oxazole alcohol prepared in Example 10 (212 g, 977 mmol), ADDP (335 g, 1.33 mol), Ph₃P (348 g, 1.33 mol) in 6.0 L anhydrous THF was stirred at rt under Ar. The reaction was followed by ^]H NMR. No further progress was observed after 2 days. After solids were removed by filtration, THF was removed under reduced pressure. The remaining mixture was stirred in 3 L of 50/50 mixture EtOAc/hexane for 10 minutes, and more solids were formed and removed by filtration. The filtrate was concentrated and subjected to the same procedure with 25/75 mixture of EtOAc/hexane. After solvents were removed, the resulting oily mixture was purified on a silica gel (3.0 kg) column using C¾C1₂ (10.0 L) and 20% C¾CN/ CH₂C1₂ (10.0 L) as solvent. Fractions containing product were collected, and then concentrated. The crude mixture was dissolved in 4.0 L CH₂C1₂, and the unreacted hydroxy compound was removed by washing with IN NaOH (3 1 L). The C¾C1₂ layer was dried over Na₂S0₄. The product (358 g, 93%) was obtained as a light yellow oil after solvent removal and vacuum drying. Ή NMR (OMSO-d₆) δ 7.78(d, 2H), 7.30(d, 2H), 6.90(d, 1H), 6.75(d, 1H), 6.65(dd, 1H), 4.15(t, 2H), 3.60(s, 3H), 3.25(q, 1H), 2.90(t, 2H), 2.75(m, 2H), 2.40(m, 1H), 2.35(s, 3H), 2.32(s, 3H), 2.05(m, 1 H , 1.80(m, 1 H), 1.50(m, 2H), 0.80(t, 3H).

Example 12

Preparation of (25 -2-((l,y)-5-{2-[5-methyl-2-(4-methylphenyl)-l,3-oxazol-4-yI]ethoxy}-2,3-diliydro- l/ -inden-l-yI)butanoic acid

To a solution of LiOH (90.4 g, 3.76 mol) in 1.3 L water and 1.3 L MeOH, was added a solution of the ester prepared in Example 11 (325 g, 0.75 mol) in 3.9 L THF at rt. The solution turned cloudy. This mixture was heated at 60°C (pot temperature) for 4 hours, and TLC (50% EtOAc/hexane) analysis showed ca. 50% conversion. A solution of LiOH (30.1 g, 1.25 mol) in water (200 mL) was added to the reaction mixture. After 2 hours, TLC analysis showed ca. 85% reaction. Again, a solution of LiOH (30.1 g, 1.25 mol) in water (200 mL) was added to the reaction mixture. After 2 hours, TLC analysis showed very little starting ester left. After the reaction mixture was cooled to rt, THF and MeOH were removed at a reduced pressure. The residue was diluted with water until the solids dissolved (a total of 60 L of water used). Cone. HC1 solution was slowly added to this aqueous solution until pH 2.0-3.0. The solid was collected by filtration, and dried under house vacuum overnight. This solid was stirred with 15 L EtOAc and 2 L of IN HC1 solution for 30 minutes. The EtOAc layer was separated and washed with IN HC1 solution (2 x 1 L). The organic phase was then washed with water (4 x 2 L) until pH = 5.0-6.0. Under Ar protection, the EtOAc solution was reduced to 2.5 L by normal pressure distillation, then cooled to rt without disturbance. White solid precipitated out. After further cooling in an ice water bath for 2 hours, the solid was filtrated and washed with 500 mL cold EtOAc. After drying under high vacuum at 35°C to a constant weight, the final product (266 g, 81 %, 98% ee, ) was collected as a white crystal. Ή NMR (CDC1₃) δ 7.82(d, 2H), 7.20(d, 2H), 7.05(d, 1H), 6.75(d, 1H), 6.70(dd, 1H), 4.20(t, 2H), 3.42(q, 1H), 2.95(t, 2H), 2.80(m, 2H), 2.50(m, 1H), 2.35(s, 3H), 2.32(s, 3H), 2.20(m, 1 H), 1.90(m, 1 H), 1.65(m, 1H), 1.45(m, 1 H), 0.90(t, 3H). Chiral purity, 99% ee, [□¾,=+! 6.1 1(CHC1₃), mp 149.5- 1 50.5°C. Example 13

Preparation of 2-{5-[2-(5-methyl-2-phenyI-l,3-oxazol-4-yl)et oxy]-2,3-dihydro-lH-inden-l-

Step 1 , To a solution of 5-methoxy-indanone (10 g) dissolved in toluene (150 mL) was added A1C¾ (15 g). The mixture was refluxed for 4 hours until a precipitate appeared. The resulting mixture was cooled and poured into ice water (150 mL). The precipitate was filtered and washed with water, then air-dried to give the desired product (8.5 g, 90%).

Step 2. Benzyl bromide (17 g), 5-hydroxyi-indanone (15 g), K2CO₃ (20 g), and 200 mL acetone were mixed in a round-bottom flask (500 mL). The mixture was refluxed for 1 hour. The K₂C0₃ was filtered off, and the filtrate was evaporated. The resulting residue was crystallized from EtOAc to give 18 g product (75%).

Step 3. A solution of 5-benzyloxyl-indanone (1.14 g, 4.79 mmol) and diethyl malonate (0.844 g, 5.29 mmol) in THF (20 mL) was cooled to 0°C under argon, and T1CI (10 mL, 1M in C¾C1₂) was added dropwise. Pyridine (2 mL) was added finally. The resulting mixture was stirred overnight at rt. After filtration, EtOAc (30 mL) was added into the filtrate. The organic layer was washed with brine (20 mL x 3), dried with Na₂S04, and evaporated. The residue was separated by silica gel chromatography to give 800 mg product (50%).

Step 4, The product of step 3 (1.7 g) was dissolved in MeOH (25 mL), and Pd-C (300 mg) was added as a slurry in MeOH, and placed under 60 psi H₂ in a Parr shaker for 6 hours. After filtration and concentration, 3.2 g product was obtained (92%).

Step 5. P(Ph)₃ (420 mg) and ADDP (420 mg) were dissolved in THF (5 mL) at 0°C, and stirred for 10 minutes. A THF solution of oxazole (300 mg) and phenol (430 mg) was added to the flask. The resulting mixture was stirred for 24 hours, and filtered. The filtrate was evaporated and the resulting residue was separated by silica gel chromatography to give product (320 mg, 45%).

Step 6. The intermediate prepared in step 5 (160 mg) was dissolved in THF (5 mL), and iodoethane (0.5 mL) and /-BuOK (50 mg) were added to the solution and stirred overnight. After filtration, the product was separated by using TLC, providing 100 mg (65%).

Step 7. The intermediate prepared in step 6 (30 mg) was dissolved in DMSO (1 mL). LiCl (160 mg) was added into the flask. The mixture was refluxed for 5 hours. From the resulting mixture, the product was separated by TLC, giving 13 mg (52%).

Step 8, The intermediate prepared in step 7 was subjected to hydrolysis in aqueous KOH as described for Example 2 to obtain the product: LC-MS, RT 3.57 min., M+l 406; ¾ NMR (CD₂C1₂): δ 0.93 (t, 3H), 1.40-1.70 (m, 2H), 1.80-2.20 (m, 2H), 2.30 (s, 3H), 2.40 (m, 1H), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.20-3.40 (m, 1H), 4.10 (t, 2H), 6.60 (dd, 1H), 6.70 (d, 1H), 7.00 (d, 1H), 7.30 (m, 3H), 7.90 (m, 2H).

By using the procedures from Examples 1-13 together in some cases with the chiral HPLC separation method described in the general section, and by using the appropriate starting materials, the following were prepared and characterized in a similar manner:

Example 14

2-(5-{2-[5-methyl-2-(4-rnethylphenyl)-l,3-oxazoI-4-yl]ethoxy}~2,3-dihydro-lH-inden-l-yl)butanoic acid

LC-MS, RT 3.70 min., M+l 420; Ή NMR (CD₂C1₂): δ 0.93 (t, 3H), 1.40-1.70 (m, 2H), 1.80-2.20 (m, 2H), 2.30 (s, 3H),2.35 (s, 3H), 2.40 (m, 1H), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.20-3.40 (m, 1H), 4.10 (t, 2H), 6.60 (dd, 1H), 6.70 (d, 1H), 7.00 (d, 1H), 7.20 (m, 3H), 7.80 (m, 2H). Example 15

(2S)-2-{(lS)-5-[2-(5-methyi-2-phenyI-l,3-oxazol-4-yl)ethoxy)-2,3-dihydro H-inden-l-yl}butanoic acid

The enantiomer was isolated by chiral HPLC. LC-MS, RT 3.57 min., M+l 406; ^l NMR (CD₂C1₂): 5□ 0.93 (t, 3H), 1.48 (ddq, I H), 1.68 (ddq, IH), 1.93 (dddd, IH), 2.18 (dddd, IH), 2.34 (s, 3H), 2.50 (ddd, IH), 2.77 (ddd, IH), 2.87 (ddd, IH), 2.96 (t, 2H), 3.42 (ddd, IH), 4.19 (t, 2H), 6.68 (dd, IH) 6.77 (d, I H). 7.08 (d, IH), 7.42 (m, 2H), 7.44 (m, IH), 7.97 (dd, 2H). ¹³C NMR: δ Π 10.4, 12.4, 22.4, 26.6, 29.5, 31.8, 46.5, 51.8, 67.2, 110.9, 1 13.0, 124.7, 126.2, 128.1 , 129.1, 130.2, 133.2, 137.1, 145.6, 146.3, 158.7, 159.7, 180.4.

Example 16

(2S)-2-{(lR)-5-[2-(5-methyl-2-phenyI-l,3-oxazoI-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yI}butanoic acid

The enantiomer was isolated by chiral HPLC. LC-MS, RT 3.57 min., M+l 406; Ή NMR (CD₂C1₂): 6□ 0.93 (t, 3H), 1 .61 (ddq, IH), 1.69 (ddq, IH), 1.99 (dddd, I H), 2.19 (dddd, IH), 2.47 (s, 3H), 2.52 (ddd, I H), 2.73 (ddd, IH), 2.89 (ddd, IH), 3.11 (t, 2H), 3.31 (ddd, IH), 4.21 (t, 2H), 6.66 (dd, IH) 6.74 (d, IH). 7.13 (d, IH), 7.55 (m, 2H), 7.61 (m, IH), 8.05 (dd, 2H). ¹³C NMR: δ D 10.5, 12.2, 23.8, 24.8, 30.3, 31.5, 46.4, 50.9, 66.1 , 110.8, 1 12.6, 125.9, 127.4, 123.6, 129.8, 133.3, 129.7, 137.0, 148.4, 146.5, 158.2, 160.5, 181.0.

Example 17

(2R)-2-{(lR)-5-[2-(5-methyl-2-[4-methylphenyl]-l,3-oxazo!-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- yljbutanoic acid

The enantiomer was isolated by chiral HPLC. LC-MS, RT 3.70 min., M+l 420; ^!H NMR (CD₂C1₂): δ 0.95 (t, 3H), 1.40(m, IH), 1.70 (m, IH), 1.90 (m, IH), 2.20 (m, I H), 2.30 (s, 3H),2.35 (s, 3H), 2.50 (m, H), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.40 (dd, 1H), 4.20 (t, 2H), 6.60 (dd, 1H), 6.70 (d, 1H), 7.10 (d, 1H),.20 (m, 3H), 7.80 (m, 2H).

Example 18

2-(5- {2- [5-methy 1-2-phen - l,3-oxazol-4-yl] ethoxy} -2,3-dihydro-lH-inden- l-yl)propanoic acid

LC-MS, RT 3.41 min., M+1 392; H NMR (CD₂C1₂): δ 1.10 (d, 3H), 1.90 (m, 2H), 2.20 (m, 1H),.40 (s, 3H), 2.70-3.00 (m, 2H), 2.95 (t, 2H), 3.45 (m, 1H), 4.20 (t, 2H), 6.70 (dd, 1H), 6.80 (d, 1H), 7.10 (d,H), 7.45 (m, 3H), 8.00 (m, 2H).

Example 19

2-{5-[2-(5-methyl-2~phenyl-l,3-oxazoI-4-yI)ethoxy]-2,3-dihydro-lH-inden-l-yl}maIonic acid

LC-MS, RT 3.00 min., M+1 422; ^!H NMR (CD₂C1₂): δ 1.90 (m, 2H), 2.40 (t, 3H), 2.60-3.00 (m,H), 3.40(t, 2H), 3.70 (m, 1H), 4.20 (t, 2H), 6.60 (dd, 1H), 6.80 (d, 1H), 7.10 (d, 1H), 7.50 (m, 3H), 7.95 (m,H).

Example 20

3-ethoxy-2-{5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yI}-3- oxopropanoic acid

LC-MS, RT 3.39 min., M+1 450; ^!H NMR (CD₂C1₂): δ 1.20 (t, 3H), 2.00(m, 1H), 2.30 (m, 1H), 2.40s, 3H), 2.90 (m, 2H), 3.10 (t, 2H), 3.80 (m, 1H), 4.20 (t & q, 4H), 6.70 (dd, 1H), 6.80 (d,lH), 7.10(d, 1H),.50 (m, 3H), 8.00 (m, 2H). Example 21

2-{5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yI)ethoxy]-2,3-dihydro-lH-inden-l-yl}-5- phenylpentanoic acid

LC-MS, RT 3.98 min., M+l 396; Ή NMR (CD₂C1₂): δ 1.40-1.80 (m, 4H), 1.90-2.20 (m, 2H), 2.35 (s, 3H), 2.40-3.00 (m, 5H), 2.90 (t, 2H), 3.35 (m, IH), 4.10 (t, 2H), 6.60 (dd,lH), 6.70 (d, IH), 6.907.20 (m, 6H), 7.30 (m, 3H), 7.95 (m, 2H).

Example 22

2-(5-{2-[5-methyl-2-{4-methyIphenyI)-l,3-oxazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-yl)propanoic acid

LC-MS, RT 3.52 min., M+l 406; Ή NMR (CD₂C1₂): δ 1.10 (d, 3H), 1.90 (m, 2H), 2.20 (m, IH), 2.30 (s, 3H), 2.31(s, 3H), 2.70-3.00 (m, 2H), 2.95 (t, 2H), 3.40 (m, IH), 4.30 (t, 2H), 6.60 (dd, IH), 6.70 (d, IH), 7.00 (d, IH), 7.20 (d, 2H), 7.80 (d, 2H).

Example 23

2-(5-{2-[5-methyl-2-(4-methyIphenyl)-l,3- xazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-yl)hcxanoic acid

LC-MS, RT 3.92 min., M+l 448; ¹H NMR (CD₂C1₂): δ 0.93 (t, 3H), 1.10-1.30 (m, 4H), 1.40-1.70 (m, 2H), 1.80-2.20 (m, 2H), 2.30 (s, 3H), 2.31 (s, 3H), 2.40 (m, IH), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.20- 3.40 (m_t IH), 4.10 (t, 2H), 6.60 (dd, IH), 6.70 (d, IH), 7.00 (d, IH), 7.20 (d, 2H), 7.80 (d, 2H). Example 24

4-methyl-2-(5-{2-[5-methyl-2-(4-methylphenyl)-l,3-oxazoI-4-yl]ethoxy}-2 -dihydro-lH-inden-l- yi)pentanoic acid

LC-MS, RT 4.00 min., M+l 448; ^lU NMR (CD₂C1₂): δ 0.93 (m, 6H), 1.20 (m, 1H), 1.40-1.70 (m, 2H), 1.80-2.20 (m, 2H), 2.30 (s, 3H), 2.31 (s, 3H), 2.40 (m, 1H), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.20-3.40 (m, 1H), 4.10 (t, 2H), 6.60 (dd, 1H), 6.70 (d, 1H), 7.00 (d, 1H), 7.40 (d, 2H), 8.40 (d, 2H).

Example 25

4-methyl-2-(5-{2-[5-methyl-2-(4-methylphenyI)-l,3-oxazol-4-yl]ethoxy}-2_>3-di ydro-lH-inden-l-yI)-4- pentenoic acid

LC-MS, RT 3.74 min., M+l 446; ^TH NMR (CD₂C¾): δ 1.60 (s, 3H), 1.70 (m, 2H), 1.80-2.20 (m, 2H), 2.30 (s, 3H), 2.31 (s, 3H), 2.40 (m, 1H), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.20-3.40 (m, 1H), 4.10 (t, 2H), 5.60 (m, 2H), 6.60 (dd, 1H), 6.70 (d,lH), 7.00 (d, 1H), 7.20 (d, 2H), 7.80 (d, 2H).

Exam le 26

Preparation of 2-{6-chioro-5-[2-(5-methyl-2-p enyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- y]}butanoic acid

via

2-(5-methyl-2-phenyl-l,3~oxazol-4-yl)ethyl methanesulfonate and methyl 2-{6-c butanoate

Step 1. To a solution of 2-phenyl-4-methyl-5-hydroxyethyloxazole (500 mg, 2.5 mmol) in 12.5 mL THF, was added methanesulfonyl chloride (0.21 mL, 2.75 mmol) and triethylamine (0.42 mL, 3 mmol). The reaction solution was stirred at rt under argon for two hours then concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 1% aqueous hydrochloric acid (three times) and brine. It was then dried over sodium sulfate, filtered, and concentrated in vacuo to provide (617 mg, 88%): ES-MS m/z 282 ((M+H)⁺); HPLC RT 2.67; ^]H NMR (d₆-DMSO) δ 2.33 (s, 3H), 2.89 (t, 2H), 3.13 (s, 3H), 4.41 (t, 2H), 7.47-7.51 (m, 3H), 7.88-7.91 (m, 2H).

