WO2012103071A2

WO2012103071A2 - Compounds and compositions

Info

Publication number: WO2012103071A2
Application number: PCT/US2012/022333
Authority: WO
Inventors: Peter Bertinato; Takashi Satoh; Mark Spyvee
Original assignee: Eisai R&D Management Co., Ltd.
Priority date: 2011-01-25
Filing date: 2012-01-24
Publication date: 2012-08-02
Also published as: WO2012103071A3

Abstract

The present invention provides compounds of Formula (I), wherein: R_1a and R_1b are independently hydrogen or methyl; or R_1a and R_1b are taken together to form a cyclopropyl ring; R₂ is methyl or fluoromethyl; R₃is methyl; R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy; R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy; R₆ is hydrogen, halo, methyl, or methoxy; R₇ is hydrogen, halo, methyl, or methoxy; X is CH(R₈); and R₈ is hydrogen or C₁-C₆ alkyl or cycloalkyl; or pharmaceutically acceptable salts thereof. Compositions and methods of use thereof are also described.

Description

COMPOUNDS AND COMPOSITIONS

BACKGROUND OF THE INVENTION

Upon encountering antigen, naive CD4+ T helper precursor (Thp) cells are differentiated into two distinct subsets, Type 1 T helper (Thl) and Type 2 T helper (Th2). Recently, a novel T cell subset, the Thl 7 cells, has also been identified and characterized. These differentiated Th cells are defined both by their distinct functional abilities and by unique cytokine profiles. Specifically, Thl cells produce interferon-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte- dependent protective responses. In contrast, Th2 cells are known to produce IL-4, IL- 5, IL-6, IL-9, IL-10 and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses. Thl 7 cells mainly produce IL-17A, IL- 17F, IL-21, IL-22 & TNF and are required for host defense against extracellular pathogens and are critical mediators of autoimmunity. Accordingly, Thl , Th2, and Thl 7 cells are associated with different immunopathological responses.

In addition, the development of each type of Th cell is mediated by a different cytokine pathway. Specifically, it has been shown that IL-4 promotes Th2 differentiation and simultaneously blocks Thl development. In contrast, IL-12, IL-18 and IFN-gamma are the cytokines critical for the development of Thl cells. In murine, TGF-β & IL-6 are critical for the induction of Thl 7 cell differentiation, while in human, IL-1, IL-6 & IL-23 are important drivers of Thl 7 cell development. Accordingly, effective immunologic homeostasis relies on a continual balance between helper T cell activation and regulatory T cell (Treg) suppression.

Thl cells are involved in the pathogenesis of a variety of organ-specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions. In contrast, allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. Moreover, Th2 responses against still unknown antigens predominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis. Thl 7 cells cause immunopathology in different models of autoimmunity, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease and psoriasis. IL-17 (the signature Th-17 cytokine) knock-out mice show marked resistance to inflammatory arthritis development. Joint destruction in the CIA model can be ameliorated by the administration of a neutralizing anti-IL-17 antibody.

There remains a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with imbalanced Thl/Th2 and Thl7 cellular differentiation. For many of these conditions the currently available treatment options are inadequate. Accordingly, the Thl/Th2 and Thl7 paradigm provides a rationale for the development of strategies for the therapy of allergic and autoimmune disorders.

Prostaglandins have been shown to modulate various phases of the immune response. The lipid mediator prostaglandin E2 (PGE2) is an eicasanoid that is well known to suppress CD4⁺ T cell activation through elevation of intracellular cAMP and inactivation of Ick. PGE2 has been also shown to play a role in regulating Thl responses by suppression of interferon gamma (IFN-gamma) production and T cell proliferation. However PGE2 stimulation via the EP4 subtype of PGE2 receptor can also have the opposite effect, namely to promote Thl differentiation (Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of Thl and Thl 7 lymphocytes through different signaling modules, Nature Medicine, 2009, 15, 633-640) and IL-17 production in activated CD4+ cells. Prostaglandin E2 synergistically with interleukin-23 favors human Thl 7 expansion, Blood, 2008, 112, 3696-3703; Prostaglandin E2 regulates Thl 7 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling, J. Exp. Med. 2009, 206, 535-548; Prostaglandin E2 enhances Thl 7 response via modulation of IL-17 and IFN-γ production by memory CD4+ T cells, Eur. J. Immunol. 2009, 39, 1301-1312. Consistent with this, antagonism of EP4 with either a novel selective EP4 antagonist or a PGE2 -neutralizing antibody suppresses Thl differentiation, Thl 7 expansion, as well as IL-23 secretion by activated dendritic cells. Induction of Thl differentiation by PGE2 is mediated by PI3 signaling whereas stimulation of IL-17 production requires cAMP signaling. In addition, administration of an EP4 antagonist to DBA/1 or C57BL/6 mice suppressed innate and adaptive immune responses, and suppressed disease in collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) models, indicating that PGE2 EP4 signaling is critically involved in these autoimmune pathologies. These results suggest that suppression of PGE2 EP4 signaling may have therapeutic value in modifying inflammatory autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

SUMMARY OF THE INVENTION

As described ds of Formula I:

I

wherein:

Ri_a and R^ are independently hydrogen or methyl; or R_la and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R_¾ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

R₈ is hydrogen or Cj - C₆ alkyl or cycloalkyl;

or pharmaceutically acceptable salts thereof.

In some embodiments, one of R_la and R^ is hydrogen, and the other is methyl, and the carbon marked with a * is a stereogenic center. In some embodiments, one of R_la and R^ is hydrogen, and the other is methyl and the carbon marked with a * has the S-configuration. In some embodiments, one of R_la and ib is hydrogen, and the other is methyl and the carbon marked with a * has the R-configuration. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I or a subset or example thereof. In some embodiments, the invention provides a method of treating rheumatoid arthritis in a subject, comprising the step of administering to the subject a composition comprising a compound of Formula I or a subset or example thereof. In some embodiments, the invention provides a method of treating multiple sclerosis in a subject, comprising the step of administering to the subject a composition comprising a compound of Formula I or a subset or example thereof.

A further aspect of the invention is the use of a compound of Formula I or a subset or example thereof in the manufacture of a medicament for the treatment of rheumatoid arthritis. Another aspect of the invention is the use of a compound of fonnula I or a subset or example thereof in the manufacture of a medicament for the treatment of multiple sclerosis.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE

INVENTION

A. Definitions

Compounds of this invention include those described generally above, and are further illustrated by the embodiments, sub-embodiments, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.

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 mvention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "modulator of Thl differentiation or Thl7 expansion" or "modulator compound of Thl differentiation or Thl 7 expansion" or "modulator compound" as used herein refers to a compound which suppresses, reduces or inhibits, differentiation of naive CD4+ T cells into Thl cells. In some embodiments, the term "modulator of Thl differentiation or Thl 7 expansion" or "modulator compound of Thl differentiation or Thl 7 expansion" as used herein refers to a compound which suppresses, reduces or inhibits, the number of IL-17 producing CD4+ T cells or IL-17 production in activated CD4+ T cells.

"Isomers" refer to compounds having the same number and kind of atoms and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.

"Stereoisomers" refer to isomers that differ only in the arrangement of the atoms in space.

"Diastereoisomers" refer to stereoisomers that are not mirror images of each other.

"Enantiomers" refers to stereoisomers that are non-superimposable mirror images of one another.

Enantiomers include "enantiomerically pure" isomers that comprise substantially a single enantiomer, for example, greater than or equal to 90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer.

"Enantiomerically pure" as used herein means a compound, or composition of a compound, that comprises substantially a single enantiomer, for example, greater than or equal to 90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer.

"Stereomerically pure" as used herein means a compound or composition thereof that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of diastereomers, and substantially free of the enantiomer, of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. See, e.g., US Patent No. 7,189.715.

"R" and "S" as terms describing isomers are descriptors of the stereochemical configuration at an asymmetrically substituted carbon atom. The designation of an asymmetrically substituted carbon atom as "R" or "S" is done by application of the Cahn-Ingold-Prelog priority rules, as are well known to those skilled in the art, and described in the International Union of Pure and Applied Chemistry (IUPAC) Rules for the Nomenclature of Organic Chemistry. Section E, Stereochemistry.

"Enantiomeric excess" (ee) of an enantiomer is [(the mole fraction of the major enantiomer) minus (the mole fraction of the minor enantiomer)] x 100.

"Stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

"Ar" or "aryl" refer to an aromatic carbocyclic moiety having one or more closed rings. Examples include, without limitation, phenyl, naphthyl, anthracenyl, phenanthracenyl, biphenyl, and pyrenyl.

"Heteroaryl" refers to a cyclic moiety having one or more closed rings, with one or more heteroatoms (for example, oxygen, nitrogen or sulfur) in at least one of the rings, wherein at least one of the rings is aromatic, and wherein the ring or rings may independently be fused, and/or bridged. Examples include without limitation quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl, pyrazolo[l,5-a]pyridyl, thiophenylpyrazolyl, benzothienyl, benzothiazolyl, thiazolyl, 2-phenylthiazolyl, and isoxazolyl.

"Alkyl" or "alkyl group," as used herein, means a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that is completely saturated. In certain embodiments, alkyl groups contain 1-6 carbon atoms. In certain embodiments, alkyl groups contain 1-4 carbon atoms. In certain embodiments, alkyl groups contain 1-3 carbon atoms. In still other embodiments, alkyl groups contain 2-3 carbon atoms, and in yet other embodiments alkyl groups contain 1 -2 carbon atoms. In certain embodiments, the term "alkyl" or "alkyl group" refers to a cycloalkyl group, also known as carbocycle. Non-limiting examples of exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl and cyclohexyl.

"Alkenyl" or "alkenyl group," as used herein, refers to a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that has one or more double bonds. In certain embodiments, alkenyl groups contain 2-6 carbon atoms In certain embodiments, alkenyl groups contain 2-4 carbon atoms. In still other embodiments, alkenyl groups contain 3-4 carbon atoms, and in yet other embodiments alkenyl groups contain 2-3 carbon atoms. According to another aspect, the term alkenyl refers to a straight chain hydrocarbon having two double bonds, also referred to as "diene." In other embodiments, the term "alkenyl" or "alkenyl group" refers to a cycloalkenyl group. Non-limiting examples of exemplary alkenyl groups include - CH=CH₂, -CH₂CH=CH₂ (also referred to as allyl), -CH=CHCH₃, - CH₂CH₂CH=CH₂, -CH₂CH=CHCH₃, -CH=CH₂CH₂CH₃, -CH=CH₂CH=CH₂, and cyclobutenyl.

