EA038294B1 - Heterocyclic compounds useful in the treatment of diseases - Google Patents

Abstract

Heterocyclic compounds are described that are lysophosphatidic acid receptor ligands that are useful in the treatment of lysophosphatidic acid receptor-dependent diseases and conditions, including but not limited to diseases involving fibrosis, such as fibrosis of the heart, kidney, liver and lung, and scleroderma; inflammatory diseases such as diabetic nephropathy and inflammatory bowel disease; ocular diseases such as diseases involving retinal degeneration; nerve diseases such as pruritus and pain. Non-limiting examples of those compounds include (RS)-3-cyclopropyl-2-{4-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)isoxazol-5-yl]benzyloxy}propionic acid and (R)-1-(4'-{5-[1-(2-chloro-phenyl)ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-fluoro-biphenyl-4-yl)cyclopropanecarboxylic acid.

Description

Scope of invention

The invention relates to compounds with pharmacological activity, to methods for the preparation of such compounds, to pharmaceutical compositions containing them, and to their use in therapy and prevention of diseases in a subject in need thereof, in particular for the treatment of pain, itching, cancer, inflammation and fibrosing diseases in medicine and veterinary medicine.

Background of the invention

Lysophospholipids affect basic cell functions, including proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. Dysfunction affects many biological processes leading to diseases including, but not limited to, fibrosing disease, inflammation, cancer, and peripheral nerve damage. Lysophosphatidic acid (LPA) is a lysophospholipid that has been shown to act through specific G-protein coupled receptors (GPCR) in an autocrine and paracrine mechanism. LPA receptor antagonists find use in the treatment of diseases, disorders or conditions in which LPA plays a role.

Agents that interact with lysophosphatidic acid receptors [LPARs] to attenuate signaling by these receptors (ie, by competitive or non-competitive inhibition or acting as inverse agonists) ameliorate the diseases described herein. Diseases and conditions, the etiology, progression or duration of which is partially or completely influenced by signaling through the lysophosphatidic acid receptor 1 subtype (LPA1R), are considered LPA-dependent. There is a need for new agents with therapeutic utility for the treatment of these LPA-dependent and other conditions and diseases described herein.

Brief description of the invention

This document discloses compounds that inhibit the physiological activity of lysophosphatidic acid (LPA) and, therefore, useful as agents for the treatment or prevention of diseases in which it is advisable to inhibit the physiological activity of LPA.

In one aspect, these compounds are useful for the treatment of organ fibrosis (e.g., liver, kidney, lung, heart, etc.), liver diseases (e.g., acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, impaired hepatic blood flow, etc.), cell proliferative diseases such as cancers (including, but not limited to, solid tumor, metastasis of solid tumors, vascular fibroma, myeloma, multiple myeloma , Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), invasive metastasis of cancer cells, etc.), inflammatory diseases (including, without limitation, psoriasis, nephropathy, pneumonia, etc.), gastrointestinal diseases tract (including, but not limited to, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), impaired pancreatic secretion, etc.), disease kidney diseases, diseases associated with the urinary tract (including, but not limited to, benign prostatic hyperplasia or symptoms associated with neurogenic bladder disease), spinal cord tumors, herniated discs, spinal stenosis, symptoms associated with diabetes mellitus, diseases of the lower urinary tract (including, without limitation, obstruction of the lower urinary tract, etc.), inflammatory diseases of the lower urinary tract (including, without limitation, dysuria, frequent urination, etc.), diseases of the pancreas , diseases associated with impaired angiogenesis (including, without limitation, obstruction of the arteries, etc.), scleroderma, brain diseases (including, without limitation, ischemic stroke, intracerebral hemorrhage, etc.), diseases nervous system (including, without limitation, neuropathic pain, peripheral neuropathy, pruritus, etc. .), eye diseases (including, without limitation, age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), scarring pemphigoid, scarring after filtration surgery for glaucoma, etc.).

Compounds of the present invention include compounds of Formula I having the structure

where RA is -CO2H, -CO2RB, -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH2CH2SO ₃ H, or an isostere analog of a carboxylic acid group;

L ^{1 is} absent or is optionally substituted C1-C6 alkylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C1-C6 fluoroalkylene, optionally substituted C1-C6 heteroalkylene or -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (RJ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is optionally substituted C1-C3 alkylene or optionally substituted C3-C6 cycloalkylene, or W is -C (R ^L ) 2-, Z is optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₃ -C ₆

- 1 038294 cycloalkylene or C ₁ -C ₆ -fluoroαalkylene, or Z is —C (R ^L ) ₂ -; an is 0, 1, or 2;

L ^{2 is} absent or is optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₃ -C ₆ cycloalkylene, C ₁ -C ₆ fluoroalkylene, optionally substituted C ₁ -C ₆ heteroalkylene, -O-, -S -, -S (= O) -, -S (= O) ₂ -, -N (R ^B ) -, -C (= O) - or -C (= O) N (R ^B ) -;

where R ^B represents -H or optionally substituted C ₁ -C ₄ -alkyl or has one of the following structures:

Ring A is a 5- or 6-membered heteroarene having one of the following structures:

where the dotted line indicates the point of attachment of ring A to ring B;

where one of R ^C and R ^D represents -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₄ -fluoroalkyl and the other R ^C or R ^D is -N (R ^F ) C (= O) XCH (R ^G ) CY, -N (R ^F ) C (= O) XC ( R ^G ) 2-CY, -N (R ^f ) C (= O) X-CY, -C (= O) N (R ^f ) CH (R ^g ) X-CY or -C (= O) N ( R ^f ) C (R ^g ) 2X-CY, where X is absent or represents —O—, —NH— or —CH ₂ -;

RE is —H, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -fluoroalkyl;

RF is —H or C ₁ -C ₄ alkyl;

R ^g is independently selected R ^E , or one R ^G is C ₁ -C ₄ alkylene and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the other R ^G , if any, is defined for R ^E ;

CY is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ cycloalkyl, optionally substituted C ₂ -C ₁₀ heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein if CY is substituted then CY is substituted 1, 2 or 3 independently selected R ^H , where each RH is independently -H, halogen, -CN, -NO2, -OH, -OR ^J , -SR ^J , -S (= O) R ^J , -S ( = O) 2R ^j , -N (R ^j ) S (= O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , OC (= O) R ^j , -C (= O) OR ^j , -OC (= O) OR ^j , -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, -N (R ^j ) C (= O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -N (R ^j ) C (= O) OR ^j , C ₁ -C ₄ alkyl, _{C 1} -C ₄ fluoroalkyl, C _{1 -C 4} fluoro-alkoxy, C ₁ -C ₄ alkoxy or C ₁ -C ₄ heteroalkyl;

where each R ^{J is} independently optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₁ -C ₆ fluoroαalkyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted heterocycloalkyl , optionally substituted aryl, optionally substituted heteroaryl, -C ₁ -C ₄ -alkylene- (optionally substituted C3-C6 cycloalkyl), -C ₁ -C ₄ -alkylene- (optionally substituted heterocycloalkyl), -C ₁ -C ₄ -alkylene ( optionally substituted aryl) or —C ₁ -C ₄ -alkylene- (optionally substituted heteroaryl), and wherein R ^{l is} independently —H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₁ -C ₆ -fluoroalkyl, optionally substituted C ₃ -C ₆ -cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C ₁ -C ₄ -alkylene- (optionally substituted C ₃ -C ₆ - cycloalkyl), -C ₁ -C ₄ -alkyl en- (optionally substituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (optionally substituted aryl) or -C ₁ -C ₄ -alkylene- (optionally substituted heteroaryl), or if RH is -S (= O) ₂ N (R ^L ) 2, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^j ) C (= O) N (R ^l ) 2, then each R ^{L is} independently —H or C1-C ₆ -alkyl, or the R ^L groups are independently C ₁ -C ₆ -alkyl and when taken together with the N atom, to which

- 2,038,294 they are attached, form a substituted or unsubstituted heterocycle, or if W is -C (R ^L ) 2- or Z is -C (R ^L ) ² -, then each R ^{L is} independently -H or C1 -C6 -alkyl or R ^L groups are independently C1-Cb-alkyl and when taken together with the carbon atom to which they are attached form a carbocycle;

ring B is optionally substituted C ₃ -C ₁₀ cycloalkylene, optionally substituted C ₂ -C ₁₀ heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, wherein if ring B is substituted then ring B is substituted by 1, 2 or 3 independently selected R ^H , where RH is previously defined; and ring C is absent or is optionally substituted C ₃ -C ₁₀ cycloalkylene, optionally substituted C ₂ -C ₁₀ heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, wherein if ring C is substituted, ring C is substituted with 1, 2 or 3 independently selected RH, where RH is as previously defined;

where, if ring B is substituted or unsubstituted arylene, ring C is absent, L ^{2 is} absent, L ¹ is -UV-Z-, where -UV- is -N (R ^F ) C (= O) O-, where R ^F is -H, R ^D is -N (R ^F ) C (= O) XCH (R ^G ) CY, where X is -O-, R ^g is -CH ₃ , and R ^F is is -H and R ^C is -H, -CH3 or -CF3, or if ring B is an optionally substituted arylene and ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene , or ring B is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene and ring C is substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C _{1 -C 6} alkylene, and R ^C is —H or - CH3 and R ^A is —CO2H or —CO ₂ R ^B , then ring A has one of the following structures:

and if ring B is C ₂ -C ₁₀ heterocycloalkylene, ring C is substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C1-C6 alkylene, R ^C is —CH3, and R ^a is - CO ₂ H or —CO ₂ R ^B , then ring A has one of the following structures:

Other compounds of the present invention have the structures set forth herein in the numbered embodiments and claims.

- 3 038294

Detailed description of the invention

Definitions.

As used herein, and unless otherwise indicated or implied in context, expressions as used herein have the meanings defined below. Unless otherwise opposed or implied, for example by including mutually exclusive elements or possible variations, in these definitions and throughout this specification, the singular means one or more, and the expression either means and / or as the context allows. Thus, as used in this description and the appended claims, the singular includes a reference to the plural, unless the context clearly requires otherwise.

In various places of the present disclosure, for example, in any of the disclosed embodiments or in the claims, reference is made to compounds, compositions or methods containing one or more of the specified components, elements or steps. Embodiments of the present invention also specifically include these compounds, compositions, compositions or methods, which are these specified components, elements or steps, or which consist of, or which essentially consist of them. Expressions contains, consists of, and essentially consists of have the meanings generally accepted in US patent law, unless expressly indicated otherwise. An expression derived from and an expression containing are used interchangeably and are defined as equivalent expressions. For example, the disclosed compositions, devices, articles of manufacture, or methods containing a component or step are open source and include or encompass those compositions or methods, as well as additional (additional) component (s) or step (s). Likewise, the disclosed compositions, devices, articles of manufacture or methods consisting of a component or step are closed and will not include or encompass those compositions or methods that have additional (additional) component (s) or additional (additional) stage (s) in a noticeable amount. In addition, the use of the expression inclusive, as well as its other forms, such as include, include, and inclusive, is not limiting. Section headings used in this document are for organizational purposes only and should not be construed as limiting the described subject matter of the present invention. Unless otherwise indicated, traditional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used.

A bond or single bond, as used herein, means a chemical bond between two atoms or two components if the atoms linked by a bond are considered part of a larger substructure. As explicitly stated or implied in the context, if the group described in this document is a bond, then the referenced group is absent, thereby allowing the formation of a bond between the remaining identified groups.

-membered ring as used herein means any cyclic structure. It is assumed that the expression -members means the number of skeletal atoms forming a ring. Thus, by way of example and not limitation, these α-membered rings include cyclohexyl, pyridinyl, pyranyl, and thiopyranyl, which are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl, which are 5-membered rings.

A component, as used herein, means a specific segment, fragment, or functional group of a molecule or compound. Chemical components are sometimes referred to as chemical building blocks incorporated into or attached to a molecule or compound (ie, as a substituent or variable group).

Alkyl, as used herein, is a group of carbon atoms covalently bonded together in a normal, secondary, tertiary or cyclic moiety, i. E. in a linear, branched, cyclic group, or a certain combination thereof. An alkyl substituent for a structure is a chain of carbon atoms covalently attached to the structure via an sp ³ hybridized carbon atom of the substituent. Alkyl substituents, as used herein, contain one or more saturated components or groups, and may further contain unsaturated alkyl components or groups, i. E. a substituent may contain one, two, three or more independently selected double bonds or triple bonds or a combination thereof, usually one double or one triple bond if such unsaturated alkyl components or groups are present.

Unsaturated alkyl components or groups include those or groups described below for alkenyl, alkynyl, cycloalkyl and aryl components. Saturated alkyl components contain saturated carbon atoms (sp ³ -hybridized) and do not contain aromatic, sp ² - or sp-hybridized carbon atoms. The number of carbon atoms in the alkyl component or group may vary and is usually from 1 to about 50, for example, about 1-30, or about 1-20, unless otherwise indicated, for example, Ci-8 alkyl or C1-C8 alkyl means an alkyl component containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and C _1-6 alkyl or C1-C ₆ means an alkyl component containing 1, 2, 3, 4, 5 or 6 carbon atoms.

If an alkyl substituent, component or group is defined, the particle may include methyl,

- 4038294 ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl, -CH (CH ₃ ) ₂ ), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (sec-butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl (tert-butyl, -C (CH ₃ ) ₃ ), amyl, isoamyl, sec-amyl and other linear, cyclic and branched chain alkyl components. Unless otherwise indicated, alkyl groups may contain the species and groups described below for cycloalkyl, alkenyl, alkynyl groups, aryl groups, arylalkyl groups, alkylaryl groups, and the like.

Cycloalkyl, as used herein, is a monocyclic, bicyclic, or tricyclic ring system composed of only carbon atoms. The expression cycloalkyl encompasses a monocyclic or polycyclic aliphatic non-aromatic radical in which each of the ring-forming atoms (ie, skeletal atoms) is a carbon atom. The number of carbon atoms in the cycloalkyl substituent, component or group may vary and is typically from 3 to about 50, such as about 1-30, or about 1-20 unless otherwise indicated, such as C _3-8 alkyl or C 3 -C 8 alkyl means a cycloalkyl substituent, component or group containing 3, 4, 5, 6, 7 or 8 carbon atoms, and C _3-6 alkyl or C3-C6 means a cycloalkyl substituent, component or group containing 3, 4, 5 or 6 atoms carbon. Cycloalkyl substituents, components or groups will typically have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms and may contain exo - or endocyclic double bonds or endocyclic triple bonds or a combination of both types, where endocyclic double or triple bonds or a combination of both types do not form a cyclic conjugated system containing 4n + 2 electrons, where one (i.e. in the case of a spiro ring system) or two carbon atoms, and in the tricyclic ring system, a total of 2, 3 or 4 carbon atoms can be shared, usually 2 or 3.

Unless otherwise indicated, cycloalkyl substituents, components or groups may contain the components and groups described for alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, and the like, and may contain one or more other cycloalkyl components. Thus, cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can be fused to an aromatic ring, and the points of attachment to the aromatic ring are on the carbon atom or on the carbon atoms of the cycloalkyl substituent, component or group that are not carbon atoms of the aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms. Cycloalkyl substituents, components or groups include cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, or other cyclic components containing only carbon atoms. Cycloalkyls further include cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can be substituted or unsubstituted. Depending on the structure of the substituent, the cycloalkyl substituent can be a monoradical or a biradical (i.e., cycloalkylene, such as, without limitation, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl, etc.). When cycloalkyl is used as a Markush group (i.e., a substituent), the cycloalkyl is attached to the Markush formula to which it is bonded through a carbon atom participating in the cyclic system of the carbon ring of the cycloalkyl group, which is not an aromatic carbon atom.

Alkylamine, as used herein, means a group, component or substituent —N (alkyl) _x H _y , where x and y are independently selected from the group x = 1, y = 1 and x = 2, y = 0. Alkylamine includes —N (alkyl) _x H _y groups in which x = 2 and y = 0, and the alkyl groups taken together with the nitrogen atom to which they are attached form a cyclic ring system.

Heteroalkylene, as used herein, means an alkylene (i.e. alkanediyl) group, component or substituent in which one or more skeletal alkyl atoms are selected from an atom other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or their combinations. Heteroalkylene includes Cl — C ₆ heteroalkylene or Cl — C ₄ heteroalkylene. Illustrative heteroalkylenes include, without limitation, -oCh ₂ -, -OCH (CH ₃ ) -, - OC (CH ₃ ) ₂ -, -OCH2CH2-, -CH2O-, -CH (CH ₃ ) O-, C (CH3) 2O-, -CH2CH2O-, -CH2OCH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -SCH2-, -SCH (CH3) -, -SC (CH ₃ ) 2-, -SCH2CH2-, -CH2S-, -CH ( CH3) S-, -C (CH3) 2S-, -CH2CH2S-, -CH2SCH2-, -CH2SCH2CH2-, -CH2CH2SCH2-, -S (= O) 2CH2- -S (= O) 2CH (CH3) -, - S (= O) 2C (CH3) 2-, -S (= O) 2CH2CH2-, -CH2S (= O) 2-, -CH (CH3) S (= O) 2-, -C (CH3) 2S ( = O) 2-, -CH2CH2S (= O) 2-, -CH2S (= O) 2CH2-, -CH2S (= O) 2CH2CH2-, CH2CH2S (= O) 2CH2-, -NHCH2-, -NHCH (CH3) -, -NHC (CH3) 2-, -NHCH2CH2-, -CH2NH-, -CH (CH3) NH-, -C (CH3) 2NH-, -CH2CH2NH-, -CH2NHCH2-, -CH2NHCH2CH2-, -CH2CH2NHCH2- and etc.

A bioisosteric analog of a carboxylic acid group, as used herein, means a functional group, component or substituent exhibiting similar physical, biological and / or chemical properties to the carboxylic acid component. By way of example, and not limitation, bioisosteric analogs of the carboxylic acid group include

- 5 038294

Alkenyl, as used herein, means a substituent, component or group that contains one or more components with a double bond (for example, -CH = CH-) or 1, 2, 3, 4, 5 or 6 or more, usually 1 , 2 or 3 such components, and may include aryl, such as benzene, component or group, and additionally contain linked normal, secondary, tertiary or cyclic carbon atoms, i.e. linear, branched, cyclic group or any combination thereof, except when the alkenyl component is a vinyl component (for example, -CH = CH ₂ ). An alkenyl component, group or substituent with several double bonds can have contiguous (i.e., in the case of a 1,3-butadienyl component) or non-contiguous arrangement of double bonds with one or more intermediate saturated carbon atoms, or a combination thereof, provided that when adjacent the arrangement of double bonds in the cyclic group does not form a cyclic conjugated system containing 4n + 2 electrons (i.e., aromatic). The number of carbon atoms in the alkenyl group or component can vary and is usually from 2 to about 50, for example about 2-30 or about 2-20 unless otherwise indicated, for example C2 _-8 alkenyl or C2-8-alkenyl means an alkenyl component containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and C2 _is 6-alkenyl or C2-6-alkenyl means an alkenyl component containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl components or groups will typically have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.

If an alkenyl component, group or substituent is defined, the particle includes, by way of example and not limitation, any alkyl or cycloalkyl groups, components or substituents described herein having one or more double bonds, methylene (= CH ₂ ), methylmethylene ( = CH-CH ₃ ), ethylmethylene (= CH-CH ₂ -CH ₃ ), = CH-CH ₂ -CH2-CH ₃ , vinyl (-CH = CH ₂ ), allyl, 1methylvinyl, butenyl, isobutenyl, 3-methyl -2-butenyl, 1-pentenyl, cyclopentenyl, 1methylcyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl and other linear, cyclic and branched chain components containing only carbon atoms that contain at least one double bond. When alkenyl is used as a Markush group (i.e., a substituent), the alkenyl is attached to the Markush formula to which it is bonded through an unsaturated carbon atom involved in the formation of a double bond in the alkenyl component or group, unless otherwise indicated.