Step 2. Sulfuryl chloride (0.035 mL, 0.43 mmol) was added to a solution of methyl-5-hydroxy-2,3- dihydro-l-(2-butanoate) (100 mg, 0.43 mmol) in 2.15 mL acetic acid. The reaction solution was stirred at rt for 30 minutes, then concentrated in vacuo. The resulting residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. It was then dried over sodium sulfate, filtered, and concentrated in vacuo to provide 63 mg of the desired intermediate as a crude yellow oil which was carried on without further purification: GC-MS 269, ((M+H)⁺); GC RT (min.) 8.71; ^]H NMR (d₆-DMSO) δ □ 0.81 (t, 3H), 1.40-1.63 (m, 2H), 1.77-1.88 (m, 1H), 2.00-2.15 (m, 1H), 2.40-2.80 (m, 3H), 3.15-3.22 (m, lH), 3.50 (s, 3H), 6.76 (s, 1H),

Step 3. A solution of the product obtained in step 2 (30.5 mg, 0.12 mmol) in 0.6 mL DMF was cooled to 0°C in an ice bath. A 60% dispersion of sodium hydride in oil (5.2 mg, 0.13 mmol) was then added and the ice bath was removed. After stirring the reaction mixture for 1 hour at rt, the mesylate from step 1 (34 mg, 0.12 mmol) was added. The reaction mixture was heated at 50°C for 24 hours, then cooled to 0°C. An additional 9.6 mg NaH (60% dispersion in oil) was added and heating was resumed for two hours, after which the reaction mixture was cooled to rt and stirred for 48 hours. At this time, ethyl acetate was added and the organic solution was washed with water and brine (three times), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified through silica gel flash chromatography by using 5: 1 hexane: ethyl acetate as the eluant to provide product (19 mg, 35%) as a mixture of diastereomers (3: 1): ES-MS m/z 454 ((M+H)⁺); HPLC RT (min.) 4.21 ; Ή NMR (d₆-DMSO) δ □ 0.80 (t, 3H), 1.38-1.63 (m, 2H), 1.79-1.90 (m, 1H), 2.02-2.14 (m, 1H), 2.34 (s, 3H), 2.51-2.57 (m, 1H), 2.63-2.84 (m, 2H), 2.91 (t, 2H), 3.19-3.25 (m, 1H), 3.49 (s, 2.3H), 3.58 (s, 0.7H), 4.22 (t, 2H), 7.00 (s, 1 H), 7.21 (s, 1H), 7.43-7.51 (m, 3H), 7.85-7.90 (m, 2H).

Step 4. Under the standard hydrolysis conditions, the ester from step 3 was converted to the acid (a mixture of diastereomers 3:2): ES-MS m/z 440 ((M+H)⁺); HPLC RT (min.) 3.69; ^!H NMR (d₆-DMSO) δ □ 0.83 (t, 3H), 2.34 (s, 3H), 2.92 (t, 2H), 4.21 (t, 2H), 7.00-7.02 (d, 1H), 7.12 (s, 0.24H), 7.21 (s, 0.37H), 7.47-7.48 (m, 3H), 7.87-7.90 (m, 2H).D

Example 27

Preparation of ethyl 2-{5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yI)ethoxy]-2,3-dihydro-lH-inden-l- noate

An oven dried 15 mL round-bottom flask and stir bar, cooled under a stream of Ar(g), was charged with ethyl 2-{5-[2-(5-metliyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl} acetate (0.070 g, 0.17 mmol) followed by addition of 0.2 mL THF. The stirred solution was then cooled to -78 °C followed by dropwise addition of lithium bis(trimethylsilyl)amide (1.0 M hexane solution, 0.86 mL, 0.86 mmol). Upon complete addition of base, the solution was allowed to stir at -78°C for ] hour, then iodopropane (0.142 g, 0.86 mmol) was added via syringe. The contents were then slowly warmed to rt and maintained for 1 hour. The contents of the flask were poured into 5 mL NH Cl(aq), then extracted with ethyl acetate (3 x 10 mL). The organic layers were combined and dried over Na₂SC>4 and concentrated in vacuo yielding 3.0 mg (4.0% yield) of a colorless film. The product had: Ή NMR (300 MHz, d6-acetone) δ 7.96 (dd, 8.1, 1.5 Hz, 2H), 7.48 (m, 3H), 6.99 (d, 8.4 Hz, 1H), 6.79 (d, 2.7 Hz, 1H), 6.70 (dd, 8.1, 2.7 Hz, 1H), 4.22 (t, 6.9 Hz, 2H), 4.1 1 (q, 7.2 Hz, 2H), 3.33 (q, 6.6 Hz, 1H), 2.94 (t, 6.9 Hz, 2H), 2.78 (m, 3H), 2.54 (m, 1H), 2.39 (s, 3H), 2.14 (m, 2 H), 1.91 (m, 1H), 1.63 (qt, 10.2, 3.9Hz, 2H), 1.21 (t, 7.2 Hz, 3 H), 0.852 (t, 7.5 Hz, 3 H); mass spectroscopy gave MlT of 448.2 (calc'd molecular weight for C_2gH₃₃N0₄ = 447.57).

Example 28

Preparation of 2-{5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- l}pentanoic acid

Hydrolysis of the product of Example 27 by the method described above for Example 2 gave a product with the following ^!H NMR (300 MHz, d6-acetone); δ 7.96 (dd, 8.1, 1.5 Hz, 2H), 7.48 (m, 3H), 7.10 (d, 8.4 Hz, IH), 6.79 (d, 2.7 Hz, 1H),6.71 (dd, 8.1, 2.7 Hz, IH), 4.22 (t, 6.9 Hz, 2H), 3.40 (m, IH), 2.91 (t, 6.9 Hz, 2H), 2.74 (m, IH), 2.58 (m, IH), 2.39 (s, 3H), 2.26 (m, IH), 2.11 (m, IH), 1.95 (m, 2H), 1.84 (m, IH), 1.62 (m, 2H), 0.859 (td, 6.9, 1.5 Hz, 3H); mass spectroscopy gave MH⁺ of 420.1 (calc'd molecular weight for C2₆H₂₉NO4 = 419.51).

Example 29

Preparation of 2-{6-bromo-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- yl}butanoic acid

via

methyl 2-(6-bromo-5-hydroxy-2,3-dihydro-lH nden-l-yl)buianoate

A B

Step 1. A solution of bromine (0.032 mL, 0.60 mmol) in dioxane (3 mL) was cooled to 0°C for 15 minutes after which a solution of 2-(5-hydroxy-indan-l-yl)-butyric acid methyl ester (141 mg, 0.60 mmol) in dioxane (3 mL) was added. After 5 minutes, the ice bath was removed and the reaction was stirred at rt for 4 hours. Solvent was removed by rotary evaporation. The residue was purified by column chromatography (8% EtOAc in hexane) to obtain a colorless oil of mono-bromo intermediate (A) (145 mg, 77%) and dibromo intermediate (B) ( 20 mg).

A: R = 0.46 (4 : 1 hexane : EtOAc); GC-MS (+C1): m/z = 313 (JVf); ^]H NMR (DMSO - ¾: δ 0.840 (m, 3H), 1.511 (m, 2H), 1.905 (m, IH), 2.091 (m, IH), 2.410 - 2.793 (m, 3H), 3.212 (m, IH), 3.505 and 3.512 (s, 3H), 6.713 and 6.753 (s, IH), 7.034 and 7.274 (s, IH), 9.932 and 9.934 (s, OH).

B: 0.30 (4 : 1 hexane : EtOAc); GC-MS(+C1): m/z = 393 (M⁺); 'H NMR (DMSO - <¾: δ 0.817 (m, 3H), 1.459 - 1.596 (m, 2H), 1.910 (m, I H), 2.101 (m, IH), 2.433 - 2.768 (m, 3H), 3.371 (m, IH), 3.400 and 3.596 (s, 3H), 7.168 and 7.357 (s, IH), 9.535 and 9.542 (s, OH).

Step 2. To a solution of (A) from step 1 above (1 i 8 mg, 0.38 mmol) in DMF (3.8 mL) at 0°C, was added NaH (60% in mineral oil, 30 mg). After 1 hour, the mesylate as prepared in step 1, Example 26 was added. The mixture was heated to 50°C for 30 hours. The solution was diluted with water, and then extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, then dried (TS^SC^). and concentrated. The residue was purified by column chromatography (10% ethyl acetate in hexane) to give product (63 mg, 34%); = 0.46 (2 : 1 hexane : EtOAc); ESLC-MS: m/z = 498 (MH⁺); 'H NMR (DMSO - d₆): 5 0.847 (m, 3H), 1.468 (m, 2H), 1 .812 (m, 1H), 2.146 (m, 1H), 2.340 (s, 3H), 2.525 - 2.788 (m, 3H), 2.902 (m, 2H), 3.236 (m, 1H), 3.481 and 3.586 (s, 3H , 4.211 (m, 2H), 6.969 (s, 1H), 7.347 and 7.386 (s, 1H), 7.452 (m, 3H), 7.833 (m, 2H).

Step 3. To a solution of product from step 2 (5.6 mg) in methanol, was added 3 N OH (1 mL) followed by addition of THF until the cloudy solution became clear. The mixture was refluxed overnight. Cone. HCl was added to adjust the pH to 2, then extracted three times with ethyl acetate. The organic layers were combined, dried, and concentrated to give white solid (4 mg). Ry = 0.18 (2: 1 hexane:EtOAc); ESLC- MS: m/z = 484 (MET^"); ^XB NMR (DMSO - d₆) 6 0.832 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H). 2.405 (m, 1 H), 2.788 (m, 2H), 2.904 (m, 2H), 3.015 (m, 1H), 3.136 and 3.138 (s, 3H), 4.209 (m, 2H), 6.987 and 7.344 (s, 1 H), 6.972 and 7.251 (s, 1H), 7.487 (m, 3H), 7.882 (m, 2H).

Example 30

Preparation of 2-{5-f2-{5-methyI-2-phenyl-l,3-oxazol-4-yl)ethoxy]-6-phenyI-2,3-dihydro-lH-inden-l- yljbutanoic acid

via

methyl 2-{5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxyj-6-phenyl-2_t3-dihydro-lH-inden-l- yljbutanoate

Step 1. A mixture of the product of step 2, Example 29 and Pd(PPh₃)4 in THF (1.5 mL) was stirred at rt for 30 minutes. Phenylboronic acid (13.2 mg, 0.108 mmol) and 2 N NaOH were then added into the solution. The mixture was heated to reflux for 14 hours. The solution was allowed to cool down, diluted with water, and extracted with ethyl acetate three times. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography eluting with 5% ethyl acetate in hexane to obtain the desired product (8.6 mg). R_f = 0.48 (2: 1 hexane:EtOAc);

ESLC-MS: m/∑ = 496 (MH⁺); Ή NMR (DMSO - d₆): δ 0.804 (m, 3H), 1.541 (m, 2H), 1.880 (m, 1H), 1.987 (m, 1 H), 2.090 (s, 3H), 2.247 - 2.698 (m, 3H), 2.791 (m,' 2H), 3.199 (m, 1H), 3.524 and 3.537 (s, 3H), 4.190 (m, 2H), 6.970 (s, 1H), 7.062 (s, 1H), 7.275 (m, 5H), 7.472 (m, 3H), 7.868 (m, 2H).

Step 2. The ester was hydrolyzed by methods described above to give product: R/ = 0.16 (2 : 1 hexane : EtOAc); ESLC-MS: mfz = 482 (ΜΐΓ); Ή NMR (DMSO - d₆): 6 0.923 (m, 3H), 1.504 (m, 2H), 1.812 (m, 1 H), 2.146 (m, 1H), 2.188 (s, 3H), 2.334 (m, 2H), 2.432 (m, 2H), 2.539 (m, 1H), 2.625 (m, 1H), 4.287 (m, 2H), 7.059 (s, ] H), 7.160 (s, 1H), 7.351 (m, 5H), 7.544 (m, 3H), 7.971 (m, 2H).

Example 31

Preparation of methyl 2-{6-(4-chIorophenyl)-5-[2-(5-methyl-2-phenyI-i,3-oxazol-4-yI)ethoxy]-2,3- dihydro-lH-inden-l-yl}butanoatc

A mixture of the product prepared in step 2, Example 29 (71.4 mg, 0.14 mmol), NaHC0₃ (14.3 mg, 0.17 mmol), 4-chlorophenylboronic acid (26.8 mg, 0.17 mmol) in ethylene glycol dimethyl ether (1.5 mL) and water (0.4 mL) was degassed for 20 minutes. Pd(dppf)Cl₂ was then added to the solution. The mixture was heated to reflux for 2 days. The mixture was then concentrated and purified with column chromatography (10% EtOAc in hexane) to obtain desired product (25 mg). R/= 0.51 (2: 1 hexane :EtO Ac); ESLC-MS: m/z = 530 (MH¹); Ή NMR (DMSO - d₆): δ 0.841 (m, 3H), 1.557 (m, 2H), 1.888 (m, 1H), 1.987 (m, mi 2.146 (s, 3H), 2.247 - 2.698 (m, 3H), 2.791 (m, 2H), 3.214 (m, 1H), 3.487 and 3.5538 (s, 3H), 4.189 (m, 2H), 6.993 (s, 1H). 7.080 (s, 1H), 7.308 (s, 4H), 7.493 (m, 3H), 7.868 (m, 2H). By using the above described methods for Examples 26-31 and substituting the appropriate starting materials, the following were made and characterized:

Example 32

2-{6-chloro-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}butanoic acid

ESLC-MS: m/z = 516 (MfT); ^lU NMR (DMSO - d₆) δ 0.847 (m, 3H), 1.557 (m, 2H), 1.888 (m, 1H), 1.987 (m, 1H), 2.137 (s, 3H), 2.247 - 2.687 (m, 3H), 2.819 (m, 2H), 3.234 (m, 1H), 4.187 (m, 2H), 6.994 (s, 1H), 7.089 (s, 1H), 7.298 and 7.308 (m, 4H), 7.484 (m, 3H), 7.869 (m, 2H).

Example 33

Methyl 2-{6-methyI-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- yljbutanoate

R = 0.23 (2:1 hexane:EtOAc); ESLC-MS: m/z = 434 (Mlf); ^]H NMR (DMSO - d₆): δ 0.804 (m, 3H), 1.522 (m, 2H), 1.830 (m, 1H), 1.987 (m, 1H), 2.037 (s, 3H), 2.335 (s, 3H), 2.410 - 2.550 (m, 3H), 2.901 (m, 2H), 3.146 (m, 1 H), 3.507 (s, 3H), 4.163 (m, 2H), 6.777 (s, 1H), 6.939 (s, 1H), 7.483 (m, 3H), 7.875 (m, 2H).

Example 34

2-{6-methyl-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}butanoic acid

R/ = 0.31 (2: 1 hexane:EtOAc); ESLC-MS: m/z = 420 (MH*); Ή NMR (DMSO - d₆)\ δ 0.827 (m, 3H , 1.508 (m, 2H), 1.828 (m, 1H), 1.987 (m, 1H), 2.017 {s, 3H), 2.333 (s, 3H), 2.410 - 2.550 (m, 3H), 2.894 (m, 2H), 3.146 (m, 1H), 4.116 (m, 2H), 6.773 (s, 1H), 6.942 (s, 1H), 7.467 (m, 3H), 7.880 (m, 2H). Example 35

Methyl 2-[5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-6-(2-thienyl)-2,3-dihydro-lH-inden-l- yl]butanoate

R/ = 0.60 (2:1 hexane:EtOAc); ESLC-MS: m/z = 502 (MH⁺); Ή NMR (DMSO - d₆): 5 0.801 (m,H), 1.535 (m, 2H), 1.891 (m, IH), 1.987 (m, IH), 2.299 (s, 3H), 2.410 - 2.550 (m, 3H), 2.988 (m, 2H),.146 (m, IH), 3.506 (s, 3H), 4.337 (m, 2H), 7.011 - 7.041 (m, 2H), 7.405 - 7.493 (m, 5H), 7.884 (m, 2H).

Example 36

2-[5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-6-(2-thienyl)-2,3-dihyd

inden-l-yl]butanoic acid

R = 0.18 (2:1 hexane:EtOAc); ESLC-MS: m/z = 488 (MH⁺); ¾ NMR (DMSO - d₆) δ 0.801 (m,H), 1.535 (m, 2H), 1.891 (m, I H), 1.987 (m, IH), 2.299 (s, 3H), 2.410 - 2.550 (m, 3H), 2.988 (m, 2H),.146 (m, IH), 4.337 (m, 2H), 7.078 (m, 2H), 7.472 (m, 5H), 7.896 (m, 2H).

Example 37

Methyl 2-{4,6-dibromo-5-[2-(5-methyl-2-phenyl-l,3-oxazoI-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- yl}butanoate

R/ = 0.35 (4: 1 hexane:EtOAc); ESLC-MS: m/z = 578 (Mif); ^]H NMR (DMSO - d₆): δ 0.847 (m,H), 1.468 (m, 2H), 1.812 (m, IH), 2.146 (m, IH), 2.350 (s, 3H), 2.407 - 2.788 (m, 3H), 2.982 (m, 2H),.225 (m, IH), 3.480 and 3.588 (s, 3H), 4.145 (m, 2H), 7.276 (s, I H), 7.458 (m, 3H), 7.866 (m, 2H). Example 38

2-{4,6-dibromo-5-[2-(5-methyI-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}butanoic acid

/ = 0.17 (2: 1 hexane:EtOAc); ESLC-MS: m/z = 564 (MH⁺); Ή NMR (DMSO - i¾: δ 0.847 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.361_; (s, 3H), 2.414 - 2.781 (m, 3H), 2.995 (m, 2H), 3.123 (m, 1H), 4.125 (m, 2H), 7.345 (s, 1H), 7.437 (m, 3H), 7.886 (m, 2H).

Example 39

Preparation of 2-{6-acetyl-5-[2-(5-methyl-2-phenyl-l,3-oxazoI-4-yI)ethoxy]-2,3-dihydro-lH-inden-l- yljbutanoic acid

via

methyl 2-(6-acetyl-5-methoxy-2,3-dihydro-lH-inden-l-yl)butanoate

Step 1. To a solution of A1C1₃ (103 mg, 0.78 mmol) in methylene chloride (2.5 mL) at 0°C, was added acetyl chloride (0.044 mL, 0.63 mmol), followed by the addition of a solution of methyl 5-methoxy- 2,3-dihydxo-lH-indene-l-yl-butanoate (130 mg, 0.52 mmol) in methylene chloride (2.7 mL) dropwise. The mixture was stirred at 0°C for 15 minutes. The ice bath was removed and the mixture stirred at rt for 16 hours. The mixture was poured over ice and 4 drops of cone. HC1 were added. This mixture was extracted with methylene chloride twice. The combined organic layers were washed with water, 0.05 N NaOH and water. The organic layer was dried, concentrated, and purified by chromatography with 10% EtOAc:hexane to give desired product ( 103 mg, 68%). R/= 0.28 (4: 1 hexane:EtOAc); GC-MS (+C1): m/z = 291 (M⁺); ¾ NMR (DMSO - d₆) δ 0.840 (m, 3H), 1.536 (m, 2H), 1.876 (m, 1 H), 2.108 (m, 1H), 2.505 (s, 3H), 2.521 (m, 1H), 2.760 - 2.889 (m, 2H), 3.236 (m, 1H), 3.511 and 3.589 (s, 3H), 3.836 (s, 3H), 7.012 and 7.253 (s, 1H), 7.440 (s, lH).