"Alkoxy", or "alkyltbio", as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur ("alkylthio") atom.

"Methylene", "ethylene", and "propylene" as used herein refer to the bivalent moieties -CH₂-, -CH₂CH₂~, and -CH₂CH₂CH₂-, respectively.

"Ethenylene", "propenylene", and "butenylene" as used herein refer to the bivalent moieties -CH=CH-, -CH=CHCH₂-, -CH₂CH-CH-, -CH=CHCH₂CH₂- , -CH₂CH=CH₂CH2-, and -CH₂CH₂CH=CH-, where each ethenylene, propenylene, and butenylene group can be in the cis or trans configuration. In certain embodiments, an ethenylene, propenylene, or butenylene group can be in the trans configuration.

"Alkylidene" refers to a bivalent hydrocarbon group formed by mono or dialkyl substitution of methylene. In certain embodiments, an alkylidene group has 1- 6 carbon atoms. In other embodiments, an alkylidene group has 2-6, 1-5, 2-4, or 1-3 carbon atoms. Such groups include propylidene (CH₃CH₂CH=), ethylidene (C¾CH=), and isopropylidene (CH₃(CH₃)CH=), and the like.

"Alkenylidene" refers to a bivalent hydrocarbon group having one or more double bonds formed by mono or dialkenyl substitution of methylene. In certain embodiments, an alkenylidene group has 2-6 carbon atoms. In other embodiments, an alkenylidene group has 2-6, 2-5, 2-4, or 2-3 carbon atoms. According to one aspect, an alkenylidene has two double bonds. Exemplary alkenylidene groups include CH₃CH=C=, CH₂=CHCH= CH₂=CHCH₂CH=, and CH₂=CHCH₂CH=CHCH=

"C_1-6 alkyl ester or amide" refers to a C_1-6 alkyl ester or a C_1-6 alkyl amide where each Ci_-6 alkyl group is as defined above. Such C_]-6 alkyl ester groups are of the formula (C_1-6 alkyl)OC(=0)- or (Ci_-6 alkyl)C(=0)0-. Such C_1-6 alkyl amide groups are of the formula (C_1-6 alkyl)NHC(=0 or (C_1-6 alkyl)C(=0)NH-.

"C_2-6 alkenyl ester or amide" refers to a C_2-6 alkenyl ester or a C_2-6 alkenyl amide where each C_2-6 alkenyl group is as defined above. Such C_2-6 alkenyl ester groups are of the formula (C_2-6 aikenyl)OC(=0)- or (C_2-6 alkenyl)C(=0)0-. Such C_2-6 alkenyl amide groups are of the formula (C₂.₆ alkenyl)NHC(=0)- or (C_2-6 alkenyl)C(=0) H-.

"Fluoromethyl" as used herein refers to a methyl group substituted with one or more fluoro atoms (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl).

"Fluoromethoxy" as used herein, refers to an fluoromethyl group, as previously defined, attached to the principal carbon chain through an oxygen atom.

"Treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, inhibiting the progress of, or prevent ng a disease or disorder as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, hi other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

"Patient" or "subject", as used herein, means an animal subject, preferably 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).

"Pharmaceutically acceptable carrier" as used herein refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

"Pharmaceutically acceptable salt" refers to an acid or base salt of a compound of the invention, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable. The salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane- sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. In some embodiments, the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides.

Unless indicated otherwise, nomenclature used to describe chemical groups or moieties as used herein follow the convention where, reading the name from left to right, the point of attachment to the rest of the molecule is at the right-hand side of the name. For example, the group "(Ci-3 alkoxy)C_1-3 alkyl," is attached to the rest of the molecule at the alkyl end. Further examples include methoxyethyl, where the point of attachment is at the ethyl end, and methylamino, where the point of attachment is at the amine end.

Unless indicated otherwise, where a bivalent group is described by its chemical formula, including two terminal bond moieties indicated by it will be understood that the attachment is read from left to right.

Unless otherwise stated, structures depicted herein are also meant to include all enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

B. Compounds

In one embodiment, the present invention provides a compound of Formula I:

Ri_a and are independently hydrogen or methyl; or j_a and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₆ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R_g); and

R₈ is hydrogen or Ci - C₆ alkyl or cycloall yl;

or a pharmaceutically acceptable salt thereof.

In some embodiments, one of R_la and R^ is hydrogen, and the other is methyl.

In some embodiments, one of R_{) a} and Ri_b is hydrogen, and the other is methyl, and the carbon of Formula I marked with a * has substantially the S -configuration. In some embodiments, one of R_la and ^ is hydrogen, and the other is methyl, and the carbon of Formula I marked with a * has substantially the Reconfiguration.

C. Pharmaceutical formulations

Active compounds of the present invention can be combined with a pharmaceutically acceptable carrier to provide pharmaceutical formulations thereof. The particular choice of carrier and formulation will depend upon the particular route of administration for which the composition is intended.

The compositions of the present invention may be suitable for oral, parenteral, inhalation spray, topical, rectal, nasal, buccal, vaginal or implanted reservoir administration, etc. Preferably, the compositions are administered orally, intraperitoneal ly or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotomc, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

D. Subjects and methods of use.

Prostaglandins have been shown to modulate various phases of the immune response. The lipid mediator prostaglandin E2 (PGE2) is an eicasanoid that is well known to suppress CD4⁺ T cell activation through elevation of intracellular cAMP and inactivation of Ick. PGE2 has been also shown to play a role in regulating Thl responses by suppression of interferon gamma (IFN-gamma) production and T cell proliferation. However PGE2 stimulation via the EP4 subtype of PGE2 receptor can also have the opposite effect, namely to promote Thl differentiation (Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of Thl and Thl 7 lymphocytes through different signaling modules, Nature Medicine, 2009, 15, 633-640) and IL-17 production in activated CD4+ cells (Prostaglandin E2 synergistically with interleukin-23 favors human Thl 7 expansion, Blood, 2008, 112, 3696-3703, Prostaglandin E2 regulates Thl7 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling, J Exp. Med. 2009, 206, 535-548, Prostaglandin E2 enhances Thl 7 response via modulation of IL-17 and IFN-γ production by memory CD4+ T cells, Eur. J. Immunol. 2009, 39, 1301-1312). Consistent with this, antagonism of EP4 with either a novel selective EP4 antagonist or a PGE2-neutralizing antibody suppresses Thl differentiation, Thl 7 expansion, as well as IL-23 secretion by activated dendritic cells. Induction of Thl differentiation by PGE2 is mediated by PI3K signaling whereas stimulation of IL-17 production requires cAMP signaling. In addition, administration of an EP4 antagonist to DBA/1 or C57BL/6 mice suppressed innate and adaptive immune responses, and suppressed disease in collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) models, indicating that PGE2/EP4 signaling is critically involved in these autoimmune pathologies. These results suggest that suppression of PGE2/EP4 signaling may have therapeutic value in modifying inflammatory autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

Active compounds of the present invention may be administered to patients or subjects to treat a variety of different condition, particularly patients or subjects afflicted with:

(a) rheumatoid arthritis (see, e.g., Targeting rheumatoid arthritis and joint inflammation in the mouse, J. Clin. Invest. 2002, 110, 651-658) ; Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin- 23/interleukin-17 axis, Arthritis Rheum. 2007. 56:2608-2619);

(b) multiple sclerosis (see, e.g., Narumiya, S. In The Prostanoid Receptors in Signaling Network of Chronic Inflammation - The Role of FP in Bleomycin-induced Pulmonary Fibrosis and The Role of EP4 in Experimental Autoimmune Encephalomyelitis in Mice, Eicosanoids and Chronic Inflammation, Montana, February, 2008), Keystone Symposia, Montana, February, 2008; Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of Thl and Thl 7 lymphocytes through different signaling modules, Nature Medicine, 2009, 15, 633-640);

(c) systemic lupus erythematosus (see, e.g., T-bet regulates IgG class switching and pathogenic auto Ab production, Proc. Natl. Acad. Set USA 2002, 99, 5545-50; Imbalance of Thl/Th2 transcription factors in patients with lupus nephritis, Rheumatology (Oxford) 2006, 45, 951-7);

(d) type 1 diabetes (see, e.g., Identification of a novel type 1 diabetes susceptibility gene, T-bet, Human Genetics 2004, 111, 177-84; T-bet controls autoaggressive CD8 lymphocyte response in type I diabetes, J. Exp. Med. 2004, 199, 1 153-62);

(e) psoriasis (see, e.g., A molecule solves psoriasis? Systemic therapies for psoriasis inducing interleukin 4 and Th2 responses, J Mol. Me 2003, 81, 471-80); The IL-23/Thl7 axis in the immunopathogenesis of psoriasis, J Invest Dermatol 2009, doi:10.1038/jid.2009.59;

(f) atherosclerosis (see, e.g., T-bet deficiency reduces athersclerosis and alters plaque antigen-specific immune responses, Proc. Natl. Acad. Sci. USA 2005, 102, 1596-601); (g) Crohn's disease (see, e.g., IL-23/IL-17 immunity as a hallmark of Crohn's disease, Inflamm Bowl Dis. 2009, 14, 1175-1184, The proinflammatory effect of prostaglandin E2 in experimental inflammatory bowel disease is mediated through the IL-23-IL-17 axis, J Immunol. 2007, 178, 8138-8147);

(h) inflammatory pain {see, e.g., Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity, J Pharmacol Exp. Ther. 2006, 319, 1096-1103);

(0 neuropathic pain (see, e.g., Localisation and modulation of prostanoid receptors EP1 and EP4 in the rat chronic constriction injury model of neuropathic pain, Eur. J. Pain 2007, 11, 605-613);

(J) migraine-associated pain (see, e.g., BGC20-1531, a novel, potent, and selective EP4 receptor antagonist: a putative new treatment for migraine headache, Br. J. Pharmacol. 2009, 156, 316-327);

(k) Spondyloarthropathies (see, e.g., Nonsteroidal Antiinflammatory Drugs reduce radiographic progression in patients with ankylosing spondylitis, Arthritis Rhuem. 2005, 52, 1756-1765; Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six- week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum. 2001, 44, 180-185, Increased numbers of circulating polyfunctional Thl7 memory cells in patients with seronegative spondylarthritides, Arthritis Rheum, 2008, 58, 2307-2317,);

(I) Skin cancer (see, e.g., Chemoprevention of nonmelanoma skin cancer with Celecoxib: A randomized, double-blind, placebo-controlled trial, J Natl Cancer Inst, 2010, 702, 1-10).