Alkynyl, as used herein, means a substituent, component or group that contains one or more triple bond components (i.e. -C = C-), for example 1, 2, 3, 4, 5, 6 or more , usually 1 or 2 triple bonds, optionally contain 1, 2, 3, 4, 5, 6 or more double bonds, while the remaining bonds (if any) are single bonds and contain linked normal, secondary, tertiary or cyclic carbon atoms, those. linear, branched, cyclic moieties or any combination thereof, except when the alkynyl component is ethynyl. The number of carbon atoms in the alkynyl group or component can vary and is generally from 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise indicated, e.g. C2 _- 8-alkynyl or C2-8-alkynyl means alkynyl component containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Alkynyl groups will typically have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.

If an alkynyl component or group is defined, the particle includes, by way of example and not limitation, any alkyl components, groups or substituents described herein having one or more double bonds, ethynyl, propynyl, butynyl, isobutynyl, 3-methyl-2butynyl , 1-pentynyl, cyclopentynyl, 1-methylcyclopentynyl, 1-hexynyl, 3-hexynyl, cyclohexynyl and other linear, cyclic and branched chain components containing only carbon atoms that contain at least one triple bond. When alkynyl is used as a Markush group (i.e., a substituent), the alkynyl is attached to the Markush formula to which it is attached via one of the unsaturated carbon atoms of the alkynyl functional group.

Aromatic, as used herein, refers to a planar ring having a delocalized pi-electron system containing 4n + 2 pi-electrons, where n is a positive integer. Aromatic rings can be formed by 5, 6, 7, 8, 9, 10, or more than 10 atoms. Aromatic groups are optionally substituted. The expression aromatic includes both carbocyclic aryl (aryl, eg phenyl) and heterocyclic aryl (or heteroaryl, or heteroaromatic) groups (eg pyridine). Expression

- 6 038294 includes monocyclic or polycyclic groups with fused rings (ie, rings with a common pair of adjacent carbon atoms).

Aryl, as used herein, means an aromatic ring system or a fused ring system without ring heteroatoms containing 1, 2, 3, or 4 to 6 rings, usually 1 to 3 rings, where the rings are composed of only carbon atoms; and refers to a cyclic conjugated system containing 4n + 2 electrons (Hückel's rule), usually 6, 10 or 14 electrons, some of which can additionally take part in conjugation with exocyclic groups (cross-conjugated compounds (e.g. quinone)). Aryl substituents, components or groups are usually formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl substituents, components or groups are optionally substituted. Illustrative aryls include C ₆ -Cl ₀ aryls such as phenyl and naphthalenyl, as well as phenanthryl. Depending on the structure, the aryl group can be a monoradical or a biradical (i.e., an arylene group). Illustrative arylenes include, but are not limited to, phenyl-1,2-ene, phenyl-1,3-ene, and phenyl-1,4-ene. When aryl is used as a Markush group (i.e., a substituent), then the aryl is attached to the Markush formula to which it is attached via the aromatic carbon of the aryl group.

Arylalkyl, as used herein, means a substituent, component or group in which the aryl moiety is linked to the alkyl moiety, i. E. -alkyl-aryl, where the alkyl and aryl groups are as described above, for example —CH ₂ —C ₆ H5 or —CH ₂ CH (CH ₃ ) C6H5. When an arylalkyl is used as a Markush group (ie, a substituent), the alkyl moiety of the arylalkyl is attached to the Markush formula to which it is bonded via the sp ³ hybridized carbon atom of the alkyl moiety.

Alkylaryl, as used herein, means a substituent, component or group in which an alkyl component is linked to an aryl component, i. E. -aryl-alkyl, where the aryl and alkyl groups are as described above, for example —C ₆ H ₄ —CH ₃ or —C6H ₄ —CH ₂ CH (CH ₃ ). When an alkylaryl is used as a Markush group (ie, a substituent), the aryl component of the alkylaryl is attached to the Markush formula to which it is bonded via the sp ² hybridized carbon atom of the aryl component.

Substituted alkyl, substituted cycloalkyl, substituted alkenyl, substituted alkynyl, substituted alkylaryl, substituted arylalkyl, substituted heterocycle, substituted aryl, and the like, as used herein, means alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, heterocyclic, aryl or other group or component, as defined or disclosed herein, which have a substituent (s), substituting (s) hydrogen atom (s), or substituent (s) breaking (s) a chain of carbon atoms. Alkenyl and alkynyl groups containing a substituent (s) are optionally substituted at a carbon atom that is separated from the double bond by one or more methylene components.

Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl, optionally substituted heteroarylalkyl, and the like, as used herein mean alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl, heterocyclic, aryl, heteroaryl, alkylheteroaryl, heteroarylalkyl or other substituent, component or group, defined or disclosed herein, which have a substituent (s), optionally substituting (s) an atom ( atoms) hydrogen, or substituent (s), breaking (breaking) the chain of carbon atoms. Such substituents are described in this document. With regard to the phenyl component, the position of any two substituents present on the aromatic ring may be ortho (o-), met- (m-), or para- (p-). An optionally substituted fluoroalkyl is an alkyl or cycloalkyl moiety, typically linear alkyl, wherein one or more hydrogen atoms have been replaced by a fluorine atom and at least one other atom other than carbon and fluorine.

An optionally substituted or substituted substituent, component or group includes those having one or more additional groups replacing them with hydrogen atom (s), separately and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic group, hydroxy, alkoxy, aryloxy, alkylthio , arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halogen, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy and amino, including mono- and disubstituted amino groups, and their protected derivatives. By way of example, and not limitation, optional (optional) substituent (s) may (may) be a halide, -CN, -NO2, or LsRs, where each Ls is independently selected from a bond, -O-, -C (= O) -, -C (= O) O-, -S-, -S (= O) -, -S (= O) ₂ -, -NH-, -NHC (= O) -, -C (= O) NH-, S (= O) ₂ NH-, —NHS (= O) ₂ , —OC (= O) NH—, —NHC (= O) O— or - (Cl — C ₆ alkylene) -; and each Rs is selected from -H, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl,

- 7 038294 heteroaryl or heterocycloalkyl. The protecting groups that protected derivatives of the above substituents can form can be found in sources such as Greene and Wuts, cited above. Optional substituents include those selected from the group consisting of halogen, —CN, —NH2, —OH, —N (CH ₃ ) 2, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone selected from the group consisting of halogen, -CN, -NH ₂ , -OH, NH (CH ₃ ), -N (CH ₃ ) ₂ , -CO2H, -CO ₂ alkyl, -C (= O) NH ₂ , -C (= O) NH-alkyl, -C (= O) N (alkyl) ₂ , -S (= O) 2NH2, -S (= O) ₂ NH (alkyl), - S (= O) ₂ N (alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, -S-alkyl and -S (= O) ₂ alkyl, or selected from the group consisting of halogen, -CN, -NH2, -OH, -NH (CH ₃ ), -N (CH ₃ ) ₂ , -CH3, -CH2CH3, -CF ₃ , -OCH3 and -OCF3. An optionally substituted substituent, component or group is typically substituted with one or two previous groups, or more typically one of the previous groups. An optional substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) further includes oxo (= O).

Heterocycle or heterocyclic, as used herein, means a cycloalkyl or aromatic ring system where one or more, usually 1, 2, or 3, but not all of the carbon atoms forming the ring system are replaced by a heteroatom, which is an atom other than a carbon atom including N, O, S, Se, B, Si, P, usually N, O, or S, where two or more heteroatoms may be adjacent to each other or separated by one or more carbon atoms, usually 1-17 carbon atoms , 1-7 atoms or 1-3 atoms. Heterocycles include heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring (s), where each heteroatom in the ring (s) is selected from O, S and N, where each heterocyclic group has 4 to 10 atoms in its ring system, and provided that no ring contains two adjacent O or S atoms.

Non-aromatic heterocyclic substituents, components, or groups (also known as heterocycloalkyls) have at least 3 atoms in their ring system, and aromatic heterocyclic groups have at least 5 atoms in their ring system and include benzo-fused ring systems. Heterocyclic groups with 3, 4, 5, 6 and 10 atoms include aziridinyl, azetidinyl, thiazolyl, pyridyl, and quinolinyl, respectively. Nonaromatic heterocyclic substituents, components or groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinones, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, tioksanil, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oksepanil, tiepanil, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianil, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0) hexanyl, 3-azabicyclo [4.1.0) heptanyl, 3H-indolyl, and quinolizinyl. Aromatic heterocyclic groups include, by way of example, and not limitation, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indoquinolinylbenzene, benzene cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolinylinyl, quininothiurinyl Non-aromatic heterocycles can be substituted with one or two oxo components (= O) and include pyrrolidin-2-one.

If a heterocycle is used as a Markush group (i.e., a substituent), then the heterocycle is attached to the Markush formula to which it is bonded via a carbon atom or heteroatom of the heterocycle, and such addition does not cause an unstable or forbidden formal oxidation state of this carbon atom, or heteroatom. The C-linked heterocycle is connected to the molecule through a carbon atom and includes components such as - (CH ₂ ) _n heterocycle, where n is 1, 2, or 3, or -C <heterocycle, where C <represents a carbon atom in the heterocyclic ring. An N-linked heterocycle is a nitrogen-containing heterocycle linked by a nitrogen atom of a heterocyclic ring, sometimes described as -N <heterocycle, where N <is a nitrogen atom in the heterocyclic ring. Thus, nitrogen-containing heterocycles can be C-linked or N-linked and include pyrrole substituents, which can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked), imidazole substituents, which can be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked).

Heteroaryl, as used herein, means an aryl ring system in which one or more, usually 1, 2 or 3, but not all of the carbon atoms forming the aryl ring system are replaced by a heteroatom, which is an atom other than carbon , including N, O, S, Se, B, Si, P, usually an oxygen (-O-), nitrogen (-NX-) or sulfur (-S-) atom, where X is

- 8 038294 is -H, a protecting group, or an optionally substituted C _1-6 alkyl, where the heteroatom participates in the formation of a conjugated system by forming pi bonds with an adjacent atom in the ring system or via the lone pair of electrons of the heteroatom, and which may be optionally substituted at one or more carbon atoms or heteroatoms or a combination of both types while maintaining the cyclic conjugated system.

Heterocycles and heteroaryls include, by way of example, and not limitation, the heterocycles and heteroaryls described in Paquette, Leo A .; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), in particular in chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. 1960, 82: 5545-5473, in particular 5566-5573). Examples of heteroaryls include, by way of example, and not limitation, pyridyl, thiazolyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, purinyl, imidazolyl, benzofuranyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothriazinyl, benzothriazinyl, benzothriazinyl , pyrazolopyrimidinyl, quinoxalinyl, thiadiazolyl, triazolyl and the like. Non-heteroaryl heterocycles include, by way of example, and not limitation, tetrahydrothiophenyl, tetrahydrofuranyl, indolenyl, piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl-2-imoquinolinyl, decahydroquinolinyl-2-imoquinolynyl, , imidazolinyl, pyrazolidinyl, piperazinyl, quinuclidinyl, morpholinyl, oxazolidinyl and the like.

Other heteroaryls include, by way of example, and not limitation, the following components:

Monocyclic heteroaryls include, by way of example and not limitation, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, triazinylazyl, and fatizinyl. Heteroaryls include substituents, components or groups containing 0-3 N atoms, 1-3 N atoms, or 0-3 N atoms, 0-1 O atoms, and 0-1 S atoms. Heteroaryl can be monocyclic or bicyclic. The ring system of heteroaryls typically contains 1-9 carbon atoms in the ring (ie, in the case of C ₁ -C ₉ heteroaryl). Monocyclic heteroaryls include C ₁ -C 5 heteroaryls. Monocyclic heteroaryls include those having 5-membered or 6-membered ring systems. Bicyclic heteroaryls include C ₆ -C ₉ heteroaryls. Depending on the structure, the heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).

Heterocycloalkyl or heteroalicyclic, as used herein, means a cycloalkyl group, component or substituent in which at least one carbon atom of the cycloalkyl chain is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms. Heterocycloalkyl can be fused with aryl or heteroaryl. Heterocycloalkyls, also called non-aromatic heterocycles, include by way of example and not limitation:

Heterocycloalkyl includes, by way of example and not limitation, oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,

- 9 038294 morpholinyl, thiomorpholinyl, piperazinyl and indolinyl. Heteroalicyclic compounds further include all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Heterocycloalkyl is typically C ₂ -C ₁₀ heterocycloalkyl and includes C ₄ -CI 0 heterocycloalkyl. Heterocycloalkyl may contain 0-2 N atoms, 0-2 O atoms, or 0-1 S atoms.

Heteroarylalkyl, as used herein, means a substituent, component or group in which the heteroaryl component is linked to an alkyl component, i. E. -alkylheteroaryl, where the alkyl and heteroaryl groups are as described above. When heteroarylalkyl is used as a Markush group (ie, a substituent), the alkyl moiety of the heteroarylalkyl is attached to the Markush formula to which it is bonded via the sp ³ hybridized carbon atom of the alkyl moiety.

Alkylheteroaryl, as used herein, means a substituent, component or group in which the heteroaryl component is linked to an alkyl component, i. E. -heteroarylalkyl, where the heteroaryl and alkyl groups are as described above. When heteroarylalkyl is used as a Markush group (ie, a substituent), then the heteroaryl moiety of the heteroarylalkyl is attached to the Markush formula to which it is bonded via an sp ² -hybridized carbon atom or heteroatom of the alkyl moiety.

Halogen or halogen radical as used herein means fluorine, chlorine, bromine or iodine.

Haloalkyl, as used herein, means an alkyl substituent, component or group in which one or more hydrogen atoms are replaced by one or more independently selected halogen atoms. Haloalkyl includes C ₁ -C ₄ -haloalkyl. Non-limiting examples of C ₁ -C ₄ haloalkyls are —CH ₂ Cl, CH ₂ Br, —CH ₂ I, —CHBrCl, —CHCl — CH ₂ Cl, and —CHCl — CH ₂ I.

Haloalkylene, as used herein, means an alkylene substituent, component or group in which one or more hydrogen atoms are replaced by one or more halogen atoms. T alogenalkilen includes C1 -C ₆ haloalkyl or C | -C ₄ -haloalkylenes.

Fluoroalkyl, as used herein, means alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. Fluoroalkyl includes C ₁ -C ₆ - and C ₁ -C ₄ -fluoroalkyl. Non-limiting examples of fluoroalkyls include —CH ₃ F, —CH 2 F 2, and —CF ₃ , as well as perfluoroalkyls.

Fluoroalkylene, as used herein, means alkylene in which one or more hydrogen atoms are replaced by a fluorine atom. Fluoroalkylene includes C ₁ -C ₆ -fluoroalkylenes or C ₁ -C ₄ -fluoroalkylene.

The expression heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from an atom other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. In one aspect, heteroalkyl is C ₁ -C ₆ heteroalkyl.

A protecting group, as used herein, means a component that prevents the participation of the atom or functional group to which it is associated, in undesirable reactions or reduces their ability to do so. Non-limiting examples are given in the case of —OR ^P R, where R ^pr is a protecting group for an oxygen atom in a hydroxyl group, while in the case of —C (O) —OR ^pr R ^pr may be a protecting group for a carboxylic acid group; in the case of -SR ^pr R ^pr may represent a protecting group for a sulfur atom in thiol groups, and in the case of -NHR ^pr or -N (R ^pr ) ₂ - at least one of R ^pr represents a protecting group for a nitrogen atom in primary or secondary amino groups. Hydroxyl groups, amino groups, keto groups, and other reactive groups may need to be protected from reactions occurring elsewhere in the molecule. Protecting groups for oxygen, sulfur or nitrogen atoms are commonly used to prevent unwanted reactions with electrophilic compounds such as acylating agents. Typical protecting groups for atoms or functional groups are given in Greene (1999), Protective groups in organic synthesis, 3 ^rd ed., Wiley Interscience.

An ester, as used herein, means a substituent, component or group containing the structure -C (O) -O- (i.e., an ester functional group), where the carbon atom of the structure is not directly bonded to another heteroatom and is directly bonded to -H or another carbon atom. Esters usually contain an organic component containing 1-50 carbon atoms, 1-20 carbon atoms or 1-8 carbon atoms and 0-10 independently selected heteroatoms (e.g. O, S, N, P, Si), usually 0-2 where the organic component is linked through the structure -C (O) -O-, or consists of it and includes ester components such as the organic component-C (O) -O-. The organic component generally comprises one or more of any of the organic groups described herein, e.g. Cl _-20 -alkyl components, C _2-20 alkenyl components, C ₂ - ₂₀ alkynyl components, components aryl, C _3-8 -heterocycles or substituted derivatives of any of them, for example, containing 1, 2, 3, 4 or more substituents, where each substituent is independently selected. Illustrative non-limiting substituents on hydrogen or carbon atoms on these organic groups are described above for substituted alkyl and other substituted components and are independently selected. The substituents listed above are usually substituents that can be used to replace one or more carbon atoms,

- 10 038294 eg —O— or —C (O) -, or one or more hydrogen atoms, eg halogen, —NH ₂ or —OH. Illustrative esters include, by way of example, and not limitation, one or more independently selected esters of acetic acid, propionic acid, isopropionic acid, isobutyric acid, butyric acid, valeric acid, isovaleric acid, caproic acid, isocaproic acid, hexanoic acid, heptanoic acid, octanoic acid, phenylacetic acid or benzoic acid esters. When an ester is used as a Markush group (i.e., a substituent), then the single bond oxygen atom of the ester functional group is attached to the Markush formula to which it is bonded.

Acetal, thioacetal, ketal, thioketal, and the like, as used herein, means a component, group or substituent containing a carbon atom to which two identical or different heteroatoms are bonded, or consisting of them, wherein the heteroatoms are independently selected from S and O. In the case of an acetal, two oxygen atoms, a hydrogen atom and an organic component are linked to a carbon atom. In the case of a ketal, two oxygen atoms and two independently selected organic components are bonded to a carbon atom, where the organic component is described herein for an alkyl or optionally substituted alkyl group. In the case of thioacetals and thioketals, one or both of the oxygen atoms in the acetal or ketal, respectively, are replaced by a sulfur atom. The oxygen or sulfur atoms in ketals and thioketals are sometimes linked by an optionally substituted alkyl moiety. The alkyl component is usually an optionally substituted C _1-8 alkyl or a branched alkyl structure such as -C (CH ₃ ) ₂ -, -CH (CH ₃ ) -, -CH2-, -CH2-CH2-, -C [( C ₂ -C ₄ -alkyl) ₂ ] ₁ , ₂ , ₃ - or - [CH (C ₂ -C ₄ alkyl)] ₁ , ₂ , ₃ -. Some of these components can serve as protecting groups for aldehydes or ketones, include, by way of example, and not limitation, acetals for aldehydes and ketals for ketones, and contain the components -O-CH2-CH2-CH2-O- or -O- CH2-CH2-O-, which form a spiro ring with a carbonyl carbon atom, and can be removed by chemical synthesis methods or by metabolism in cells or biological fluids.

An ether, as used herein, means an organic component, group or substituent containing 1, 2, 3, 4 or more components -O-, usually 1 or 2, or consisting of them, where no two components -O - are not directly adjacent (i.e. directly attached) to each other. Ethers usually contain an organic component containing 1-50 carbon atoms, 1-20 carbon atoms or 1-8 carbon atoms and 0-10 independently selected heteroatoms (e.g. O, S, N, P, Si), usually 0-2 ... An ether component, group or substituent includes an organic component —O—, where the organic component is described herein for an alkyl or optionally substituted alkyl group. When an ether is used as a Markush group (i.e., a substituent), then the oxygen atom of the ether functional group is attached to the Markush formula to which it is attached. When an ether is used as a substituent on a Markush group, it is sometimes referred to as an alkoxy group. Alkoxy includes C ₁ -C ₄ ether substituents such as, by way of example and not limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. The ether additionally includes substituents, components or groups containing one (with the exception of ketal) or more consecutive —OCH2CH2O— components (ie, polyethylene or PEG components).

Carbonate, as used herein, means a substituent, component or group containing the structure —O — C (= O) —O— (i.e., carbonate functionality). Carbonate groups, as used herein, typically contain an organic component containing 1-50 carbon atoms, 1-20 carbon atoms, or 1-8 carbon atoms, and 0-10 independently selected heteroatoms (e.g., O, S, N, P, Si), usually 0-2, connected by the structure -OC (= O) -O-, or consist of it, for example the organic component -OC (= O) -O-. If the carbonate is used as a Markush group (i.e., a substituent), then one of the single bond oxygen atoms of the carbonate functional group is attached to the Markush formula to which it is bonded.