Step 2. To a solution of A1C1₃ (238 mg, 1.77 mmol) in CH₂C1₂ (1 mL), was added the product of step 1 (103 mg, 0.35 mmol) in CH₂C1₂ (2 mL). The mixture was cooled to 0°C for 5 minutes, then EtSH (0.13 mL, 1.77 mmol) was added slowly. The mixture was stirred at this temperature for 4.5 hours. The mixture was then poured over ice water, stirred for 10 mmutes, and extracted with 0¾Ο₂ twice. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated to give product (86 mg, 89%). R_f = 0.51 (4: 1 hexane:EtOAc); GC-MS (+C1): m/z = 276 ( ⁺); ¾ NM (DMSO - d₆): δ 0.841 (m, 3H), 1.574 (m, 2H), 1.888 (m, 1H), 2.094 (m, 1H), 2.585 (s, 3H), 2.639 (m, 1H), 2.729 - 2.847 (m, 2H), 3.244 (m, 1H), 3.513 and 3.628 (s, 3H), 6.774 and 7.503 (s, 1H), 6.792 and 7.715 (s, 1H), 12.117 and 12.143 (s, 1H).

Step 3. The coupling of the hydroxy indene acetic acid ester of step 2 with the mesylate of step 2, Example 26. ESLC-MS: m/z = 462 (Mrf);

Step 4. The hydrolysis of the product from step 3 was carried out in similar fashion as described above to give product: R_f = 0.08 (2: 1 hexane:EtOAc); ESLC-MS: m/z = 448 (MH⁺); Ή NMR (DMSO - d₆) δ 0.848 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.305 (s, 3H), 2.368 (s, 3H), 2.405 (m, 1H), 2.788 (m, 2H), 2.971 (m, 2H), 3.015 (m, 1H), 4.332 (m, 2H), 7.039 and 7.441 (s, 1H), 7.446 (s, 1H), 7.465 (m, 3H), 7.875 (m, 2H).

Using a combination of the above described procedures and substituting the appropriate starting materials, a variety of compounds were prepared and are described below.

Example 40

Methyl 2~{5-[2-(2,5-diphenyl-l,3-oxazol-4-yl)ethoxy]-2,3"dihydro-lH-inden-l-yI}butanoate

Yield: 0.09 g, 46%; ^]H NMR (CDC1₃, 400 MHz) δ 0.83-0.93 (t, 3 H), 1.55-1.78 (m, 2 H), 1.87-1.97 (m, 1 H), 2.10-2.22 (m, 1 H), 2.44-2.52 (m, 1 H), 2.67-2.80 (m, 1 H), 2.81-2.93 (m, 1 H), 3.21-3.29 (m, 1 H), 3.23-3.33 (t, 2 H), 3.62 (s, 3 H), 4.34-4.43 (t, 2 H), 6.66-6.72 (m, 1 H), 6.76 (s, 1 H), 7.05-7.14 (d, 1 H), 7.33-7.39 (t, 1 H), 7.43-7.51 (m, 5 H), 7.78-7.84 (d, 2 H), 8.06-8.12 (m, 2 H).

Example 41

2-{5-[2-(2,5-diphenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-jnden-l-yl}butanoic acid

Yield: 0.07 g, 70%; H NMR (CDC1₃, 400 MHz) δ 0.85-0.98 (m, 3 H), 1.23-1.47 (m, 1 H), 1.57-1.78 (m, 1 H), 1.88-2.07 (m, 1 H), 2.12-2.27 (m, 1 H), 2.43-2.56 (m, 1 H), 2.68-2.97 (m, 2 H), 3.27-3.35 (t, 2 H), 3.42-3.50 (m, 1 H), 4.34-4.41 (t, 2 H), 6.66-6.73 (d, 1 H), 6.77 (s, 1 H), 7.02-7.16 (d, 1 H), 7.34-7.40 (t, 1 H), 7.43-7.52 (m, 5 H), 7.78-7.83 (d, 2 H), 8.05-8.12 (m, 2 H).

Example 42

Methy! 2-{5-[2-(5-isopropyl-2-phenyH,3-oxazol-4-yI)ethoxy]-2,3-dihydro-lH-inden-l-yl}butanoate

Yield: 0.09 g, 45%; Ή NMR (CDC1₃, 400 MHz) δ 0.78-0.96 (t, 3 H), 1.26-1.32 (d, 6 H), 1.51-1.62 (m, 1 H), 1.64-1.75 (m, 1 H), 1.81-1.93 (m, 1 H), 2.07-2.21 (m, 1 H), 2.40-2.51 (m, 1 H), 2.65-2.75 (m, 1 H), 2.77-2.98 (m, 1 H), 2.91-2.98 (t, 2 H), 3.09-3.16 (m, 1 H), 3.21-3.28 (m, 1 H), 3.62 (s, 3 H), 4.10-4.17 (t, 2 H), 6.60-6.68 (d, 1 H), 6.72 (s, 1 H), 7.01-7.13 (d, 1 H), 7.33-7.45 (m, 3 H), 7.94-8.00 (d, 2 H).

Example 43

2-{5-[2-(5-isopropyl-2-phenyl-l,3- xazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl} butanoic acid

Yield: 0.08 g, 97%; ¾ NMR (CDC1₃, 400 MHz) δ 0.91-0.98 (t, 3 H), 1.30-1.36 (d, 6 H), 1.58-1.79 (m, 2 H), 1.89-2.05 (m, 1 H), 2.12-2.27 (m, 1 H), 2.44-2.57 (m, 1 H), 2.69-2.80 (m, 1 H), 2.83-2.96 (m, 1 H), 2.97-3.02 (t, 2 H), 3.10-3.21 (m, 1 H), 3.24-3.32 (m, 1 H), 4.14-4.21 (t, 2 H), 6.63-6.71 (d, 1 H), 6.75 (s 1 H), 7.04-7.16 (d, 1 H), 7.36-7.45 (m, 3 H), 7.94-8.00 (d, 2 H).

Example 44

Methyl 2-{5-[2-(5-ethyl-2-phenyl-l,3-oxazol-4-yi)ethoxy]-2,3-dihydro-lH-indenyl}butanoate

Yield: 0.14 g, 60%; ^!H MR (CDC1₃, 400 MHz) 5 0.85-0.91 (t, 3 H), 1.25-1.35 (t, 3 H), 1.58-1.77 (m, 2 H), 1.85-1.97 (m, 1 H), 2.10-2.22 (m, 1 H), 2.44-2.64 (m, 2 H), 2.68-2.80 (q, 2 H), 2.82-2.93 (m, 1 H), 2.95-3.01 (t, 2 H), 3.25-3.34 (m, 1 H), 3.62 (s, 3 H), 4J 6-4.25 (t, 2 H), 6.66-6.71 (d, 1 H), 6.75 (s, 1 H), 7.08-7.14 (d, 1 H), 7.38-7.46 (m, 3 H), 7.95-8.01 (m, 2 H).

Example 45

2-{5-[2-{5-ethyl-2-pheny!-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}

butanoic acid

Yield: 0.05 g, 60%; 'H NMR CCDCIj, 400 MHz) δ 0.85-0.98 (m, 3 H), 1.21-1.33 (m, 3 H), 1.37-1.54 (tn, 1 H), 1.56-1.78 (m, 2 H), 1.87-2.29 (m, 2 H), 2.45-2.60 (m, 1 H), 2.69-2.79 (q, 2 H), 2.85-2.95 (m, 1 H), 2.96-3.01 (t, 2 H), 3.27-3.49 (m, 1 H), 4.Ϊ4-4.23 (t, 2 H), 6.65-6.71 (d, 1 H), 6.75 (s, 1 H), 7.03-7.17 (d, 1 H), 7.38-7.46 (m, 3 H), 7.95-8.01 (d, 2 H).

Example 46

Methyl 2-{5-[2-(2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-indenyl}butanoate

Yield: 0.18 g, 80%; ^!H NMR (CDC1₃, 400 MHz) δ 0.82-0.92 (t, 3 H), 1.56-1.66 (m, 1 H), 1.67-1.77 (m, 1 H). 1.88-1.99 (m, 1 H), 2.12-2.23 (m, 1 H), 2.43-2.52 (m, 1 H), 2.68-2.81 (m, 1 H), 2.84-2.97 (m, 1 H), 3.02-3.11 (t, 2 H), 3.25-3.33 (m, 1 H), 3.63 (s, 3 H), 4.21 -4.30 (t, 2 H), 6.69-6.74 (d, 1 H), 6.79 (s, 1 H), 7.11-7.16 (d, 1 H), 7.41-7.47 (m, 3 H), 7.55-7.58 (m, 1 H), 7.99-8.05 (m, 2 H). Example 47

2~{5-[2-(2-phenyl-l,3 n-l-yl}butanoic acid

Yield: 0.07 g, 46%; 'H NMR {CDC1₃, 400 MHz) δ 0.84-1 .01 (m, 3 H), 1.36-1.51 (m, 1 H), 1 .59-1.81 (m, 1 H), 1.88-2.00 (m, 1 H), 2.1 1-2.29 (m, 1 H), 2 43-2.64 (m, 1 H), 2.68-2.81 (m, 1 H), 2.82-3.00 (m, 2 H), 3.02-3.1 1 (t, 2 H), 3.23-3.37 (m, 1 H), 4. 1 7-4.28 (t, 2 H), 6.66-6.74 (d, 1 H), 6.78 (s, 1 H), 7.04-7.19 (m, 1 H), 7.39-7.47 (m, 2 H), 7.55 (s, 1 H), 7.98-8.05 (m, 2 H).

Example 48

Methyl 2-(5-{2-[2-(2,3-dihydro-l-benzofuran-6-yl)-5-methyl-l,3-oxazol-4-yl]ethoxy}-2,3-dihydro-lH- inden-l-yl)butanoate

Yield: 0.17 g, 58%; *H NM (CDC1₃, 400 MHz) δ 0.86-0.97 (t, 3 H), 1.41 -3.53 (m, 1 H), 1.61-1.77 (m, 1 H), 1.92-2.01 (m, 1 H), 2.04-2.20 (m, 1 H), 2.40 (s, 3 H), 2.49-2.56 (m, 1 H), 2.71-2.92 (m, 2 H), 3.93- 3.00 (t, 2 H), 3.21-3.32 (t, 2 H), 3.34-3.49 (m, 1 H), 3.75 (s, 3 H), 4.18-4.24 (t, 2 H), 4.54-4.70 (t, 2 H , 6.70- 6.76 (d, 1 H), 6.79 (s, 1 H), 6.82-6.89 (d, 1 H), 6.92-7.01 (d, 1 H), 7.75-7.80 (d, 1 H), 7.87 (s, 1 H).

Exampie 49

2-(5-{2-[2-(2,3-dihydro-l-benzofuran-6-yi)-S-methyl-i,3-oxazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l- yI)butanoic acid

Yield: 0.10 g, 99%; ¾ NMR (CDC1₃, 400 MHz) δ 0.90-1.04 (t, 3 H), 1.41-1.54 (m, 1 H), 1.60-1.76 (m, 1 H), 1.83-1.97 (m, 1 H), 2.12-2.23 (m, 1 H), 2.35 (s, 3 H), 2.48-2.60 (m, 1 H), 2.69-2.90 (m, 2 H), 2.92- 3.01 (t, 2 H), 3.18-3.28 (t, 2 H), 3.39-3.50 (m, 1 H), 4.08-4.12 (t, 2 H), 4.46-4.64 (t, 2 H), 6.76-6.71 (d, 1 H), 6.73 (s, 1 H), 6.77-6.84 (d, 1 H), 7.01-7.09 (d, 1 H), 7.71-7.78 (d, 1 H), 7.83 (s, 1 H). Example 50

Preparation of ethoxy{5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy)-2,3-dihydro-lH-inden-l- yl}acetic acid

via

ethyl [5-{benzyloxy)-2,3-dihydro-lH-inden-l-yIidene](ethoxy)ethanoate

Step 1. LDA (prepared from 11 mmol DIA and 11 mmole BuLi) was added to methyl 2- ethoxyacetate (10 mmol) in 50 mL THF at -78°C, stirred for 1 hour, then TMSCl (30 mmol) was added. The mixture was concentrated in vac directly witliout purification.

Step 2. 5-BenzyIoxy-l-indanone in CH₂C1₂ (5 mL) was slowly added to TiCl in CH₂C1₂ (10 mL) at -78°C, stirred at -60°C for 10 minutes, and cooled to -78°C. The product of step 1 in CH₂C1₂ (5 mL) was slowly added and stirred for 10 minutes. The reaction was quenched with saturated K2CO₃, filtered, extracted with ethyl acetate, and dried over sodium sulfate. Column chromatography yielded a colorless oil as product. LC-MSMH⁺=353.1, RT = 4.00 min.; NMR (CDC)₃, 400 MHz) δ 7.9 (1H, d), 7.25 (5H, m), 6.78 (2 H, m), 4.93 (2H, s), 4.15 (2H, q), 3.75 (2H, q), 3.05 (2H, m), 2.85 (2H, m), 1.22 (6H, m)

Step 3. Using the product of step 2 as starting material and procedures similar to that described for Example 13, steps 4-8, the desired final product was prepared and characterized: LC-MS [MET] = 422.2, RT = 3.25 min.; NMR (CDC) 3, 400 MHz) δ 8.26 (1 H, d), 7.55 (2H, m), 7.16 (2H,d), 6.70 (3H, m), 4.16 (2H,q), 3.63 (2H, t) 3.5 (2H, m), 3.30 (1H, m), 3.20 (1H, m), 2.50 (3H, s), 1.10 (3H, m). Example 51

Preparation of 2~{5-[2-(5-methyI-2-phenyl-l,3-oxazoi-4-yl)ethoxy]-2,3-dihydro-lH-inden-l- yl}butanoic acid

via

2-(4-methyI-2-phenyl-l,3-oxazoI-5-yI)ethanoi

Step 1. To a solution of sodium hydroxide (8.98 g, 224.49 mmol) in water (1 12.25 mL), was added at rt DL-Alanine (10 g, 1 12.25 mmol). The resulting solution was heated at 75°C and the benzoyl chloride (15.77 g, 112.25 mmol) was slowly added. The reaction was heated for 30 minutes, and cooled down to 0°C with an ice bath. Cone. HC1 was added to adjust the pH to 1, then the white solid was filtrated through a fritted glass funnel and vacuum dried with P₂0₅ overnight. No purification was needed. This gave N- benzoylalanine (19.6 g, 90.4% yield) as white solid. ¾ NMR (DMSO-rf_tf) δ 12.61 (s br, 1H), 8.64 (d, 1H), 7.87-7.85 (m, 2H), 7.52-7.43 (m, 3H), 4.40 (q, 1H), 1.39 (d, 3H).

Step 2. In the first flask, N-benzoylalanine (2 g, 10.35 mmol) was dissolved in THF (20 mL), and carbonyl diimidazole (CDI) (1.84 g, 1 1.39 mmol) was added. The resulting mixture was stirred 1 hour at rt and cooled down to -78°C. Into a second flask, ethyl acetate (3.83 g, 43.48 mmol) in THF (40 mL) was cooled down to -78°C and LDA (24.3 mL, 48.51 mmol, 2 M in THF) pre-cooled to -78°C was added. The resulting solution was stirred 30 minutes at -78°C, and the lithium enolate generated was cannulated into the first flask. The resulting white slurry was stirred 30 minutes at -78°C and warmed up to -10°C. The reaction was quenched with a saturated aqueous solution of NH4CI. Phases were separated and the organics were dried over MgS0 and solvents removed under reduced pressure. The crude product was carried to the next step without purification. This gave ethyl 4-(benzoylamino)-3-oxopentanoate (2.6 g, 95.5% yield) as a white solid. ES-MS m/z 263.4 ((MH)⁺); HPLC RT (min.) 1.53;Ή NMR (Acetone-^) δ 8.13 (s br, 1H), 7.93-7.91 (m, 2H), 7.58-7.43 (m, 3H), 4.72 (m, 1H), 4.19-4.01 (q, 2H), 3.67 (s, 2H), 1.47 (d, 3H), 1.15 (t,

3H).

Step 3. To a crude mixture of ethyl 4-(benzoylamino)-3-oxopentanoate (0.6 g, 2.28 mmol) in DMF

(4 mL) at rt, was added POCl₃ (1 .04 g, 6.84 mmol)_. The resulting solution was heated at 90°C for 1 hour, then cooled down to rt, and poured into ice for 30 minutes. The aqueous solution was carefully added to a saturated aqueous solution of NaHCOj. Phases were separated with EtOAc and the combined organic extracts were dried over MgS04 and solvent removed under reduced pressure. The crude material was purified on Biotage small column using a solvent gradient of 0 to 50% EtOAc/Hexane. This gave ethyl (4- methyl-2-phenyl-l,3-oxazol-5-yl)acetate (0.269 g 48% yield) as yellowish oil. ES-MS m/z 246.2 ((MH)⁺); HPLC RT (min.) 2.77;¹H NMR (CDC1₃) δ 8.01-7.98 (m, 2H), 7.45-7.41 (m, 3H), 4.20 (q, 2H), 3.71 (s, 2H), 2.21 (s, 3H), 1.28 (t, 3H).

Step 4. Ethyl (4-methyl-2-phenyl-l ,3-oxazol-5-yl)acetate (0.922 g, 3.76 mmol) in THF (6 mL) at rt, was added LiBEL_t 2 /THF (9.41 mL, 4.70 mmol). The reaction was stirred overnight at rt, then treated with 2 N HO until pH 7. The solvent THF was removed under reduced pressure, EtOAc was added, and phases separated. The combined organic extracts were dried over MgS<¾ and solvent concentrated in vacuo. The crude material was purified by Biotage using a gradient of 10 to 100% EtOAc/Hexane as solvent mixture. This gave 2-(4-methyl-2-phenyl- l ,3-oxazoI-5-yl)ethanoI (0.193 g, 25% yield) as colorless oil. ES-MS m/z 204.2 (MH)⁺); HPLC RT (min.) 2.02;¹H NMR (Acetone-i/i) δ D7.98-7.95 (m, 2H), 7.52-7.42 (m, 3H), 3.95 (s br, 1H), 3.82 (t, 2H)m, 2.90 (t, 2H), 2.13 (s, 3H).