(m) Breast cancer (see, e.g.. Potential new drug targets against hormone- dependent breast cancer identified, Exp. Rev. Anticancer Ther. 2008, 8, 507-509; Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res. Treat. 2009, 117, 235-242; Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis, Cancer Res. 2006, 66, 2923-2927);

(n) Colorectal cancer (see, e.g., Increased EP4 receptor expression in colorectal cancer progession promotes cell growth and anchorage independence, Cancer Res. 2006, 66, 3106-3113); (o) Prostate cancer (see, e.g., Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model, Cancer Res. 2010, 70, 1606-1615).

(p) Kidney cancer (see, e.g., Prostaglandin E2 regulates renal cell carcinoma invasion through a EP4-Rap signal transduction pathway, J. Bio. Chem. Aug. 10, 2011 (epub))

(q) Cervical cancer (see, e.g., COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer, Microvasc Res, 2011, 82,131-40).

(r) Ovarian cancer (see, e.g., Ovarian epithelial cancer; a role for PGE2 synthesis and signaling in malignant transformation and progression, Mol Cancer, 2006, 5, 62.)

(s) Endometrial cancer (see, e.g., Prostaglandin E2 induces proliferation of Glandular epithelial cells of human endometrium via extracellular regulated kinase 1/2-mediated patheway. J Clin Endocrinol & Metabol. 2003, 88, 4481-4487).

(t) Glioblastoma (see, e.g. Microsomal prostaglandin E synthase- 1 regulates human glioma cell growth via prostaglandin E₂-dependent activation of type II protein kinase A. Mol. Cancer Ther. 2006, 5, 1817-1826).

(u) Head and neck cancer (see, e.g. Expression of prostaglandin E₂ receptors in oral squamous cell carcinomas and growth inhibitory effects of a selective EP3 antagonist, ONO-AE3-240. Int. J. Oncology 2009, 34, 847-852).

(v) Medulloblastoma (see, e.g. Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets. Neuro- Oncol. 2008, 661-674).

(w) Lung cancer (see, e.g. Tumor cyclooxygenase-2/prostaglandin E2- dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer. Cancer Res. 2005, 65, 5211 - 5220). (x) Urinary tract cancers (see, e.g. Pathological function of prostaglandin E₂ receptors in transitional cell carcinoma of the upper urinary tract. Virchows Archiv. 2006, 448, 822 - 829).

In addition, PGE2 has been implicated as an important consituent in the immunosuppressive environment created by many solid tumors: Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression. Expert Opinion in Biological Therapy. 2010. 10, 1019-35. EP4 receptor antagonism has been shown to reduce tumor metastasis: Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res. 2006, 66, 9665 - 9672.

Active compounds may be administered to subjects by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, 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. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

The active compounds are administered to the subjects in a treatment effective, or therapeutically effective, amount. The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, and the particular route of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. In certain embodiments, the compositions of the present invention provide a dosage of between 0.01 mg and 50 mg is provided. In other embodiments, a dosage of between 0.1 and 25 mg or between 5 mg and 40 mg is provided.

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, sex, 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.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXAMPLES 1-237

General:

Microwave heating was done using Biotage Emrys Liberator or Initiator microwave. Column chromatography was carried out using Biotage SP4. Solvent removal was carried out using either a Biichii rotary evaporator or a Genevac centrifugal evaporator. Preparative LC/MS was conducted using a Waters autopurifier and 19 x 100mm XTerra 5 micron MS CI 8 column under acidic mobile phase condition. NMR spectra were recorded using Varian 400MHz spectrometer.

When the term "inerted" is used to describe a reactor (e.g., a reaction vessel, flask, glass reactor, and the like) it is meant that the air in the reactor has been replaced with an essentially moisture-free or dry, inert gas (such as nitrogen, argon, and the like).

General methods and experimentals for preparing compounds of the present invention are set forth below. In certain cases, a particular compound is described by way of example. However, it will be appreciated that in each case a series of compounds of the present invention were prepared in accordance with the schemes and experimentals described below.

The following abbreviations are used herein:

Definitions: The following abbreviations have the indicated meanings:

HATU: N,N,N',N'-Tetramethyl-0-(7-azabenzotriazol- l-yl)uronium

Hexafluorophosphate

HBTU: Benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium Hexafluorophosphate DIEA: N,N-diisopropylethylamine TEA: triethylamine

DMAP: 4-Dimethylaminopyridine

DMF: N,N-dimethylformamide

NMP: N-methylpyrrolidine

THF: tetrahydrofuran

DCM: dichloromethane

TFA: trifluoroacetic acid

TFAA: trifluoroacetic anhydride

MTBE: methyl tert-butyl ether

Materials: The following compounds are commercially available:

Methyl acetoacetate (Sigma- Aldrich)

(S)-methyl 4-(l-aminoethyl)benzoate hydrochloride (NetChem, Inc)

(S)-4-(l-aminoethyl)-3-fluorobenzoic acid hydrochloride (NetChem, Inc)

(S)-4-(l-aminoethyl)-2-fluorobenzoic acid hydrochloride (NetChem, Inc)

(S)-4-(l -aminoethyl)-2-methoxybenzoic acid hydrochloride (NetChem, Inc)

(S)-4-(l-aminoethyl)-3-methylbenzoic acid hydrochloride (NetChem, Inc)

(S)-methyl 4-(l-aminoethyl)-2-methylbenzoate hydrochloride (NetChem, Inc) (S)-l-(4-bromo-2-fluorophenyl)ethanamine hydrochloride (NetChem, Inc)

4-(l-amh ocyclopropyl)benzoic acid (Allweys LLC)

All the 2-phenylacetonitriles were commercially available.

Compounds of the invention were made according to the general synthetic scheme shown in Scheme I:

Preparation of representative non-limiting examples of the compounds of the invention are described below.

EXAMPLES 1 - 111

Production Scheme.

Exemplary Procedure for the preparation of methyl 2-acetyl-3- phenylbut-2 -enoate. Production Example 1: methyl 2-acetyl-3-amino-4-(4-fluoro phenyl) but-2-enoate

The titled compound was prepared using the procedure reported by Manferdini et. al. (Heterocycles, 2000, 2775-2780). Methyl acetoacetate (3.24 mL, 0.0300 mol) and 2- (4-fluorophenyl)acetonitrile (3.60 mL, 0.0300 mol) were stirred in Toluene (40 mL) at room temperature. Tin tetrachloride (3.51 mL, 0.0300 mol) was added and the reaction mixture was stirred at room temperature for further 30 minutes. The reaction mixture was then refluxed for 90 minutes. The precipitate was filtered and washed with MTBE and heptane, and dried. The solid was suspended in 200 ml of saturated aqueous NaHC03 and stirred at room temperature for 30 minutes. The suspension was extracted with ethyl acetate and the organic layer was washed with water, dried over Na2S04 and evaporated to give methyl 2-acetyl-3-amino-4-(4- (trifluoromethyl)phenyl)but-2-enoate (5.1g, 68%) as pale yellow viscous oil which was used without further purification.

Production Example 2: methyl 2-acetyl-3-amino-4-(4-

(trifluoromethyl)phenyI)but-2-enoate

The title compound was prepared using 2-(4-(trifluoromethyl)phenyl)acetonitrile in the manner similar to the method in Production Example 1 above.

Production Example 3: methyl 2-acetyl-3-amino-4-(4-chlorophenyl)but-2-enoate

The title compound was prepared using 2-(4-chlorophenyl)acetonitrile in the manner similar to the method in Production Example 1 above.

Production Example 4: methyl 2-acetyl-3-amino-4-(3-

(trifluoromethy l)ph enyl)but-2 -eno ate

The title compound was prepared using 2-(3-(trifluoromethyl)phenyl)acetonitrile in the manner similar to the method in Production Example 1 above. Production Example 5: methyl 2-acetyl-3-amino-4-(3-chlorophenyl)but-2-enoate

The title compound was prepared using 2-(3-chlorophenyl)acetonitrile in the manner similar to the method in Production Example 1 above.

Production Example 6: methyl 2-acetyl-3-amino-4-(3,4-dichIorophenyl)but-2- enoate

The title compound was prepared using 2-(3,4-dichlorophenyl)acetonitrile in the manner similar to the method in Production Example 1 above.

Production Example 7: methyl 2-acetyl-3-amino-4-(4-

(trifluoromethoxy)phenyl)but-2-enoate

The title compound was prepared using 2-(4-(trifluoromethoxy)phenyl)acetonitrile in the manner similar to the method in Production Example 1 above.

Production Example 8: (Z)-ethyl 3-amino-4-(4-chlorophenyI)-2-(2,2,2- trifluoroacetyI)but-2-enoate

The titled compound was prepared using the procedure reported by Chun et. al. (Chem. Commun., 2008, 5098-5100). Zinc powder (2.0 g, 0.031 mol) was suspended in 30 ml of THF and methanesulfonic acid (50 uL, 0.0008 mol) in 2 ml of THF was added. The mixture was refluxed for 10 minutes. While maintaining reflux, 2-(4- chlorophenyl)acetonitrile (2.0 mL, 0.016 mol) was added in one portion and a solution of ethyl bromoacetate (2.6 mL, 0.024 mol) in 4 ml of THF was added slowly over 1 hour using a syringe pump. The mixture was further refluxed for 1 hour. After cooling to room temperature, the reaction mixture was cooled to 0°C over ice/water bath. 1.6 M n-Butyllithium in Hexane (10 mL, 0.02 mol) followed by TFAA (2.8 mL, 0.020 mol) were added and the reaction mixture was stirred at room temperature for 3 hours. Saturated NH4C1 solution was added and aqueous layer was extracted with EtOAc. The org. layer was dried over MgS04 and evaporated. The resulting oil was purified by column chromatography. (10% to 50% ethyl acetate/heptane). Polar peak was collected to give (Z) -ethyl 3-amino-4-(4-chlorophenyl)-2-(2₅2,2- trifluoroacetyl)but-2-enoate (961mg, 18%) as yellow oil.