Carbamate or urethane, as used herein, means a substituent, component or group containing the structure -OC (= O) N (R ^P R) -, -OC (= O) N (R ^pr ) ₂ , -OC (= O) NH (optionally substituted alkyl) or -OC (= O) N (optionally substituted alkyl) ₂ - (i.e., carbamate functionality), where R ^pr and optionally substituted alkyl are independently selected and RPR is independently -H , a protecting group, or an organic component as described for an ester, alkyl or optionally substituted alkyl. Carbamate groups, as used herein, typically contain an organic component containing about 1-50 carbon atoms, 1-20 carbon atoms, or 1-8 carbon atoms, and 0-10 independently selected heteroatoms (e.g., O, S, N, P , Si), usually 0-2, connected by the structure -OC (= O) -NR ^pr -, or consist of it, for example, the organic component m-OC (= O) -NR ^PR - or -OC (= O) -NR ^{PR is an} organic component. If carbamate is used as a Markush group (i.e., a substituent), then the single bond oxygen (O-linked) or nitrogen (N-linked) atom of the carbamate functional group is attached to the Markush formula to which it is linked. The bond of the carbamate substituent is indicated explicitly (N- or Bound) or implicitly in the context in which the substituent is mentioned.

For any substituent, group or component described by the given range of atoms

- 11,038294 carbon, the specified range means that any single number of carbon atoms is described. Thus, reference, for example, to optionally substituted C ₁ -C ₄ alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C ₃ -C ₈ heterocycle in a particular case means the presence of 1, 2, 3 or 4 carbon atoms in an optionally substituted alkyl component as defined herein, or the presence of 2, 3, 4, 5, or 6 carbon atoms in an alkenyl component or 3, 4, 5, 6, 7, or 8 carbon atoms in a component comprising a heterocycle or an optionally substituted alkenyl components defined in this document. All such designations are intended to explicitly disclose all individual groups of carbon atoms, and therefore optionally substituted C1-C4 alkyl includes, for example, 3-carbon alkyl, 4-carbon substituted alkyl, and 4-carbon alkyl, including all positional isomers, and the like. . disclosed and may be mentioned or named explicitly. In the case of esters, carbonates and carbamates defined by the recited range of carbon atoms, the recited range includes the carbonyl carbon atom of the corresponding functional group. Thus, ester C1 refers to an ester of formic acid and ester C2 refers to an ester of acetic acid. Organic substituents, components and groups described in this document, as well as any other components described in this document, as a rule, will not contain unstable components, unless such unstable components are intermediate particles that can be used to obtain compounds with sufficient chemical stability for one or more of the uses described in this document. Substituents, components or groups which, by virtue of the definitions given in this document, are due to the presence of a pentavalent carbon atom are expressly excluded.

LPA-dependent, LPA-mediated or similar expressions used in this document means a disease or condition, the etiology, progression or duration of which is partially or completely influenced by signaling by one or more subtypes of lysophosphatidic acid receptors, including, as for example, and not limitation, 1-6 subtypes of lysophosphatidic acid receptor (LPAR). LPA-dependent or LPA-mediated diseases and conditions include, without limitation, fibrosis of organs (e.g., liver, kidney, lung, heart, etc.), liver diseases (e.g., acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis of the liver , portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, impaired hepatic blood flow, etc.), cell proliferative diseases (for example, cancer forms, including, but not limited to, a solid tumor, metastasis of solid tumors, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), invasive metastasis of cancer cells, etc.), inflammatory diseases (for example, psoriasis, nephropathy, pneumonia, etc.), gastrointestinal diseases tract (eg, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), impaired pancreatic secretion, etc.), kidney disease, disease urinary tract infections (eg, benign prostatic hyperplasia or symptoms associated with neurogenic bladder disease), spinal cord tumors, herniated discs, spinal stenosis, diabetes-related symptoms, lower urinary tract disorders (eg, obstruction lower urinary tract, etc.), inflammatory diseases of the lower urinary tract (for example, dysuria, frequent urination, etc.), diseases of the pancreas, diseases associated with impaired angiogenesis (for example, obstruction of the arteries, etc.) , scleroderma, brain diseases (for example, ischemic stroke, intracerebral hemorrhage, etc.), diseases of the nervous system (for example, neuropathic pain, peripheral neuropathy, pruritus, etc.), eye diseases (for example, age-related macular degeneration (AMD ), diabetic retinopathy, proliferative vitreoretinopathy (PVR), scarring pemphigoid, scarring after filtration surgical treatment of glaucoma, etc.).

LPA1R selective agents, LPA1R selective compounds and similar expressions used herein mean agents or compounds that interact with subtype 1 lysophosphatidic acid receptors in preference to subtypes 2-6 lysophosphatidic acid receptors. This preference is usually expressed in the fact that the binding affinity of the agent for LPA1R compared to other known LPARs, as measured by experimentally determined KD values, is 10 times stronger.

A pharmaceutically acceptable formulation, as used herein, means a composition containing an active pharmaceutical ingredient, such as a compound having formula IVI, along with one or more pharmaceutically acceptable excipients, or refers to a composition prepared from an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients, where the composition is suitable for administration to a subject, such as a human or animal, in need thereof. For a pharmaceutically acceptable formulation to be suitable for administration to a human, the formulation must have biological activity to treat or prevent a disease or condition disclosed herein, or the expectation must exist,

- 12 038294 that the composition will have the desired activity against the disease or condition to be treated. The disease or condition to be treated is typically a condition or disease mediated by lysophosphatidic acid receptors. The disease or condition to be treated or prevented is more typically a type 1 lysophosphatidic acid receptor mediated disease or condition. A pharmaceutically acceptable formulation suitable for administration to an animal does not need to have biological activity to treat or prevent a disease or condition, and may be administered to an animal to assess the potential pharmacological or biological activity of a compound of Formula I-XII. These formulations should therefore be suitable for the treatment or prevention of a disease or condition disclosed herein in an animal in need thereof, or suitable for evaluating the pharmacological or biological activity of a compound of formula IXII. Compositions suitable only for use in in vitro assays or containing a carrier, component or excipient in an amount not permitted in a drug product are specifically excluded from the definition of a pharmaceutically acceptable formulation.

A pharmaceutically acceptable composition can be formed from or prepared from one, two or more compounds of formula I-XII, typically one or two, and from one or more pharmaceutically acceptable excipients. More typically, the formulations will essentially consist of or consist of one compound of Formula I-XII and one or more pharmaceutically acceptable excipients. Other compositions can be formed from, essentially consist of or consist of one, two or three compounds of formula I-XII and one, two or more compounds currently used for the treatment of diseases or conditions mediated by the type 1 lysophosphatidic acid receptor disclosed in this document, as well as one or more pharmaceutically acceptable excipients. These formulations will generally consist essentially of or consist of one compound of Formula I-XII, one compound currently used in the treatment of diseases or conditions mediated by type 1 lysophosphatidic acid receptors, and one or more pharmaceutically acceptable excipients.

Solid formulation, as used herein, refers to a pharmaceutically acceptable formulation comprising at least one compound of Formula I-XII and one or more pharmaceutically acceptable excipients in solid form, wherein the formulation is in a unit dosage form suitable for administration of a solid. Dosage units include tablets, capsules, capsule tablets, gelatin capsules, suspensions, and other dosage units usually associated with parenteral or enteral (oral) administration of a solid.

Liquid formulation, as used herein, refers to a pharmaceutically acceptable formulation wherein at least one compound of Formula I-XII has been mixed or contacted with one or more pharmaceutically acceptable excipients, wherein at least one of the excipients is in liquid form in the relative content required for the liquid formulation, i.e. so that most of the mass amount of the compound (s) of the formula I-XII is dissolved in the non-solid filler. Dosage units containing a liquid formulation include syrups, gels, ointments, and other dosage units typically associated with parenteral or enteral administration of a pharmaceutical formulation to a subject in need thereof in liquid form.

Caution, warning and similar expressions used in this document have their usual and generally accepted meanings in the medical field, and therefore do not require that every case to which the expression refers to be avoided with confidence.

Numbered embodiments.

The following embodiments explain the present invention by way of examples and are not intended to limit the present invention in any way. In certain embodiments, the compounds provided herein have one or more stereocenters, and each center independently exists in the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric and epimeric forms, as well as their respective mixtures. Stereoisomers are prepared, if necessary, by methods such as stereoselective synthesis and / or separation of stereoisomers using chiral chromatography columns. The methods and formulations described herein involve the use of pharmaceutically acceptable salts of compounds having a structure corresponding to formulas (I-VI), as well as active metabolites of these compounds having the same type of activity. In some cases, the compounds can exist as tautomers. All tautomers are included within the scope of the compounds provided herein. In specific embodiments, the compounds described herein exist as salts, including pharmaceutically acceptable salts. Salt forms include inorganic addition salts such as F ^- , Cl ^- , Br ^- , I ^- and sulfuric acid salts, and organic addition salts such as mesylate, besylate, tosylate, citrate, succinate, fumarate and malonate. In other embodiments, the compounds described herein exist as quaternary ammonium salts.

1) A compound of formula I having the structure

- 13 038294

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH ₂ CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

L ^{1 is} absent or is substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C1-C6 fluoroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C1-C6 heteroalkylene or -UV-Z-, where - UV- is defined as -OW-, -WO-, -N (R ^J ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C1-C3 alkylene, or W is -C (R ^L ) 2-; Z is substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₃ -C ₈ cycloalkylene or C 1 -C 6 fluoroalkylene, or Z is —C (R ^L ) ₂ -; an is 0, 1, or 2;

L ² is absent or represents a substituted or unsubstituted C ₁ -C ₆ -alkulen, substituted or unsubstituted C ₃ -C ₈ -cycloalkyl, C ₁ -C ₆ -ftoralkilen, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkylene, -O-, -S-, -SO-, -SO2-, -NRJ-, -C (= O) or -C (= O) N (R ^J ) -;

where R ^B represents substituted or unsubstituted C ₁ -C ₄ -alkyl or has one of the following structures:

Ring A is a 5- or 6-membered heteroarene having one of the following structures:

where the dotted line indicates the point of attachment of ring A to ring B;

where one of RC and RD is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ alkyl, C ₁ —C ₄ alkyl, C ₃ —C ₆ cycloalkyl, or C ₁ -C ₄ -fluoroalkyl and the other RC or RD is -NR ^F C (= O) XCH (R ^G ) -CY, -N (R ^F ) C (= O) XC (R ^G ) ₂ -CY , or -NR ^f C (= O) X-CY, -C (= O) -N (R ^f ) -CH (R ^g ) X-CY, or -C (= O) -N (R ^f ) - C (R ^g ) 2X-CY, where X is absent or represents -O-, -NH- or -CH ₂ -;

R ^e represents —H, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -fluoroalkyl;

RF is -H or C ₁ -C ₄ -alkyl, and

R ^g is independently selected R ^E , or one R ^G is C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the other R ^G , if any, is defined for R ^E ;

where CY is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₃ -C ₁₀ -cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ -heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, while if CY is substituted, then CY is substituted with 1, 2 or 3 independently selected R ^H ,

R ^H independently represents -H, halogen, -CN, -NO2, -OH, -OR ^J , -SR ^J , -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^j ) S (= O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , OC (= O) R ^j , -CO2RJ, -OCO2RJ, -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, N (R ^j ) C (= O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -N (R ^j ) C (= O) OR ^j , C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C ₁ -C ₄ -alkoxy or C ₁ -C ₄ -heteroalkyl, where each R ^{J is} independently substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, for

- 14 038294-substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, _-C1-C4 alkylene (substituted or unsubstituted C ₃ -C ₆ cycloalkyl) _-C1-C4 -alkilen- (substituted or unsubstituted heterocycloalkyl), -C1 -C ₄ -alkylene- (substituted or unsubstituted aryl) and -C _{1 -C 4} -alkylene (substituted or unsubstituted heteroaryl), and where each RL is independently -H, C _{1 -C 6} -alkyl, C ₁ -C ₆ -heteroalkyl, C1-C6 fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene (substituted or unsubstituted heteroaryl) , or if RH is -S (= O) ₂ N (R ^L ) 2, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^J ) C (= O) N (R ^L ) 2, then each R ^{L is} independent dently represents -H or C1-C ₆ -αlkil group or R ^L are independently C ₁ -C ₆ alkyl and wherein, when taken together with the atom N, to which they are attached form a substituted or unsubstituted heterocycle, or when W or Z is —C (R ^L ) 2-, then each R ^{L is} independently —H or C1-C ₆ -alkyl, or the R ^L groups are independently C ₁ -C ₆ -alkyl and, when taken together with the carbon atom to which they are attached form a carbocycle;

ring B is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloαalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring B is substituted, ring B is substituted with 1, 2 or 3 independently selected RH, where RH is as previously defined; and ring C is absent or is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring C is substituted, ring C substituted with 1, 2 or 3 independently selected R ^H , where RH is as previously defined, where if ring B is substituted or unsubstituted arylene, ring C is absent, L ^{2 is} absent, L ¹ is -UV-Z-, where -UV- is is -N (R ^F ) -C (= O) O-, where R ^F is -H, R ^D is -N (R ^F ) C (= O) XCH (R ^G ) -CY, where X is is -O-, R ^g is -CH ₃ and R ^F is -H and RC is -H, -CH3 or -CF3, or if ring B is substituted or unsubstituted arylene and ring C is substituted or unsubstituted arylene or is a substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene, or ring B is substituted or unsubstituted C3C ₁₀ -cycloαalkylene and ring C is substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C ₁ -C ₆ alkylene, and RC is —H or —CH3, and R ^A is is -CO2H or -CO2RB, ring A has one of the following structures:

r ^e I

and if ring B is C ₂ -C ₁₀ heterocycloαalkylene, ring C is substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C ₁ -C ₆ alkylene, RC is —CH ₃ , and R ^a is is -CO2H or -CO2RB, ring A has one of the following structures:

- 15 038294

In some embodiments, R ^C is -H, -CN, -F, -Cl, -Br, -I, -OC1-C4 alkyl, C1-C4 alkyl, C3-C6 cycloαalkyl, or C1-C4 fluoroalkyl, a R ^D is -N (R ^F ) C (= O) XCH (R ^g ) CY, -N (R ^f ) C (= O) XC (R ^g ) 2-CY or -N (R ^f ) C ( = O) X-CY, where RF and each R ^G independently represent -H or C ₁ -C ₄ -αalkyl.

In some embodiments, R ^A is —CO2H, —CO2RB, —CN, tetrazolyl, —C (= O) NH2, —C (= O) NHR ^b , C (= O) NHSO2R ^b , or C (= O) NHCH2CH2SO3H, or isostere analog of the carboxylic acid group.

In preferred embodiments, R ^A is —CO2H, —CO2RB, —CN, or —C (= O) NHSO2R ^b ', where R ^B is substituted or unsubstituted C ₁ -C ₄ alkyl, or has one of the following structures:

In some embodiments, L ^{1 is} absent or is substituted or unsubstituted C ₁ -C 6 alkylene, C ₁ -C 6 fluoroalkylene, or substituted or unsubstituted C ₁ -C 6 hetero alkylene.

In some preferred embodiments, L ^{1 is} absent or is substituted or unsubstituted C1-C6 alkylene or -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^J ) W-, - WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C ₁ -C ₃ alkylene, Z is substituted or unsubstituted C ₁ -C ₆ alkylene or C 1 -C 6 fluoroalkylene; and n is 0, 1, or 2.

In particularly preferred embodiments, L ¹ is -CH2-, dimethylmethane (i.e., -C (CH ₃ ) ₂ -), or -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C ₁ -C ₃ alkylene; a Z is substituted or unsubstituted C ₁ -C6-α-alkyl.

In some embodiments, L ^{2 is} absent or is substituted or unsubstituted C ₁ -C6 alkylene, C ₁ -C6 fluoroalkylene, substituted or unsubstituted C ₁ -C6 heteroalkylene, O-, -S-, -S (= O) -, S (= O) 2-, -N (R ^B ) - or -C (= O) -.

In some preferred embodiments, L ^{2 is} absent or is -O-, -S-, -S (= O) -, S (= O) 2-, -N (R ^J ) - or -C (= O) - ...

In some embodiments, Ring A is a 5- or 6-membered heteroarene having one of the following structures:

- 16 038294

In some embodiments, compounds of Formula I comprise R ^C defined as —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ alkyl, C ₁ -C ₄ alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₄ -fluoroalkyl.

In more preferred embodiments, the compounds of Formula I contain R ^C defined as —H, —F, —CN, —CH _3, or —CF ₃ .

In some embodiments, compounds of Formula I comprise RD defined as -N (R ^f ) C (= O) XCH (R ^g ) -CY, -N (R ^f ) C (= O) XC (R ^g ) 2-CY or -N (R ^f ) C (= O) X-CY, where X is absent or is -O-, -NH- or -CH2-, where RF is -H or C1-C ₄ -αalkyl, and X , CY and R ^{G were} previously defined.

In more preferred embodiments, the compounds of Formula I contain RD, defined as -N (R ^f ) C (= O) OCH (R ^g ) CY, -N (R ^f ) C (= O) NHC (R ^g ) CY, or - N (R ^f ) C (= O) CH ₂ -CY where RF is —H or C ₁ -C ₄ alkyl and X, CY and R ^{G are} as previously defined.

In some embodiments, compounds of Formula I comprise R ^E , defined as —H or C ₁ -C ₄ alkyl, C ₁ -C ₆ cycloalkyl, or C ₁ -C ₄ fluoroalkyl.

In more preferred embodiments, the compounds of Formula I contain R ^E defined as —H, —CH3, cyclopropyl, or —CF ₃ .

In some embodiments, compounds of Formula I comprise RF, defined as H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl.

In more preferred embodiments, the compounds of Formula I contain RF, defined as —H.

In some embodiments of compounds of Formula I, one R ^G is —C1-C4 alkyl and, taken together with CY and the carbon atom to which R ^G and CY are attached, forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if present, is -H.

In other embodiments of compounds of Formula IR, ^{G is} independently —H or C ₁ -C ₄ alkyl.

In some embodiments of compounds of Formula I, ring B is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring B is substituted then ring B is substituted with 1, 2 or 3 independently selected R ^H

In some embodiments of compounds of Formula I, ring C is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring C is substituted then ring C is substituted with 1, 2 or 3 independently selected R ^H

In some embodiments of compounds of Formula I, CY is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2, or 3 independently selected R ^H

In some preferred embodiments, ring A has one of the following structures:

- 17 038294

Particularly preferred compounds of formula I contain ring B and ring C, each independently defined as 1,4-substituted aryl or heteroaryl, R ^A is —CO2H, RC is —F or —CN, RD is —NR ^F C (= O) OCH (R ^G ) CY, RE is -CH3, and R ^f , R ^g and CY are previously defined.

Other particularly preferred compounds of formula I contain ring B, defined as 1,4-substituted aryl or heteroaryl, L ¹ is -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or - C (= O) N (R ^J ) -, where W is CH2, Z is substituted or unsubstituted C ₁ -C ₆ -αalkylene, R ^A is -CO2H, RD is -N (R ^f ) C ( = O) OCH (R ^g ) CY, R ^e is -CH3, and R ^C , RF, R ^G and CY are previously defined.

2) A compound according to embodiment 1, wherein ring A has one of the following structures:

3) A compound according to embodiments 1 or 2, wherein RC is —H, —CN, —F, —CH3, or —CF3.

4) A compound according to embodiments 1, 2, or 3, wherein R ^C is —F or —CN.

5) The compound according to options 1, 2, 3 or 4, where L ^{2 is} absent.

6) A compound according to embodiments 1, 2, 3, 4 or 5, wherein L ¹ , if present, is a geminally substituted alkyl, cycloalkyl or heterocycloalkyl group, or is UV-Z-, where -UV- is defined as -OW -, -WO-, -N (R ^J ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or - C (= O) N (R ^J ) -, where W is substituted or unsubstituted C1-C ₃ -alkylene, or W is —C (R ^L ) ₂ -, where RL is independently —H or C ₁ - C ₄ -alkyl, or two RL independently represent C ₁ -C ₄ -alkyl and taken together with the carbon atom to which RL are attached form a carbocycle, Z is substituted or unsubstituted C ₁ -C ₆ -alkylene or C ₁ -C ₆ -fluoroalkylene; and n is 0, 1, or 2.