Step 5. DEAD (0.84 mL, 5.28 mmol) in THF (1.5 mL) was slowly added to a solution of the product of step 3 (4.95 mmol), methyl 5-hydroxy-2,3-dihydro-inden-lyl-2-butanoate (0.78 g, 3.3 mmol), PPI13 (1.4 g, 5.28 mmol) in THF (13 mL). The mixture was stirred at rt overnight. The mixture was filtered, washed with water, brine, dried over sodium sulfate, and concentrated. Column chromatography yielded a colorless oil as product. LC-MS [C₂₆H₂₉N0₄H]⁺ = 420.4, RT = 4.00 min.; ^]H NMR (CDCI₃): δ 7.9 (2H, d), 7.45 (2H, dd), 7.1(d), 6.6-6.8 (3H, m), 4.2 (2H, t), 3.62 (3H, s), 3.3 (1H, m), 3.15 (2H,t), 2.6-3.0 (2H, m, br), 2.5 (1H, m),2.21 (3H, s), 1.95 (1H, m), 1.56-1.6 (3H, br, m), 0.88 (3H, t).

Step 6. KOH (0.5 mL, 3 N) was added to a solution of the product of step 4 (42 mg, 0.1 mmol) in THF/MeOH (1 mL, THF:MeOH 8:2). The mixture was stirred at 70°C for 6 hours, then cooled down. The pH was adjusted to 4 with 1 N HC1. The mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Column chromatography (2:8/hexane:ethyl acetate) gave a white solid as the product (33 mg, 81%). LC-MS [C₂₅H₂₇N0₄H]⁺ = 406.3, RT = 3.37 min.; Ή NMR (CDC1₃): δ 8.0 ( 2H, d), 7.45 (2H, dd), 7.15 (1H, d), 6.7- 6.8 (3H, m), 4.2 (2H, t), 3.3 (1H, m), 3.15 (2H,t), 2.6-3.0 (2H, m, br), 2.5 (1H, m), 2.21 (3H, s), 1.95 (1H, m), 1.56-1.6 (3H, br, m), 0.88 (3H, t)

By using the procedure described above for Example 51 and substituting the appropriate starting materials, the following were similarly prepared and characterized.

LC-MS [C₂₆¾N0₄H]⁺ = 420.3, RT = 3.52 min.; ^!H NMR (CDC1₃): 8 7.87 ( 2H,d), 7.25 (2H,dd), 7.1(l H,d), 6.6-6.8 (3H, m), 4.2 (2H, t), 3.45 (lH,m), 3.30 (1H, m). 3.15 (2H,t), 2.7-3.0 (2H, m, br), 2.5 (1H, m), 2.4 (3H, s) 1.95 (1H, m), 1.56-1.60 (3H, br ,m), 0.88 (3H,t)

Example 53

2-{5-[2-(4-methyl-2-propyl-l,3-oxazol-5-yl)ethoxy]-2_>3-dihydro-lH-inden-l-yl}butanoic acid

LC-MS [C₂₂H₂₉N0₄H]⁺ = 372.3, RT = 3.16 min.; ^lH NMR (CDCJ₃): δ 7.1 ( lH,d), 6.6 (2H,d), 4.2 (2H, t), 3.3 (lH,m), 3.3 (1H, m), 2.8 (2H,t), 2.7 (1H, m), 2.6 (2H, t), 2.4 (2H,m), 2.2 (3H, s), 2.0-1.8 (2H,br,m), 0.88 (3H,t) By using the methods described above for Examples 1-53 and by substituting the appropriate starting materials, compounds of Foraiula la, listed in Table 3 below, were similarly prepared.

Table 3

Prepara ula (la)

(la)

Ex. No. R R' R² R³ R⁴ R^s X LC-MS [M+H]⁺ or NMR

68 H <:¾x,_: H Me Ph H 0 526.4

69 H Et H Me Ph H s 422.3

70 Et H Me Ph H s

0.82 (t, 3H), 3.54 (s, 3H),

71 Me Et H Me Ph H 0

4.16 (t, 2H), 7.90 (m, 2H)

72 H Et H i-Pr Ph H 0 434.3

73 H Et H Ph ^' Ph H 0 468.3

74 H Me H Me Ph H s 422.3

75 Me Me H Me Ph H s

76 Me Et MeC(O)- Me Ph H o 462.4

77 Me Et 4-MeO-Ph Me Ph H o 526.4

78 H Et 4-MeO-Ph Me Ph H 0 512.3

79 Me Et 4-pyridyl Me Ph H o 497.3

80 H Et H Me cyc-Pentyl H 0 398

81 H Et H Me cyoHexyl H o 412

82 H Et H Me 4-Ph-Ph- H o 482

83 Et Et0₂C- H Me 4-Me-Ph- H 0 492.3

84 H PhCHa- H Me 4-Me-Ph- H o 482.4

85 Et tt-Bu H Me 4-Me-Ph- H 0 476.3

86 Et Me H Me 4-Me-Ph- H 0 434.3

87 Et PhCH₂- H Me 4-Me-Ph- H o 510.4

88 H Et H Me 4-MeO-Ph H 0 436.1

89 H Et H Me 4-i-Pr-Ph H o 448.2

4-F-

90 H Et H Me H 0 438.3

PhCH₂-

91 H Et H Me 4-F-Ph H 0 424.3

92 H Et H Me 4-Et-Ph H o 434.3

4-C1-

93 H Et H Me H o 470.2

PhOCH₂-

Example 129

Preparation of ethyl (5-methoxy-2,3-dihydro-lH-inden-l-yIidene)ethanoate

To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under Ar atmosphere and refluxed for 15 minutes; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring overnight at rt, TLC showed the presence of desired product, indicating the formation of reactive zinc species. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35°C). After 4 hours, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol total) was added dropwise. An exotherm was observed (internal temperature increased to 35°C). When the stirred mixture cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated in vacuo to a volume of ~ 2L. The liquid was then poured into sufficient IN aqueous hydrochloric acid (cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2 x 1 L, 1 x 500 mL). The combined extracts were washed with water, brine (1 L each), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark red oil which solidified gradually (438.3 g; theoretical yield = 432 g). ^!H NMR (CDC1₃): δ D7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1 H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (CI) m/z 233 [M+H]⁺.

Example 130

Preparation of ethyl (5~methoxy-2,3-dihydro-lH-inden-l-yl)acetate

The crude product of Example 129 was dissolved in absolute ethanol (2.6 L) and hydrogenated at 40 psi of hydrogen over 10% palladium on carbon (21.6 g). Filtration through Celite and concentration of the filtrate afforded 433.3 g of brown oil (99% yield for 2 steps). ¾ R (CDC1₃): δ 7.1 (dd, 1H), 6.8 (d, 1H), 6.7 (dd, 1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.5 (m, 1H), 2.9 (m, 2H), 2.7 (dd, 1H), 2.4 (m, 2H), 1.7 (m, 1H), 1.3 (t, 3H). MS (CI) m/z 235 [M+H]⁺.

Example 131

Preparation of (5-met inden-l-yl)acetic acid

To a solution of the crude ester (416 g, 1.77 mol) prepared in Example 130 in 1 L EtOH, was added a solution of NaOH (142 g, 3.54 mol) in 1.5 L water. The cloudy reaction mixture was heated to reflux, during which time the color changed to dark red, and the reaction became homogeneous. After 1 hour, the reaction was cooled to rt, and the EtOH was removed under reduced pressure. The basic aqueous layer was washed with Et₂0 (3 x 500 mL), then acidified with cone. HC1 to pH ~4 upon which an oil residue formed. The mixture was extracted with Et^O (4 x 500 mL). The combined extracts were washed with water (2 x 300 mL), brine, then dried over Na₂SO,}. Filtration and evaporation of solvent under reduced pressure gave the title compound (305 g, 83%) as a yellow solid after overnight drying under vacuum. Ή NMR (CDCI₃) □ 5 7.34(d, 1H), 6.71(s, 1H), 6.65(dd, 1H), 3.71(s, 3H), 3.47(m, 1H), 2.80(m, 3H), 2.35(m, 2H), 1.71(m, 1H). MS (CI) m/z 207 [M+H]⁺. Example 132

Preparation of [(15)-5-methoxy-2,3-dihydro-lH-inden-l-yl]acetic acid

To a solution of the acid (341 .0 g, 1.65 mol) prepared in Example 131 in 8.2 L reagent grade acetone, was added (S)-(-)-a-methylbenzylamine (223.8 mL, 1.74 mol) dropwise at rt with stirring. A thick white precipitate formed during the addition. An additional 500 mL acetone was added and stirring continued for 1 hour. The solids were collected by filtration, washed with 300 mL acetone, and dried under suction. The solids were then suspended in acetone (8.2 L) and warmed to reflux until all solids dissolved. The solution was cooled slowly overnight, during which time a white precipitate formed. The suspension was cooled to 0°C, then filtered, and the solids were washed with 500 mL acetone. After drying under suction, a sample analyzed by HPLC showed 95% ee. The recrystallization process was repeated as above using 6.7 L acetone. HPLC analysis showed 99% ee. After drying under suction, 192 g salt were obtained. The salt was suspended in 2 L EtOAc and 1 L of 1 N HCl solution, and shaken in a separatoiy funnel, whereupon the salt dissolved. The organic layer was separated, washed with 1 N HCl (500 mL), water (2 x 300 mL), and brine, then dried over Na₂SC>4. The solvent was evaporated under reduced pressure, giving an oil which soon solidified. The title product (120.5 g, 35%) was obtained as an off-white solid after vacuum drying. ¾ NMR (CDC1₃) δ 7.10(d, 1H), 6.79(d, 1H), 6.73(dd, 1H), 3.79(s, 3H), 3.55(m, 1H), 2.89(m, 2H), 2.79(dd, 1 H), 2.46(dd, 1H), 2.43(m, 1H), 1.80(m, 1 H). MS (ESI) w^z 207 [M+H]⁺.

Example 133

Preparation of [(15)-5-methoxy-2,3-dihydro-lH-inden-l-yl]acetic acid

As an alternative to Example 132, the title compound may also be prepared via an enzymatic process. Thus, a cloudy mixture of the crude ester (500.0 g, 2.13 mol; 87% pure as determined by HPLC) prepared in Example 130, in 1 L reagent grade acetone, 2.5 L Phosphate Buffer (pH 7.0, 0.05 M) and 2.5 L deionized water was treated in one portion with Amano Lipase PS (350 g), and the mixture stirred efficiently at rt overnight. HPLC analysis of an aliquot (homogeneous aliquot prepared by dissolving aliquot in IPA followed by filtration) showed one peak corresponding to unreacted R-ester and another peak corresponding to desired S-acid. Trace amounts of S-ester and R-acid were noted. 2 N HCl (500 mL, ensure a pH ~2) was added in one portion to the reaction and stirred for 20 minutes. The mixture was filtered and the solids were washed with EtOAc (2 x 500 mL), then water (500 mL). The combined filtrates were further diluted with 1 L EtOAc, and the layers stirred together vigorously. Stirring was stopped and the layers allowed to separate. Emulsions were noted, but could be broken with the addition of solid NaCl and stirring. The aqueous layer was removed, then extracted with EtOAc (3 x 1 L) in the same fashion. The combined organic extractions were washed with water (4 x 500 mL), then with brine. The resulting organic layer was extracted with a 5% Na2CC>3 solution (8 x 500 mL). HPLC analysis of the organic layer showed that it contained none of the S- enantiomer acid. The combined Na₂C0₃ extracts were washed with EtOAc (2 1 L), then acidified to pH ~2 by the addition of 2N HCl. A white solid precipitated, accompanied by C0₂ evolution. The mixture was extracted with EtOAc (3 x 1 L). The combined extracts were washed with water (2 x 1 L) and brine, then dried over Na₂S0₄. HPLC analysis of this solution showed the material was 98% ee. The solvent was evaporated under reduced pressure, giving an oil which soon solidified. The title product (172.9 g) was obtained as an off-white solid after vacuum drying. This material was recrystallized from boiling hexanes (8.8 L). After overnight cooling, light yellow needles .were collected via filtration, washed with hexanes (200 mL), and dried under suction. The title product (146.9 g, 38% from crude starting ester) was obtained as light yellow needles after vacuum drying. Ή NMR results as above.

Example 134

Preparation of ethyl [(LS)-5-methoxy-2,3-dihydro-lH-inden-l-yI]acetate

To a solution of the acid (305 g, 1.48 mol) prepared in either Example 132 or 133 in 4.8 L absolute EtOH at rt under argon, was added chlorotr nethylsilane (413 mL, 3.25 mol) dropwise. An approximate 5°C rise in temperature was noted during the addition. The reaction was stirred overnight. EtOH was evaporated under reduced pressure, giving a bi-phasic liquid mixture. This was diluted in 500 mL ice-water, then extracted with EtOAc (2 x 750 mL). The combined extracts were washed with water (3 x 300 mL), then with saturated NaHC0₃ (200 mL). The organic was washed once more with water (300 mL), then brine, and dried over Na₂S0₄. The title compound (354 g, 102%) was obtained as a light yellow oil after solvent removal and vacuum drying. Ή NMR (CDC1₃) δ 7.07(d, 1H), 6.78(d, 1H), 6.71(dd, 1H), 4.18(q, 2H), 3.78(s, 3H), 3.52(m, 1H), 2.89(m, 2H), 2.72(dd, 1H), 2.37(o, 2H), 1.74(m, I H), 1.28(t, 3H). MS (CI) m/z 235 [M+H]⁺.

Example 135

Preparation of ethyl [(15)-5-hydroxy-2,3-dihydro-lH-inden-l-yl]acetate

To a cold solution (ice water bath) of the compound (346 g, 1.48 mol) prepared in Example 134 in 4.2 L CH₂C1₂, was added A1C1₃ (984.6 g, 7.38 mol) portionwise under Ar such that the reaction temperature was maintained below 10°C. The light brown suspension was stirred 10 minutes, then EtSH (546 mL, 7.38 mol) was added dropwise at such a rate that the reaction temperature was maintained below 5°C. After 2.5 hours of stirring below 10°C, the reaction mixture was slowly poured into 6 L ice water with strong agitation. The organic layer was separated, and the aqueous layer was extracted with CH2CI2 (3 x 1 L). The combined CH2CI2 layers were washed with water (2 x 1 L), then dried over Na SC> . The solvent was removed under reduced pressure, giving a brown oil, which was filtered through a pad of silica gel (eluted with 0-10% EtOAc/Hexanes). Fractions were collected and the title compound (314 g, 96%) was obtained as a thick yellow oil after solvent removal and vacuum drying. Ή NMR (CDC1₃) D5 6.92(d, 1 H), 6.62(d, 1H), 6.55(dd, 1H), 4.10(q, 2H), 3.43(q, 1H), 2.75(m, 2H), 2.64(dd, 1H), 2.31(dd, 1H), 2.29(m, 1H), 1.67(m, 1H), 1.20 (t, 3H). MS (CI) m/z 221 [M+H]⁺.

Example 136

Preparation of ethyl 2-((15}-5-{2-[5-methyl-2-(4-methylphenyl)(l ,3-oxazol-4- yl)] ethoxy}indanyI)acetate

COOEt

A suspension of the ethyl [(lS)-5-hydroxy-2,3-dihydro-lH-inden-l-yl]acetate prepared in Example 135 (507.5 mg, 2.30 mmol), and 2-[5-methyl-2-(4-methylphenyl)-l,3-oxazol-4-yl]ethanol prepared in Example 10 (500 mg, 2.30 mmol), TMAD (792.6 mg, 4.60 mmol), and Fh₃P (1.21 g, 4.60 mmol) in 15 mL anhydrous DCM was stirred at rt under Ar for 12 hours. DCM was removed under reduced pressure. Flash chromatograph of the residue over silica gel using 1% CH₃CN/CH₂C1₂ gave ethyl 2-((lS)-5-{2-[5-metliyl-2- (4-methylphenyl)(l,3-oxazol-4-yl)]ethoxy}indanyl)acetate (776.3 mg, 1.85 mmol, 80.5%). HPLC/MS (M+H)⁺ m/z 420.5.

Example 137

Preparation of 2-((15)-5-{2-[5-methyl-2-(4-methyIphenyI)(l,3-oxazol-4-yl)]ethoxy}indanyl)acetic acid

COOH

Ethyl 2-((lS)-5-{2-[5-methyl-2-(4-methyiphenyl)(l ,3-oxazol-4-yI)]ethoxy} indanyl)acetate

(Example 136, 776.3 mg, 1.85 mmol) in THF (4.0 ml) was added to a mixture of aqueous LiOH (2 M, 3.7 ml, 7.4 mmol), water (2.0 ml), and EtOH (4.0 ml) at rt. The resulting mixture turned cloudy. This mixture was heated at 40°C (oil-bath temperature). The reaction was completed after 1.5 hours. After cooling to rt, 1 N HQ solution was slowly added to the mixture until pH 4,0. The compound was extracted with EtOAc (3 x 20 ml). The combined EtOAc layers were dried (Na2SC>4) and evaporated. Flash chromatography of the residue gave 2-((lS)-5-{2-[5-methyl-2-(4-methylphenyl)( l ,3-oxazol-4-yl)]ethoxy}indanyl)acetic acid (616.8 mg, 1.57 mmol, 85%) as a white solid. ¾ NM (CDC1₃) δ 7.83(d, 2H), 7.21(d, 2H), 7.03(d, IH), 6.74(d, IH), 6.69(dd, IH), 4.19(t, 2H), 3.45(q, IH), 2.93(t, 2H), 2.78(m, 2H), 2.51(m, 2H), 2.30(s, 3H), 2.25(s, 3H), 1.53(m, 2H).

By using the methods described above for Examples 129-137 and by substituting the appropriate starting materials, compounds of Formula la, listed in Table 4 below, were similarly prepared.

Table 4

Preparative Examples of Compounds of Formula (la)

(la)

Ex. No. R³ R⁴ LC MS [M+H]

151 Me cyc-Pentyl 370.5

152 Me cyc-hexyl 384.5

153 Me PhCH₂ 392.5

154 Me 4-F-3-Me-Ph 410.5

155 Me 3-F-4-Me-Ph 410.5

156 Me 4-F-Ph 396.5

157 Et Ph 392.5

158 Me 3,4-(Cl)₂-Ph 447.4

159 n-Pr Ph 406.5

160 Me 4-Ph-Ph 454.5

161 Me 3-Cl-Ph 432.4

162 Me 3-Me-Ph 392.5

163 Me 4-CN-Ph 403.4

164 Me 3-CN-Ph 403.4

165 Me 4-Cl-Ph 412.4

166 Me 3-CF3-Ph 446.4

167 Et 4-Et-Ph 420.5

168 Et 4-Me-Ph 406.5

422.4

169 Et 4-MeO-Ph

Example 170

Preparation of methyl 4-bromo-3-oxopentanoate

A dry three-neck flask under an Ar atmosphere was charged with a solution of methyl propionylacetate (20 g, 154 mmol) in CHC1₃ (100 mL). Using an addition funnel, bromine (7.9 mL, 24.6 g, 154 mmol) was added dropwise over a period of 2 hours at 0°C. The reaction was then allowed to warm slowly to it, and the reaction mixture was stirred overnight. A saturated solution of Na₂C0₃ (40 mL) was slowly added, and after stirring the reaction mixture for an additional 1 minutes, the solvents layers were separated and the aqueous layer was extracted with CH2CL (50 mL). The combined organic layers were dried (TS^SC^), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (10: 1 hexanes/EtOAc) to give the desired bromide as a light yellow oil (25 g, 78%). Ή NMR (CDC¾): δ 1.80 (d, 3H), 3.64-3.92 (m, 2H), 3.78 (s, 3H), 4.61 (q, 1H).