Production Example 9: (Z)-elhyl 3-amino-2-(2,2,2-trifluoroacetyl)-4-(3- (trifluoromethyl)phenyl)but-2-enoate

The title compound was prepared using 2-(3-(trifluoromethyl)phenyl)acetonitrile in the manner similar to the method in Production Example 8 above.

Production Example 10: (Z)-ethyl 3-amino-4-(3-chIorophenyl)-2-(2,2,2- trifluoroacetyl)but-2-enoate

The title compound was prepared using 2-(3-chlorophenyl)acetonitrile in the manner similar to the method in Production Example 8 above.

Production Example 11: (Z)-ethyl 3-amino-4-(3,4-dichlorophenyl)-2-(2,2,2- trifluoroacetyl)but-2-enoate

The title compound was prepared using 2-(3,4-dichlorophenyl)acetonitrile in the manner similar to the method in Production Example 8 above.

Production Example 12: (Z)-ethyl 3-amino-2-(2,2,2-trifluoroacetyl)-4-(4- (trifluorometbyl)phenyl)but-2-enoate

The title compound was prepared using 2-(4-(trifluoromethyl)phenyl)acetonitrile in the manner similar to the method in Production Example 8 above.

Production Example 13: (Z)-ethyl 3-amino-4-(4-chlorophenyl)-2-(2,2- difluoroacetyl)but-2-enoate

The title compound was prepared using 2-(4-chlorophenyl)acetonitrile and 2,2- difluoroacetic anhydride in the manner similar to the method in Production Example 8 above.

Production Example 14: (Z)-ethyl 3-amino-4-(3-chlorophenyl)-2-(2,2- difluoroacetyl)but-2-en oate The title compound was prepared using 2-(3-chlorophenyl)acetonitrile and 2,2- difluoroacetic anhydride in the manner similar to the method in Production Example 8 above.

Production Example 15: (Z)-ethyl 3-amino-4-(3,4-dich!orophenyl)-2-(2,2- diflu oro acety l)but-2-enoate

The title compound was prepared using 2-(3,4-dichlorophenyl)acetonitrile and 2,2- difluoroacetic anhydride in the manner similar to the method in Production Example 8 above.

Production Example 16: (Z)-ethyl 3-amino-2-(2,2-difIuoroacetyl)-4-(4- (trifluoromethyl)phenyl)but-2-enoate

The title compound was prepared using 2-(4-(trifluoromethyl)phenyl)acetonitrile and 2,2-difluoroacetic anhydride in the manner similar to the method in Production Example 8 above.

Production Example 17: (Z)-ethyl 3-amino-2-(2,2-difluoroacetyl)-4-(3- (trifluoromethyl)phenyl)but-2-enoate

The title compound was prepared using 2-(3-(trifluoromethyl)phenyl)acetonitrile and 2,2-difluoroacetic anhydride in the manner similar to the method in Production Example 8 above.

Exemplary Procedure for the preparation of pyrazole-4-carboxylic acid esters.

Production Example 18: methyl 3-(4-fluorobenzyl)-l,5-dimethyl-lH-pyrazole-4- carboxylate

Methyl 2-acetyl-3-amino-4-(4-(trifluoiOmethyl)phenyl)but-2-enoate (458 mg, 0.00182 mol) and N-methylhydrazine (116 uL, 0.00219 moi) were stirred in Ethanol (5.0 mL) and the mixture was heated at at 120°C using microwave for 30 minutes. The reaction mixture was evaporated and the resulting material was partitioned between ethyl acetate and brine. The organic layer was separated, dried over MgS04 and evaporated. The resulting residue was purified by column chromatography (20% to 50% ethyl acetate/heptane) to. give methyl 3 -(4-fluorobenzyl)- 1,5 -dimethyl- 1H- pyrazole-4-carboxylate (363mg, 76%) as a clear crystal.

Production Example 19: methyl l,5-dimethyl-3-(4-(trifluoromethyI)benzyl)-lH- pyrazole-4-carboxylate

The title compound was prepared using methyl 2-acetyl-3-amino-4-(4- (trifluoromethyl)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above.

Production Example 20: methyl 3-(4-chIorobenzyl)-l,5-dimethyl-lH-pyrazoIe-4- carboxylate

The title compound was prepared using methyl 2-acetyl-3-amino-4-(4- chlorophenyl)but-2-enoate in the manner similar to the method in Production Example 18 above.

Production Example 21: methyl 3-(4-chlorobenzyl)-l,5-dimethyl-lH-pyrazole-4- carboxylate

Production Example 22: methyl l,5-dimethyl-3-(3-(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxylate

The title compound was prepared using methyl 2-acetyl-3-amino-4-(3- (trifluoromethoxy)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above. Production Example 23: methyl 3-(3-chlorobenzyl)-l,5-dimethyMH-pyrazole-4- carboxylate

The title compound was prepared using methyl 2-acetyl-3-amino-4-(3- chlorophenyl)but-2-enoate in the manner similar to the method in Production Example 18 above.

Production Example 24: methyl 3-(3,4-dichIorobenzyl)-l,5-dimethyl-lH- py razole-4- carboxylate

The title compound was prepared using methyl 2-acetyl-3-amino-4-(3₅4- dichlorophenyl)but-2-enoate in the manner similar to the method in Production Example 18 above.

Production Example 25: ethyl 3-(4-chlorobenzyl)-l-methyl-5-(trifluoromethyl)- lH-pyrazole-4-carboxylate

The title compound was prepared using (Z)-ethyl 3-amino-4-(4-chIorophenyl)-2- (2,2₅2-trifluoroacetyL)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 26: ethyl l-methyl-5-(trifluoromethyl)-3-(3- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate

The title compound was prepared using (Z) -ethyl 3-amino-2-(2,2,2-trifluoroacetyl)-4- (3-(trifluoromethyl)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 27: methyl l,5-dimethyl-3-(4-(trifluoromethoxy)benzyl)-lH- pyrazole-4-carboxylate

The title compound was prepared using methyl 2-acetyl-3-amino-4-(4- (trifluoromethoxy)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above. Production Example 28: ethyl 3-(4-chlorobenzyl)-5-(difluoromethyl)-l-methyl- lH-pyrazole-4-carboxylate

The title compound was prepared using (Z)-ethyl 3-amino-4-(4-chlorophenyl)-2-(2,2- difluoroacetyl)but-2-enoate in the manner similar to the method in Production Example above 18 except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 29: ethyl 3-(3-c lorobenzyl)-l-methyl-5-(trifluoromethyl)- 1 H-py razoIe-4-carboxy late

The title compound was prepared using (Z)-ethyl 3-amino-4-(3-chlorophenyl)-2- (2,2,2-trifluoroacetyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 30: ethyl 3-(3,4-dichlorobenzyl)-l-methyl-5- (trifluoromethyI)-lH-pyrazole-4-carboxylate

The title compound was prepared using (Z)-ethyl 3-amino-4-(3,4-dichlorophenyl)-2- (2,2,2-trifluoroacetyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 31: ethyl l-methyl-5-(trifluoromethyl)-3-(4- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate

The title compound was prepared using (Z)-ethyl 3-amino-2-(2,2,2-trifluoroacetyl)-4- (4-(trifluoromethyl)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 32: ethyl l-methyl-5-(trifluoromethyl)-3-(4- (trifluoromethyl)benzyl)-lH-pyrazoIe-4-carboxylate

Production Example 33: ethyl 3-(3-chlorobenzyl)-5-(difluoromethyl)-l-methyl- 1 H-pyrazole-4-carb oxylate

The title compound was prepared using (Z)-ethyl 3-amino-4-(3-chlorophenyl)-2-(2,2- difluoroacetyl)but-2-enoate in the manner similar to the method in Production Example above 18 except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 34: ethyl 3-(3,4-dichlo obenzyl)-5-(difluoromethyl)-l- metliyl-lH-pyrazole-4-carboxylate

The title compound was prepared using (Z)-ethyl 3-amino-4-(3.4-dichlorophenyl)-2- (2₅2-difluoroacetyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 35: ethyl 5-(difluoromethyl)-l-methyl-3-(4- (trifIuoromethyl)benzyl)-lH-pyrazole-4-carbox late

The title compound was prepared using (Z)-ethyl 3-amino-2-(2,2-difluoroacetyl)-4-(4- (trifluoromethyl)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Production Example 36: ethyl 5-(difluoromethyl)-l-methyl-3-(3- (trifluoromethyl)benzyl)~lH-pyrazole-4-carboxylate

The title compound was prepared using (Z)-ethyl 3-amino-2-(2,2-difluoroacetyl)-4-(3- (trifluoromethyl)phenyl)but-2-enoate in the manner similar to the method in Production Example 18 above except the reaction was carried out in the presence of catalytic amount of toluenesulfonic acid.

Exemplary Procedure for the preparation of pyrazole-4-carbox lic acid. Production Example 37: l,5-dimethyl-3-(4-(trifluoromethyl)benzyl)-lH- pyrazoIe-4-carboxylic acid

Methyl 3-(4-fluorobenzyl)-l,5-dimethyl-lH-pyrazole-4-carboxylate (363 mg, 0.00138 mol) was dissolved in methanol (5 mL) and THF (5 mL). 2.0 M aqueous solution of Lithium hydroxide (2.8 mL, 0.0055 mol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then heated at 120°C for 10 minutes using microwave. The reaction mixture was neutralized with IN HCl aq (5.6 ml) and the resulting precipitate was collected, washed with water and dried under vacuum to give l₅5-dimethyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4- carboxylic acid (275mg, 80%) as white solid.