7) A compound according to embodiment 6 wherein L ¹ , if present, is -CH2-, or dimethylmethane, or -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or - C (= O) N (R ^J ) -, where W is —CH2—, Z is substituted or unsubstituted C ₁ -C ₆ alkylene.

8) A compound according to any one of embodiments 1-7, wherein RF is —H.

9) A compound according to any one of Embodiments 1-8, wherein R ^G is —CH3.

10) A compound according to any one of embodiments 1-9, wherein CY is substituted or unsubstituted phenyl.

11) A compound according to any one of embodiments 1-10, wherein R ^H is -H, halogen, -CN, -NO2, -OH, -OR ^J , -SR ^J , -S (= O) R ^J , -S ^{(= O) 2R J, -N} (R L) 2, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4ftoralkoksi, C1-C ₄ -alkoxy and C ₁ -C ₄ heteroalkyl.

12) A compound according to any one of embodiments 1-11, wherein R ^{H is} independently selected from —H, halogen, or substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted C ₁ -C ₄ alkoxy.

13) A compound according to any one of embodiments 1-12, wherein R ^{H is} independently —H, —Cl, —F, —CH3, —CF3, —OCH3, or —OCF3.

14) A compound of formula II having the structure

1_ — r ^a

Formula II, or a pharmaceutically acceptable salt or prodrug thereof, wherein R ^a is -CO2H, -CO2RB, -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^b , or -C (= O) NHCH ₂ CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

RB is optionally substituted C ₁ -C ₄ -alkyl or has one of the following structures:

L ^{1 is} absent or is optionally substituted C1-C6 -alkylene; optionally substituted C1-C6 fluoroalkylene, or optionally substituted C1-C6 heteroalkylene, or -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^J ) W-, -WN ( R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is optionally substituted C1-C ₃ -alkylene, or W represents -C (R ^L) ₂ -,

- 18 038294

Z represents an optionally substituted _C1-C6 alkylene or _C1-C6 -ftoralkilen, or Z represents a -C (R ^l) ₂ -; an is 0, 1, or 2;

Ring A is a 5- or 6-membered heteroarene having one of the following structures:

where RC is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ —αalkyl, C ₁ —C ₄ alkyl, C ₃ —C ₆ cycloalkyl, or C ₁ - C ₄ -fluoroalkyl;

R ^d is -N (R ^F ) C (= O) XCH (R ^G ) -CY, -N (R ^F ) C (= O) XC (R ^G ) 2-CY or -N (R ^F ) C (= O) X-CY; where X is absent or represents -O-, -NH- or -CH ₂ -;

R ^e is —H or C ₁ -C ₄ -alkyl, C ₁ -C ₆ -cycloalkyl or C ₁ -C ₄ -fluoroalkyl;

R ^f is —H, C ₁ -C ₄ -alkyl or C ₁ -C ₆ -cycloalkyl;

R ^g is independently selected R ^E , or one of R ^G is C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for R ^E ;

ring B is optionally substituted C ₃ -C ₁₀ cycloalkylene, optionally substituted C ₂ -C ₁₀ heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, wherein if ring B is substituted then ring B is substituted by 1, 2 or 3 independently selected R ^H ;

ring C is absent or is optionally substituted C ₃ -C ₁₀ cycloalkylene, optionally substituted C ₂ -C ₁₀ heterocycloalkylene, optionally substituted arylene or optionally substituted heteroarylene, wherein if ring C is substituted then ring C is substituted by 1, 2 or 3 independently selected R ^H ;

CY is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein if CY is substituted then CY is substituted 1, 2 or 3 independently selected R ^H , or where each R ^H is independently selected -H, halogen, -CN, -NO2, -OH, -OR ^J , -SRJ, -S (= O) R ^J , -S (= O) 2R ^j , -N (R ^j ) S (= O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , -OC (= O) R ^j , -C (= O) OR ^j , -OC (= O) OR ^j , -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, -N (R ^j ) C (= O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -N (R ^j ) C (= O) OR ^j , C1- C4 alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ alkoxy or C ₁ -C ₄ heteroalkyl, and wherein R ^J is optionally substituted C ₁ -C ₆ - alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C 1 -C 6 fluoroalkyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted heterocycloalkyl, neo optionally substituted aryl, optionally substituted heteroaryl, -C ₁ -C ₄ -alkylene- (optionally substituted C ₃ -C _{6 -cycloalkyl), -C 1} -C4 alkylene- (optionally substituted heterocycloalkyl), -C 1 -C ₄ -alkylene- ( substituted or unsubstituted aryl) or —C ₁ -C ₄ -alkylene- (optionally substituted heteroaryl), and each R ^l independently is —H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl optionally substituted C ₁ -C ₆ fluoroalkyl, optionally substituted C ₃ -C ₆ cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C ₁ -C ₄ -alkylene (optionally substituted C 3 -C 6 cycloalkyl), -C ₁ -C ₄ -alkylene- (optionally substituted heterocycloalkyl), -C ₁ -C ₄ -alkylene (optionally substituted aryl), or -C ₁ -C ₄ -alkylene- (optionally substituted heteroaryl), or if R ^H is -S (C)) L '(k'b, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N ( R ^j ) C (= O) N (R ^l ) 2, then each R ^L independently represents -H or C1-C ₆ -alkyl or the R ^L groups independently represent C ₁ -C ₆ -alkyl and, when taken together with the N atom to which they are attached, form an optionally substituted heterocycle, or if W or Z is -C (R ^L ) 2-, then each R ^{L is} independently -H or C1-C ₆ -alkyl or the R ^L groups are independently C ₁ -C ₆ -alkyl and at the same time, being taken

- 19 038294 together with the carbon atom to which they are attached form a carbocycle;

where if ring B is substituted or unsubstituted arylene, ring C is absent, L ¹ is -UV-Z-, where -UV- is -N (R ^F ) C (= O) O-, where R ^F is -H, R ^d is -N (R ^F ) C (= O) XCH (R ^G ) CY, where X is -O-, RG is -CH3, and R ^f is -H, and RC is is -H, -CH3 or -CF3, or if ring B is substituted or unsubstituted arylene and ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene, or ring B is substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene and ring C is substituted or unsubstituted arylene and L ¹ is C1-C6 alkylene and RC is -H or -CH3 and RA is -CO2H or -CO2RB, then ring A has one of the following structures:

and if ring B is C ₂ -C ₁₀ heterocycloαalkylene, ring C is substituted or unsubstituted arylene, L ¹ is C ₁ -C ₆ alkylene, RC is —CH3, and R ^a is —CO2H or - CO2RB, ring A has one of the following structures:

In preferred embodiments, ring A has one of the following structures:

Particularly preferred compounds of formula II contain ring B and ring C, each of which is defined as 1,4-substituted aryl or heteroaryl, RA is CO2H, and R ^D is -N (R ^f ) C (= O) OCH (R ^g ) -CY.

Particularly preferred compounds of formula II contain ring B, defined as 1,4-substituted aryl or heteroaryl, L ¹ is -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) or -C (= O ) N (R ^J ) -, where W is -CH2-, Z is substituted or unsubstituted C ₁ -C ₆ -alkylene, RA is -CO2H, R ^D is -N (R ^f ) C (= O ) OCH (R ^g ) CY.

15) A compound of formula III having the structure

- 20 038294

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH ₂ CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

R ^B is substituted or unsubstituted C ₁ -C ₄ alkyl, or has one of the following structures:

L ^{1 is} absent or represents a substituted or unsubstituted C ₁ -C ₆ alkylene, C1-C6 fluoroalkylene; or substituted or unsubstituted C ₁ -C ₆ heteroalkylene, or -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^J ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C1-C3- alkylene, or W is —C (R ^L ) 2-, Z is substituted or unsubstituted C ₁ -C ₆ alkylene or C ₁ -C ₆ fluoroαalkylene, and n is 0, 1 or 2;

Ring A is a 5-6 membered heteroarene having one of the following structures:

where R ^C represents -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C- ₄ fluoroalkyl;

RD is -N (R ^F ) C (= O) XCH (R ^G ) CY, -N (R ^F ) C (= O) XC (R ^G ) 2-CY or -N (RF) C (= O ) X-CY, where X is absent or represents -O-, -NH- or -CH2-;

R ^e is —H or C ₁ -C ₄ alkyl, C ₁ -C ₆ cycloalkyl or C ₁ -C ₄ fluoroalkyl;

RF is —H, C ₁ -C ₄ alkyl, or C ₁ -C ₆ cycloalkyl;

R ^g is independently selected R ^E , or one R ^G is —C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for R ^E ;

A ¹ , A ² and A ³ independently represent = NH-, -N =, = CH- or -CH =;

ring C is absent or is substituted or unsubstituted C3-C10 cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring C is substituted, ring C is substituted by 1, 2 or 3 independently selected R ^H ;

CY is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2 or 3 R ^H ;

where each R ^H independently represents -H, halogen, -CN, -NO2, -OH, -OR ^J , -SRJ, -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^J ) S (= O) 2R ^J , -S (= O) 2N (R ^L ) 2, -C (= O) R ^J , -OC (= O) R ^J , -C (= O) OR ^J , -OC (= O) OR ^J , -N (R ^L ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, N (R ^j ) C ( = O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -NR ^j C (= O) OR ^j , C1-C4-alkyl, C1-C4 fluoroalkyl, C ₁ -C ₄ -fluoroalkoxy, C ₁ -C ₄ -alkoxy or C ₁ -C ₄ -heteroalkyl;

each R ^{J is} independently substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted

- 21 038294 or unsubstituted C ₃ -C ₆ cycloalkyl) _-C1-C4 -alkilen- (substituted or unsubstituted heterocycloalkyl), _-C1-C4 -alkilen- (substituted or unsubstituted aryl) or C ₁ -C ₄ - alkylene- (substituted or unsubstituted heteroaryl);

each RL is independently —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroαalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if R ^H is -S (= O) ₂ N (R ^L ) 2, -N ( R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or N (R ^J ) C (= O) N (R ^L ) 2, then each R ^L is independently an -H or C1-c ₆ -alkil group or R ^L are independently c ₁ -C ₆ -alkil and wherein, when taken together with the atom N, to which they are attached form a substituted or unsubstituted heterocycle, or if W or Z represents co fight -C (R ^L ) 2-, then each R ^L independently represents -H or C1-C ₆ -alkyl or the R ^L groups independently represent C ₁ -C ₆ -alkyl and, when taken together with a carbon atom to which they are attached form a carbocycle;

where if A ¹ , A ² and A ³ are = CH- or -CH =, ring C is absent, L ¹ is -UV-Z, where -UV- is -N (R ^F ) C (= O) O-, where R ^F is -H, R ^D is -N (R ^f ) C (= O) XCH (R ^g ) CY, where X is -O-, R ^G is -CH3, and R ^F is —H and R ^C is —H, —CH3, or —CF3, or if ring C is substituted or unsubstituted arylene or substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene and R ^C is —H or -CH3 and R ^A is -CO2H or -CO2RB, then ring A has one of the following structures:

and if ring C is substituted or unsubstituted arylene, L ¹ is C ₁ -C ₆ -alkylene, R ^C is —CH3, and RA is —CO2H or —CO2RB, then ring A has one of the following structures:

In preferred embodiments, ring A has one of the following structures:

- 22 038294

Particularly preferred compounds of formula III contain ring C, defined as 1,4-substituted phenyl or pyridyl, R ^A is —CO2H, and RD is —N (R ^f ) C (= O) XCH (R ^g ) —CY; L ¹ is -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or -C (= O) N (R ^j ) -, where W is -CH2-, Z is substituted or unsubstituted C ₁ -C ₆ alkylene, R ^A is —CO2H and RD is —N (R ^f ) C (= O) OCH (R ^g ) —CY.

16) A compound of formula IV having the structure

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2RB, -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^b , -C (= O) NHSO2R ^b , or —C (= O) NHCH ₂ CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

R ^B is optionally substituted —C ₁ -C ₄ -alkyl, or has one of the following structures:

L ¹ is -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^j ) W-, -WN (R ^j ) -, -N (R ^j ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^j ) -, where W is substituted or unsubstituted C1-C ₃ alkylene, or W is -C (R ^l ) 2-, Z is substituted or unsubstituted C1-C6 alkylene or substituted or unsubstituted C1-C6 fluoroalkylene, or Z is —C (R ^l ) 2-; an is 0, 1, or 2;

A ¹ independently represents = N- or = CH-;

Ring A is a 5- or 6-membered heteroarene having one of the following structures:

where R ^C represents -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -αalkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₄ -fluoroalkyl;

RD is -N (R ^f ) C (= O) XCH (R ^g ) CY, -N (R ^f ) C (= O) XC (R ^g ) ₂ -CY or -N (R ^f ) C (= O) X-CY, where X is absent or represents -O-, -NH- or -CH2-;

R ^e is —H or C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₄ -fluoroαalkyl;

R ^f is —H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl;

R ^g is independently selected R ^E , or one R ^G is —C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for R ^E ;

CY is C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2 or 3 RH;

- 23 038294 where each R ^H independently represents -H, halogen, -CN, -NO2, -OH, -OR ^j , -SR ^J , -S (= O) R ^j , -S (= O) 2R ^j , -N (R ^j ) S (= O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , -OC (= O) R ^j , -C (= O ) OR ^j , -OC (= O) OR ^j , -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, N (R ^j ) C (= O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -N (R ^j ) C (= O) OR ^j , C ₁ -C ₄ -αalkyl, C1-C4 fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ alkoxy or C ₁ -C ₄ heteroalkyl;

where R ^{J is} independently substituted or unsubstituted C ₁ -C ₆ -αalkyl, substituted or unsubstituted C ₁ -C ₆ -heteroαalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), —C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl), or C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl); and each RL is independently —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if R ^H is -S (= O) 2N (R ^l ) 2 , -N (R ^l ) 2, -C (= O) N (R ^l ) 2,

-OC (= O) N (R ^l ) 2 or -N (R ^j ) C (= O) N (R ^l ) 2, then each RL independently represents -H or C ₁ -C ₆ -alkyl or RL groups independently represent C ₁ -C ₆ -alkyl and, when taken together with the N atom to which they are attached, form a substituted or unsubstituted heterocycle, or if W or Z is —C (R ^l ) ₂ -, then each RL is independently —H or C ₁ -C ₆ -alkyl, or the RL groups are independently C ₁ -C ₆ -alkyl and when taken together with the carbon atom to which they are attached form a carbocycle;

or if R ^H is -S (= O) 2N (R ^l ) 2, -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2 or -N (R ^j ) C (= O) N (R ^l ) 2, then each RL independently represents -H or C ₁ -C ₆ -alkyl or RL groups independently represent C ₁ -C ₆ -alkyl and when taken together with the N atom to which they are attached form a substituted or unsubstituted heterocycle, or if W is —C (R ^l ) ₂ -, then each RL is independently —H, C1-C ₆ alkyl or the RL groups are independently C ₁ -C ₆ -alkyl and when taken together with the carbon atom to which they are attached form a carbocycle;

where A ¹ is = CH-, L ¹ is -UV-Z, where -UV- is -N (R ^f ) C (= O) O-, where R ^f is -H, RD is - N (R ^f ) -C (= O) XCH (R ^g ) CY, where X is -O-, R ^g is -CH3, and R ^F is -H, and R ^C is -H, - CH3 or —CF ₃ and R ^C is —H or —CH3 and RA is —CO2H or —CO ₂ R ^b , ring A has one of the following structures:

r ^e I

In preferred embodiments, ring A has one of the following structures:

Particularly preferred compounds of formula IV contain L ¹ , defined as -UV-Z-, where -UV -defined as -WO-, -WN (R ^j ) - or -C (= O) N (R ^j ) -, where W is -CH2-, Z is substituted or unsubstituted C ₁ -C ₆ -alkylene, RA is -CO2H, and RD is

24 038294 is -N (R ^f ) C (= O) OCH (R ^g ) CY.

17) A compound of formula V having the structure

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2RB, -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^b , -C (= O) NHSO2R ^b , or —C (= O) NHCH ₂ CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

where R ^B is optionally substituted C ₁ -C ₄ -alkyl or has one of the following structures:

L ¹ is -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^j ) W-, -WN (R ^j ) -, -N (R ^j ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^j ) -, where W is substituted or unsubstituted C ₁ -C ₃ alkylene, or W is - C (R ^l ) 2-, Z is substituted or unsubstituted C1-C6 alkylene or substituted or unsubstituted C1-C6 fluoroalkylene, or Z is —C (R ^l ) 2-; an is 0, 1, or 2;

A ¹ represents = N- or = CH-;

Ring A is a 5-membered heteroarene having one of the following structures:

where RC is -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ - C ₄ -fluoroalkyl;

RD is -N (R ^f ) C (= O) XCH (R ^g ) CY, -N (R ^f ) C (= O) XC (R ^g ) 2-CY or -N (R ^f ) C (= O) X-CY, where X is absent or represents -O-, -NH- or -CH2-;

R ^e is —H or C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₄ fluoroalkyl;

R ^f is —H, C ₁ -C ₄ -alkyl or —C ₃ -C ₆ -cycloalkyl;

R ^g is independently selected R ^E , or one R ^G is —C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for R ^E ;

CY is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2 or 3 independently selected R ^H ,

R ^H independently represents -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^j , -S (= O) 2R ^j , -N (R ^j ) S (= O) ₂ R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , -OC (= O) R ^j , -C (= O) OR ^j , -OC (= O) OR ^j , -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, NR ^j C (= O) N ( R ^l ) 2, -NR ^j C (= O) R ^j , -NR ^j C (= O) OR ^j , C1-C4-alkyl, C ^ -fluoroalkyl, C1-C4 fluoroalkoxy, C ₁ -C ₄ -alkoxy and C ₁ -C ₄ heteroalkyl;

where each RJ is independently substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl ), —C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or C ₁ -C ₄ -alkylene (substituted or unsubstituted heteroaryl);

where each RL is independently —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl,

- 25 038294 substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -αalkylene (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene (substituted or unsubstituted heteroaryl);

or if R ^H is -S (= O) ₂ N (R ^L ) 2, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^j ) C (= O) N (R ^l ) ₂ , then each RL independently represents -H or C ₁ -C ₆ -alkyl or RL groups independently represent C ₁ -C ₆ - alkyl and when taken together with the N atom to which they are attached form a substituted or unsubstituted heterocycle, or if W or Z is -C (R ^L ) 2-, then each R ^L independently represents -H or C ₁ -C ₆ -alkyl or RL groups are independently C ₁ -C ₆ -alkyl and when taken together with the carbon atom to which they are attached form a carbocycle, where if A ¹ is = CH-, L ¹ is -UV-Z, where -UV- is -NHC (= O) - and RC is -H, -CH3, or -CF ₃ , then ring A has one of the following structures:

Particularly preferred compounds of formula V contain L ¹ , defined as UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or -C (= O) N (R ^J ) -, where W is is -CH2-, Z is substituted or unsubstituted C ₁ -C ₆ -αalkylene, R ^A is -CO2H, and RD is -N (R ^f ) C (= O) OCH (R ^g ) -CY.