Example 171

Preparation of meth -amiiio-5-niethyI-l,3-thiazol-4-yl)acetate

To a solution of bromide of Example 170 (18 g, 86 mmol) in toluene (100 mL) was added thiourea (10.5 g, 138 mmol). The reaction mixture was heated to 100°C for 1 hour, cooled to rt, and the solvent removed under reduced pressure. The residue was dissolved with CH2CI2 (100 mL), a saturated solution NaHCC>3 (75 mL) added, and the mixture was vigorously stirred for 10 minutes. The organic layer was separated, dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The residue was then recrystallized from CH₂C /hexanes to provide the product (10 g, 63%) as a white solid. (C7H1₀N2O2S): LC- MS, RT 0.76 min, M+H 187.0; ^!H NMR (CDC1₃): δ 2.23 (s, 3H), 3.70 (s, 2H), 3.75 (s, 3H), 4.83-4.95 (broad s, 2H).

Example 172

Preparation of methy -bromo-5-methyl-l,3-thiazol-4-yl)acetate

To a solution of CuBr₂ (4.03 g, 18.1 mmol) and i-butyl nitrite (2.82 mL, 23.8 mmol) in MeCN (210 mL) was added the compound of Example 170 (2.95 g, 15.9 mmol) at -20°C. The reaction mixture was slowly warmed to 15°C, at which point the evolution of N₂ was observed. After stirring for an additional 2 hours at 15°C, the reaction mixture was diluted with Et₂0 (400 mL) and washed with a 10% solution of HC1 (200 mL). The solvent layers were separated, the aqueous re-extracted with Et₂0 (2 x 300 mL), and the combined organic layers dried (MgS<¾), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (98:2, hexanes/EtOAc) to afford bromide Example 172 (1.6 g, 40%) as a colorless oil that solidifies upon standing. (C₇H₈BrN0₂S): LC-MS, RT 2.56 min., M+H 250.3; ^lU NMR (CDCI₃): δ 2.26 (s, 3H), 3.60 (s, 2H), 3.61 (s, 3H). Exam le 173

Preparation of 2-(2 thiazol-4-yl)ethanol

To a solution of ester prepared in Example 172 (3.80 g, 15.2 mmol) in CH₂C1₂ (100 mL) was added DIBAL-H (33.4 mL, 33.4 mmol of a 1.0 M solution in toluene) at -78°C. After 15 minutes, the solution was warmed to 0°C and stirred for an additional 90 minutes. An aqueous solution of 2 N HC1 (50 mL) was then added dropwise to quench the excess DIBAL-H. The solvent layers were separated and the aqueous layer extracted with (¾(¾ (2 x 200 mL). The combined organic layers were dried (MgSC^), filtered, and concentrated under reduced pressure. The residue was .purified by silica gel flash chromatography (5:2 hexanes/EtOAc) to yield the product (2.5 g, 74%) as a yellowish oil that solidifies upon standing. (C₆¾BrNOS) LC-MS, RT 3 .38 min., M+H 221.0; ¾ NMR (CDC1₃): δ 2.31 (s, 3H), 2.82 (t, 2H), 2.90-3.00 (broad s, 1H), 3.89 (t, 2H).

Example 174

Preparation of ethyl {(15 -5-[2-(2-bromo-5-methyI-l,3-thiazol-4-yI)ethoxy]-2,3-dihydro-lH-inden-l- yljacetate

C0₂Et

Step 1. To a solution of Example 173 (975 mg, 4.39 mmol) and ethyl [(lS)-5-hydroxy-2,3-dihydro- lH-inden-l-yI]acetate (1.06 g, 4.83 mmol) in THF (20 mL) were added Ph₃P (1.88 g, 7.46 mmol) and ADDP (1.96 g, 7.46 mmol). The mixture was vigorously stirred at rt for 72 hours, the solvent removed under reduced pressure, and the residue purified by silica gel flash chromatography (6: 1 hexanes/EtOAc) to yield the product (1.4 g, 76%) as a colorless oil that solidifies upon standing. (Ci₉H₂₂BrN0₃S) LC-MS, RT 3.92 min., M+H 424.5; Ή NMR (CDC1₃): δ 1.26 (t, 3H), 1.65-1.81 (m, 1 H), 2.28-2.45 (m, 2H), 2.37 (s, 3H), 2.69 (dd, 1H), 2.75-2.93 (m, 2H), 3.07 (t, 2H), 3.44-3.56 (m, 1H), 4.15 (t, 2H), 4.18 (q, 2H), 6.67 (dd, 1H), 6.73 (d, 1 H), 7.03 (d, 1H).

Preparation of ethyl ((15 -5-{2-[2-(4-isopropylphenyl)-5-methyl-l,3-thiazol-4-yl]ethoxy}-2,3-dihydro-

LH-inden-l-yi)acetate

C0₂Et

Step 2. To a mixture of toluene (15 mL) and 1,4-dioxane (3 mL), were added the compound of step 1 (300 mg, 0.708 mmol), 4-isopropylbenzene boronic acid (464 mg, 2.83 mmol), and PdCl₂(dppf).CH_zCl₂ (52 mg, 0.071 mmol). A flow of Ar was passed tlirough the mixture for 30 minutes, then a 2 N solution of Na₂C0₃ (3.7 mL, 7.08 mmol) was added and the reaction was heated to 75°C for 18 hours. The reaction mixture was then cooled to rt, diluted with EtOAc (200 mL), and washed with a saturated solution of NaHC0₃ (50 mL). The organic layer was dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (8: 1 hexanes/EtOAc), to provide the product (305 mg, 93%) as a colorless oil. (C₂₈H₃₃NO₃S : LC-MS, RT 5.17 min., M+H 464.5; ^!H NMR (CDC1₃): δ 1.17-1.31 (m, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 1.65-1.82 (m, 1H), 2.30-2.43 (m, 2H), 2.46 (s, 3H), 2.72 (dd, 1H), 2.78-3.00 (m, 3H), 3.17 (t, 2H), 3.46-3.57 (m, 1H), 4.17 (q, 2H), 4.27 (t, 2H), 6.71 (d, 1H), 6.78 (s, 1H), 7.04 (d, 1H), 7.55 (AB quartet, 4H).

Example 175

Preparation of ((15 -5-{2-[2-(4-isopropylphenyl)-5-methyl-l,3-thiazol-4-yl]ethoxy}-2,3-dihydro-lH- inden-l-yl)acetic acid

C0₂H

To a solution of Example 174 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiOH (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 hours, diluted with water (20 mL), and washed with Et20 (10 mL). The aqueous phase was then acidified to pH ~1 using 1 N HQ, and then extracted with C¾Q₂ (4 x 50 mL). The combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH₂Cl₂/MeOH) to afford product (189 mg, 66%) as a white solid. (C₂₆H₂₉NO₃S): LC-MS, RT 3.95 min., M+H 436.4; Ή NMR (CDCI₃): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1 H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).

Example 176

Preparation of methyi [5-methyl-2-(4-methylpbenyl)-l, 3- thiazol-4-yI] acetate

To a solution of bromide of Example 170 (1.15 g, 5.52 mmol) in toluene (20 mL) was added 4- methyl thiobenzamide (1.0 g, 6.6 mmol). The reaction mixture was heated to reflux for 15 hours, cooled to rt, diluted with EtOAc (150 mL), and washed with a saturated solution of NaHC0₃ (50 mL), then with a saturated solution of NH₄CI (50 mL). The organic layer was dried ( a₂S0₄), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (9: 1 hexanes/EtOAc) to afford the product as a pinkish oil that solidified upon standing (1.14 g, 62%). ^l NMR (CDCI₃): δ 2.38 (s, 3H), 3.45 (s, 3H), 3.74 (s, 3H), 3.80 (s, 2H), 7.49 (AB quartet, 4H); R_f (0.4, eluant 9:1 hexanes/EtOAc) . Example 177

Preparation of 2-[5-methyl-2-(4-methylphenyl)-I,3-thiazol-4-yl]et anoI

To a solution of the thiazole of Example 176 (1.14 g, 4.37 mmol) in THF (60 mL) at 0°C, was added portion-wise LiAlH₄ (663 mg, 17.5 mmol). After 30 minutes, the reaction mixture was warmed to rt and stirred for an additional 60 minutes. The reaction mixture was then cooled to 0°C, and tlie excess L1AIH4 was quenched by dropwise addition of water (5 mL), IN NaOH (10 mL), and water (5 mL) sequentially. The mixture was then diluted with a saturated solution of Rochelle salt and extracted with EtOAc (4 x 75 mL). The combined organic phases were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (3:2 hexanes EtOAc) to afford tlie product as a white solid (830 mg, 82%). (C₁₃H₁₅NOS): LC-MS, RT 2.50 min., M+H 234.2; Ή NMR (CDC1₃): δ 2.34 (s, 3H), 2.37 (s, 3H), 2.83 (t, 2H), 3.92-4.01 (broad t, 2H), 4.04-4.15 (broad s, 1H), 7.45 (AB quartet, 4H).

The following compounds below were synthesized using one of the two procedures of Examples 170-177 described above.

Example 178

{(15)-5-[2-(5-Methy!-2-phenyl-l,3-thiazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l-yI}acetic acid

C0₂H

(C₂₃H₂₃N0₃S): LC-MS RT 3.56 min., M + H 394.2; H NMR (CDCI₃): δ 1.61-1.78 (m, 1H), 2.19- 2.50 (m, 2H), 2.30 (s, 3H), 2.62-2.91 (m, 3H), 3.12 (t, 2H), 3.17-3.26 (m, 1H), 4.12 (t, 2H), 6.70 (d, 1H), 6.79 (s, 1H), 6.98 (d, 1H), 7.21-7.40 (m, 3H), 7.74-7.83 (m, 2H).

Example 179

((15)-5-{2-[5-Methyl-2-(4-methylphenyl)-1 -thiazol-4-yl]ethoxy}-2 -dihydro-lH-inden-l-yl)acetic acid

C0₂H

(C24H₂₅NO₃S): LC-MS, RT 3.57 min., M+H 408.5; 'H NMR (CDCI₃): δ 1.61-1.68 (m, 1H), 2.29 (s, 3H), 2.36 (s, 3H), 2.25-2.37[hidden] (m, 2H), 2.63-2.79 (m, 3H), 3.09 (t, 2H), 3.35-3.47 (m, 1H), 4.18 (t, 2H), 6.60 (dd, 1H), 6.68 (s, 1H), 6.97 (d, 1H), 7.42 (AB quartet, 4H), 7.81-8.30 (br, lH). Example 180

((l-S 5-{2-[2-(l,3-Benzodioxoi-5-yI)-5-met^

yl)acetic acid

C0₂H

(C₂4H₂₃ 0₅S): LC-MS, RT 4.04 min., M+H 438.5; Ή NMR (CDC1₃): δ 1.71-1.83 (m, 1H), 2.36- 2.51 (m, 2H), 2.45 (s, 3H), 2.76-2.96 (m, 3H), 3.15 (t, 2H), 3.48-3.58 (m, 1H), 4.29 (t, 2H), 6.00 (s, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 6.82 (d, 1H), 7.07 (d, 1H), 7.32-7.40 (m, 2H).

Example 181

((15)-5-{2-[2-(4-Methoxypheny!)-5-methyl-l,3-thiazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-yl)acetic acid

C0₂H

(C₂₄H₂₅N0₄S): LC-MS, RT 4.01 min., M+H 424.5; Ή NMR (CDC1₃): δ 1.67-1.82 (m, 1H), 2.43 (s, 3H), 2.34-2.47 (m, 2H), 2.72-2.95 (m, 3H), 3.09 (t, 2H), 3.42-3.57 (m, 1H), 3.84 (s, 3H), 4.13 (t, 2H), 6.72 (d, 1H), 6.79 (s, 1H), 7.12 (d, 1H), 7.37 (AB quartet, 4H).

Example 1S2

[(15}-5-(2-{5-Methyl-2-[4-(trinuoromethyI)phenyl]-l,3-thiazol-4-yl}ethoxy)-2,3-dihydro-lH-inden-l- yljacetic acid

C0₂H

(C₂₄H₂₂F₃N0₃S):LC-MS, RT 4.47 min., M+H 462.4; ^]H NMR (DMSO^): δ 1.63-1.81 (m, 1H), 2.28-2.43 (m, 2H), 2.50 (s, 3H), 2.69 (dd, 1H), 2.74-2.95 (m, 2H), 3.19 (t, 2H), 3.31-3.36 (m, 1H), 4.31 (t, 2H), 6.7) (dd, lH), 6.78 (s, 1H), 7.08 (d, 1H), 7.87 (AB quartet, 4H).

Example 183

({l₁S -5-{2-[2-(4-Cyanophenyl)-5~met yI-1 -thiazol-4-yl]ethoxy}--2,3-dihydro-lH-indeii-l-yl)acetic acid

C0₂H

(C₂₄H₂₂N₂0₃S):LC-MS, RT 3.43 min., M+H 419.6; ¾ NMR (CDC1₃): δ 1.68-1.85 (m, 1H), 2.31- 2.49 (m, 2H), 2.51 (s, 3H), 2.77 (dd, 1H), 2.83-2.94 (m, 2H), 3.18 (t, 2H), 3.43-3.56 (m, lH), 4.31 (t, 2H), 6.71 (dd, 1H), 6.79 (s, IH), 7.10 (d, 1H), 7.86 (AB quartet, 4H).

£xample 184

((liS -5- {2-[2-(4-IsopropylphenyI)-5-methyI- 1 ,3~thiazol-4-yi] ethoxy}-2,3-dihy d ro- IH-inden- 1 -yl)acetic acid

C0₂H

(C2₆H2₉NO₃S): LC-MS, RT 3.95 min., M+H 436.4; Ή NMR (CDC1₃): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).

Example 185

((l^-5 2-[2-(3-Chloro-4-fluorophenyl)-5-methyJ-l^-thiazol-4-yl]ethoxy}-2^-dihydro-m-inden-l- yl)acetic acid

(C₂₃H₂₁C1FN0₃S): LC-MS, RT 3.89 min., M+H 446.4; Ή NMR (CDC1₃): δ 1.68-1.86 (m, 1H), 2.32-2.46 (m, 2H), 2.50 (s, 3H), 2.80 (dd, 1H), 2.84-2.96 (m, 2H), 3.18 (t, 2H), 3.47-3.59 (m, 1H), 4.32 (t, 2H), 6.72 (d, I H), 6.82 (s, 1H), 7.12 (d, 1 H), 7.23 (t, 1H), 7.72-7.82 (m, 1H), 7.97-8.04 (m, 1H).

Example 186

((15 -5-{2-[2-(3,4-Dichlorophenyl)-5-methyl-1 -tW

acid

C0₂H

(C₂₃H₂iCI₂N0₃S): LC-MS, RT 4.12 min., M+H 462.0; ^!H NMR (CDC1₃): δ 1.74-1.88 (m, 1H), 2.36-2.48 (m, 2H), 2.50 (s, 3H), 2.73-2.93 (m, 3H), 3.19 (t, 2H), 3.48-3.55 (m, 1H), 4.30 (t, 2H), 6.71 (d, 1H), 6.79 (s, 1H), 7.09 (d, 1H), 7.52 (d, 1H), 7.61 (dd, 1H), 8.02 (d, 1H). Example 187

((l^-5-{2-[2-(4-FIuorophenyl)-5-methyl-1 -thiazoI-4-yl]ethoxy}-2 -dihydro-lH-inden-l-yl)acetic acid

C0₂H

(C₂₃H₂₂FN0₃S): LC-MS, RT 3.58 min., M+H 412.4; ^]H NMR (CDC1₃): δ 1.70-1.77 (m, IH), 2.37- .45 (m, IH), 2.44 (s, 3H), 2.70-2.90 (m, 4H), 3.16 (t, 2H), 3.47-3.52 (m, IH), 4.27 (t, 2H), 6.70 (d, IH), 6.76 (s, IH), 7.00-7.10 (m, 3H), 7.82-7.87 (m, 2H).

Example 188

{(lS)-5-{2-[2-(3,4-DimethyIphenyI)-5-methyl-l,3-thiaz

acid

C0₂H

(C₂5H₂₇N0₃S): LC-MS, RT 4.39 min., M+H 422.3; Ή NMR (CDC1₃): δ 1.70-1.83 (m, IH), 2.29 (s, 3H), 2.32 (s, 3H), 2.37-2.50 [hidden] (m, 2H), 2.46 (s, 3H), 2.70.-2.90 (m, 3H), 3.32 (t, 2H), 3.45-3.60 (m, IH), 4.30 (t, 2H), 6.73 (d, IH), 6.79 (s, IH), 7.07 (d, IH), 7.17 (d, IH), 7.59 (d, IH), 7.68 (s, IH).

Example 189

((15 -5-{2-[2-(4~Acetylphenyl)-5-methyl-l,3-thiazol-4-yl]ethoxy}-2,3-di ydro-lH-inden-l-yl)acetic acid

C0₂H

(C₂₅H₂₅N0₄S): LC-MS, RT 4.01 min., M+H 436.3; Ή NMR (CDC1₃): δ 1.70-1.82 (m, IH), 2.37- 2.49 (m, 2H), 2.50 (s, 3H), 2.63 (s, 3H), 2.70-2.90 (m, 3H), 3.20 (t, 2H), 3.45-3.60 (m, IH), 4.30 (t, 2H), 6.72 (d, IH), 6.78 (s, IH), 7.08 (d, IH), 7.95-8.03 (m, 4H).

Example 190

[(15)-5-(2-{2-[4-(Dimethylamiiio)phenyl]-5-methyl-l,3-thiazol-4-yI}ethoxy)-2 -dihydro-lH-inden-l- yl] acetic acid

C0₂H

(C₂₅H_2SN₂0₃S): LC-MS, RT 2.95 min., +H 437.2; ^lU NMR (DMSO^): δ 1.53-1.65 (m, 1H),.12-2.24 (m, 2H), 2.36 (s, 3H), 2.63-2.84 (m, 3H), 2.94 (s, 6H), 3.03 (t, 2H), 3.27-3.38 (m, I H), 4.18 (t,H), 6.65 (d, IH), 6.75 (s, IH), 7.08 (d, IH), 7.17 (AB quartet, 4H).