Production Example 38: l,5-dimethyl-3-(4-(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxylic acid

The title compound was prepared using methyl l,5-dimethyl-3-(4- (trifluorometliyl)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 39: 3-(4-chlorobenzyl)-l,5-dimethyl-lH-pyrazole-4- carboxylic acid

The title compound was prepared using methyl 3-(4-chlorobenzyl)-l,5-dimethyl-lH- pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above. Production Example 40: l,5-dimethyl-3-(3-(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxylic acid

The title compound was prepared using methyl l,5-dimethyl-3-(3- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 41: 3-(3-chlorobenzyl)-l,5-dimethyl-lH-pyrazo!e-4- carboxylic acid

The title compound was prepared using methyl 3-(3-chlorobenzyl)-l,5-dimethyl-lH- pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 42: 3-(3,4-dichlorobenzyl)-l,5-dimethyl~lH-pyrazole-4- carboxylic acid

The title compound was prepared using methyl 3-(3,4-dichlorobenzyl)-l,5-dimethyl- lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 43: 3-(4-chlorobenzyI)-l-methyl-5-(trifluoromethyI)-lH- pyrazole-4-carbox lic acid

The title compound was prepared using ethyl 3-(4-chlorobenzyl)-l-methyl-5- (trifluoromethyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 44: l-methyl-5-(trifluoromethyl)-3-(3-

(triiluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid

The title compound was prepared using ethyl l-methyl-5-(trifluoromethyl)-3-(3- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above. Production Example 45: l,5-dimeth l-3-(4-(trifluoromethoxy)benzyI)-lH- pyrazole-4-carboxylic acid

The title compound was prepared using methyl l,5-dimethyl-3-(4- (trifluoromethoxy)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 46: 3-(4-chlorobenzyl)-5-(difluoromethyl)-l-methyl-lH- pyrazole-4-carboxylic acid

The title compound was prepared using ethyl 3-(4-chlo.robenzyl)-5-(difluoromethyl)- 1 -methyl- 1 H-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 47: 3-(3-chlorobenzyl)-l-methyl-5-(trifluoromethyl)-lH- pyrazole-4-carboxylic acid

The title compound was prepared using ethyl 3-(3-chlorobenzyl)-l-methyl-5- (trifluoromethyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 48: 3-(3,4-dichlorobenzyl)-l-methyl-5-(trifluoromethyl)-lH- pyrazole-4-carboxylic acid

The title compound was prepared using ethyl 3-(3,4-dichlorobenzyl)-l-methyl-5- (trifluoromethyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 49: l-methyl-5-(trifluoromethyl)-3-(4-

(trifluoromethyl)benzy])-lH-pyrazole-4-carboxylic acid

The title compound was prepared using ethyl l-methyl-5-(trifluoromethyl)-3-(4- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above. Production Example 50: 3-(3-chlorob enzyl)-5-(diflu orome thy 1)-1 -methyl- 1H- pyrazole-4-carboxyIic acid

The title compound was prepared using ethyl 3-(3-chlorobenzyl)-5-(difluoromethyl)- 1 -methyl- lH-pyrazole-4-carbox late in the manner similar to the method in Production Example 37 above.

Production Example 51: 3-(3,4-dichlorobenzyl)-5-(difluoromethyl)-l-methyl~lH- pyrazole-4-carboxylic acid

The title compound was prepared using ethyl 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 52: 5-(difluoromethyl)-l-methyl-3-(4-

(trifluoromethyl)benzyl)-lH-pyrazoIe-4-carboxylic acid

The title compound was prepared using ethyl 5-(difluoromethyl)-l-methyl-3-(4- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Example 53: 5-(difluoromethyl)-l-methyl-3-(3-

(trifluoromethyI)benzyl)-lH-pyrazoIe-4-carboxylic acid

The title compound was prepared using ethyl 5-(difluoromethyl)-l-methyl-3-(3- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylate in the manner similar to the method in Production Example 37 above.

Production Scheme♦

Exemplary Procedure for Amide Coupling and Ester Hydrolysis. -885287).

3- (4-fluorobenzyl)-l,5-dimethyl-lH-pyrazole-4-carboxylic acid (47 mg, 0.0002 mol), HATU (79 mg, 0.00021 mol) and DIEA (36 μΐ,, 0.00021 mol) were stirred in DMF (1.0 mL) for 20min at room temperature. Solution of (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride (49 mg, 0.00023 mol) and DIEA (40 ί, 0.00023 mol) in DMF (1.0 mL) was added and the reaction mixture was stirred at room temperature for 12 hours. Water was added and the resulting precipitate was collected, washed with water and dried under vacuum to give 67 mg of the methyl ester as white solid.

This methyl ester was suspended in methanol (2.0 mL) and THF (4.0 mL). 2.0 M lithium hydroxide solution (330 μL, 0.00065 mol) was added and the mixture was stirred at 120°C using microwave for 10 minutes. The reaction mixture was neutralized with IN hydrochloric acid solution (660 ul) and resulting precipitate was collected, washed with water and dried under vacuum to give the titled compound (33 mg, two steps 43%).

Example 2 (ER-885313). Example 2 was prepared using 3-(4- (trifluoromethyl)benzyl)- 1,5 -dimethyl- lH-pyrazole-4-carboxylic acid and (S)-methyl

4- (l-aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 3 (ER-885708). Example 3 was prepared using 3-(4-chlorobenzyl)-l,5- dimethyl-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 4 (ER-885709). Example 4 was prepared using l,5-dimethyl-3-(3~ (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above. Example 5 (ER-885736). Example 5 was prepared using 3-(3-chlorobenzyl)-l,5- dimethyl-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 6 (ER-885737). Example 6 was prepared using 3-(3-chlorobenzyl)-l,5- dimethyl-lH-pyrazole-4-carboxylic and methyl 4-(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 7 (ER-885739). Example 7 was prepared using l,5-dimethyl-3-(4- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 8 (ER-885745). Example 8 was prepared using 3-(3,4-dichlorobenzyl)-l,5- dimethyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l -aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 9 (ER-885747). Example 9 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 10 (ER-886050). Example 10 was prepared using 3-(3,4-dichlorobenzyl)- 1,5 -dimethyl- lH-pyrazole-4-carboxylic acid and methyl 4-(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 11 (ER-886051). Example 11 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 12 (ER-886052). Example 12 was prepared using l,5-dimethyl-3-(4- (trifluoromethyl)ben2;yl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above: Example 13 (ER-886053). Example 13 was prepared using 3-(4-chlorobenzyl)-l,5- dimethyl-lH-pyrazole-4-carboxylic acid and methyl 4-(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 14 (ER-886054). Example 14 was prepared using l-methyl-5- (trifluoromemyl)-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 15 (ER-886055). Example 15 was prepared using l-methyl-5- (trifluoromethyl)-3 -(3 -(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and methyl 4-(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 16 (ER-886058). Example 16 was prepared using l,5-dimethyl-3-(4- (trifmoromethoxy)benzyi)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 17 (ER-886059). Example 17 was prepared using l,5-dimethyl-3-(4- (trifluoromethoxy)benzyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 18 (ER-886063). Example 18 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 19 (ER-886064). Example 19 was prepared using 3~(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxy lie acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above. Example 20 (ER-886065). Example 20 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifIuoromet yl)-lH-pyrazole-4-carboxylic acid and (R)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 21 (ER-886076). Example 21 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 22 (ER-888025). Example 22 was prepared using l-methyl-5- (trifluoromethyl)-3-(3-(trifluoromethyl)benzyl)-l H-pyrazole-4-carboxylic acid and methyl 4-(l-aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 23 (ER-888026). Example 23 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 24 (ER-888029). Example 24 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 25 (ER-888030). Example 25 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above. Example 26 (ER-888031). Example 26 was prepared using 3-(3-chlorobenzyl)-l- methyl-5 - (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid and methyl 4- .

(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 27 (ER-888032). Example 27 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl- 5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid and (S)-methyl 4-( 1 - aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 28 (ER-888033). Example 28 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 29 (ER-888034). Example 29 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 30 (ER-888349). Example 30 was prepared using l-methyl-5- (trifluoromethyl)-3 -(4-(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 31 (ER-888350). Example 31 was prepared using l-methyl-5- (trifluoromethyl)-3 -(4-(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and methyl 4-(l-aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 32 (ER-888351). Example 32 was prepared using l-methyl-5- (trifluoromethyl)-3 -(4-(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and methyl 4-(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 33 (ER-888352). Example 33 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 34 (ER-888353). Example 34 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 35 (ER-888354). Example 35 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 36 (ER-888358). Example 36 was prepared using 3-(3,4-dichlorobenzyl)-5~ (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 37 (ER-888359). Example 37 was prepared using 3-(3,4-dicblorobenzyl)-5- (difiuorotnethyl)-l -methyl- lH-pyrazole-4-carboxy lie acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 38 (ER-888360). Example 38 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- 1 H-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above. Example 39 (ER-888372). Example 39 was prepared using 3-(4-chlorobenzyl)-l- met yl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 40 (ER-888377). Example 40 was prepared using 5-(difluoromethyl)-l- methyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole~4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 41 (ER-888379). Example 41 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyi 4-(l -aminoethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 42 (ER-888380). Example 42 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and methyl 4-(l- aminocyclopropyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 43 (ER-888381). Example 43 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 44 (ER-888383). Example 44 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazoie-4-carboxylic acid and methyl 4- (aminomethyl)"3-methoxybenzoate hydrochloride in a manner similar to the Example 1 above.

Example 45 (ER-888384). Example 45 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 46 (ER-888385). Example 46 was prepared using 3-(3,4-dichlorobenzyI)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 47 (ER-888386). Example 47 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above.

Example 48 (ER-888387). Example 48 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 49 (ER-888560). Example 49 was prepared using l-methyl-5- (trifluoromethyl)-3-(4-(trifluoromethyl)benzyl)-l H-pyrazole-4-carboxylic acid and methyl 4-(ammomethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 50 (ER-888561). Example 50 was prepared using l-methyl-5- (trifluoromethyl)-3-(4-(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and methyl 4-(aminomethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 51 (ER-888563). Example 51 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l-methyl-lH-pyi-azole-4-carboxylic acid and methyl 4- (aminomethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 52 (ER-888564). Example 52 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 53 (ER-888565). Example 53 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 54 (ER-888566). Example 54 was prepared using 3-(4-chiorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 55 (ER-888567). Example 55 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyI)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 56 (ER-888568). Example 56 was prepared using 5-(difluoromethyl)-l- methy 1-3 -(4- (trifluoromethyl)benzyl)- 1 -methyl- 1 H-pyrazole-4-carboxylic acid and methyl 4-(aminomethyl)benzoate hydrochloride in a manner similar to the Example 1 above.

Example 57 (ER-888570). Example 57 was prepared using 5-(difluoromethy3)-l- methyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1. above.

Example 58 (ER-888571). Example 58 was prepared using 5-(difluoromethyl)-l- methyl-3-(4-(trijQuoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 59 (ER-888578). Example 59 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-fIuorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 60 (ER-888579). Example 60 was prepared using 3-(3-chlorobenzyl)-l- methyl- 5 -(tiifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-3-fruorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 61 (ER-888580). Example 61 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and methyl 4- (aminomethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 62 (ER-888581). Example 62 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except hydrolysis was carried out at 50°C for 4 hours.