18) A compound of formula VI having the structure:

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2RB, -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH2CH2SO3H, or isostere analogue of the carboxylic acid group, where

R ^B is optionally substituted C ₁ -C ₄ -αalkyl, or has one of the following structures:

L ¹ is -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^J ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C1-C3 -alkylene, or W is -C ( R ^L ) 2-, Z is substituted or unsubstituted C ₁ -C ₆ -alkylene or substituted or unsubstituted C ₁ -C ₆ -fluoroalkylene, or Z is -C (R ^l ) ₂ -; an is 0, 1, or 2;

A ¹ independently represents = N- or = CH-;

Ring A is a 5-membered heteroarene having one of the following structures:

- 26 038294

where R ^{C is} defined as -H, -CN, -F, -Cl, -Br, -I, -OC1-C ₄ -alkyl, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or

_C1-C4 -fluoroalkyl;

where R ^d represents the substituent -N (R ^F ) C (= O) CH (R ^G ) CY in formula VI, where CY is phenyl substituted with one R ^H ;

R ^g is an independently selected RE, or one R ^G is —C 1 -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for RE;

RF is —H, _{—C 1} -C ₄ -alkyl or —C _{3 -C 6} -cycloalkyl;

RH is independently selected from -H, halogen, -CN, -NO ₂ , -OH, -OR ^J , -SR ^J , -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^j ) S (= O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^J , OC (= O) R ^J , - (O'R'_ -OC (= O) OR ^J , -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2, N (R ^j ) C (= O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -N (R ^j ) C (= O) OR ^j , C1-C4-alkyl, C ^ -fluoroalkyl, C1-C4-fluoroalkoxy , _C1-C4 alkoxy and _C1-C4 heteroalkyl;

wherein RJ is a substituted or unsubstituted _C1-C6 alkyl, substituted or unsubstituted C1-Sa-heteroalkyl, substituted or unsubstituted C1-Sa-fluoroalkyl, substituted or unsubstituted C ₃ -Sb cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, _-C1-C4 -alkilen- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl) _-C1-C4 -alkilen- (substituted or unsubstituted heterocycloalkyl), -C1-S4alkilen- (substituted or unsubstituted aryl) or _C1-C4 -alkilen- (substituted or unsubstituted heteroaryl);

wherein each R ^L is independently -H, substituted or unsubstituted _C1-C6 alkyl, substituted or unsubstituted _C1-C6 heteroalkyl, substituted or unsubstituted C1-C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), _{-C 1 -C 4} -alkylene- (substituted or unsubstituted heterocycloalkyl), _C1-C4 -alkilen- (substituted or unsubstituted aryl), or _-C1-C4 -alkilen- (substituted or unsubstituted heteroaryl), or if RH represents -S (= O) ₂ N (R ^L) 2 , -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^J ) C (= O) N (R ^L ) ₂ , then each R ^L independently represents -H or C1-Cb-alkyl, or the R ^L groups independently represent C1-Cb-alkyl and, when taken together with the N atom to which they are attached, form substituted or unsubstituted heterocycle, or if W or Z is yayut is -C (R ^L) 2-, each R ^L is independently an -H or C1-C6 alkyl group, or R ^L are independently _C1-C6 alkyl and wherein, when taken together with the carbon atom, to which they are attached form a carbocycle.

In preferred embodiments, ring A has one of the following structures:

Particularly preferred compounds of formula VI contain L ¹ as -UV-Z-, where -UV- is -C (= O) NH-, -CH2O- or -CH2NH-, Z is substituted -CH-, and RA represents -CO2H.

19) A compound of formula VII having the structure

- 27 038294

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B or -C (= O) NHCH2CH2SO ₃ H, or isosteric analogue of carboxylic acid groups;

R ^B is optionally substituted C ₁ -C ₄ alkyl or has one of the following structures:

A independently represents = N- or = CH-; ring A has one of the following structures:

RC is -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C _4- fluoroalkyl;

where RD is the substituent -N (R ^F ) C (= O) CH (R ^G ) -CY in formula VII, where CY is phenyl substituted with one R ^H ;

R ^e , R ^f and R ^{g are} independently —H or C ₁ -C ₄ -alkyl;

Z represents -C (R ^L ) ₂ -;

R ^H independently represents -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^J ) S (= O) 2R ^J , -S (= O) 2N (R ^L ) 2, -C (= O) R ^J , -OC (= O) R ^J , -CO2R ^J , -OCO2R ^J , -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^l ) 2, NR ^j C (= O) N (R ^l ) 2, -NR ^j C (= O) R ^j , -NR ^j C (= O) OR ^j , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ heteroalkyl;

R ^J is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C1-C4 alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl);

R ^l is —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C1-C4 alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if RH is -S (= O) ₂ N (R ^L ) 2 , -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^J ) C (= O) N (R ^L ) 2, then each R ^l independently represents -H or C1-C ₆ -alkyl or the R ^L groups independently represent C ₁ -C ₆ -alkyl and, when taken together with the N atom to which they are attached, form substituted or unsubstituted heterocycle, or each R ^l in Z is independently represented ulation is -H, or C1-C6-alkyl group, or R ^L are independently a C1-C ₆ alkyl, and wherein, when taken together with the carbon atom to which they are attached, form a carbocycle.

In some embodiments, compounds of Formula VII comprise RF, defined as —H, C ₁ -C ₄ alkyl, or C ₁ -C ₆ cycloalkyl, and R ^H , RJ, and R ^{L are} each previously defined.

In particularly preferred compounds of formula VII, R ^A is —CO2H.

- 28 038294

20) A compound of formula VIII having the structure

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^b , or -C (= O) NHCH2CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

R ^B is optionally substituted C ₁ -C ₄ -αalkyl, or has one of the following structures:

A ¹ represents = N- or = CH-;

ring A has one of the following structures:

RC is -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, or C ₁ -C _4- fluoroalkyl;

where RD is the substituent -N (R ^F ) C (= O) CH (R ^G ) CY in formula VII, where CY is phenyl substituted with one R ^H ;

RF and R ^{e are} independently —H or C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl;

R ^g is —H or C ₁ -C ₄ -alkyl, or is C ₁ -C ₄ -alkyl, which when taken together with the substituted R ^H phenyl moiety of the substituent RD of Ring A and the carbon atom to which R ^G and said phenyl component, forms a carbocycle;

W represents -C (R ^l ) ² -;

Z represents -C (R ^l ) ₂ -;

R ^H is -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^J , -S (= O) 2R ^j , -N (R ^j ) S ( = O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , -OC (= O) R ^j , -CO2R ^j , -OCO2R ^j , -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, NR ^j C (= o) n (R ^l ) 2, -NR ^j C (= O ) R ^j , -NR ^j C (= O) OR ^j , C1-C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C1-C4 alkoxy and C ₁ -C ₄ heteroalkyl;

R ^J is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, is substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), —C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl), or C ₁ -C ₄ -αalkylene- (substituted or unsubstituted heteroaryl);

R ^{l is} independently —H, substituted or unsubstituted C ₁ -C ₆ -αalkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ - cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if R ^H is -S (= O) 2N (R ^l ) 2, -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) ₂ or -N (R ^j ) C (= O ) N (R ^l ) 2, then each R ^L independently represents -H or C1-C ₆ -alkyl, or the R ^L groups independently represent C ₁ -C ₆ -alkyl and, when taken together with the N atom, to to whom

- 29 038294 they are attached, form a substituted or unsubstituted heterocycle, or each RL in W or Z is independently —H or C ₁ -C ₆ -alkyl, or the R ^L groups are independently C ₁ -C ₆ -alkyl and wherein taken together with the carbon atom to which they are attached form a carbocycle.

In some embodiments, compounds of Formula VIII contain R ^F defined as —H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl.

In particularly preferred compounds of formula VIII, R ^A is —CO2H and RJ is —H.

21) A compound of formula IX having the structure

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH ₂ CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

R ^B is optionally substituted C ₁ -C ₄ alkyl or has one of the following structures:

the ring has one of the following structures:

RC is -H, -CN, -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C _4- fluoroalkyl;

where RD is the substituent -N (R ^F ) C (= O) CH (R ^G ) -CY in formula IX, where CY is phenyl substituted with one RH;

R ^e , R ^f and R ^g independently represent -H, C1-C4 alkyl or C1-C6 cycloalkyl, or R ^E and R ^F independently represent -H, C1-C ₄ alkyl or C ₁ -C ₆ -cycloalkyl, and R ^G is C1-C4 alkyl, which, when taken together with the RH-substituted phenyl moiety of the substituent RD of Ring A and the carbon atom to which R ^G and said phenyl moiety are attached, forms a carbocycle;

RH is independently -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^J ) S ( = O) 2R ^J , -S (= O) 2N (R ^L ) 2, -C (= O) R ^J , -OC (= O) R ^J , -CO2R ^J , -OCO2R ^J , -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^l ) 2, NR ^j C (= O) N (R ^l ) 2, -NR ^j C (= O ^{) R j, -NR j C (} = O) OR j, C1-C4- alkyl, ^^ - fluoroalkyl, C1-C4ftoralkoksi, C1-C ₄ -alkoxy and C ₁ -C ₄ heteroalkyl;

RJ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene (substituted or unsubstituted aryl) or C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl);

W represents -C (R ^L ) ₂ -;

Z represents -C (R ^L ) ₂ -;

R ^{l is} independently —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ - cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or

- 30 038294 unsubstituted C ₃ -C6 -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C1-C ₄ - alkylene- (substituted or unsubstituted heteroaryl), or each of RL in W or Z is independently C1-C6 alkyl, which when taken together with the carbon atom to which they are attached form a carbocycle.

In preferred compounds of formula IX, R ^A is —CO2H.

22) A compound of formula X having the structure

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^b , or -C (= O) NHCH2CH ₂ SO ₃ H, or an isostere analog of the carboxylic acid group;

R ^B is optionally substituted C ₁ -C ₄ alkyl or has one of the following structures:

L ^{1 is} absent or is optionally substituted C ₁ -C ₆ alkylene; C1-C6ftoralkilen or optionally substituted C ₁ -C ₆ -geteroαlkilen or

L ¹ , if present, is -CH2-,

or disubstituted dimethylmethane.

A1 represents = N- or = CH-; ring A has one of the following structures:

R ^C is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ —αalkyl, C ₁ —C ₄ alkyl, C ₃ —C ₆ cycloalkyl, or C ₁ - C ₄ -fluoroalkyl;

RD is -NR ^F C (= O) XCH (R ^G ) -CY, -NR ^F C (= O) XC (R ^G ) ₂ -CY or -NR ^F C (= O) X-CY; where X is absent or represents -O-, -NH- or -CH2-;

R ^e, R ^f and R ^g are each independently -H, or C1-C4-alkyl or C3-C6-cycloalkyl, or R ^E and RF are independently -H, C1-C ₄ -alkyl or C ₁ -C ₆ -cycloαalkyl, and one R ^G is C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, defined for R ^E ;

R ^H is -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^J ) S ( = O) 2RJ, -S (= O) 2N (R ^L ) 2, -C (= O) R ^J , -OC (= O) R ^J , -CO2R ^J , -OCO2R ^J , -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2, NR ^j C (= o) n (R ^l ) 2, -NR ^j C (= O) ^{R j, -NR j C (=} O) OR j, C1-C ₄ alkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -ftoralkoksi, C1-C4 alkoxy and C ₁ -C ₄ heteroalkyl;

R ^J is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted

- 31 038294

C ₃ -C6-cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene (substituted or unsubstituted aryl) or C1-C ₄ -alkylene- (substituted or unsubstituted heteroaryl);

RL is independently —H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl ), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if R ^H is -S (= O) ₂ N (R ^L ) 2, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^j ) C (= O) N (R ^l ) 2, then each R ^L independently represents -H or C1-C ₆ -alkyl or the R ^L groups independently represent C ₁ -C ₆ -alkyl and, when taken together with the N atom to which they attached to form a substituted or unsubstituted heterocycle;

CY is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2 or 3 R ^H , where if L ^{1 is} not absent and RC is -H or -CH3 and R ^A is -CO2H or -CO2RB, then ring A has one of the following structures :

In preferred embodiments, ring A has one of the following structures:

23. A compound of formula XI having the structure:

or a pharmaceutically acceptable salt or prodrug thereof, where R ^A is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH2CH2SO3H, or an isostere analog of the carboxylic acid group;

R ^B is optionally substituted C ₁ -C ₄ alkyl or has one of the following structures:

L ^{1 is} absent or is optionally substituted C ₁ -C ₆ alkylene; C1-C6ftoralkilen or optionally substituted C ₁ -C ₆ heteroalkyls, or

L ¹ , if present, is -CH2-,

- 32 038294

or disubstituted dimethylmethane.

A ¹ represents = N- or = CH-; ring A has one of the following structures:

RC is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ —αalkyl, C ₁ —C ₄ alkyl, C ₃ —C ₆ cycloalkyl, or C ₁ —C _4- fluoroalkyl;

RD is -N (R ^F ) C (= O) XCH (R ^G ) CY, -N (R ^F ) C (= O) XC (R ^G ) 2-CY, or -N (R ^F ) C (= O) X-CY; where X is absent or represents -O-, -NH- or -CH ₂ -;

R ^e, R ^f and R ^g are each independently -H, or C1-C4-Alkyl, or C3-C6-cycloalkyl, or R ^E and RF are each independently -H, or C1-C ₄ -alkil or C ₁ -C ₆ -cycloalkyl, and one R ^G is C ₁ -C ₄ -alkyl and taken together with CY and the carbon atom to which R ^G and CY are attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for R ^E ;

R ^H is -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^J ) S ( = O) 2R ^J , -S (= O) 2N (RL) 2, -C (= O) R ^J , -OC (= O) R ^J , -CO.R'_ -OCO.RJ -N (RLb -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2, NR ^J C (= O) N (R ^L ) 2, -NR ^j C (= O) R ^j , —NR ^j C (= O) OR ^j , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C1-C4 alkoxy and C ₁ -C ₄ heteroalkyl;

R ^J is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl) , —C ₁ -C ₄ -alkylene (substituted or unsubstituted aryl) or C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl);

RL is independently —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C6 -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if R ^H is -S (= O) 2N (R ^L ) 2, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2 or -N (R ^j ) C (= O) N (R ^l ) ₂ , then each RL is independently —H or C ₁ -C6 -alkyl, or the RL groups are independently C ₁ -C ₆ -alkyl and, when taken together with the N atom to which they are attached, form a substituted or unsubstituted heterocycle,

CY is C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₃ -C ₁₀ -cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ -heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2 or 3 R ^H , where if L ^{1 is} not absent and R ^C is —H or —CH3 and RA is —CO2H or —CO2RB, then ring A has one of the following structures:

R ^e

I. ...

In particularly preferred compounds of formula XI, RA is —CO ₂ H and RD is —NR ^F C (= O) OCH (R ^G ) CY.

24) A compound of formula XII having the structure

- 33 038294

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B , or -C (= O) NHCH2CH2SO3H, or an isostere analog of the carboxylic acid group;

R ^B is optionally substituted C ₁ -C ₄ -αalkyl, or has one of the following structures:

L ^{1 is} absent or represents an optionally substituted C ₁ -C ₆ -alkylene; C1-C6ftoralkilen or optionally substituted C ₁ -C ₆ -geteroalkilen or

L ¹ , if present, is -CH2-,

or disubstituted dimethylmethane.

A ¹ represents = N- or = CH-; ring A has one of the following structures:

RC is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ alkyl, C ₁ —C ₄ alkyl, C ₃ —C ₆ cycloalkyl, or C ₁ —C _4- fluoroalkyl;

where RD is the substituent -N (R ^F ) C (= O) CH (R ^G ) CY in formula XII, where CY is phenyl substituted with one RH;

R ^e, RF and R ^g are each independently -H, or C1-C4-Alkyl, or C3-C6-cycloalkyl, or R ^E and RF are each independently -H, or C1-C ₄ -alkil or C ₁ - C ₆ -cycloalkyl, and one R ^G is —C ₁ -C ₄ -alkyl and, taken together with the RH-substituted phenyl moiety of the substituent RD of Ring A and the carbon atom to which R ^G and said phenyl moiety are attached, forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other R ^G , if any, is defined for R ^E ;

RH is -H, halogen, -CN, -NO2, -OH, -ORJ, -SRJ, -S (= O) R ^J , -S (= O) 2R ^J , -N (R ^J ) S (= O) 2R ^J , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , -OC (= O) R ^j , -CO2RJ, -OCO2RJ, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L ) 2, NR ^j C (= O) N (R ^l ) 2, -NR ^j C (= O) R ^{j , -NR j C (= O)} OR j, C1-C4- alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4 alkoxy and C ₁ -C ₄ heteroalkyl;

R ^J is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C4-alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene (substituted or unsubstituted aryl) or C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl);

R _{l is} independently —H, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₁ -C ₆ -fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ - cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl),

- 34 038294 or if R ^H is -S (= O) ₂ N (R ^L ) 2, -N (R ^L ) 2, -C (= O) N (R ^L ) 2, -OC (= O) N (R ^L) 2, or -N (RJ) C (= O ) N (R L) _2, then each R ^L is independently an -H or C1-C6 alkyl group, or R ^L are independently C ₁ -C ₆ -alkyl and when taken together with the N atom to which they are attached form a substituted or unsubstituted heterocycle, where if L ^{1 is} not absent and RC is —H or —CH3 and R ^A is —CO2H or -CO2RB, then ring A has one of the following structures:

In particularly preferred compounds of formula XII, R ^A is —CO2H.

25) A composition containing one or more compounds of the formula I-XII and one or more excipients, essentially consisting of or consisting of them.

In preferred embodiments, the composition comprises one compound of Formula IXII and one or more excipients essentially consists of or consists of them.

In other preferred embodiments, the composition is a pharmaceutically acceptable formulation comprising one compound of Formula I-XII and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

26) A compound of formula I-XII, or a pharmaceutically acceptable salt or prodrug thereof, wherein the binding affinity of the compound for the lysophosphatidic acid receptor 1 (LPA1R) is from about 10 μM to 1 pM or less.

27) The compound according to embodiment 19, wherein the compound is a lysophosphatidic acid receptor 1 (LPA1R) selective compound.

28) A compound of formula I-XII, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound is a lysophosphatidic acid receptor 1 (LPA1R) selective compound.

29) A compound according to embodiments 20, 21, or 22, wherein the compound is a lysophosphatidic acid receptor 1 (LPA1R) selective compound, wherein the binding affinity (i.e., KD) of the compound to LPA1R is from about 1 μM to 1 pM, or less. In preferred embodiments, the K _D is 100 nM or less, more preferably 10 nM or less.

30) The connection from table. 1.

31) The compound according to Embodiment 30, wherein the compound is 1- (4- {4 [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) cyclopropanecarboxylic acid, 2- (4- {4 - [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indan-2carboxylic acid, 2- (S) - (4- {4 - [(R, S) -1- (2 -chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5yl} benzoylamino) phenylacetic acid, 2- (R) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazole-5- yl} benzoylamino) phenylpropanoic acid, 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 2 ( S) - [[4- [3-methyl-4 - ((R) phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2- {4- [3 methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3-phenylpropionic acid, (S) -2- {4- [3-methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxαzole -5-yl] benzoylamino} -3-phenylpropionic acid, (R) -2- (4- {4 - [(R) -1- (2- chlorophenyl) ethoxycarbonylamino] -3-methylisoxαzol-5-yl} benzoylamino) -3-phenylpropionic acid, (R) -2- (4- {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3 methylisoxazole -5-yl} benzoylamino) -3- (4-fluorophenyl) propionic acid, (R) -3- (4-chlorophenyl) -2- (4 {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino ] -3 -methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 (3,4-difluorophenyl) propionic acid, (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -3- (4-bromophenyl) -2 (4- {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazole- 5-yl} benzoylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) 3 - (2 -fluorophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-p-tolylpropionic acid , (R) -2- (4- {4 - [(R) -1- ( 2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3- (4-trifluoromethylphenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2- chlorophenyl) ethoxycarbonylamino] -3-methylisoxαzol-5-yl} benzoylamino) -3 (4-cyanophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino ] -3methylisoxazol-5-yl} benzoylamino) -3-cyclopropylpropionic acid.

32) The compound according to Embodiment 30, wherein the compound is (R) -2 - [[4 [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] - 3-phenylpropane

- 35 038294 acid, (R) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylα-amino) nyrαzol-3-yl] benzoyl] amino] -3- (4fluorophenyl) propane acid, (R) -3- (4-bromophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid , (R) -3- (4-chlorophenyl) -2 - [[4- [2,5-dimethyl4 - ((R) -1-phenylethoxycarbonylamino) nyrazol-3-yl] benzoyl] αmino] pronanoic acid or (R ) -3- (3,4difluorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) npyrazol-3-yl] benzoyl] αmino] npropanoic acid.