Example 191

((lS)-5-{2-[2-(3-Amino-4-methylphenyl)-5-methyl-l,3-thra^

yl)acetic acid

TFA

CaH_MNzOaS.QjFaOa): LC-MS, RT 3.5 min., M+H 423.3; H NMR (CD₃OD): δ 1.67-1.82 (m, IH),.25-2.37 (m, 2H), 2.38 (s, 3H), 2.50 (s, 3H), 2.67-2.90 (m, 3H), 3.20 (t, 2H), 3.41-3.56 (m, IH), 4.32 (t,H), 6.71 (d, IH), 6.79 (s, IH), 7.09 (d, IH), 7.42 (d, IH), 7.69 (dd, IH), 7.77 (d, IH).

Example 192

((l₁S}-5-{2-[2-(2-Fluoropheny))-5-methyl-l,3-thiazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-yl)acetic acid

(C₂₃H₂₂FN0₃S): LC-MS, RT 4.25 min,, M+H 412.2; Ή NMR (CDC1₃): δ 1.70- 1.82 (m, IH), 2.37-.48 (m, 2H), 2.49 (s, 3H), 2.74-2.94 (m, 3H), 3.21 (t, 2H), 3.42-3.60 (m, IH), 4.31 (t, 2H), 6.72 (d, IH),.79 (s, IH), 7.06-7.35 (m, 4H), 8.2 ] (t, IH).

Example 193

((l₄S)-5-{2-[2-(4-Chlorophenyl)-5-methyl-1 -thiazoJ-4-yl]ethoxy}-2_i3-dihydro-lH-iiiden-l-y])acetic acid

C0₂H

(C₂₃H₂₂C1N0₃S): LC-MS, RT 4.44 min., M+H 428.2; Ή NMR (CDC1₃): 8 1.70-1.81 (m, IH), 2.35-.45 (m, 2H), 2.46 (s, 3H), 2.74-2.89 (m, 3H), 3.17 (t, 2H), 3.42-3.60 (m, IH), 4.28 (t, 2H), 6.71 (d, IH),.77 (s, IH), 7.07 (d, IH), 7.36 (d, 2H), 7.79 (d, 2H). Example 194

((15)-5-{2-[2-(4-EthoxyphenyJ)-5-metfayI-1 -thiazol-4-ylJethoxy}-2 -dihydro-lH-inden-l-yi)acetic acid

C0₂H

(C₂₅H₂₇N0₄S): LC-MS, RT 3.55 min., M+H 438.5; 'H NMR (CDC1₃): δ 1.40 (t, 3H), 1.70-1.82 (m, IH), 2.35-2.47 (m, 2H), 2.45 (s, 3H), 2.74-2.89 (m, 3H), 3.20 (t, 2H), 3.42-3.59 (m, IH), 4.07 (q, 2H), 4.29 (t, 2H), 6.71 (d, I H), 6.76 (s, IH), 6.91 (d, IH), 7.06 (d, 2H), 7.82 (d, 2H).

Example 195

((15 -5-{2-[2-(3,4-Dimethoxyphenyl)-5-methyH,3-thiazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-

(C₂₅H₂₇N0₅S): LC-MS, RT 3.86 min., M+H 454.2; ^lU NMR (CDC1₃): δ 1.67-1.82 (m, IH), 2.37- 2.48 (m, 2H), 2.49 (s, 3H), 2.71-2.87 (m, 3H), 3.27 (t, 2H), 3.42-3.57 (m, IH), 3.93 (s, 3H), 3.96 (s, 3H), 4.29 (t, 2H), 6.35-6.64 (broad s, IH), 6.67 (d, I H), 6.75 (s, IH), 6.89 (d, I H), 7.05 (d, IH), 7.39 (d, IH), 7.56 (s, IH).

Example 196

((15)-5-{2-[5- Methyl-2 3-methylphenyl)-l^-thiazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-yl)acetic acid

(C₂4H₂₅N0₃S): LC-MS, RT 3.71 min, M+H 408.2; Ή NMR (CDC1₃): δ 1.70-1.82 (m, IH), 2.38- 2.52 (m, 2H), 2.40 (s, 3H), 2.47 (s, 3H), 2.75-2.87 (m, 3H), 3.19 (t, 2H), 3.45-3.60 (m, IH), 4.29 (t, 2H), 6.72 (d, IH), 6.78 (s, IH), 7.07 (d, IH), 7.19 (d, IH), 7.30 (t, IH), 7.64 (d, IH), 7.75 (s, IH).

Example 197

[{l^-5-(2-{5-Methyl-2-[3-(trifluoromethyl)phenyl3-l,3-thiazol-4-yl}ethoxy)-2,3-dihydro-lH-inden-l- yl] acetic acid

(C24H22F3NO3S): LC-MS, RT 3.90 min., M+H 462.1; *Η NMR (CDC1₃): 5 1.70-1.82 (m, 1H), 2.38- .48 (m, 2H), 2.49 (s, 3H), 2.75-2.87 (m, 3H), 3.19 (t, 2H), 3.44-3.59 (m, 1H), 4.30 (t, 2H), 6.72 (d, 1H), 6.79 (s, 1H), 7.07 (d, 1H), 7.52 (t, 1H), 7.61 (d, 1H), 8.01 (d, 1H), 8.13 (s, 1H).

Example 198

({l₁S)-5-{2-[2-(3-Fluorophenyl)-5-methyi-l,3-thiazol-4-yl]ethoxy}-2,3-dihydro-lH-inden-l-yi)acetic acid

C0₂H

(C₂₃H₂₂FN0₃S): LC-MS, RT 3.66 min., M+H 412.1; ¹H NMR (CDC1₃): δ 1.70-1.82 (m, 1H), 2.39- 2.47 (m, 2H), 2.48 (s, 3H), 2.76-2.87 (m, 3H), 3.18 (t, 2H), 3.45-3.60 (m, 1H), 4.30 (t 2H), 6.72 (d, 1H), 6.78 (s, 1 H), 7.04-7.09 (m, 2H), 7.36-7.42 (m, 1H), 7.58-7.62 (m, 2H).

Example 199

((15 -5-{2-[2-(3,5-Dimethylphenyl)-5-methyI^

acid

(C₂₅H₂₇N0₃S): LC-MS, RT 3.88 min., M+H 422.2; Ή NMR (CDC1₃): δ 1 .72-1.84 (m, 1H), 2.36 (s, 6H), 2.37-2.45 (m, 2H), 2.46 (s, 3H), 2.75-2.87 (m. 3H), 3.19 (t 2H), 3.45-3.60 (m, 1H), 4.28 (t, 2H), 6.72 (d, 1H), 6.79 (s, 1 H), 7.01 (s, 1H), 7.07 (d, 1H), 7.48 (s, 2H).

Example 20Θ

[(15)-5-(2-{5-Methyl-2-[4-(trifluoromethoxy)phenyl]-l,3-thiazol-4-yI}ethoxy)-2,3-dihydro-lH-inden-l- yl] acetic acid

C0₂H

(C24H22F₃NO4S): LC-MS, RT 3.95 min., M+H 478.1 ; Ή NMR (CDCI₃): δ 1.72-1.84 (m, 1H), 2.38- 2.46 (m, 2H), 2.47 (s, 3H), 2.75-2.87 (m, 3H), 3.18 (t 2H), 3.45-3.60 (m, 1H), 4.29 (t, 2H), 6.72 (d, 1H), 6.77 (s, 1H), 7.07 (d, 1H), 7.24 (d, 2H), 7.88 (d, 2H). Example 201

((15)-5-{2-[2-(3-Methoxyphenyl)-5-methy^^

acid

(C₂4H₂₅N0₄S): LC-MS, RT 3.56 min., M+H 424.2; ^lH NMR (CDC1₃): δ 1 .70-1.82 (m, 1H), 2.37- 2.52 (m, 2H), 2.49 (s, 3H), 2.75-2.87 (m, 3H), 3.19 (t, 2H), 3.45-3.57 (m, 1H), 3.87 (s, 3H), 4.30 (t, 2H), 6.72 (d, 1H), 6.79 (s, 1H), 6.95 (d, 1H), 7.10 (d, 1H), 7.32 (t, 1H), 7.40-7.45 (m, 2H).

Example 202

({l^-5-{2-[2-(l '-Biphenyl-4-yl)-5-met yl-l,3^

acid

(C₂9H₂₇N0₃S): LC-MS, RT 3.96 min., M+H 470.3; ^lK NMR (CDC1₃): δ 1.70-1.81 (m, 1H), 2.38- 2.48 (m, 2H), 2.49 (s, 3H), 2.75-2.87 (m, 3H), 3.20(t, 2H), 3.43-3.59 (m, 1H), 4.31 (t, 2H), 6.72 (d, 1H), 6.79 (s, 1H), 7.08 (d, 1 H), 7.36 (t, 1H), 7.45 (t, 2H), 7.61-7.65 (m, 4H), 7.93 (d, 2H).

Example 203

Preparation of ethyl {(15 -5-[2-(4-methyl-2-phenyH,3-oxazol-5-yI)ethoxy]-2,3-dihydro-lH-inden-l-

ADDP (0.205 g, 0.81 mmol) was added to a mixture of PPh₃ (0.212 g, 0.81 mmol), ethyl [(15)-5- hydroxy-2,3-dihydro-lH-inden-l-yl] acetate (0.107 g, 0.49 mmol), and 2-(4-methyi-2-phenyl-l,3-oxazol-5- yl)ethanol (step 4, Example 51, 0.110 g, 0.54 mmol) in THF (5 mL). The reaction was stirred overnight at rt, and additional ADDP (0.136 g, 0.54 mmol) and PPh₃ (0.141 g, 0.54 mmol) were added with CH₂C1₂ (5 mL). The solution was stirred for 24 hours at rt and filtered. The filtrate was evaporated and the resulting mixture was purified by Biotage using a gradient 0 to 50% EtOAc/hexane. Gave ethyl {(lS)-5-[2-(4- methyl-2-phenyl-l,3-oxazol-5-yl)ethoxy]-2,3-dihydro-lH-inden-l -yl}acetate (0.145 g, 66% yield) as yellowish oil. ES-MS mfz 406.2 ((MFt)⁺); HPLC RT (min.) 3.89;^!H NMR (Acetone-^) δ 7.85-7.82 (m, 2H), 7.36-7.30 (m, 3H), 6.94 (d, IH), 6.65 (s, IH), 6.60-6.55 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.31-3.27 (m, 1H), 3.03 (t, 2H), 3.27-2.51 (m, 3H), 2.24-2.14 (m, 2H), 2.18 (s, 3H), 1.58-1.53 (m, IH), 1.08 (t, 3H).

Example 204

Preparation of {(15)-5-[2-(4-methyl-2-phenyl-l,3-oxazol-5-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}acetic acid

Ethyl {(lS)-5-[2-(4-methyl-2-phenyl-] ,3-oxazol-5-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}acetate (0.135 g, 0.33 mmol) was dissolved in EtOH (6 mL) and LiOH (0.024 g, 1.0 mmol) was added. Water (3 mL) was added and THF was added until the cloudy solution became clear. The resulting mixture was stirred overnight at rt. HC1 (2 N) was added to adjust the pH to 2, then extracted three times with ethyl acetate. The organic layers were combined, dried, and concentrated to give {(lS)-5-[2-(4-methyl-2-phenyl- l,3-oxazol-5-yl)ethoxy]-2,3-dihydro-lH-inden-l-yl}acetic acid (0.039 g, 30.6% yield) as colorless oil. ES- MS m/z 378.2 ((MH)⁺); HPLC RT (min.) 3.22; ¾ NMR (Acetone-ίί;) δ 8.1 (s br IH) 8.0-7.95 (m, 2H), 7.52- 7.43 (m, 3H), 7.15(d, I H), 6.81 (s, IH), 6.73 (d, IH), 4.27 (t, 2H) 3.47-3.40 (m, IH), 3.18 (t, 2H), 2.90-2.68 (m, 3H), 2.41-2.29 (m, 2H), 2.18 (s, 3H), 1.77-1.68 (m, IH).

By using the procedure described above for Examples 51, 203, and 204 and substituting the appropriate starting materials, the following compounds were similarly prepared and characterized.

Example 205

Preparati -(4-methyIbenzoyl)alanine

Ή NMR (DMSO-d₆)G δ 12.60 (s br, I H), 8.57 (d, I H), 7.81 (d, 2H), 7.28 (d, 2H), 4.38 (q, IH), 2.35 (s, 3H), 1.38 (d, 3H).

Example 206

Preparation o ~(3-fluoro-4-methylbenzoyl)alanine

Ή NMR (DMSO-d₆)D δ 12.54 (s br, IH), 8.67 (d, IH), 7.65-7.62 (m, 2H), 7.39 (t, IH), 4.38 (q, I H), 2.27 (s, 3H), 1.38 (d, 3H).

Example 207

Preparation -[4-(trifluoromethyl)benzoyl]alanine

Ή NMR (DMSO-d₆)D δ 12.64 (s br, IH), 8.91 (d, IH), 8.08 (d, 2H), 7.85 (d, 2H), 4.42 (q, IH), 1.40 (d, 3H).

Example 208

Preparation of -oxopentanoate

ES-MS m/z 278.38 ((MH)⁺); HPLC RT (min.) 2.04. ^]H NMR (Acetone-d₆)□ δ 8.08 (s br, IH), 7.90 (d, 2H), 7.28 (d, 2H), 4.72-4.67 (m, IH), 4.13 (q, 2H), 3.66 (s, 2H), 2.40 (s, 3H), 1.41 (d, 3H), 1.12 (t, 3H).

Example 2Θ9

Preparation of ethyl -[(3-fluoro-4-methylbenzoyl)amino]-3-oxopentanoate

ES-MS m/z 296.4 ((MH)⁺); HPLC RT (min.) 2.26. ^!H NMR (Acetone-d₆)D δ 7.75-7.60 (m, 2H), 7.38 (t, IH), 4.20 (q, 2H), 3.65 (s, 2H), 2.23 (s, 3H), 1.45 (d, 3H), 1.20 (t, 3H).

Example 210

Preparation of ethyl 3-oxo-4-{[4»(trifluoromethyl)benzoyI]amino}pentanoate

ES-MS m/z 332.4 ((MH)⁺); HPLC RT (min.) 2.45. Ή NMR (Acetone-d₆)D δ 8.14 (d, 2H), 7.84 (d, 2H), 4.80-4.74 (m, 2H), 4.20 (q, 2H), 3.70 (s, 2H), 1.48 (d, 3H), 1.21 (t, 3H). Example 211

Preparation of ethyl [4-methyl-2-(4-niethylphenyl)-l,3-oxazoI-5-yl] acetate

ES-MS m/z 260.2 ((MH)⁺); HPLC RT (min.) 2.96. ^!HNMR (Acetone-d₆)n δ 7.86 (d, 2H), 7.30 (d, H), 4.15 (q, 2H), 3.81 (s, 2H), 2.37 (s, 3H), 2.14 (s, 3H), 1.24 (t, 3H).D

Example 212

Preparation of ethyl [2-(3-fluoro-4-methylphenyi)-4-methyl-l,3-oxazol-5-yl]acetate

ES-MS m/z 278.3 ((MH)¹); HPLC RT (min.) 2.89. Ή NMR (Acetone-d₆)□ δ 7.69 (d, IH), 7.60 (d, IH), 7.37 (t, IH), 4.15 (q, 2H), 3.83 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 1.23 (t, 3H).

Example 213

Preparation of ethyl {4-methyl-2-[4-(trifluoromethyl)phenyl]-l,3-oxazol-5-yl}acetate

ES-MS m/z 314.3 ((MH)⁺); HPLC RT (min.) 3.27. Ή NMR (Acetone-d₆)n δ 8.18 (d, 2H), 7.84 (d, 2H), 4.17 (q, 2H)_S 3.88 (s, 2H), 2.20 (s, 3H), 1.23 (t, 3H).

Example 214

Preparation of 2-[4-methyl-2-(4-methyIpheiiyI)-l,3-oxazol~5-yl]ethanol

ES-MS m/z 218.2 ((MH)⁺); HPLC RT (min.) 2.35. Ή NMR (Acetone d₆)D δ 7.85 (d, 2H), 7.27 (d, 2H), 3.99 (s br, IH), 3.83 (t, 2H), 2.90 (t, 2H), 2.37 (s, 3H), 2.12 (s, 3H). Example 215

Preparation of 2-[2-(3-fluoro-4-methy!phenyl)-4-methyI-l,3-oxazol-5-yl]ethanol

ES-MS m/z 236.2 ((MH)⁺); HPLC RT (min.) 2.46. ¾ N R (CDC1₃)D δ 7.54 (d, IH), 7.43 (d, IH),.17 (t, IH), 3.91 (d, 2H), 3.09 (s br, IH), 2.88 (t, 2H), 2.29 (s, 3H), 2.13 (s, 3H).

Example 216

Preparation of 2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-l,3-oxazol-5-yl}ethanol

ES-MS m/z 272.2 ((MH)⁺); HPLC RT (min.) 2.71. H NMR (CDC1₃)D δ 8.03 (2, 2H), 7.66 (d, 2H),.95 (t, 2H), 2.96 (t, 2H), 2.21 (s, 3H), 1 .97 (s br, IH).

Example 217

Preparation of ethyl [(15 -5-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-l,3-oxazol-5-yi}ethoxy)-2,3- dihydro-lH-inden-l-yl] acetate

ES-MS m/z 474.5 ((MH)⁺); HPLC RT (min.) 4.10. Ή NMR (Acetone^)□ δ 8.16 (d, 2H), 7.83 (d,H), 7.09 (d, IH), 6.80 (s, IH), 6.72 (dd, IH), 4.28 (t, 2H), 4.12 (q, 2H), 3.46-3.41 (m, IH), 3.21 (t, 2H),.86-2.65 (m, 3H), 2.39-2.26 (m, 2H), 2.20 (s, 3H), 1.75-1.63 (m, IH), ] .22 (t, 3H). Example 218

Preparation of ethyl ((l₁y)-5-{2-[4-methyI-2-(4-raethylphenyl)-l,3"Oxazol-5-yl]ethoxy}-2,3-dihyd

-l-yl)acetate

TCL Rf = 0.22 Hexane/EtOAc 4: 1

Example 219

Preparation of ethyl ((liS -5-{2-[2-(3-flHoro-4-methylphenyI)-4-methyl-l,3-oxazol-5~yl]ethoxy}-2,3- dihydro-lH-inden-l-yl)acetate

ES-MS m/z 438.2 ((MH)⁺); HPLC RT (min.) 4.18. ¾ NMR (Acetone-^)□ δ 6.67 (dd, IH), 7.59 (dd, IH), 7.37 (t, IH), 7.08 (d, IH), 6.80 (s, IH), 6.72 (dd, IH), 4.26 (t, 2H), 4.12 (q, 2H), 3.46-3.38 (m, IH), 3.17 (t, 2H), 2.89-2.65 (m, 3H), 2.39-2.23 (m, 5H), 2.17 (s, 3H), 1.75-1.63 (m, I H), 1.23 (t, 3H).