Example 63 (ER-888588). Example 63 was prepared using 3-(4-chJorobenzyl)-5- (difluoromethyl)- 1 -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 64 (ER-888591). Example 64 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(I- aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 65 (ER-888592). Example 65 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 66 (ER-888593). Example 66 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 67 (ER-888595). Example 67 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxyiic acid and (S)-methyl 4-(l- aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 68 (ER-888596). Example 68 was prepared using 3-(3-chlorobenzyl)-5- (difiuoromethyl)-l -methyl- 1 H-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 69 (ER-888597). Example 69 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-l H-pyrazole-4-carboxylic acid and (S)-methyl 4-(l - aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 70 (ER-888598). Example 70 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carbox lic acid and (S)-methyl 4-(l- aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 71 (ER-889220). Example 71 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 72 (ER-889221). Example 72 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 73 (ER-889222). Example 73 was prepared using 5-(difluoromethyl)-l- methyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyi)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 74 (ER-889223). Example 74 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 75 (ER-889224). Example 75 was prepared using 5-(difluoromethyl)-l- methyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 76 (ER-889225). Example 76 was prepared using l-methyl-5- (trifluoromethyl)-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 77 (ER-889226). Example 77 was prepared using l-metliyl-5- (trifluoromethyl)-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-fiuorobenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 78 (ER-889227). Example 78 was prepared using 1 -methyl-5- (trifluoromethyl)- 3 -(3 -(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 79 (ER-889228). Example 79 was prepared using l-methyl-5- (trifluoromethyl)-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 80 (ER-889229). Example 80 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- ammoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 81 (ER-889230). Example 81 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 82 (ER-889231). Example 82 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 83 (ER-889232). Example 83 was prepared using 3-(3,4-dichlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 84 (ER-889233). Example 84 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 85 (ER-889234). Example 85 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 86 (ER-889235). Example 86 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-metliylbenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 87 (ER-889236). Example 87 was prepared using 3-(3,4-dichlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 88 (ER-889237). Example 88 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 89 (ER-889238). Example 89 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 90 (ER-889239). Example 90 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 91 (ER-889240). Example 91 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 92 (ER-889255). Example 92 was prepared using 1 -methyl-5- (trifiuoromethyl)-3-(4-(trifiuoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-methylbenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 93 (ER-889256). Example 93 was prepared using l-methyl-5- (trifluoromethyl)-3-(4-(triftuoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 94 (ER-889257). Example 94 was prepared using l-methyl-5- (trifluoromethyl)-3-(4-(trifluoromethyl)benzyl)- 1 H-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 95 (ER-889258). Example 95 was prepared using l-methyl-5- (trifluoromethyl)-3-(4-(trifluoromethyl)benzyl)- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 96 (ER-889259). Example 96 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 97 (ER-889260). Example 97 was prepared using 5-(difluoromethyl)-l- methyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 98 (E -889261). Example 98 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-3-methylbenzoate hydrochloride in a manner similar to the Example 1 above.

Example 99 (ER-889476). Example 99 was prepared using 1 -methyl- 5- (trifluoromethyl)-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2~methoxybenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 100 (ER-889477). Example 100 was prepared using l-methyl-5- (trifluoromethyl)-3-(4-(trifluoromethyl)benzyl)- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above except HBTU was used instead of HATU and the hydrolysis was carried out using 2.0M sodium hydroxide solution at 50°C for 4 hours.

Example 101 (ER-889479). Example 101 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above.

Example 102 (ER-889480). Example 102 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(trifiuoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above. Example 103 ER-889481). Example 103 was prepared using 5-(difluoromet yl)-l- metliyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above.

Example 104 (ER-889484). Example 104 was prepared using 5-(difluoromethyl)-l- methyl-3-(3-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl

4- (l-aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 105 (ER-889485). Example 105 was prepared using 3-(3,4-dichlorobenzyI)- l-methyl-5-(trifluoromethyl)-lH-pyi^,azole-4-carbox lic acid and (S)-methyl 4-(l- aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 106 (ER-889486). Example 106 was prepared using 3-(3,4-dichlorobenzyl)-

5 - (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 107 (ER-889487). Example 107 was prepared using 3-(3-chlorobenzyl)-5- (difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours.

Example 108 (ER-889488). Example 108 was prepared using 3-(3-chlorobenzyl)-l- methyl-5-(triiluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-methoxybenzoate hydrochloride in a manner similar to the Example 1 above except the hydrolysis was carried out at 50°C for 4 hours. Example 109 (ER-889598). Example 109 was prepared using 3-(4-chlorobenzyl)-l- methyl-5-(txifluoromethyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 110 (ER-889599). Example 110 was prepared using 5-(difluoromethyl)-l- methyl-3-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l-aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Example 111 (ER-889600). Example 111 was prepared using 3-(4-chlorobenzyl)-5- (difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylic acid and (S)-methyl 4-(l- aminoethyl)-2-fluorobenzoate hydrochloride in a manner similar to the Example 1 above.

Production Example 54: methyl 4-(l-aminocyclopropyl)benzoate hydrochloride.

Step 1 :

4-(l-aminocyclopropyl)benzoic acid (1.75 g, 0.00988 mol) was stirred in THF (20 mL) and methanol (10 mL) over ice/water bath. 2.00 M of trimethylsilyldiazomethane in hexane (9.9 mL, 0.020 mol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated down to viscous oil which solidified upon standing to give a crystalline solid. Crude material was dried on high vacuum line for 12 hours to give methyl 4-(l- aminocyclopropyl)benzoate (1.65 g, 87%) as pale brown solid. Step 2:

To a solution of ER-886774-00 (1.63 g, 0.0085 mol) in ethyl acetate (10 mL) was added 2.0 M of hydrogen chloride in Ether (6.0 mL, 0.012 mol). After stirring for several minutes, the reaction mixture was concentrated to give the title compound (quantitative yield) as pale brown solid.

Exemplary Procedure for the esterifications of (S)-4-(l-aminoethyl)benzoic acid hydrochloride

Production Example 55: (S)-methyl 4-(l-aminoethyl)-2-fluorobenzoate hydrochloride

(S)-4-(l-aminoethyl)benzoic acid hydrochloride (1.00 g, 0.00455 mol) was dissolved in methanol (40 mL, 1 mol). 4 M hydrogen chloride in 1,4-dioxane (5 mL) was added and the mixture was heated to reflux for 8 hours. After cooling, the mixture was concentrated to a viscous oil. Ethyl acetate was added and dissolved off under reduced pressure. As the ethyl acetate was being removed a pale yellow solid precipitated. The solid was dried under reduced pressure and used without further purification.

Production Example 56: (S)-methyl 4-(l-aminoethyl)-3-fluorobenzoate hydrochloride

The title compound was prepared using (S)-4-(l-aminoethyl)-3-fluorobenzoic acid hydrochloride in the manner similar to the method in Production Example 54 above. Production Example 57: (S)-methyl 4-(l-aminoethyl)-3-methylbenzoate hydrochloride

The title compound was prepared using (S)-4-(l-aminoethyi)-3-methylbenzoic acid hydrochloride in the manner similar to the method in Production Example 54 above.

Production Example 58: (S)-methyl 4-(l-aminoethyl)-2-methoxybenzoate hydrochloride

The title compound was prepared using (S)-4-(l-aminoethyl)-3-methoxybenzoic acid hydrochloride in the manner similar to the method in Production Example 54 above.

Production Example 59: methyl 4-(aminomethyl)-2-methylbenzoate.

The titled compound was prepared according to the procedure described in WO 1999/0026923.

Step 1:

Ethyl 2,4-dimethylbenzoate (3.00 g, 0.0168 mol), N-bromosuccinimide (3.3 g, 0.018 mol) and benzoyl peroxide (0.04 g, 0.0002 mol) were stirred in carbon tetrachloride (30 mL, 0.3 mol). The mixture was heated to reflux. After 2 hours, the mixture was cooled to room temperature, filtered and concentrated. The crude oil was heated to 140 ⁰ C for 1.5 hours. After cooling, the crude oil was stirred with heptane. The resulting solid was removed by filtration and the filtrate was concentrated. The remaining residue was purified by column chromatography (0 to 5% ethyl acetate/heptane). The non-polar peak was collected to give 324mg of bromide.

Step 2:

This bromide was dissolved in DMF (2.5 mL) and sodium azide (9.0E1 mg) was added. The mixture was stirred for 20 hours at room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate/heptanes three times. The combined organic layer was washed with water, dried over MgS04 and evaporated to give 23 lmg of azide which was used without further purification.

Step 3:

To a solution of this azide in THF (15 mL) and water (1.5 mL) was added triphenylphosphine (0.3040 g). The mixture was stirred for 72 hours at room temperature. The mixture was concentrated and the residue was taken up in ethyl acetate and IN HCl. The organic layer was back extracted with IN HCl. The pH of the aqueous layer was made basic and the mixture was extracted with ethyl acetate. The organic layer was dried over MgS04 and evaporated to give the title compounds as oil which was used without further purification.

Exemplary Procedure for the esterifications of benzoic acid

Production Example 60: methyl 4-cyano-3-fluorobenzoate

4-cyano-3-fluorobenzoic acid (1.03 g, 0.00624 mol) was stirred in THF (12 mL) and methanol (6.0 mL) over ice bath. 2.0 M of timethylsilyldiazomethane in Ether (6.06 mL, 0.0129 mol) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated and the resulting oil was purified by column chromatography (10 to 50% ethyl acetate heptane). The desired fracs were pooled to give of the titled compound (861mg, 77%) as white crystal. Production Example 61: methyl 4-cyano-2-fluorobenzoate

The title compound was prepared using 4-cyano-2-fluorobenzoic acid in the manner similar to the method in Production Example 58 above.

Production Example 62: methyl 4-bromo-3-methylbenzoate

The title compound was prepared using 4-bromo-3-methylbenzoic acid in the manner similar to the method in Production Example 58 above.

Exemplary Procedure for the prep ration of methyl 4-cyanobenzoate

Production Example 63: methyl 4-cyano-3-methoxybenzoate

The titled compound was prepared according to the procedure described in WO2009/043889. The resin bound triphenyl phosphine (142 mg, 2.15 mM/g) and palladium acetate (0.032 g, 0.00014 mol) was placed in a microwave vial. The vial was capped and purged with N2. DMF (6.00 mL) was added and the mixture was stirred for 2 hours at room temperature. The vial was uncapped and methyl 4-bromo- 3-methoxybenzoate (0.500 g, 0.00204 mol) and zinc cyanide (0.240 g, 0.00204 mol) was added. The vial was capped, purged with N2 and heated at 140°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through sintered glass funnel. The filtrate was diluted with equal volume of heptanes and washed twice with water, once with brine, dried over MgS04 and evaporated to give titled compound (352mg, 90%) as a white solid which was used without further purification.