33. A compound according to embodiment 30, wherein the compound is 2- [4- [4 [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] acetic acid, 2- [4 - [4- [4 [1- (2-chlorophenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3-yl] phenyl] phenyl] acetic acid, 2- [4 [4- [4- [1 - (2- fluorophenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3-yl] phenyl] phenyl] acetic acid, 2- [4- [4- [4- [1- (2,6-difluorophenyl) ethoxycarbonylamino] -2.5- dimethylpyrazol-3-yl] phenyl] phenyl] acetic acid, 2- [4- [4- [4- [1- (2-methoxyphenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3-yl] phenyl] phenyl] acetic acid acid, 1- [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, 1- [4- [6- [2.5 - dimethyl 4 - (1-phenylethoxycarbonylamino) pyrazol-3 yl] -3-pyridyl] phenyl] cyclopropanecarboxylic acid, 1- [4- [4- [4- [1 - (2-chlorophenyl) ethoxycarbonyl-amino] -2, 5-dimethylpyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, 1- [4- [4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -2, 5-dimethylpyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, 1- [4- [4- [4- [1- (2,6-difluorophenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3-yl] phenyl ] phenyl] cyclopropanecarboxylic acid, 1- [4- [4- [4- [1- (2-methoxyphenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3yl] phenyl] phenyl] cyclopropanecarboxylic acid, 2- [4- [4 - [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] -2-methylpropanoic acid, 2- [4- [4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3-yl] phenyl] phenyl] -2-methylpropanoic acid, 2- [4- [4- [4- [1- (2fluorophenyl) ethoxycarbonylamino] -2,5-dimethylpyrazole-3 -yl] phenyl] phenyl] -2-methylpropanoic acid, 2- [4- [4- [4- [1 - (2,6-difluorophenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3-yl] phenyl] phenyl ] -2-methylpropanoic acid or 2- [4- [4- [4- [1- (2-methoxyphenyl) ethoxycarbonylamino] -2,5-dimethylpyrazol-3yl] phenyl] phenyl] -2-methylpropanoic acid.

34) The compound according to Embodiment 30, wherein the compound is (R) -2 - [[4 [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] - 3-phenylpropanoic acid, (R) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylαmino) pyrαzol-3-yl] benzoyl] amino] -3- (4fluorophenyl) propane acid, (R) -3- (4-bromophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid , (R) -3- (4-chlorophenyl) -2 - [[4- [1,5-dimethyl4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] αmino] propanoic acid or (R ) -3- (3,4difluorophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] αmino] propanoic acid.

35) The compound according to Embodiment 30, wherein the compound is (R) -2- (4 {5 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -4-methylpyrazol-1 -yl} benzoylamino) -3 -phenylpropionic acid.

36) The compound according to Embodiment 30, wherein the compound is (R) -2- {4 [3 -methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3-phenylpropionic ki- slot, (R) -3- (2-fluorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) - 2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxαzol-5yl] benzylamino} -3- (4-trifluoromethylphenyl) propionic acid, (R) -3-cyclopropyl-2- {4 - [3-methyl-4 ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -3- (2-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -3- (4-chlorophenyl) -2- {4- [3-methyl-4 - ((R) - 1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3-phenylpropionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3- (2 -fluorophene yl) propionic acid, (R) -2- (4- {4 [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazol-5-yl} benzylamino) -3 - (4-trifluoromethylphenyl) propionic acid, (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl} benzylamino) propionic acid or (R ) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3-cyclopropylpropionic acid.

37) The compound according to Embodiment 30, wherein the compound is 2- {4- [3methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid, 2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid, (RS) -3-cyclopropyl-2- {4- [3-methyl-4- ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid or (RS) -3-cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole -5-yl] benzyloxy} propionic acid.

38) The compound according to Embodiment 30, wherein the compound is 2- [4- [4 [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetic acid, (R ) -1 [4- [4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, (R) -1- [4- [4- [2 , 5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyc

- 36 038294 lopropanecarboxylic acid, (R) -1- (4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1 yl} -3-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, ( R) -1 - (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- ( 2chloro-4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4' - {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-methyldiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1 - (4 '- {5- [1 - (2- chlorophenyl) ethoxycarbonylamino] -4fluoropyrazol-1-yl} -diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- {4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] -diphenyl -4-yl} cyclopropanecarboxylic acid, (R) -1- {2fluoro-4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid or (R) -1- (4- {5- [5- (1-phenylethoxycarbonylamino) pyrazol-1-yl] pyridin-2-yl} phenyl) cyclopropanecarboxylic acid.

39) The compound according to Embodiment 30, wherein the compound is 2 - [[4- [3methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 3cyclopropyl-2 - [[ 4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl ] benzoyl] amino] -3-phenoxypropanoic acid, 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] 4-phenylbutanoic acid, 2 - [[4 - [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3-cyclopropylpropanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl ] amino] -4-phenylbutanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3-phenoxypropanoic acid, 2 [[ 4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-m methylisoxazol-5-yl] benzoyl] amino] -4-phenylbutanoic acid, 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3phenoxypropane acid, 3-cyclopropyl-2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 3- (4-methoxyphenyl) -2 - [[4- [3-methyl-4 (1- phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (4-fluorophenyl) -2 [[4- [3-methyl-4 - (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 3 (2,6-difluorophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (3-cyanophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (2-chlorophenyl) -2 - [[4- [3-methyl -4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (4-chlorophenyl) -2 - [[4- [3-methyl-4- (1-phenyl ethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3- [4- ( trifluoromethyl) phenyl] propanoic acid, 3- (4hydroxyphenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (3.4 -difluorophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5yl] benzoyl] amino] propanoic acid, 3- (4-bromophenyl) -2 - [[4- [3- methyl 4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3- [4- (trifluoromethoxy) phenyl] propanoic acid, 2 - [[4- [4- [1 (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- (4 -methoxyphenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- (2,6-difluorophenyl) propane slot, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- (3-cyanophenyl) propanoic acid, 3- (2- chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (4-chlorophenyl) -2 - [[ 4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazol-5-yl] benzoyl] amino] -3- [4- (trifluoromethyl) phenyl] propanoic acid, 2 - [[4- [4 [1 - (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazole-5 - yl] benzoyl] amino] -3 - (4-hydroxyphenyl) propanoic acid, 3- (4-bromophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5 -yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] -3- (3,4-difluorophenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- [4- (trifluoromethoxy) phenyl] propanoic acid, 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- (4-methoxyphenyl) propanoic acid, 3- (4-fluorophenyl) -2 - [[4 - [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (2,6-difluorophenyl) -2 - [[4- [4 [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 3 (3-cyanophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (2-chlorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5- yl] benzoyl] amino] propanoic acid, 3- (4-chlorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3- [4- (trifluoromethyl) phenyl] propano

- 37 038294 acid, 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] -3 (4-hydroxyphenyl) propanoic acid, 3- (3,4-difluorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 3- (4-bromophenyl) -2 - [[4- [4- [1 (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl] benzoyl] amino] propanoic acid, 2 - [[4 [4- [1 - (2-fluorophenyl ) ethoxycarbonylamino] -3 -methylisoxazol-5 -yl] benzoyl] amino] -3- [4- (trifluoromethoxy) phenyl] propanoic acid, (±) - (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) acetic acid, (±) -2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -2-methylpropionic acid , (±) -2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid, (±) -2- (4- {4- [ 1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-hydroxypropionic acid, (±) -1- (4- {4- [1 - (2-chlorophenyl) ethoxycarb onylamino] -3-methylisoxazol-5 -yl} benzoyl) pyrrolidine-2-carboxylic acid or (±) -2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl } benzoylamino) propionic acid.

40. A compound according to Embodiment 30, wherein the compound is 2- {p- [3fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoylamino} -3-phenylpropionic acid, 2 (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} benzoylamino) -3-phenylpropionic acid, 3-cyclopropyl-2- {p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoylamino} propionic acid, 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid, 2 - [({p- [3- fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid, 2- {[(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 -isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid, 3-cyclopropyl-2 - [({p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl) amino] propionic acid, 2 - {[(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} phenyl) methyl] amino} 3-cyclopropylpropionic acid, 2 - ({p- [3 -fluoro-4- (1-phen ylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid, 2 - [(p- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3 fluoro-5-isoxazolyl} phenyl) methoxy] -3 -phenylpropionic acid, 3-cyclopropyl-2 - ({p- [3-fluoro-4- (1phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) propionic acid, or 2 - [(p- {4- [1- (chlorophenyl ) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid.

41. The compound according to Embodiment 30, wherein the compound is 2-benzyl3- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2-benzyl-3 - (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridylamino) propionic acid, 2- (cyclopropylmethyl) -3- {5- [3-fluoro-4 - (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5isoxazolyl} -2-pyridylamino) - 2- (cyclopropylmethyl) propionic acid, 2-benzyl-3- {5- [3-fluoro-4 (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2-benzyl-3- (5- {4 [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 -isoxazolyl} -2-pyridyloxy) propionic acid, 2benzyl-3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] - 3-fluoro-5-isoxazolyl} -2-pyridyloxy) propionic acid, 2- (cyclopropylmethyl) -3- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2pyridyloxy} propionic acid, 3- (5- {4 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 -isoxazolyl} -2-pyridyloxy) -2- (cyclopropylmethyl) propionic acid, 2- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino ) -5 -isoxazolyl] -2-pyridylamino} -3-phenylpropionic acid, 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridylamino) - 3-phenylpropionic acid, 3-cyclopropyl-2- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridylamino} propionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridylamino) -3-cyclopropylpropionic acid, 2- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] - 2-pyridyloxy} -3-phenylpropionic acid, 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] 3-fluoro-5-isoxazolyl} -2-pyridyloxy) -3-phenylpropionic acid, 3-cyclopropyl -2- {5- [3-fluoro-4- (1 phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2- (5- {4- [1- (chlorophenyl) ethoxycarbonylamino] -3-fluoro -5-isoxazolyl} -2-pyridyloxy) -3 -cyclopropylprop ionic acid, 2- {p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] benzoylamino} -3-phenylpropionic acid, 2- (p- {4- [1- (o-chlorophenyl ) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} benzoylamino) 3-phenylpropionic acid, 3-cyclopropyl-2- {p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoylamino} propionic acid, 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid, 2 - [({p- [3-fluoro-4- (1- phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid, 2 - {[(p- {4- [1- (chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid, 3-cyclopropyl-2 - [({p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl) amino] propionic acid, 2- {[( p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} phenyl) methyl] amino} -3-cyclopropylpropionic acid, 2 - ({p- [3-fluoro-4- ( 1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -3-fe nylpropionic acid, 2 - [(p- {4- [1- (o-chlorophe

- 38 038294 nyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} phenyl) methoxy] -3-phenylpropionic acid, 3-cyclopropyl-2 - ({p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl ] phenyl} methoxy) propionic acid, 2 - [(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} phenyl) methoxy] -3cyclopropylpropionic acid, 2-benzyl-3- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2-benzyl-3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridylamino) propionic acid, 2- (cyclopropylmethyl) -3- {5- [3fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid , 3- (5- {4 [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridylamino) -2- (cyclopropylmethyl) propionic acid, 2-benzyl-3- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2-benzyl-3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro- 5isoxazolyl} -2-pyridyloxy) propionic acid, 2- (c iclopropylmethyl) -3- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino ] -3-fluoro-5-isoxazolyl} -2-pyridyloxy) -2- (cyclopropylmethyl) propionic acid, 2- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino } -3-phenylpropionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridylamino) -3-phenylpropionic acid, 3-cyclopropyl-2 - {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3- fluoro-5-isoxazolyl} -2-pyridylamino) -3-cyclopropylpropionic acid, 2- {5- [3-fluoro4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} -3-phenylpropionic acid, 2- (5 {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2-pyridyloxy) -3-phenylpropionic acid, 3-cyclopropyl-2- {5- [3 -fluoro-4 - (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propion ovic acid or 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} 2-pyridyloxy) -3-cyclopropylpropionic acid.

42) The compound according to Embodiment 30, wherein the compound is 2- {p- [3cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoylamino} -3-phenylpropionic acid, 2 (p- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} benzoylamino) -3-phenylpropionic acid, 2- {p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoylamino} -3 -cyclopropylpropionic acid, 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid, 2 - [({p- [3-cyano -4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid, 2- {[(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano - 5 -isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid, 2 - [({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} methyl) amino] -3-cyclopropylpropionic acid acid, 2- {[(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} phenyl) methyl] amino} -3-cyclopropylpropionic acid , 2 - ({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid, 2 - [(p- {4- [1- (o-chlorophenyl ) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} phenyl) methoxy] -3-phenylpropionic acid, 2 ({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -3 -cyclopropylpropionic acid or 2 - [(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid.

43) The compound according to Embodiment 30, wherein the compound is 2-benzyl3- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2-benzyl-3 - (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridylamino) propionic acid, 3- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} -2 (cyclopropylmethyl) propionic acid, 3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5isoxazolyl} -2-pyridylamino) -2 - (cyclopropylmethyl) propionic acid, 2-benzyl-3- {5- [3-cyano-4 (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2-benzyl-3- (5- { 4 [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridyloxy) propionic acid, 3- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} -2- (cyclopropylmethyl) propionic acid, 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) about pionic acid, 2- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridylamino} -3-phenylpropionic acid, 2- (5- {4- [1 - (o- chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridylamino) -3-phenylpropionic acid, 2- {5- [3 - cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino } -3-cyclopropylpropionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridylamino) -3cyclopropylpropionic acid, 2- {5- [3 -cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5isoxazolyl} - 2-pyridyloxy) -3-phenylpropionic acid, 2- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} -3-cyclopropylpropionic acid, 2- (5- {4 - [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridyloxy) -3-cyclopropylpropionic acid, 2- {p- [3-cyano-4 - (1-phenylethoxycarbonylamino) -5 -isoxazolyl] benzoylamino} -3 -phenylpropionic acid, 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} benzoylamino) -3phenylpropionic acid, 2- {p- [3-cyano-4- ( 1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoyl- 39 038294 amino} -3-cyclopropylpropionic acid, 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5isoxazolyl} benzoylamino) -3 -cyclopropylpropionic acid, 2 - [({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid, 2 - {[(p- {4- [1- (chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid, 2 - [({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -methyl) amino] -3 -cyclopropylpropionic acid, 2- {[(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5isoxazolyl} phenyl) methyl] amino} - 3-cyclopropylpropionic acid, 2 - ({p- [3-cyano-4- (1phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid, 2 - [(p- {4- [1 (o- chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazo lil} phenyl) methoxy] -3-phenylpropionic acid, 2 - ({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -3-cyclopropylpropionic acid, 2 - [(p - {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid, 2-benzyl-3 - {5- [3-cyano-4- ( 1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2-benzyl-3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano -5 -isoxazolyl} - 2-pyridylamino) propionic acid, 3- {5- [3cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} -2- (cyclopropylmethyl) propionic acid, 3- (5- {4- [ 1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridylamino) -2- (cyclopropylmethyl) propionic acid, 2-benzyl-3- {5- [3-cyano-4- (1 -phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2-benzyl-3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2- pyridyloxy) propionic acid, 3- {5- [3 cyano-4- (1-phenylethoxy arbonylamino) -5-isoxazolyl] -2-pyridyloxy} -2- (cyclopropylmethyl) propionic acid, 3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2 -pyridyloxy) -2- (cyclopropylmethyl) propionic acid, 2- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] -2-pyridylamino} -3-phenylpropionic acid, 2- (5- {4 - [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridylamino) -3-phenylpropionic acid, 2- {5- [3-cyano-4- (1phenylethoxycarbonylamino) -5-isoxazolyl ] -2-pyridylamino} -3-cyclopropylpropionic acid, 2 (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridylamino) -3-cyclopropylpropionic acid, 2 - {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} 3-phenylpropionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] - 3-cyano-5-isoxazolyl} 2-pyridyloxy) -3-phenylpropionic acid, 2- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} -3-cyclopropylpropionic acid or 2- (5- {4- [1- (o-chloropheny k) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2-pyridyloxy) -3-cyclopropylpropionic acid.

44. A compound according to Embodiment 30, wherein the compound is 2-benzyl3- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2-benzyl-3- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridylamino) propionic acid, 2- (cyclopropylmethyl) -3 - {5- [3-methyl-4 - (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl5-isoxazolyl} -2-pyridylamino) - 2- (cyclopropylmethyl) propionic acid, 2-benzyl-3- {5- [3-methyl4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2-benzyl-3- (5 {4 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridyloxy) propionic acid, 2- (cyclopropylmethyl) -3- {5- [3-methyl-4- (1- phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl )NS ropionic acid, 2- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} -3-phenylpropionic acid, 2- (5- {4- [1- (o- chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridylamino) -3-phenylpropionic acid, 2- (5- {4- [1 (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridylamino) -3-cyclopropylpropionic acid, 2- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} -3-phenylpropionic acid, 2- (5- { 4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid, 3-cyclopropyl-2- {5- [3-methyl-4- (1-phenylethoxycarbonylamino ) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridyloxy) -3 -cyclopropylpropionic acid, 2-benzyl-3 - {5 [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2benzyl-3 - (5- {4- [1 - (o -chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridylam ino) propionic acid, 2- (cyclopropylmethyl) -3 - {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3 -methyl5-isoxazolyl} -2-pyridylamino) -2- (cyclopropylmethyl) propionic acid, 2-benzyl-3- {5- [3-methyl4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2-benzyl-3- (5 {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridyloxy) propionic acid , 2- (cyclopropylmethyl) -3- {5- [3-methyl-4 - (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridyloxy} propionic acid, 3- (5- {4- [1- (o -chlorophenyl) ethoxycarbonylamino] -3 -methyl-5 -isoxazolyl} -2 pyridyloxy) -2- (cyclopropylmethyl) propionic acid, 2- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] - 2-pyridylamino} -3-phenylpropionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridylamino) -3-phenylpropionic acid, 3

- 40 038294 cyclopropyl-2- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} propionic acid, 2- (5- {4- [1- (o-chlorophenyl ) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2-pyridylamino) -3-cyclopropylpropionic acid, 2- {5- [3-methyl-4 - (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridyloxy } -3-phenylpropionic acid, 2- (5- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3methyl-5-isoxazolyl} -2-pyridyloxy) -3-phenylpropionic acid, 3-cyclopropyl-2- { 5- [3-methyl-4 (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} propionic acid, 2- (5- {4- [1- (chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl } -2-pyridyloxy) -3-cyclopropylpropionic acid, 3- {p- [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] benzoylamino} -4-phenylbutyric acid, 4-cyclopropyl-3- {p - [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] benzoylamino} butyric acid, 3 - [({p- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl ) amino] -4-phenylbutyric acid, 4- cyclopropyl-3 - [({p- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl) amino] butyric acid, 3 - ({p- [3-methyl-4- ( 1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) -4-phenylbutyric acid, 4-cyclopropyl-3 - ({p- [3methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methoxy) butyric acid , 3- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridylamino} -4-phenylbutyric acid, 4cyclopropyl-3 - {5- [3-methyl-4- (1 -phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridylamino} butyric acid, 3- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyloxy} -4-phenylbutyric acid, 4 -cyclopropyl-3- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2pyridyloxy} butyric acid.