Example 220

Preparation of ((15)-5-{2-[4-methyl-2-(4-methyIphenyJ)-l,3-oxazol-5-yl]ethoxy}-2,3-dihydro-lH- -l-yl)acetic acid

ES-MS m/z 392.2 ((MH)⁺); HPLC RT (min.) 3.36. ^!H NMR (Acetone-rf_d)D δ 7.72 (d, 2H), 7.15 (d, 2H), 6.99 (d, IH), 6.67 (s, IH), 6.59 (dd, IH), 4.12 (t, 2H), 3.33-3.28 (m, IH), 3.03 (t, 2H), 2.73-2.54 (m, 3H), 2.27-2.21 (m, 5H), 2.02 (s, 3H), 1.64-1.54 (m, IH). Example 221

Preparation of ((15)-5-{2-[2-(3-fluoro-4-niethylphenyl)-4-methyl-l,3-oxazol-5-yl]ethoxy}-2,3-dihydro- ll-inden-l-yl)acetic acid

ES-MS mfz 410.2 ((MH)⁺); HPLC RT (min.) 3.49. ^]H NMR (Acetone-^)□ δ 7.68 (dd, IH), 7.59 (dd, IH), 7.36 (t, IH), 7.12 (d, IH), 6.80 (s, IH), 6.72 (dd, IH), 4.26 (t, 2H), 3.47-3.41 (m, IH, 3.18 (t, 2H), 2.86-2.67 (m, 3H), 2.40-2.28 (m, 5H), 2.17 (s, 3H), 1.18-1.65 (m, IH).

Example 222

Preparation of [(l!S)-5-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-l,3-oxazol-5-yl}ethoxy)-2,3- dihydro-lH-ind en- 1-yl] acetic acid

ES-MS m/z 446.5 ((MH)⁺); HPLC RT (min.) 3.47. ⁵H NMR (Acetone-^) 0 5 8.17 (d, 2H), 7.84 (d, 2H), 7.13 (s, IH), 6.80 (s, IH), 6.72 (dd, IH), 4.28 (t, 2H), 3.46-3.41 (m, IH), 3.21 (t, 2H), 2.86-2.67 (m, 3H), 2.40-2.28 (m, 2H), 2.20 (s, 3H), 1.77-1.67 (m, IH).

Example 223

Preparation of (25 -2-{(15)-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yi)ethoxy]-2,3-dihydro-lH-inden-l- yl} ropanoic acid and {2i)-2-{(l -)-5-[2-(5-methyl-2-phenyH,3-oxazol-4-yI)ethoxy]-2,3-dihydro-lH- inden-l-yl} propanoic acid

Step 1. Preparation of (2S)-2-[(l S)-5-methoxy-2,3-dihydro-lH-inden-l-yl]propanoic acid and (2R)- 2-[(lR)-5-methoxy-2,3-dihydro-l H-inden- l-yl]propanoic acid

The starting acid (Example 2 b) was reacted using a similar procedure as described in Example 4, under 60 psi H₂, and using 4.5 g starting material, 1.04 g catalyst, and 4.5 mL triethylamine in 45 mL ethanol and 5 mL THF. The standard extractive workup gave 3.22 g product. LC MS retention time 2.41 min., NMR (d6-DMSO): 0.87 (d, 3H, a-methyl), 1.75 (m, 1H), 2.04 (m, 1H), 3.66 (s, 3H, methoxy), 6.65 (m, 1H, aryl), 6.76 (s, 1H, aryl), 7.04 (d, 1H, aryl,) 12.18 (bs, 1H, acid.)

Step 2: Preparation of methyl (2S)-2-[(l S)-5-methoxy-2,3-dihydro-lH-inden-l-yl]propanoate and methyl (2R)-2-[( 1 R)-5 -methoxy-2 ,3 -dihydro- 1 H-inden- 1 -yfjpropanoate

The compound was prepared by the reaction of 1.5 g starting acid, 0.93 mL iodomethane, and 1.75 g sodium bicarbonate in 10 mL methanol under standard esterification conditions as described in Example 6. Workup gave 1.53 g, 96%. (NMR (CD₂C1₂): 1.05 (d, 3H, a-methyl), 1.88 (m, 1H). 2.19 (m, 1H), 3.44 (m, 1H), 3.68 (s, 3H, methoxy), 3.77 (s, 3H, ester).

Step 3. Preparation of: methyl (2S)-2-[(l S)-5-hydroxy-2,3-dihydro- l H-inden-l-yl]propanoate and methyl (2R)-2- [( 1 R)-5 -hydrxy-2,3 -dihydro- 1 H-inden- 1 -yfjpropanoate

Using the demethylation conditions as described in Example 7 (1.53 g starting material, 4.35 g A1C1₃, and 2.4 mL ethanethiol in 20 mL dichloromethane), 1.21 g of product (84%) was obtained. (NMR (CD₂C1₂): 1.05 (d, 3H, a -methyl), 1 .88 (m, 1H), 2.18 (m, 1H), 3.45 (m, 1H), 3.67 (s, 3H, ester), 6.60 (m, lH, aryl), 6.69 (s, 1H, aryl), 6.93 (d, 1H, aryl.) Step 4: Preparation of methyl (2S)-2-{(l S)-5-[2-(5-methyl-2-phenyl-l ,3-oxazol-4-yl)ethoxy]-2,3- dihydro- 1 H-inden- 1 -yl}propanoate and methyl (2R)-2- { ( 1 R)-5 - [2-(5 -methy 1-2 -phenyl- 1 ,3-oxazol-4- yl)ethox -2,3-dihydro-lH-inden- l -yl}propanoate

Using the standard Mitsunobu coupling procedure as described in Example 11 (0.100 g starting phenol, 0.110 g oxazolylethanol, 0.143 g triphenylphosphine, and 0.137 g ADDP in 2 mL dichloromethane), 0.107 g (58%) of product was obtained after chromatography in 35% EtOAc/hexane. NMR (CD₂C1₂): 1.62- 1 .87 (m, 4H), 2.40 (s, 3H, oxazole methyl), 2.98 (t, 2¾, methylene), 3.23 (m, IH), 3.63 (s, 3H, ester), 6.60 (s, IH, aryl), 6.64 (m, IH, aryl), 7.42 (m, 3H, aryl), 8.00 (m, 2H, aryl).

Step 5. (2S)-2-{(l S)-5-[2-(5-methyl-2-phenyl-l ,3-oxazol-4-yl)ethoxy]-2,3-dihydro-lH-inden-l - yl}propanoic acid and (2R)-2-{(l R)-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]-2,3-dihydro-l H- inden-l -yl} propanoic acid

The LiOH hydrolysis conditions were applied to 0.090 g of starting ester, yielding 0.082 g (95%) product. NMR (CD₃OD): 0.4-0.75 (m, 4H), 1.18 (s, 3H), 1.75 (t, 2H, methylene), 2.00 (m, IH), 2.99 (t, 2H, methylene), 5.39 (s, IH, aryl), 5.48 (m, IH, aryl), 5.83 (d, 3 H, aryl), 6.27 (m, 3H, aryl), 6.76 (m, 2H, aryl).

Using the methods described above and the appropriate starting materials, additional (2S, IS) and (2R, IR) were similarly prepared, either as diastereomeric (i.e., syn, {(2S, I S)/ (2R, IR)} and or anti {(2R, IS)/ (2S, IR)}) mixtures, or as individual enantiomers. These compounds are summarized in Table 5. Table 5

Example 248

Preparation of ethyl [{15)-5-(2-{2-[4'-(5-acetyl-2-thienyI)-l,l'-biphenyl-4-yl]-5-methyl-l,3- oxazoI-4-yl}ethoxy)-2,3-dihydro-lH-inden-l-yl]acetate

To a solution containing ethyl ((liS}-5-{2-[2-(4-bromophenyl)-5-methyl-l,3-oxazol-4-yl]ethoxy}- 2,3-dihydro-lH-inden-l-yl)acetate (0.100 g, 0.21 mmol) [prepared from 2-[5-methyl-2-(4-bromophenyl)- l,3-oxazol-4-yl]ethanol and ethyl [(l.S)-5-hydroxy-2,3-dihydro-lH-inden-l -yl]acetate (Example 135)], 1,1 '- bis(diphenylphosphino)-ferrocene]dichloro palladium(II) (16.9 mg, 0.02 mmol), and 5-acetyl-2- thienylboronic acid (0.062 g, 0.41 mmol) in degassed toluene and dioxane (4: 1 , 2 mL) was added aqueous 2 M sodium carbonate (0.5 mL). The mixture was heated at 85°C for 16 hours. Solvents were evaporated under vacuum and the residue was dissolved in methanol and acetonitrile and filtered through a C8 reverse phase extraction cartridge. Solvents were evaporated and the residue was dissolved in acetonitrile and purified by HPLC to obtain ethyl [(lS)-5-(2-{2-[4'-(5-acetyl-2-tiiienyl)-l ,l'-biphenyl-4-yl]-5-methyl-l,3- oxazol-4-yl}ethoxy)-2,3-dihydro-lH-inden-l-yl]acetate in 46% yield. (50 mg, 0.09 mmol) MS (electro spray) 530.4 (M+H)⁺, ^!H NMR (CDC1₃) δ 1.24 (t, 3H), 1.71 (m, 1H), 2.37 (m, 5H), 2.57 (s, 3H), 2.68 (m, 1 H), 2.83 (m, 2H), 3.03 (m, 2H), 3.48 (m, 1H), 4.17(m, 4H), 6.67 (m, 2H), 7.02 (d, 1H), 7.39 (d, 1H), 7.67 (d, 1H), 7.73 (d, 2H), 8.01 (d, 2H).

Other compounds, prepared by using analogous starting materials and the method described in Example 248 together with the hydrolysis described in Example 11, are described below in Table 6.

Examples 252-256

HPLC-electrospray mass spectra (HPLC ES-MS) are obtained using a Hewlett-Packard 1 100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro CI 8 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes is used on the HPLC. Buffer A is 98% water, 2% Acetonitrile, and 0.02% TFA, and Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra are scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.

Proton (^JH) nuclear magnetic resonance (NMR) spectra are measured with a General Electric GN- Omega 300 (300 MHz) spectiOmeter with either Me₄Si (5 0.00) or residual protonated solvent (CHC1₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (^!3C) NMR spectra are measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1₃ δ 77.0; d₃-MeOD; δ 49.0; d₆-DMSO δ 39.5) as standard.

Chiral separations are performed using a commercially available Chiracel® AD HPLC column, eluting with a gradient of isopropanol in hexane (from 1% to 15%) with addition of 0.1% trifluoroacetic acid.

For example 256, the following analytical instruments are used:

(1) HPLC: Instrument: Perkin-Elmer Series 200, Column: YMC Pro CI 8, S-3um, 12mm (4.6 x 150 mm/AS12503-1546WT); Mobile A: 0.1% TFA in HPLC H₂0, Mobile B: 0.1% TFA in HPLC CH₃CN, Temperature = Ambient; Wavelength = 220 nm

Gradient:

(2) NMR: Bruker 400 MHz

(3) Mass Spectrometer: Waters Micromass ZQ

ABBREVIATIONS AND ACRONYMS

When the following abbreviations are used herein, they have the following meaning:

Ac₂0 acetic anhydride

ADDP 1,1 '-(azodicarbonyl)dipiperidine

anhy anhydrous

BOC ½ -butoxycarbonyl «-BuOH n-butanol

i-BuOH iert-butanol

i-BuOK potassium feri-butoxide

CDI carbonyl di imidazole

CD₃OD methanol-c¾

Celite^® diatomaceous earth filter agent, ^®Celite Corp.

CH₂C1₂ methylene chloride

CI-MS chemical ionization mass spectroscopy

cone concentrated

DCC dicyclohexylcarbodiimide

DCM dichloromethane

de diastereomeric excess

DEAD diethyl azodicarboxylate

dec decomposition

DIA diisopropyl amine

DIBAL-H diisobutylaluminum hydroxide

DMAP 4-(NN-dimethylamino)pyidine

DME d i methoxyethane

DMF N N-dimethylformamide

DMSO dimethylsulfoxide

EDC1 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ee enantiomeric excess

ELSD evaporative light scattering detector

ES-MS electrospray mass spectroscopy

EtOAc ethyl acetate

EtOH ethanol (100%)

EtSH ethanethiol

Et₂0 diethyl ether

Et₃N triethylamine

GC-MS gas chromatography-mass spectroscopy

I IPLC high performance liquid chromatography

IPA isopropylamine

LAH lithium aluminum hydride

LC-MS liquid chromatography-mass spectroscopy

LDA lithium diisopropylamide

m/z mass-to-charge ratio

MeCN acetonitrile

NMM 4-methylmorpholine Ph₃P triphenylphosphine

Pd(dppf)Cl₂ [ 1 , Γ -b i s(diphenylphosph ino)ferrocene] dichloropalladium(n)

Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)

Pd(OAc)₂ palladium acetate

P(0)C1₃ phosphorous oxychloride

Rf retention factor (TLC)

RT retention time (HPLC)

rt room temperature

TEA triethyl amine

THF tetrahydrofuran

TFA trifluoroacetic acid

TLC thin layer chromatography

TMAD Ν,Ν,Ν' ,Ν' -tetramethylethy lenediamine

TMSC1 trimethylsilyl chloride

Example 252.

Preparation of compound 252 (5-{2-[5-Ethyl-2~(4-hydroxy-phenyl)-oxazol-4-yl]-ethoxy}-indan-l-yl)- acetic acid

compound 252

Reaction Scheme 7 begins with compound 252a reacting with compound 252b to provide compound 252c by using an organic or inorganic base in a suitable solvent under suitable reaction conditions (e.g., CS2CO3 in acetonitrile (ACN) at an elevated temperature of about 70°C). Compound 252c is treated with an appropriate base under suitable reaction conditions (e.g. NaOH EtOH at about 65 °C) to hydrolyze the ester moiety, and then followed by acidification (e.g. HCl) to produce compound 252d. Subsequently, compound 252d is treated with boron tribromide (BBrj) in dichloromethane (DCM) to give compound 252. Alternatively, compound 252d may be treated with aluminum chloride/ dodecyl thiol in an appropriate solvent to give compound 252.

Compounds 252a and 252b may be prepared according to methods described in the literature with modifications known to those skilled in the art (e.g. U.S. Patent No. 6,828,335). Reaction Scheme 7

252d

BBr₃ / CH₂C1₂

alternatively: AlCl₃/dodecyl thiol COOH

252

Example 253

Synthesis of compound 253 (5-{2-[2-(4-BenzySoxy-phenyl)-5-ethyl-oxazol-4-yi]-ethoxy}-indan-l-yl)- acetic acid

Compound 253

Reaction Scheme 8 begins with compound 252 a coupling with compound 253b under suitable reaction conditions (e.g., Cs₂C0₃ in acetonitrile (ACN) at an elevated temperature of 70°C) to provide compound 253c. Then, compound 253c is treated with an appropriate base under suitable reaction conditions (e.g. NaOH EtOH at about 65 °C) to hydrolyze the ester moiety. Subsequent acidification (with, e.g., HCI) provides compound 253.

Compound 253b may be prepared according to methods described in the literature with modifications known to those skilled in the art (e.g., U.S. Patent No. 6,828,335).

Reaction Scheme 8

253

Example 254 Alternative synthesis of compound 252

According to Reaction Scheme 9, compound 252 may also be prepared by hydrogenolysis of compound 253c to produce compound 254b. Then, compound 254b may be treated with an appropriate base under suitable reaction conditions (e.g. NaOH/EtOH at about 65 °C) to hydrolyze the ester moiety. Subsequent acidification (with, e.g. HCI) produces compound 253. Alternatively, compound 252 may be prepared by hydrogenation of compound 253 to give compound 252.

252

Example 255 preparation of salts of compound 252-254

Exemplary procedures of preparing salts of compound 252-254 are shown in Reaction Scheme 10. Compounds 252-254 may be converted to salts by treatment with an appropriate base in a suitable solvent (e.g. NaOEt in ethanol) followed by precipitation using an appropriate anti-solvent (e.g. ethers) to produce salts of compounds 252-254.

Reaction Scheme 10

C C

C

Compund 252: R⁴ is OH

Compound 253: R⁴ is -OBn

Compound 254: R⁴ is -OCD₃ Example 256. Preparation of compound 255

(5-{2-[5-Ethyl-2-{D3-4-raethoxy-phenyl)-oxazol-4-yl]-ethoxy}-indan-l-yI)-acetic acid

Compound 255 may be similarly prepared as compounds 252d and 253 by starting from appropriate deuterated starting materials or intermediates as shown in Reaction Scheme 11.

MS: m/z: 425.3 (M+H); 'HNMR (CDCI₃) δ 7.906(d, 2H), 7.07(d, H), 6.93(d, 2H), 6.72(d, 1H), 6.70(dd, 1H), 4.19(t, 2H), 3.51(q, 1H), 2.86(t, 2H), 2.75(m, 5H), 2.48(m, 2H), 1.75(t, 1H), 1.29(t, 3H).