Production Example 64: methyl 4-cyano-2-methoxybenzoate

The title compound was prepared using methyl 4-bromo-2-methoxybenzoate in the manner similar to the method in Production Example 61 above. Production Example 65: methyl 4-cyano-3-methylbenzoate

The title compound was prepared using methyl 4-bromo-3-methylbenzoate in the manner similar to the method in Production Example 61 above.

Exemplary Procedure for the hydrogenation of methyl 4-cyanobenzoate

Production Example 66: methyl 4-(aminomethyl)-3-fluorobenzoate hydrochloride

Methyl 4-cyano-3-fluorobenzoate (400 mg, 0.002 mol) was dissolved in methanol (45 mL) and concentrated hydrogen chloride solution (180 uL) was added. The hydogenation reaction was carried out by using H-Cube with 20% Pd(OH)2 cartridge (medium size) at 20 bars and flow rate of lml/min. Single pass was enough for complete conversion. The collected eiuent was evaporated to give solid which was collected and washed with ether to give the titled compound (333mg, 70%) as pale yellow solid.

Production Example 67: methyl 4-(aminomethyl)-2-fluorobenzoate hydrochloride

The title compound was prepared using methyl 4-cyano-2-fluorobenzoate in the manner similar to the method in Production Example 64 above.

Production Example 68: methyl 4-(aminomethyl)-2-fluorobenzoate hydrochloride

The title compound was prepared using methyl 4-cyano-2-fluorobenzoate in the manner similar to the method in Production Example 64 above. Production Example 69: methyl 4-(aminomethyI)-3-methoxybenzoate hydrochloride

The title compound was prepared using methyl 4-cyano-3-methoxybenzoate in the manner similar to the method in Production Example 64 above except the reaction was carried out using Raney nickel cartridge (medium size) at 50 bars and heated at 50°C.

Production Example 70: methyl 4-(ammomethyl)-2-methoxybenzoate hydrochloride

The title compound was prepared using methyl 4-cyano-2-methoxybenzoate in the manner similar to the method in Production Example 64 above except the reaction was carried out using Raney nickel cartridge (medium size) at 50 bars and heated at 50°C.

Production Example 71: methyl 4-(aminomethyI)-3-methylbenzoate hydrochloride

The title compound was prepared using methyl 4-cyano-3-methylbenzoate in the manner similar to the method in Production Example 64 above except the reaction was carried out using Raney nickel cartridge (medium size) at 50 bar and heated at 50°C.

Table 1. Analytical Data for Exemplary Compounds of Formula I

EXAMPLES 112 - 236

In vitro Biological Activity

C E-PLAP reporter assay: SE302 is a clone of the HE /293 cell line that harbors a reporter construct containing a promoter with cAMP response elements (CRE) driving secreted alkaline phosphatase (PLAP), constructed by T. Arai, Eisai Pharamceuticals, Japan. These cells express endogenous EP4 and show induction of PLAP in response to PGE2 and other agonists of EP4, but not of EPl, 2 or 3 (data not shown). Cells were maintained in DMEM/F12 (50:50) (MediaTech) supplemented with 10% FBS (Tissue Culture Biologicals) plus penicillin/streptomycin. When used for assays, cells were plated in a 96-well plate at 2x10⁴ cells/100 μΕ/well in serum- free assay medium (DMEM/FT 2 supplemented with 0.1% BSA plus penicillin/streptomycin) and incubated for 4-6 h. Cells were then stimulated with 3 ng.mL^"1 of PGE2 in the presence or absence of various concentrations of test compounds overnight, and PLAP activity was measured by mixing 15 μΕ of culture supernatants with 75 μ∑ of Lumi-phos (Lumigen, Inc.) and 60 μΐ, of assay buffer containing 8 mmol.L^"1 MgS0₄ in 0.1 mol.L^"1 carbonate-bicarbonate buffer pHl l in a new 96-well black plate and incubated for 2h at room temperature. Luminescence was read with an Envision 2102 Multilabel reader.

Exemplary compounds of the present invention were assayed according to the methods set forth above in the CRE-PLAP reporter assay described above. Table 2 below sets forth exemplary compounds of the present invention having an IC50 of up to 5.0 μΜ as determined by the normalized CRE-PLAP assay described above.

Table 2. ICgo Values of Exemplary Compounds

Radioligand EP4 receptor binding assay: The radioligand EP₄ binding assay was performed using Chemi Screen recombinant human EP₄ receptor membrane preparations from Millipore, according to manufacturer's instructions. Briefly, membranes prepared from Chem-1 cells overexpressing human EP₄ cDNA (Millipore) were mixed with 1,8 nmol.L^"1 [³H]- PGE₂ and 5 umoLL^"1 unlabelled PGE₂ in the presence or absence of various concentrations of testing compounds in binding buffer (50 mmol.L^"1 HEPES, pH 7.4, 5 mmol.L^"1 MgCl₂, 1 mmol.L^"1 CaCl_2j 0.2% BSA) in a nonbinding 96- well plate, and incubated for 1-2 h at room temperature. Prior to filtration, a GF/C 96-well filter plate was coated with 0.33% polyethyleneimine for 30 min, then washed with 50 mmol.L^"1 HEPES, pH 7.4, 0.5% BSA. Binding reactions were transferred to the filter plate, and washed 3 times with Wash Buffer (1 mL per well per wash). The plate was dried and radioactivity counted. Binding of testing compounds to other related prostanoid receptors was performed by MDS Pharma Services (Bothell, WA) using a similar radiolabeled ligand displacement method.

Exemplary compounds of the present invention were assayed according to the methods set forth above in the radioligand EP4 receptor binding assay described above. Table 3 below sets forth exemplary compounds of the present invention having Ki values as determined by the radioligand EP4 receptor binding assay described above.

Table 3. Ki Values of Exemplary Compounds

EXAMPLE 237

In vivo Biological Activity

Example 237 : Suppression of arthritis development in CIA: Male DBA 1 mice were immunized by injection at the base of the tail with 0.1 mL emulsion containing 150 g bovine type II collagen (bCII) emulsified in CFA. Three weeks after the 1^st immunization, all mice were boosted with bovine type II collagen emulsified in Freund's incomplete adjuvant. ER-885747 was orally administered daily at a dose of 10, 30 or 100 mg.kg^"1 from day 20 after primary immunization but before disease onset (prophylactic evaluation). The severity of arthritic symptoms in the paws of each mouse was graded every other days, double-blind, according to Williams RO (Collagen-induced arthritis as a model for rheumatoid arthritis. Methods Mol Med 2004, 98:207-216).

Days after 2nd immunization

Certain embodiments of the invention

1. A compound of formula I:

I

wherein:

Ria and Rj_b are independently hydrogen or methyl; or R_la and R_lb are taken together to form a cyclopropyl ring; R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R5 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rg is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or pharmaceutically acceptable salts thereof.

2. The compound of embodiment 1, wherein

Ri_a and R^ are independently hydrogen or methyl;

R₂ is methyl, difluoromethyl, or trifluoromethyl;

R₃ is methyl;

is chloro, fluoro, trifluoromethyl, difluoromethyl, methyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R₅ is hydrogen, chloro, fluoro, methyl, or methoxy;

R_¾ and R₇ are hydrogen, methyl, or fluoro; and X is CH₂;

or a pharmaceutically acceptable salt thereof.

3. The compound of embodiment 2, wherein R₅ is hydrogen or chloro; or a pharmaceutically acceptable salt thereof

4. The compound of embodiment 3, wherein R4 is selected from chloro, fluoro, trifluoromethyl, difluoromethyl, difluoromethoxy, and trifluoromethoxy;

or a pharmaceutically acceptable salt thereof. 5. The compound of any one of embodiments 1 - 4, wherein, one of R_la and is hydrogen, and the other is methyl, and the compound of Formula

I consists of a mixture of stereoisomers;

or a pharmaceutically acceptable salt thereof.

6. The compound of any one of embodiments 1 - 4, wherein,

one of Ria and Rjb is hydrogen, and the other is methyl, and the compound of Formula I consists of a substantially pure stereoisomer;

or a pharmaceutically acceptable salt thereof.

7. The compound of embodiment 6, wherein,

one of R_la and n_> is hydrogen, and the other is methyl, and the carbon of the compound of Formula I marked with a * has substantially the S-configuration;

or a pharmaceutically acceptable salt thereof.

8. The compound of embodiment 6, wherein,

one of Ria and Rib is hydrogen, and the other is methyl, and the carbon of the compound of Formula I marked with a * has substantially the R-configuration;

or a pharmaceutically acceptable salt thereof.

9. The compound of embodiment 1, wherein

Ria and Rib are taken together to form a cyclopropyl ring;

R₂ is methyl, difluoromethyl, or trifluoromethyl;

R₃ is methyl; Rzi is chloro, fluoro, trifluoromethyl, difluoromethyl, methyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R₅ is hydrogen, chloro, fluoro, methyl, or methoxy;

Ri, and R₇ are hydrogen, methyl, or fluoro; and

X is CH₂;

or a pharmaceutically acceptable salt thereof.

The compound of embodiment 1, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

11. The compound of embodiment 10, which is:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of formula I:

I

wherein:

Ri_a and Ri_b are independently hydrogen or methyl; or Ri_a and R^ together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy; R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy; Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

R₈ is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition comprising a compound of embodiment 10, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

15. A method of treating multiple sclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:

I

wherein: Ri_a and R^ are independently hydrogen or methyl; or R_la and Ri_b are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₆ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(¾); and

Rg is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

16. A method of treating multiple sclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10;

or a pharmaceutically acceptable salt thereof.

17. A method of treating multiple sclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutical salt thereof. 18. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of multiple sclerosis.

19. A method of treating rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:

I

wherein:

R_la and Rib are independently hydrogen or methyl; or R_la and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

¾ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(Rg); and

R₈ is hydrogen or C_\ - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

20. A method of treating rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising comprising a compound of embodiment 10; or a pharmaceutically acceptable salt thereof.

21. . A method of treating rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof.

22. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of rheumatoid arthritis.

23. A method of treating systemic lupus erythematosus in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:

I

wherein: i_a and Ru, are independently hydrogen or methyl; or R]_a and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₆ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rg is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

24. A method of treating systemic lupus erythematosus in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10,

or a pharmaceutically acceptable salt thereof.

25. A method of treating systemic lupus erythematosus in a mammal, comprising the step of administering to a mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof.

26. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of systemic lupus erythematosus. 27. A method of treating type 1 diabetes in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:

I

wherein:

R_la and R^ are independently hydrogen or methyl; or R_la and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R3 is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

Rf_y is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rs is hydrogen or Q - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

28. A method of treating type 1 diabetes in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10; or a pharmaceutically acceptable salt thereof. 29. A method of treating type 1 diabetes in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof.

30. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of type 1 diabetes.

31. A method of treating psoriasis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:

I

wherein: R_la and Ri_b are independently hydrogen or methyl; or R_la and Rib are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rg is hydrogen or Q - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

32. A method of treating psoriasis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10; or a pharmaceutically acceptable salt thereof,

33. A method of treating psoriasis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof. 34. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of psoriasis.

35. A method of treating atherosclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:

I

wherein:

Ri_a and are independently hydrogen or methyl; or Rj_a and are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fiuoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fiuoromethoxy;

R₆ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rs is hydrogen or Cj - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

36. A method of treating atherosclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10;

or a pharmaceutically acceptable salt thereof. 37. A method of treating atherosclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof.

38. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of atherosclerosis.

39. A method of treating inflammatory pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:

I

wherein: i_a and Rj_b are independently hydrogen or methyl; or R_la and are taken together to form a cyclopropyl ring; R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

¾ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(Rg); and

Rg is hydrogen or Cj - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

40. A method of treating inflammatory pain in a mammal, comprising the step of administering to the mammal a pharmaceuticai composition comprising a compound of embodiment 10;

or a pharmaceutically acceptable salt thereof.

41. A method of treating inflammatory pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof.

42. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of inflammatory pain.

43. A method of treating neuropathic pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:

I

wherein:

Ri_a and Rj_b are independently hydrogen or methyl; or R_la and R^ together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₆ is hydrogen, halo, methyl, or methoxy; R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(¾); and

R₈ is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

44, A method of treating neuropathic pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10;

or a pharmaceutically acceptable salt thereof.

45. A method of treating neuropathic pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is:

or a pharmaceutically acceptable salt thereof.

46. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of neuropathic pain.

47. A method of treating migraine-associated pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:

Ri_a and are independently hydrogen or methyl; or R_la and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rg is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

48. A method of treating migraine-associated pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of embodiment 10;

or a pharmaceutically acceptable salt thereof.

49. A method of treating migraine-associated pain in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound of Formula I which is:

or a pharmaceutically acceptable salt thereof.

50. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of migraine-associated pain.

51. A method of treating cancer in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:

I

wherein:

R_la and ¾_& are independently hydrogen or methyl; or R_la and R^ together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

¾ is hydrogen, halo, methyl, or methoxy; R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(Rg)- and

Rg is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

52. A method of treating cancer in a mammal, comprising the step of

administering to the mammal a pharmaceutical composition comprising comprising a compound of embodiment 10;

or a pharmaceutically acceptable salt thereof.

53. A method of treating cancer in a mammal, comprising the step of

administering to the mammal a pharmaceutical composition comprising the compound of Formula I which is:

or a pharmaceutically acceptable salt thereof.

54. Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of cancer.

55. The method of any of embodiments 51 - 54, wherein the cancer is selected from the group consisting of skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, glioblastoma, lung cancer, head and neck cancer, medulloblastoma, and urinary tract cancer. 56. The method of embodiment 55, wherein the cancer is skin cancer. 7. The method of embodiment 55, wherein the cancer is breast cancer.

58. The method of embodiment 55, wherein the cancer is colorectal cancer.

59. The method of embodiment 55, wherein the cancer is prostate cancer.

60. The method of embodiment 55, wherein the cancer is kidney cancer.

61. The method of embodiment 55, wherein the cancer is ovarian cancer.

62. The method of embodiment 55, wherein the cancer is cervical cancer.

63. The method of embodiment 55, wherein the cancer is endometrial cancer.

64. The method of embodiment 55, wherein the cancer is glioblastoma.

65. The method of embodiment 55, wherein the cancer is lung cancer.

66. The method of embodiment 55, wherein the cancer is head and neck cancer.

67. The method of embodiment 55, wherein the cancer is medulloblastoma.

68. The method of embodiment 55, wherein the cancer is urinary tract cancer.

Other embodiments. While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

O 2012/103071 ): 9626-97WO PCT/US2012/022333

We claim:

1. A compound of formula I:

I

wherein:

R_la and Rib are independently hydrogen or methyl; or R_la and Ru, are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

¾ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(Rg); and

Rs is hydrogen or Q - C₆ alkyl or cycloalkyl ;

or pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein:

R_la and R^ are independently hydrogen or methyl;

R₂ is methyl, difluoromethyl, or trifluoromethyl;

R₃ is methyl;

R4 is chloro, fluoro, trifluoromethyl, difluoromethyl, methyl, methoxy, difluoromethoxy, or trifluoromethoxy; O 2012/1030711: 9626-97WO PCT/US2012/022333

R-5 is hydrogen, chloro, fluoro, methyl, or methoxy;

Re and R₇ are hydrogen, methyl, or fluoro; and

X is CH₂;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein R₅ is hydrogen or chloro; or a

pharmaceutically acceptable salt thereof

4. The compound of claim 3, wherein R4 is selected from chloro, fluoro, trifluoromethyl, difluoromethyl, difluoromethoxy, and trifluoromethoxy;

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1 - 4, wherein:

one of Rj_a and R^ is hydrogen, and the other is methyl, and the compound of Formula

I consists of a mixture of stereoisomers;

or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 - 4, wherein:

one of R_la and Ri_b is hydrogen, and the other is methyl, and the compound of Formula I consists of a substantially pure stereoisomer;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein:

one of R_la and R^ is hydrogen, and the other is methyl, and the carbon of the compound of Formula I marked with a * has substantially the S-configuration; O 2012/103071 »: 9626-97WO PCT/US2012/022333 or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, wherein:

one of R_la and Rj is hydrogen, and the other is methyl, and the carbon of the compound of Formula I marked with a * has substantially the R-configuration;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein:

R_la and R^ are taken together to form a cyclopropyl ring;

R₂ is methyl, difluoromethyl, or trifluoromethyl;

R₃ is methyl;

4 is chloro, fluoro, trifluoromethyl, difluoromethyl, methyl, methoxy,

difluoromethoxy, or trifluoromethoxy;

R₅ is hydrogen, chloro, fluoro, methyl, or methoxy;

Re and R₇ are hydrogen, methyl, or fluoro; and

X is CH₂;

or a pharmaceutically acceptable salt thereof.

/103071 »: 9626-97WO PCT/US2012/022333

The compound of claim 1, selected from the group consisting of:

O 2012/103071·: 9626-97WO PCT/US2012/022333

A pharmaceutical composition comprising a compound of formula I:

I

wherein:

R_la and Rib are independently hydrogen or methyl; or Rj_a and R^ are together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₆ is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(Rg); and

Rs is hydrogen or Cj - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound of claim 10, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the compound which is: O 2012/103071»: 9626-97WO PCT/US2012/022333

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

I

wherein:

Ri_a and are independently hydrogen or methyl; or R_la and R^ together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and O 2012/103071 »: 9626-97WO PCT/US2012/022333

R₈ is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

16. A method of treating multiple sclerosis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of claim 10; or a pharmaceutically acceptable salt thereof.

or a pharmaceutical salt thereof.

18. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of multiple sclerosis.

19. A method of treatmg rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I: O 2012/103071»: 9626-97WO PCT/US2012/022333

I

wherein:

R_la and R^ are independently hydrogen or methyl; or ¾_a and Ri_b are taken together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R₄ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R5 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rg is hydrogen or Cj - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

20. A method of treating rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising comprising a compound of claim 10;

or a pharmaceutically acceptable salt thereof.

21. A method of treating rheumatoid arthritis in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the compound which is: O 2012/103071»: 9626-97WO PCT/US2012/022333

or a pharmaceutically acceptable salt thereof.

22. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of rheumatoid arthritis.

23. A method of treating cancer in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:

I

wherein:

R_{] a} and Rib are independently hydrogen or methyl; or R_ia and Ri_b together to form a cyclopropyl ring;

R₂ is methyl or fluoromethyl;

R₃ is methyl;

R4 is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy;

R₅ is hydrogen, halo, fluoromethyl, methoxy, or fluoromethoxy; O 2012/10307H: 9626-97WO PCT/US2012/022333

Re is hydrogen, halo, methyl, or methoxy;

R₇ is hydrogen, halo, methyl, or methoxy;

X is CH(R₈); and

Rg is hydrogen or Ci - C₆ alkyl or cycloalkyl ;

or a pharmaceutically acceptable salt thereof.

24. A method of treating cancer in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising comprising a compound of claim 10;

or a pharmaceutically acceptable salt thereof.

25. A method of treating cancer in a mammal, comprising the step of

administering to the mammal a pharmaceutical composition comprising the

compound of Formula I which is:

or a pharmaceutically acceptable salt thereof.

26. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of cancer.

27. The method of any of claims 23 - 26, wherein the cancer is selected from the group consisting of skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, glioblastoma, lung cancer, head and neck cancer, medulloblastoma, and urinary tract cancer.

28. The method of claim 23, wherein the cancer is skin cancer.

29. The method of claim 23, wherein the cancer is breast cancer.

30. The method of claim 23, wherein the cancer is colorectal cancer.

31. The method of claim 23, wherein the cancer is prostate cancer.

32. The method of claim 23, wherein the cancer is kidney cancer.

33. The method of claim 23, wherein the cancer is ovarian cancer.

34. The method of claim 23, wherein the cancer is cervical cancer.

35. The method of claim 23, wherein the cancer is endometrial cancer.

36. The method of claim 23, wherein the cancer is glioblastoma.

37. The method of claim 23, wherein the cancer is lung cancer.

38. The method of claim 23, wherein the cancer is head and neck cancer.

39. The method of claim 23, wherein the cancer is medulloblastoma.

40. The method of claim 23, wherein the cancer is urinary tract cancer.