45) The compound according to Embodiment 30, wherein the compound is 2 - [[4- [1,5dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3 - (4-methoxyphenyl) propanoic acid , 2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, 3- (2,6-difluorophenyl ) -2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (3-cyanophenyl) -2 - [[4- [ 1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (2-chlorophenyl) -2 - [[4- [1,5-dimethyl4- (1- phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (4-chlorophenyl) -2 [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, 2 [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- [4- (trifluoromethyl) phenyl] propanoic acid, 2- [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-hydroxyphenyl) propanoic acid, 3- (3,4-difluorophenyl) -2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (4-bromophenyl) -2 - [[4- [1,5dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, 2 - [[4- [1,5dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- [4- (trifluoromethoxy) phenyl] propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazole- 3-yl] benzoyl] amino] -3- (4-methoxyphenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] 1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- (2,6-difluorophenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- (3cyanophenyl) propanoic acid, 3- (2-chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1.5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (4 -chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoc sicarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2chlorophenyl) ethoxycarbonylamino] - 1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- [4- (trifluoromethyl) phenyl] propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- (4-hydroxyphenyl) propanoic acid, 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] 1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- (3, 4-difluorophenyl) propanoic acid, 3- (4-bromophenyl) -2 [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid , 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- [4 (trifluoromethoxy) phenyl] propanoic acid, 2- [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] -3- (4-methoxyphenyl) propanoic acid, 3- (4-fluorophenyl) -2 - [[4 [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (2,6-difluorophenyl) -2 - [[4 - [4- [1- (2-fluorophenyl) et oxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (3-cyanophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1, 5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (2-chlorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] - 1,5-dimethylpyrazol-3-yl ] benzoyl] amino] propanoic acid, 3 - (4-chlorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- [4- (trifluoromethyl) phenyl] propanoic acid , 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] 1,5-dimethylpyrazol-3-yl] benzoyl] amino] -3- (4-hydroxyphenyl) propanoic acid, 3- (3, 4-difluorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid, 3- (4-bromophenyl) - 2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3yl] benzoyl] amino] propanoic acid, 2 - [[4- [4- [1- (2- fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyr azol-3-yl] benzoyl] amino] -3- [4- (trifluoromethoxy) phenyl] propanoic acid, 2- {p- [1-methyl-5-methyl-

- 41 038294

4- (1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoylamino} -3-phenylpropionic acid, 3 cyclopropyl-2- {p- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) -1H -pyrazol-3-yl] benzoylamino} propionic acid, 2- (p- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl-1H-pyrazol3-yl} benzoylamino) -3 - phenylpropionic acid, 2- (p- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1methyl-5-methyl-1H-pyrazol-3-yl} benzoylamino) -3-cyclopropylpropionic acid, 2 - [({p - [1-methyl-5methyl-4- (1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] phenyl} methyl) amino] -3-phenylpropionic acid, 3-cyclopropyl-2 - [({p- [1 -methyl-5-methyl-4- (1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] phenyl} methyl) amino] propionic acid, 2 - {[(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -1-methyl-5methyl-1H-pyrazol-3-yl} phenyl) methyl] amino} -3-phenylpropionic acid, 2 - {[(p- {4- [1- (chlorophenyl) ethoxycarbonylamino] -1 - methyl 5-methyl-1H-pyrazol-3-yl} phenyl) methyl] amino} -3-cyclopropylpropionic acid, 2 - ({p- [1 -methyl-5-methyl-4 - (1-phenylethoxycarbonylamino) -1H-pyrazol-3 yl] phenyl} methoxy) -3-phenylpropionic acid, 3-cyclopropyl-2 - ({p- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) -1Н-pyrazol-3-yl] phenyl} methoxy) propionic acid, 2 - [(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -1-methyl-5-methyl-1Н-pyrazole-3 - yl} phenyl) methoxy] -3-phenylpropionic acid, 2 - [(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -1-methyl-5-methyl-1H-pyrazol-3-yl} phenyl) methoxy] -3 -cyclopropylpropionic acid, 3- {p- [1 -methyl-5-methyl-4- (1-phenylethoxycarbonylamino) 1H-pyrazol-3-yl] benzoylamino} -4-phenylbutyric acid, 4-cyclopropyl-3 - {p- [1-methyl-5-methyl-4- (1phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoylamino} butyric acid, 3 - [({p- [1 -methyl-5 methyl-4- ( 1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] phenyl} methyl) amino] -4-phenylbutyric acid, 4-cyclopropyl-3 - [({p- [1 -methyl-5-methyl-4- (1 - phenylethoxycarbonylamino) -1Н-pyrazol-3-yl] phenyl} methyl) amino] butyric acid, 3 - ({p- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) -1Н-pyrazol-3-yl] phenyl} methoxy) -4-phenylbutyric acid or 4-cyclopropyl-3 - ({p- [1-methyl-5-methyl-4- (1phenylethoxycarbonylamino) -1Н-pyrazole-3 - yl] phenyl} methoxy) butyric acid.

46) The compound according to Embodiment 30, wherein the compound is 2- [4- [4 [4-cyano-5 - (1-phenylethoxycarbonylamino) pyrazol-1-yl] phenyl] phenyl] acetic acid, 1- [4- [ 4- [4-cyano-5- (1-phenylethoxycarbonylamino) pyrazol-1 -yl] phenyl] phenyl] cyclopropanecarboxylic acid, 1- [4 [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4- cyanopyrazol-1-yl] phenyl] phenyl] cyclopropanecarboxylic acid, 2- [4- [4- [4-cyano-5- (1-phenylethoxycarbonylamino) pyrazol-1-yl] phenyl] phenyl] -2-methylpropanoic acid, 2- [4- [4- [5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] 2-methylpropanoic acid, 1- {4 '- [4-fluoro- 5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -4-diphenylyl} cyclopropanecarboxylic acid, 1- (4 '- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4 -fluoro-1Hpyrazole- 1 -yl} -4-diphenylyl) cyclopropanecarboxylic acid, 1- {3-fluoro-4 '- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -4-diphenylyl} cyclopropanecarboxylic acid , 1 - (4 '- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino ] -4-fluoro-1H-pyrazol-1 -yl} -3-fluoro-4-diphenylyl) cyclopropanecarboxylic acid, 1 - {2-fluoro-4 '- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H -pyrazol-1 -yl] -4-diphenylyl} -cyclopropanecarboxylic acid, 1- (4 '- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1H-pyrazol-1-yl} 2- fluoro-4-diphenylyl) cyclopropanecarboxylic acid, 1 - (2-chloro-4 '- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1H-pyrazol-1-yl} -4-diphenylyl) cyclopropanecarboxylic acid, 1- (4- {p- [4-fluoro-5 (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] phenyl} tolyl) cyclopropanecarboxylic acid, 1- [4 (p- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1H-pyrazol-1-yl} phenyl) tolyl] cyclopropanecarboxylic acid, 1- (p- {5- [5- (1-phenylethoxycarbonylamino) -1H-pyrazole-1 -yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [p- (5- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1H-pyrazol-1-yl} -2-pyridyl) -phenyl ] cyclopropanecarboxylic acid, 1- (p- {5- [4-methyl-5- (1-phenylethoxycarbonylamino) 1H-pyrazol-1-yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [p- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4-methyl-1H-pyrazol-1-yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid, 1 - (2fluoro-4- {5- [ 5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [4- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -1H- pyrazol-1-yl} -2-pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid, 1 - (3-fluoro-4- {5- [5- (1-phenylethoxycarbonylamino) -1H-pyrazol1-yl] -2-pyridyl } phenyl) cyclopropanecarboxylic acid, 1- [4- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -1H-pyrazol-1-yl} -2-pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid, 1 - (p- {5- [4methyl-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1 - (p- {5- [4-methyl-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [p- (5- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-methyl -1H-pyrazol-1 yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid, 1- (2-fluoro-4- {5- [4-methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazole-1 -yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [4- (5- {5- [1- (chlorophenyl) ethoxycarbonylamino] -4-methyl-1H-pyrazol-1-yl} -2-pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid, 1 - (3-fluoro-4- {5- [4-methyl-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid , 1- [4- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4methyl-1H-pyrazol-1-yl} -2-pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid, 1- (p - {5- [4-fluoro-5 (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [p- (5- {5- [1- (o -chlorophenyl) ethoxycarbonylamino] -4-fluoro-1H-pyrazol-1-yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid, 1 - (2-fluoro-4- {5- [4-fluoro-5- (1 - phenylethoxycarbonylamino) -1H-pyrazol-1-yl]

- 42 038294

2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [4- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] 4-fluoro-1H-pyrazol-1-yl} -2-pyridyl) -2- fluorophenyl] cyclopropanecarboxylic acid, 1- (3-fluoro-4- {5- [4fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrαzol-1-yl] -2-pyridyl} phenyl) cyclopropαncarboxylic acid, 1- [4 - (5- {5- [1- (o-chlorophenyl) ethoxycarbonylαmino] -4-fluoro-1H-pyrazol-1-yl} -2-pyridyl) -3fluorophenyl] cyclopropanecarboxylic acid, 1- (p- {5- [ 4-cyano-5- (1-phenylethoxycarbonylamino) -1Hpyrazol-1-yl] -2-pyridyl} phenyl) cyclopropanecarboxylic acid, 1- [p- (5- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] - 4-cyano-1H-pyrazol-1 -yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid, 1- (4- {5 [4-cyano-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -2-pyridyl} -2-fluorophenyl) cyclopropanecarboxylic acid, 1- [4- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4-cyano-1H-pyrαzol-1-yl} -2- pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid, 1- (4- {5- [4-cyano-5- (1-phenylethoxycarbonylamino) 1H-pyrazol-1-yl] -2-pyridyl} -3-fluorophenyl) cyclopropanecar boxylic acid or 1- [4- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4-cyαno-1H-pyrαzol-1-yl} -2-pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid.

47) The compound according to Embodiment 30, wherein the compound is 3-phenyl2 - [[4- [5- (1-phenylethoxycarbonylamino) oxazol-4-yl] benzoyl] amino] propanoic acid, 3-cyclopropyl-2 - [[4 - [5- (1-phenylethoxycarbonylamino) oxazol-4-yl] benzoyl] amino] propanoic acid, 4-phenyl2 - [[4- [5- (1-phenylethoxycarbonylamino) oxazol-4-yl] benzoyl] amino] butanoic acid , 3-phenoxy-2 [[4- [5- (1-phenylethoxycarbonylamino) oxazol-4-yl] benzoyl] amino] propanoic acid, 3-phenyl-2 - [({p [5- (1-phenylethoxycarbonylamino) - 1,3-oxazol-4-yl] phenyl} methyl) amino] propionic acid, 3 cyclopropyl-2 - [({p- [5- (1-phenylethoxycarbonylamino) -1,3-oxazol-4-yl] phenyl} methyl) amino] propionic acid, 3-phenyl-2 - ({p- [5- (1-phenylethoxycarbonylamino) -1,3-oxazol-4-yl] phenyl} methoxy) propionic acid, 4-phenyl-3 - ( {p- [5- (1-phenylethoxycarbonylamino) -1,3-oxazol-4-yl] phenyl} methoxy) butyric acid or 4-cyclopropyl-3 - ({p- [5- (1-phenylethoxycarbonylamino) - 1,3-oxazol-4-yl] phenyl} methoxy) butyric acid.

48) The compound according to Embodiment 30, wherein the compound is 2 - [[4- [1methyl-5 - (1-phenylethoxycarbonylamino) imidazol-4-yl] benzoyl] amino] -3-phenylpropanoic acid, 3 cyclopropyl-2- [ [4- [1-methyl-5- (1-phenylethoxycarbonylamino) imidazol-4-yl] benzoyl] amino] propanoic acid, 2 - [[4- [1-methyl-5- (1-phenylethoxycarbonylamino) imidazole-4- yl] benzoyl] amino] -4-phenylbutanoic acid, 2 - [[4- [1-methyl-5- (1-phenylethoxycarbonylamino) imidazol-4-yl] benzoyl] amino] -3 phenoxypropanoic acid, 2 - [({ p- [1-methyl-5- (1-phenylethoxycarbonylamino) -1H-imide azol-4-yl] phenyl} methyl) amino] -3-phenylpropionic acid, 3-cyclopropyl-2 - [({p- [1 - methyl 5 - (1-phenylethoxycarbonylamino) -S-imid azol-4-yl] phenyl} methyl) amino] propionic acid, 2 - ({p- [1-methyl-5- (1phenylethoxycarbonylamino) -1H-imidazole-4 -yl] phenyl} methoxy) -3-phenylpropionic acid, 3-cyclopropyl-2 - ({p- [1 -methyl-5- (1-phenylethoxycarbonylamino) -1H-imidazol-4-yl] phenyl} methoxy) propionic acid , 3 - [({p- [1-methyl-5- (1-phenylethoxy rbonylamino) -1H-imidazol-4-yl] phenyl} methyl) amino] -4-phenylbutyric acid, 4-cyclopropyl-3 - [({p- [1-methyl-5- (1-phenylethoxycarbonylamino) -1Himidazole-4 -yl] phenyl} methyl) amino] butyric acid, 3 - ({p- [1-methyl-5- (1-phenylethoxycarbonylamino) -1H-imidazol-4-yl] phenyl} methoxy) -4-phenylbutyric acid or 4 -cyclopropyl-3 - ({p- [1-methyl-5 (1-phenylethoxycarbonylamino) -1H-imidazol-4-yl] phenyl} methoxy) butyric acid.

49) The compound according to Embodiment 30, wherein the compound is 2 - [[4- [1,2dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) pyrazol-4-yl] benzoyl] amino] -3-phenylpropanoic acid, 3-cyclopropyl-2 - [[4- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) pyrazol-4-yl] benzoyl] amino] propanoic acid, 2 - [[4- [1, 2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) pyrazole-4yl] benzoyl] amino] -4-phenylbutanoic acid, 2 - [[4- [1,2-dimethyl-3-oxo-5- (1 -phenylethoxycarbonylamino) pyrazol-4-yl] benzoyl] amino] -3-phenoxypropanoic acid, 2 - [({p- [1,2-dimethyl-3-oxo-5- (1phenylethoxycarbonylamino) -1,2-dihydropyrazole-4 -yl] phenyl} -methyl) amino] -3-phenylpropionic acid, 3-cyclopropyl-2 - [({p- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2- dihydropyrazol4-yl] phenyl} methyl) amino] propionic acid, 2 - ({p- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2-dihydropyrazol-4-yl] phenyl} methoxy) -3-phenylpropionic acid, 3-cyclopropyl-2 ({p- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonyl but) -1,2-dihydropyrazol-4-yl] phenyl} methoxy) propionic acid, 3 - [({p- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2- dihydropyrazole-4yl] phenyl} methyl) amino] -4-phenylbutyric acid, 4-cyclopropyl-3 - [({p- [1,2-dimethyl-3-oxo-5- (1phenylethoxycarbonylamino) -1,2-dihydropyrazole- 4-yl] phenyl} methyl) amino] butyric acid, 3 - ({p [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2-dihydropyrazol-4-yl] phenyl} - methoxy) -4-phenylbutyric acid or 4-cyclopropyl-3 - ({p- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) 1,2-dihydropyrazol-4-yl] phenyl} methoxy) butyric acid.

50) The compound according to Embodiment 30, wherein the compound is 3-phenyl2 - [[4- [5- (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino] propanoic acid, 3-cyclopropyl-2 - [[4 - [5- (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino] propanoic acid, 4phenyl-2 - [[4- [5 - (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino] butanoic acid , 3 phenoxy-2- [[4- [5- (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino] propanoic acid, 3-phenyl-2 - [({p- [5- (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methyl) amino] propionic

- 43 038294 acid, 3-cyclopropyl-2 - [({p- [5- (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methyl) amino] propionic acid, 3-phenyl-2 - ({p- [5 - (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methoxy) propionic acid, 3-cyclopropyl-2 - ({p- [5- (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methoxy) propionic acid, 4- phenyl-3 - [({p- [5- (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methyl) amino] butyric acid, 4-cyclopropyl-3 - [({p- [5- (1-phenylethoxycarbonylamino) 4-pyrimidinyl] phenyl} methyl) amino] butyric acid, 4-phenyl-3 - ({p- [5- (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methoxy) butyric acid, 4-cyclopropyl-3- ( {p- [5- (1-phenylethoxycarbonylamino) -4-pyrimidinyl] phenyl} methoxy) butyric acid, 2 - [[4- [6-methyl-5- (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino ] -3-phenylpropanoic acid, 3-cyclopropyl-2 - [[4- [6methyl-5- (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino] propanoic acid, 2 - [[4- [6methyl-5 - (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amy but] -4-phenylbutanoic acid or 2 - [[4- [6-methyl-5- (1-phenylethoxycarbonylamino) pyrimidin-4-yl] benzoyl] amino] -3-phenoxypropanoic acid.

51) The compound according to Embodiment 30, wherein the compound is 3-phenyl2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5-yl] benzoyl] amino] propanoic acid, 3-cyclopropyl-2 - [[4 - [4- (1-phenylethoxycarbonylamino) pyrimidin-5-yl] benzoyl] amino] propanoic acid, 4phenyl-2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5-yl] benzoyl] amino] butanoic acid or 3-phenoxy-2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5-yl] benzoyl] amino] propanoic acid.

52) The compound according to Embodiment 30, wherein the compound is 3-phenyl2 - [[4- [3- (1-phenylethoxycarbonylamino) pyrazin-2-yl] benzoyl] amino] propanoic acid, 3-cyclopropyl-2- [[4 - [3- (1-phenylethoxycarbonylamino) pyrazin-2-yl] benzoyl] amino] propanoic acid, 4-phenyl2 - [[4- [3- (1-phenylethoxycarbonylamino) pyrazin-2-yl] benzoyl] amino] butanoic acid or 3-phenoxy2 - [[4- [3- (1-phenylethoxycarbonylamino) pyrazin-2-yl] benzoyl] amino] propanoic acid.

53) The compound according to Embodiment 30, wherein the compound is 1- {p- [3methyl-4 - (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4-piperidinecarboxylic acid, (1- {p [3 -methyl- 4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4-piperidyl) acetic acid, 1- (1 {p- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4 -piperidyl) cyclopropanecarboxylic acid, [1- (1- {p- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2pyridyl} -4-piperidinecarboxylic acid, (1- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridyl} -4-piperidyl) acetic acid, 1- (1- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) 5-isoxazolyl] -2-pyridyl} -4-piperidyl) cyclopropanecarboxylic acid, [1- (1- {5- [3-methyl-4- (1 phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {p- [3-fluoro- 4- (1-phenylethoxycar bonylamino) -5-isoxazolyl] phenyl} -4-piperidinecarboxylic acid, (1 - {p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4-piperidyl) acetic acid, 1- (1- {p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4piperidyl) cyclopropanecarboxylic acid, [1- (1- {p- [3 -fluoro-4 - (1 - phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidinecarboxylic acid , (1- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidyl) acetic acid, 1- (1- {5- [3 -fluoro- 4- (1 phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidyl) cyclopropanecarboxylic acid, [1- (1- {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl]] -2-pyridyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4-piperidinecarboxylic acid, (1- {p - [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] pheny l} -4piperidyl) acetic acid, 1- (1- {p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} 4-piperidyl) cyclopropanecarboxylic acid, [1- (1- {p - [3-cyano-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridyl} -4-piperidinecarboxylic acid, (1- {5- [3-cyano-4- (1 phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidyl) acetic acid, 1- (1 - {5- [3cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidyl) cyclopropanecarboxylic acid, [1- (1- {5- [3-cyano-4- (1 -phenylethoxycarbonylamino) -5-isoxazolyl] -2-pyridyl} -4-piperidyl) cyclopropyl] acetic acid, 1 - {p- [5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] phenyl} -4piperidinecarboxylic acid , (1- {p- [5- (1-phenylethoxycarbonylamino) -1H-pyrαzol-1 -yl] phenyl} -4piperidyl) acetic acid, 1- (1- {p- [5- (1-phenylethoxycarbonylamino) -1H -pyrazol-1 -yl] phenyl} -4piperidyl) cyclopropanecarboxylic acid, [1- (1- {p- [5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 yl] phenyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {5- [5- (1- phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -2-pyridyl} -4-piperidinecarboxylic acid, (1- {5- [5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -2-pyridyl} -4 -piperidyl) acetic acid, 1- (1- {5- [5- (1-phenylethoxycarbonylamino) S-pyrazol-1-yl] -2-pyridyl} -4-piperidyl) cyclopropanecarboxylic acid, [1- (1- { 5- [5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {p- [4methyl-5 - (1-phenylethoxycarbonylαmino) - 1H-pyrazol-1 -yl] phenyl} -4-piperidinecarboxylic acid, (1 {p- [4-methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] phenyl} -4-piperidyl) acetic acid,

- 44 038294

1- (1 - {p- [4-methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] phenyl} -4-piperidyl) cyclopropanecarboxylic acid, [1 - (1- {p- [4 -methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] phenyl} -4piperidyl) cyclopropyl] acetic acid, 1 - {5- [4-methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazole -1 -yl] -2-pyridyl} -4-piperidinecarboxylic acid, (1- {5- [4-methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} -4 -piperidyl) acetic acid, 1- (1- {5- [4-methyl-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} -4-piperidyl) cyclopropanecarboxylic acid, [1 - (1- {5 [4-methyl-5 - (1-phenylethoxycarbonylamino) -III-pyrazol-1 -yl] -2-pyridyl} -4-piperidyl) cyclopropyl] acetic acid, 1- {p- [4- fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] phenyl} -4-piperidinecarboxylic acid, (1- {p- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazole-1 -yl] phenyl} -4-piperidyl) acetic acid, 1- (1- {p- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] phenyl} -4piperidyl) cyclopropanecarbon acid, [1- (1- {p- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1Hpyrazol-1-yl] phenyl} -4-piperidyl) cyclopropyl] acetic acid, 1 - {5- [4 -fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -2-pyridyl} -4-piperidinecarboxylic acid, (1 - {5- [4-fluoro-5- (1 phenylethoxycarbonylamino) -1H- pyrazol-1-yl] -2-pyridyl} -4-piperidyl) acetic acid, 1- (1- {5- [4fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl } -4-piperidyl) cyclopropanecarboxylic acid, [1- (1- {5- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} -4-piperidyl) cyclopropyl ] acetic acid, 1- {p- [4-cyano-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 yl] phenyl} -4-piperidinecarboxylic acid, (1- {p- [4-cyano-5- (1-phenylethoxycarbonylamino) -1Hpyrazol-1 -yl] phenyl} -4-piperidyl) acetic acid, 1 - (1- {p- [4-cyano-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl ] phenyl} -4-piperidyl) cyclopropanecarboxylic acid, [1 - (1- {p- [4-cyano-5- (1 phenylethoxycarbonylamino) -1H-pyrazol-1-yl] phenyl} -4-piperidyl) cyclopropyl ] acetic acid, 1 {5- [4-cyano-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} -4-piperidinecarboxylic acid, (1- {5- [4-cyano -5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -2-pyridyl} -4-piperidyl) acetic acid, 1- (1 - {5- [4-cyano-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid or [1- (1- {5- [4-cyano-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl]) -2-pyridyl} -4-piperidyl) cyclopropyl] acetic acid.