Reaction Scheme 11

255

The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be constmed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

THAT WHICH IS CLAIMED IS:

1. A method of treating or preventing an autoimmune disorder comprising administering to a subject in need thereof an effective amount of a com ound of Formula I:

Formula I

wherein in Formula I

R is H or Ci - C₆ alkyl;

R^l is H, COOR, C₃-C₈ cycloalkyl, or

C1-C6 alkyl, C₂-C6 alkenyl, or Ci-Ce alkoxy, each of which may be unsubstituted or substituted with fluoro, methylenedioxyphenyl, or phenyl which may be unsubstituted or substituted with R⁶;

R² is H, halo, or C_rC6 alkyl which may be unsubstituted or substituted with C]~C alkoxy, oxo, fluoro, or

R² is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyi, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyi, tetrahydrothiopyranyl, piperazinyl, or morpholinyl, each of which may be unsubstituted or substituted with R⁶;

R³ is H, C C₆ alkyl, or phenyl which may be unsubstituted or substituted with R⁶;

X is O or S;

R⁴ is Ci-Cg alkyl or C₃-Q cycloalkyl, either of which may be unsubstituted or substituted with fluoro, oxo, or C]-C alkoxy which may be unsubstituted or substituted with C_f-Ce alkoxy, or phenyl optionally substituted with R⁶, or

each of which may be substituted with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyi, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyi, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indoly), indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazoiyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1 ,4-benzodioxanyI,

each of which may be unsubstituted or further substituted with R⁶, or

C C₆ alkyl may also be substituted with C₃-Cg cycloalkyl or with phenoxy which may be unsubstituted or substituted with R⁶ or with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrotliienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl,benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyi, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or

R⁴ is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, , benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazoiyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyi, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or with phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, benzodioxolyl, dihydrobenzofuranyl, indolyl, pyrimidinyl or phenoxy, each of which may be unsubstituted or substituted with R⁶;

R⁵ is H, halo or Ci-Ce alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, Ci-G₆ alkyl optionally substituted with oxo or hydroxy, or

C C_fi alkoxy optionally substituted with f!uoro;

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

2. The method of claim 1, wherein the compound has the following structure:

3. The method of claim 1 or 2, wherein

is H,

R¹ is H,

R² is H,

R³ is C C₆ alkyl, X is O, and

R is a phenyl substituted with R⁶, wherein R⁶ is Ci-C₆ alkoxyl or C Q alkyl

a pharmaceutically acceptable salt thereof.

The method of claim 1, wherein the compound has the following structure:

5. The method of any one of claims 1-4, wherein the compound is a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts with organic bases, basic nitrogen containing groups in the conjugate base that is quatemized with agents selected from the group consisting of alkyl halides and aralkyl.

6. The method of claim 5, wherein the compound of Formula I is a meglumine, potassium or sodium salt thereof.

7. The method of any one of claims 1 to 6, wherein the compound of Formula I is administered in combination with another medication for treating autoimmune disorders.

8. The method of claim 7, wherein the other medication is a medication for treating multiple sclerosis selected from the group consisting of corticosteroids, beta interferons, glatiramer acetate, methotrexate, azathioprine, cyclophosphamide, cladribine, baclofen, tizanidine, amitriptyline, carbamazepine, natalizumab, and mitoxantrone.

9. The method of claim 7, wherein the other medication is a medication for treating rheumatoid arthritis selected from the group consisting of non-steroidal anti-inflammatory drugs, gold compounds, methotrexate, hydroxychloroquine, sulfasalazine, penicillamine, corticosteroids, cytotoxic and immunosuppressive drugs.

10. The method of claim 7, wherein the other medication is a medication for treating rheumatoid arthritis selected from the group consisting of leflunomide (Arava), etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), rituximab (Rituxan), abatacept (Orencia), golimumab (Simponi), certolizumab pegol (Cimzia), and tocilizumab (Actemra).

11. The method of any one of claims 7 to 10, wherein the other medication is administered concurrently.

12. A method of treating or preventing an autoimmune disorder comprising administering to a subject in need thereof an effective amount of a com ound of Formula VI:

Formula VI

wherein

R^] and R² are independently H, C -C_& alkyl, or C3-C6 cycloalkyl;

L is a linker and selected from the group consisting of -(CH2)_m- -₅ -Y-(CH₂)_n-X-,and

wherein

X is selected from the group O, S, S(=0), and S(=0)₂,

Y is selected from the group O, MR⁵, S, S(=0), and S(=0)₂,

m is 1, 2, or 3,

n is 2, 3, or 4,

t is 0 or 1,

p is 0,1, 2, or 3, q is 1, 2, 3, or 4,

wherein the sum of p and q is 1, 2, 3, or 4;

Ar is phenyl or a 6-membered heteroaryl containing up to three N atoms,

wherein said Ar is optionally substituted at any available position by 1 to 5 independently selected R³ groups, and

optionally fused to a 5- or 6-membered saturated carbocyclic ring,

a 5- or 6-membered unsaturated carbocyclic ring, or

a 5- or 6-membered heterocyclic ring containing up to 3 additional

heteroatoms selected from N, O, and S,

wherein said fused ring may be optionally substituted at any available position by 1 to 4 independently selected R⁴ groups;

R³ is selected from the group consisting of hydroxy, SH, halo, CN, N0₂, C(=0)OH, C(=0)-OC C₆ alkyl, C(=0)-OC C₆ cycloalkyl, NR⁶R⁷, C(=0)NR⁶R⁷, C(=S)NR R⁷, C_rC₆ alkyl optionally substituted with halo, OH, NR⁶R⁷, or C_rC₆ alkoxy, C,-C₆ haloalkyl, C,-C₆ alkoxy, C C₆ thioalkyl, C₂-C₆ alkenyl, C,-C₆ haloalkoxy, C₃-C₈ cycloalkyl, C₃-Cg cycloalkoxy, phenoxy optionally substituted on the phenyl ring with halo, Ci-C₆ alkyl, or Ci-C₆ alkoxy, and

a mono or bicyclic ring radical selected from the group consisting of

a) phenyl optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1 -3 heteroatoms selected from N, O, and S, and b) a 5- or 6-membered heterocyclic ring radical containing up to 4

heteroatoms selected from N, O, or S, optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S,

said mono or bicyclic ring radical being optionally substituted with up to 5 groups independently selected from the group consisting of halo, hydroxy, oxo, CN, Ci-Ce alkyl optionally substituted with halo, OH, NR⁶R⁷, C_rQ alkoxy, C_rC₆ haloalkyl, C_rQ alkoxy, C C₆ thioalkyl, C C₆ haloalkoxy, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkoxy, C C₆ acyl, C(-0)OH, CH₂C(=0)OH, NR⁶R⁷, C(=0)NR⁶R⁷, C(=0)OC_rC₆ alkyl, and C(=0)OC₃-C₆ cycloalkyl;

R⁴ is selected from the group consisting of oxo, hydroxy, halo, CN, NR⁶R⁷, C C₆ alkyl optionally substituted with OH, NR⁶R⁷, or C_rC₆ alkoxy, Q-Q haloalkyl, Ci-C₆ alkoxy, Q-Q thioalkyl, Q-Qs haloalkoxy, C₃-Cg cycloalkyl, and C₃-Cg cycloalkoxy;

R⁵ is selected from the group consisting of H, C]-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl, Ci-C₆ acyl, benzyl optionally substituted with halo, C]-C₆ alkoxy, C Cealkyl, CN, N¾, N[(C C₃)alkyl]₂, N0₂, or CF₃, C₃-C₅ cycloalkyl, and C(=0)OC,-C₆ alkyl; R⁶ and R⁷ are independently selected from the group consisting of FL, Cj-Ce alkyl optionally substituted with C₃-C₆ cycloalkyl, C_rC₆ acyl, benzyl optionally substituted with halo, C_rC₆ alkoxy, (C C₆)alkyl, CN, NH₂, N[(C_rC₃)alkyl]₂, N0₂, or CF₃, C₃-C₆ cycloalkyl, and phenyl optionally substituted with halo, C_rC₆ alkoxy, (C_rC₆)alkyl, CN, N[(Ci-C₃)alkyl]₂, N0₂, or CF₃, or

R⁶ and R⁷ may be taken together with the nitrogen atom to which they are attached to form a 5- or 6- membered heterocyclic ring optionally interrupted by NR⁵ or O;

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

13. The method of claim 12, wherein the compound of Formula VI has the following structure:

14. The method of any one of claim 12 or 13, wherein

R¹ and R² are H,

L is -0-(CH₂)_n-0, wherein n is 2, 3 or 4,

Ar is a phenyl substituted with one to five R³,

wherein each occurrence of R³ is independently Cj-Q alkyl or a 5- or 6-member heterocyclic ring containing up to 4 hetero atoms selected from the group consisting of N, O and S, wherein the heterocyclic ring is substituted with -Ce alkyl.

15. The method of any one of claims 12 to 14, wherein the compound have the following structure:

or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 12-15, wherein the compound of Formula VI is a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts with organic bases, basic nitrogen containing groups in the conjugate base that is quaternized with agents selected from the group consisting of alkyl halides and aralkyl.

17. The method of claim 16, wherein the pharmaceutically acceptable salt is a meglumine, potassium or sodium salt.

18. The method of any one of claims 12-17, wherein said autoimmune disorder is selected from the group consisting of acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis ubiterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, fibrosing alveolitis, Juvenile RA, Guillain-Barre syndrome, Hashimoto's thyroiditis, celiac disease, Crohn's disease, ulcerative colitis, Sclerosing cholangitis, autoimmune hepatitis, temporal arteritis, and giant cell arteritis.

19. The method of any one of claims 12 to 17, wherein said autoimmune disorder is an autoimmune disorder involving a systemic autoimmune disorder.

20. The method of any one of claims 12 to 17, wherein said autoimmue disease is selected from the group consisting of systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.

21. The method of any one of claims 12 to 17, wherein the compound of Formula VI is administered in combination with another medication for treating autoimmune disorders.

22. The method of claim 21 , wherein the other medication is a medication for treating multiple sclerosis selected from the group consisting of corticosteroids, beta interferons, glatiramer acetate, methotrexate, azathioprine, cyclophosphamide, cladribine, baclofen, tizanidine, amitriptyline, carbamazepine, natalizumab, and mitoxantrone.

23. The method of claim 21, wherein the other medication is a medication for treating rheumatoid arthritis selected from the group consisting of non-steroidal anti-infiammatory drugs, gold compounds, methotrexate, hydroxychloroquine, sulfasalazine, penicillamine, corticosteroids, cytotoxic and immunosuppressive drugs.

24. The method of claim 21 , wherein the other medication is a medication for treating rheumatoid arthritis selected from the group consisting of leflunomide (Arava), etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), rituximab (Rituxan), abatacept (Orencia), golimumab (Simponi), certolizumab pegol (Cimzia), and tocilizumab (Actemra).

25. The method of any one of claims 21 to 24, wherein the other medication is administered concurrently.

26. A method of treating or preventing a liver disorder comprising administering to a subject in need thereof an effective amount of a com ound of Formula I:

Formula I

wherein in Formula I

R is H or C, - C₆ alkyl;

R¹ is H, COOR, C₃-C_R cycloalkyl, or

C]-C₆ alkyl, C₂-C₆ alkenyl, or Ci-C₆ alkoxy, each of which may be unsubstituted or substituted with fluoro, methylenedioxyphenyl, or phenyl which may be unsubstituted or substituted with R⁶;

R² is H, halo, or C)-C₆ alkyl which may be unsubstituted or substituted with Ci-C₆ alkoxy, oxo, fluoro, or

R² is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyUsothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl, each of which may be unsubstituted or substituted with R⁶;

R^J is H, C]-C₆ alkyl, or phenyl which may be unsubstituted or substituted with R⁶;

X is O or S;

R⁴ is C Ce alkyl or C₃-C₈ cycloalkyl, either of which may be unsubstituted or substituted with fluoro, oxo, or Ci-Q alkoxy which may be unsubstituted or substituted with Ci-C₆ alkoxy, or phenyl optionally substituted with R⁶, or

each of which may be substituted with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1 ,4-benzodioxanyl,

each of which may be unsubstituted or further substituted with ⁶, or

Ci-Q alkyl may also be substituted with C^-Cs cycloalkyl or with phenoxy which may be unsubstituted or substituted with R⁶ or with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothippyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl,benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or

R⁴ is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,

each of which may be unsubstituted or substituted with R⁶, or with phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, benzodioxolyl, dihydrobenzofuranyl, indolyl, pyrimidinyl or phenoxy, each of which may be unsubstituted or substituted with R⁶;

R⁵ is H, halo or Q-Q alkyl optionally substituted with oxo; and

R⁵ is halo, CF₃, Ci-C₆ alkyl optionally substituted with oxo or hydroxy, or

Ci-Q alkoxy optionally substituted with fluoro;

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

27. The method of claim 26, wherein the compound has the following structure:

28. The method of claim 26 or 27, wherein,

R is H,

R¹ is H,

R² is H,

R³ is C C₆ alkyl,

X is O, and

R⁴ is a phenyl substituted with R⁶, wherein R⁶ is Q-Q alkoxyl or Ci-C₆ alkyl or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 26-28, wherein the compound has the following structure:

30. The method of any one of claims 26-29, wherein the compound is a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts with organic bases, basic nitrogen containing groups in the conjugate base that is quaternized with agents selected from the group consisting of alkyl halides and aralkyl.

31. The method of claim 30, wherein the compound is a meglumine, potassium or sodium salt thereof.

32. A method of treating or preventing liver disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula VI:

Formula VI

wherein

R¹ and R² are independently H, Q-Q alkyl, or C₃-C₆ cycloalkyl;

L is a linker and selected from the group consisting of -(C m-X-, -Y-(CH₂)_n-X-,and

wherein

X is selected from the group O, S, S(=0), and S(=0)₂,

Y is selected from the group O, NR⁵, S, S(=0), and S(=0)₂,

m is 1, 2, or 3,

n is 2, 3, or 4,

t is 0 or 1,

p is 0,1, 2, or 3,

q is 1, 2, 3, or 4,

wherein the sum of p and q is 1, 2, 3, or 4;

Ar is phenyl or a 6-membered heteroaryl containing up to three N atoms, wherein said Ar is optionally substituted at any available position by 1 to 5 independently selected R³ groups, and

optionally fused to a 5- or 6-membered saturated carbocyclic ring,

a 5- or 6-membered unsaturated carbocyclic ring, or

a 5- or 6-membered heterocyclic ring containing up to 3 additional

heteroatoms selected from N, O, and S,

wherein said fused ring may be optionally substituted at any available position by 1 to 4 independently selected R⁴ groups;

R³ is selected from the group consisting of hydroxy, SH, halo, CN, N0₂, C(=0)OH, C(=0)-OC_rC₆ alkyl, C(=0)-OC₃-C₆ cycloalkyl, NR⁶R⁷, C(=0)NR⁶R⁷, C(=S)NR⁶R⁷, d-C₆ alkyl optionally substituted with halo, OH, NR⁶R⁷, or C C₆ alkoxy, C C₆ haloalkyl, C_rQ alkoxy, C_rC₆ thioalkyl, C₂-C₆ alkenyl, C C₆ haloalkoxy, C₃-C₃ cycloalkyl, C₃-C₈ cycloalkoxy, phenoxy optionally substituted on the phenyl ring with halo, C]-C₆ alkyl, or d-Q; alkoxy, and

a mono or bicyclic ring radical selected from the group consisting of

a) phenyl optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S, and b) a 5- or 6-membered heterocyclic ring radical containing up to 4

heteroatoms selected from N, O, or S, optionally fused to

a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S,

said mono or bicyclic ring radical being optionally substituted with up to 5 groups independently selected from the group consisting of halo, hydroxy, oxo, CN, Cj-Ce alkyl optionally substituted with halo, OH, NR⁶R⁷, C C₆ alkoxy, d-C₆ haloalkyl, C,-C₆ alkoxy, C C₆ thioalkyl, C C₆ haloalkoxy, C₃-C₈ cycloalkyl, C₃-C₃ cycloalkoxy, C C₆ acyl, C(=0)OH, CH₂C(=0)OH, NR R⁷,

cycloalkyl;

R⁴ is selected from the group consisting of oxo, hydroxy, halo, CN, NR⁶R⁷, d-C¾ alkyl optionally substituted with OH, NR⁶R⁷, or C Q alkoxy, C_rC₆ haloalkyl, C_rC₆ alkoxy, C_rC₆ thioalkyl, C C₆ haloalkoxy, C₃-C₃ cycloalkyl, and C₃-C₈ cycloalkoxy;

R⁵ is selected from the group consisting of H, C C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl, -d acyl, benzyl optionally substituted with halo, -d alkoxy, d-C₆alkyl, CN, N¾, N[(C_r C₃)alkyl]₂, N0₂, or CF₃, C₃-C₆ cycloalkyl, and C(=0)OC_rQ alkyl;

R⁶ and R⁷ are independently selected from the group consisting of H, C C alkyl optionally substituted with C₃-Ce cycloalkyl, C_]-C6 acyl, benzyl optionally substituted with halo, C_rC<j alkoxy, (Ci- C₆)alkyl, CN, NH₂, N[(Ci-C₃)alkyl]₂, N0₂, or CF₃, C₃-C₆ cycloalkyl, and phenyl optionally substituted with halo, Ci-C* alkoxy, (C_rC₆)alkyl, CN, N[(C_rC₃)alkyI]₂, N0₂, or CF₃, or R and R⁷ may be taken together with the nitrogen atom to which they are attached to form a 5- or 6- membered heterocyclic ring optionally interrupted by NR⁵ or O; and

or a pharmaceutically acceptable salt, ester prodrug, stereoisomer, diastereomer, enantiomer, racemate or a combination thereof.

33. The method of claim 32, wherein the compound has the following structure:

34. The method of claim 32 or claim 33, wherein

R^! and R² are H,

L is -0-(CH₂)_n-0, wherein n is 2, 3 or 4,

Ar is a phenyl substituted with one to five R³,

wherein each occurrence of R³ is independently Q-Ce alkyl or a 5- or 6-member heterocyclic ring containing up to 4 hetero atoms selected from the group consisting of N, O and S, wherein the heterocyclic ring is substituted with Ci-C₆ alkyl.

35. The method of any one of claims 32-34, wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

36. The method of any one of claims 32-35, wherein the compound is a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts with organic bases, basic nitrogen containing groups in the conjugate base that is quateraized with agents selected from the group consisting of alkyl halides and aralkyl.

37. The method of claims 36, wherein the compound is a meglumine, potassium or sodium salt thereof.

38. The method of any of claims 32-37, wherein the liver disorder is fatty liver disease, NASH, liver inflammation, cirrhosis, cholestatic liver disease and/or liver failure.

39. The method of any of claims 32-37, wherein the liver disorder is fatty liver disease.

40. A compound of Formula I for treating autoimmune disorders in a subject according to any one of claims 1-11.

41. A compound of Formula VI for treating autoimmune disorders in a subject according to any one of claims 12-25.

42. A compound of Formula I for treating liver disorders in a subject according to any one of claims 26-31.

43. A compound of Fonnula VI for treating liver disorders in a subject according to any one of claims 32- 39.

44. Use of a compound of Formula I for the preparation of a medicament for treating autoimmune disorders according to any one of claims 1 -1 1.

45. Use of a compound of Formula VI for the preparation of a medicament for treating autoimmune disorders according any one of claims 12-25.

46. Use of a compound of Formula I for the preparation of a medicament for treating liver disorders according any one of claims 26-31.

47. Use of a compound of Formula VI for the preparation of a medicament for treating autoimmune disorders according to any one of claims 32-39.