54) Pharmaceutically acceptable formulation containing the compound from table. 1 and one or more pharmaceutically acceptable excipients, consisting essentially of them or consisting of them.

55) A pharmaceutically acceptable formulation comprising a compound of Embodiment 31 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

56) A pharmaceutically acceptable formulation comprising a compound according to embodiment 32 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

57) A pharmaceutically acceptable formulation comprising a compound of Embodiment 33 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

58) A pharmaceutically acceptable formulation comprising a compound of embodiment 34 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

59) A pharmaceutically acceptable formulation comprising a compound according to embodiment 35 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

60) A pharmaceutically acceptable formulation comprising a compound according to embodiment 36 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

61) A pharmaceutically acceptable formulation comprising a compound according to embodiment 37 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

62) A pharmaceutically acceptable formulation comprising a compound according to embodiment 38 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

63) A pharmaceutically acceptable formulation comprising a compound of Embodiment 39 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

64) A pharmaceutically acceptable formulation comprising a compound of Embodiment 40 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

65) A pharmaceutically acceptable formulation comprising a compound of Embodiment 41 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

66) Pharmaceutically acceptable formulation containing a compound according to an embodiment

- 45 038294 nia 42 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

67) A pharmaceutically acceptable formulation comprising a compound according to embodiment 43 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

68) A pharmaceutically acceptable formulation comprising a compound of embodiment 44 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

69) A pharmaceutically acceptable formulation comprising a compound of Embodiment 45 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

70) A pharmaceutically acceptable formulation comprising a compound of Embodiment 46 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

71) A pharmaceutically acceptable formulation comprising a compound according to embodiment 47 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

72) A pharmaceutically acceptable formulation comprising a compound according to embodiment 48 and one or more pharmaceutically acceptable excipients consisting essentially of or consisting of them.

73) A pharmaceutically acceptable formulation comprising a compound according to embodiment 49 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

74) A pharmaceutically acceptable formulation comprising a compound according to embodiment 50 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

75) A pharmaceutically acceptable formulation comprising a compound according to embodiment 51 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

76) A pharmaceutically acceptable formulation comprising a compound of Embodiment 52 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

77) A pharmaceutically acceptable formulation comprising a compound according to embodiment 53 and one or more pharmaceutically acceptable excipients, essentially consisting of or consisting of them.

78) A method comprising administering an effective amount of a compound of Formula I-XII to a subject having an LPA-dependent or LPA-mediated disease or condition.

79) The method according to embodiment 78, wherein the LPA-dependent or LPA-mediated disease or condition is a disease in which organ fibrosis occurs.

80) The method of embodiment 79, wherein the fibrosis affects the liver, kidney, lung, heart, eye, and the like.

81) The method according to embodiment 78, wherein the LPA-dependent or LPA-mediated disease or condition is chronic pain.

82) The method according to embodiment 78, wherein the LPA-dependent or LPA-mediated disease or condition is pruritus.

83) The method according to embodiment 78, wherein the LPA-mediated disease is a proliferative disease including cancer (solid tumor, metastasis of solid tumors, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), etc.) and invasive metastasis of cancer cells, including ovarian cancer, breast cancer and triple negative breast cancer, etc.

84) The method of embodiment 78, wherein the LPA-mediated disease is an inflammatory disease including psoriasis, nephropathy, pneumonia, and the like.

85) The method according to embodiment 78, wherein the LPA-mediated disease is a gastrointestinal disease such as inflammatory bowel disease.

86) The method according to embodiment 78, wherein the LPA-mediated disease is an eye disease including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), scarring pemphigoid, scarring after filtration surgery for glaucoma, uveitis, and the like.

87) The method according to embodiment 78, wherein the LPA-mediated disease is a liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, impairment hepatic blood flow and the like.

- 46 038294

88) The method of embodiment 78, wherein the LPA-mediated disease is a kidney disease including chronic kidney disease, end-stage renal disease, uremic pruritus, nephropathy including diabetic nephropathy, and the like.

89) The method of embodiment 78, wherein the LPA-mediated disease is a skin disease including scleroderma, skin scarring, atopic dermatitis, psoriasis, and the like.

90) A method according to any one of embodiments 78-89, wherein the subject is a human.

91) The method according to any one of embodiments 78-90, wherein the compound is selected from Table. 1.

92) The method according to any one of embodiments 78-90, wherein the compound is 1- (4- {4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) cyclopropanecarboxylic acid, 2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indane-2-carboxylic acid, 2- (S) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid, 2- (R) - (4- {4 - [(R, S) -1- (2- chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid, 2 (R) - [[4- [3-methyl-4 - ((R) 1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 2 (S) - [[4- [3methyl-4 - ((R) -phenylethoxycarbonylamino) isoxαzol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2 - {4- [3-methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylα-amino} -3-phenylpropionic acid, (S) -2- {4- [3-methyl-4- ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3phenylpropionic acid, (R) -2- (4- {4 - [(R) -1- (2-x lorphenyl) ethoxycarbonylamino] -3-methylisoxazol5-yl} benzoylamino) -3-phenylpropionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazole- 5-yl} benzoylamino) -3 - (4-fluorophenyl) propionic acid, (R) -3 - (4chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] - 3-methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) -3 - (3,4-difluorophenyl) propionic acid, (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R) -1- (2chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5- yl} benzoylamino) propionic acid, (R) -3 (4-bromophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxαzol-5-yl} benzoylαmino ) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) -3- (2-fluorophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-p-tolylpropionic acid, (R) -2 - (4- {4 - [(R) -1 (2-chlorophenyl) ethox sicarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (4-trifluoromethylphenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxαzol-5yl} benzoylamino) -3- (4-cyanophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole -5-yl} benzoylamino) -3-cyclopropylpropionic acid, (R) -2 - [[4- [2,5dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] - 3-phenylpropanoic acid, (R) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl ) propanoic acid, (R) -3 - (4-bromophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (4-chlorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) 1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid , (R) -3- (3,4-difluorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylαmino) pyrazol-3-yl] benzoyl] αmino] propane acid, (R) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamine o) pyrazol-3-yl] benzoyl] amino] 3-phenylpropanoic acid, (R) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, (R) -3- (4-bromophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) 1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, ((R) -3- (4-chlorophenyl) 2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazole -3-yl] benzoyl] amino] propanoic acid, (R) -3- (3,4-difluorophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3yl] benzoyl] amino] propanoic acid, (R) -2- (4- {5 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -4methylpyrazol-1-yl} benzoylamino) -3-phenylpropionic acid, (R) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3-phenylpropionic acid, (R) -3- (2- fluorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylαmino) isoxαzol-5-yl] benzylamino} propionic acid, (R) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3- (4trifluoromethylphenyl) propionic acid, (R) -3-cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -3- (2-chlorophenyl ) -2- {4- [3-methyl4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -3- (4-chlorophenyl) -2- {4- [ 3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxαzol-5-yl] benzylamino} propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylα-amino] -3-methylisoxazol-5-yl} benzylα-amino) -3phenylpropionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol5-yl} benzylamino) -3- (2-fluorophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3- (4-trifluoromethylphenyl) propionic acid, (R) -3 - (2-chlorophenyl) -2- (4- {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazole- 5 -yl} benzylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol5-yl} benzylamino) -3-cyclopropylpropionic acid, 2- {4- [3-methyl-4 - ((R) -1-phenylethoxy carbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid, 2- {4- [3-methyl-4 - ((R) -1-phenylethox

- 47 038294 icarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid, (RS) -3-cyclopropyl-2- {4 [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole-5 -yl] benzyloxy} propionic acid, (RS) 3-cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylαmino) isoxazol-5-yl] benzyloxy} npropionic acid, 2- [ 4- [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetic acid, (R) -1- [4- [4- [1,5 -dimethyl-4- (1-phenylethoxycarbonylαmino) pyrazol-3-yl] phenyl] phenylcyclopropanecarboxylic acid, (R) -1- [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylαmino) pyrazole-3yl ] phenyl] phenyl] cyclopropanecarboxylic acid, (R) -1 - (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] 4-fluoropyrazol-1-yl} -3-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid , (R) -1- (4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1 - (2-chloro-4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -diphenyl-4yl) cyclopropanecarboxylic acid, (R) -1- (4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-methyldiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4' - {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- {4 '- [5- (1 phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] -diphenyl-4-yl} cyclopropanecarboxylic acid, (R) -1- {2-fluoro-4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1 -yl] -Diphenyl-4yl} cyclopropanecarboxylic acid, (R) -1- (4- {5- [5- (1-phenylethoxycarbonylamino) pyrazol-1-yl] pyridin-2-yl} phenyl) cyclopropanecarboxylic acid.

93) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 31.

94) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 32.

95) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 33.

96) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 34.

97) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 35.

98) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 36.

99) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 37.

100) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 38.

101) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 39.

102) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 40.

103) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 41.

104) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 42.

105) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 43.

106) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 44.

107) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 45.

108) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 46.

109) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 47.

110) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 48.

111) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 49.

112) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 50.

113) A method according to any one of Embodiments 78-90, wherein the compound is selected from Embodiment 51.

114) A method according to any one of embodiments 78-90, wherein the compound is selected from embodiment 52.

115) A method according to any one of embodiments 78-90, wherein the compound is selected from var

- 48 038294 anta implementation 53.

116) A composition comprising one or more compounds of formula (I-XII) and one or more agents currently used to treat LPA-dependent or LPA-mediated disease or disease or condition described herein, essentially consisting of or consisting of of them.

117) A pharmaceutically acceptable formulation containing one or more compounds of formula (I-XII), one or more agents currently used to treat LPA-dependent or LPA-mediated disease, and one or more pharmaceutically acceptable excipients, essentially consisting of them or consisting of them.

118) A method comprising administering a compound of formula (I-XII) in combination with a currently used agent to treat an LPA-dependent or LPA-mediated disease, or co-administering them to a subject with an LPA-dependent or LPA-mediated disease or condition.

One or more additional therapeutically active agents other than the compounds of formula (I-XII) are selected from corticosteroids, immunosuppressants, pain relievers, antineoplastic agents, anti-inflammatory agents, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene receptor inhibitors, antagonists platelet activating factor, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors and lysophospholipase D (lysophospholipase D (lyso-PLD) inhibitors), autotaxin inhibitors, decongestants, mast cell membrane stabilizers, antihistamines, mucolytic agents, anticholithussics, β-2 agonists.

In preferred embodiments, the currently used agent (s) are selected from those described in the Merck Index that are known to affect signaling via lysophosphatidic acid receptors. In other preferred embodiments, the implementation of the compound of formula (I-XII) is selected from table. 1.

In other embodiments, the implementation of this document encompasses therapies in which a compound of formula (I-XII) is combined with currently used agents that act on various signaling pathways leading to the synthesis of LPA, or the signaling pathway, so as to provide complementary clinical results, for the treatment of LPA-dependent or LPA-mediated diseases or conditions.

Examples of additional therapeutic agents include, without limitation, any of the following: gossypol, jenasens, polyphenol E, chlorofusin, all trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related ligand, inducing apoptosis (TRAIL), 5-aza-2 'deoxycytidine, all-trans-retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, borzutez-70, PKK or PD 184352, Taxol ™ (paclitaxel) and Taxol ™ analogues such as Taxotere ™, U0126, PD98059, PD184352, PD0325901, ARRY142886, SB239063, SP600 125, BAY 43-9006, wortmannin or LY294002, adriamycin, dactinomycin vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adoselesine; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacytidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisanthrene hydrochloride; bisnafid dimesylate; bisellesin; bleomycin sulfate; brequinar sodium salt; bropyrimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carcelesin; cedefingol; chlorambucil; cyrolemycin; cladribine; chrisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; deazaguanine; deazaguanine mesylate; diazichon; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elzamitrucin; enloplatin; enpromat; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; sodium salt of estramustine phosphate; ethanidazole; etoposide; etoposide phosphate; etoprin; fadrozole hydrochloride; fazarabin; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; foschidon; sodium salt of fostriecin; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; sodium salt of lometrexol; lomustine; losoxantrone hydrochloride; mazoprokol; maitanzine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; sodium salt of methotrexate; metoprin; meturedepa; mitindomide; mitocarcinol; mitocromine; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxyzuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; pyroxantrone hydrochloride;

- 49 038294 plikamycin; placestan; porfimer sodium salt; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; roglethimide; safingol; safingol hydrochloride; semustin; simtrazene; sodium salt of sparphosate; sparzomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozotocin; sulofenur; talizomycin; sodium salt of tekogalan; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; theroxiron; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosol hydrochloride; uramustine; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; wingglycinate sulfate; vinlerosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozol; zeniplatin; zinostatin; zorubicin hydrochloride, mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc., ethyleneimine, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine, streptozocin or triazenes, dacarbazine, methoxorourabiline, cystogastinu, fluorophenol hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, estrogens, diethylstilbestrol, ethinylestradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, leuprolide, cisplatin, carboblatin, mitoxazidolivastrone, procarbetinate 639829, discodermolide, ABT-751, altorirtin A and altorirtin C), spongystatins 1-9, cemadotine hydrochloride, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, epothilone B N-oxide, N-oxide epothilone A, 16-azaepothilone B, 21 aminoepothilone B, 21-hydroxyepothilone D, 26-fluoroepothilone, auristatin PE, soblidotin, cryptophycin 52, vitilevuamide, tubulizin A, k anadensol, centaureidin, oncocidin AI, fijianolide B, laulimalid, narcosin, noscapine, hemiasterlin, vanadocene acetylacetonate, indanocin, eleutherobins (such as desmethyleleuterobin, desacetyleleutherobin, isoereobrio-zerobine) A, diozostatin, (-) - phenylagistin, myoseverin B, resverastatin phosphate sodium salt, aprepitant, hemp preparations, marinol and dronabinol, erythropoietin-alpha, filgrastim, rituximab, natalizumab, cyclophosphamide, ciclophosphamide, ciclosporilamine-based drugs , carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogs, inhibitors of protein synthesis, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, thymoglobulin® Atgam®, OKT3®, basilizuferin, siriximab, tacinomusimab, dactinomycin , infliximab, etanercept, adalimumab, golimumab, leflunomide, sulfasalazine, hydroxychloroquinine, minocycline, rapam icin, mycophenolic acid, mycophenolate mofetil, FTY720, cyclosporin A (CsA) or tacrolimus (FK506), aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, sodium magnesium salicylate, choline salicylate , diflunisal, carprofen, fenoprofen, calcium salt of fenoprofen, flurbiprofen, ibuprofen, ketoprofen, nabuton, ketorolac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindaclofenoic acid, melefenamic acid , valdecoxib, parecoxib, etoricoxib, lumiracoxib, betamethasone, prednisone, alclomethasone, aldosterone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, descortolone, cloprediclacostol, dezonecone , diflorazone, diflucortolone, difluprednat, fluclorolone, fludrocortisone, fludroxicort id, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, chalcinonide, halomethasone, hydrocortisone / cortisone hydrocortisone, bucortisone methylprednisolone aceponate, mometasone furoate, parametazone, prednicarbat, prednisone / prednisolone, rimexolone, thixocortol, triamcinolone, ulobetasol, pioglitazone, clofibrate, fenofibrate, gemfibrozil, folic acid, izbastogrel, ozstluatova , nisvastatin and rosuvastatin, edaravone, vitamin C, Trolox ™, citicoline and minicyclin, (2P) -2-propyloctanoic acid, propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol and acebutinol, tracrofil lamifiban, argatroban, enalapril, cyclandelate, losartan, valsartan, candesartan, irbesartan, telmis artan, olmesartan, mepiramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine, dimensionhydrinate, pheniramine, chlorphenamine (chlorpheniramine), dexchlorpheniramine, brompheniramine lizetrizetirizineta, lpheniramine alimemazine (trimeprazine), cyproheptadine, azatadine, ketotifen, acrivastine, astemizole, cetirizine, mizolastine, terfenadine, azelastine, epinastine, levocabastine, olopatadine, levocetirizine, fexofenadine, anticholinergics, rupatolite drugs, albuterol, ephedrine, epinephrine, formoterol, metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, ipratropium bromide, pseudoephedrine, theophylline, pseudoephedrine, pseudoephedrine, theophylline, pseudoephedrine

- 50 038294 tan, enrasentan, sitaxentan, tezosentan, iloprost, treprostinil, pirfenidone, epinephrine, isoproterenol, orciprenaline, xanthines, zileuton.

119) The method according to embodiments 116-118, wherein the subject is a human.

120) The method according to embodiments 116-119, wherein the compound (s) of formula IXII is selected (s) from Table. 1.

121) The method according to embodiments 116-119, wherein the compound (s) of formula IXII is (selected) from the group consisting of 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl } benzoylamino) cyclopropanecarboxylic acid, 2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indan-2-carboxylic acid, 2- (S) - (4 - {4 - [(R, S) 1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid, 2- (R) - (4- {4 - [(R, S ) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid, 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 2 (S) - [[4- [3-methyl-4 - ((R) -phenylethoxycarbonylamino) isoxazol5-yl] benzoyl] amino] -3- phenylpropanoic acid, (R) -2- {4- [3-methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3-phenylpropionic acid, (S) -2- {4 - [3-methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3-phenylprop ionic acid, (R) -2- (4- {4 - [(R) -1 (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-phenylpropionic acid, (R) -2 - (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 (4-fluorophenyl) propionic acid, (R) -3- (4 -chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -2- (4- { 4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5 -yl} benzoylamino) -3 - (3,4-difluorophenyl) propionic acid, (R) -3- (2-chlorophenyl ) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) propionic acid, (R) -3- (4-bromophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3- (2-fluorophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3p-tolylpropiono acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol5-yl} benzoylamino) -3- (4-trifluoromethylphenyl) propionic acid, ( R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (4-cyanophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3cyclopropylpropionic acid, (R) -2 - [[4- [2 , 5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, (R) -3- (4-bromophenyl) -2 - [[4- [2, 5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) n-pyrazol-3-yl] benzoyl] amino] npropanoic acid, (R) -3- (4-chlorophenyl) -2 - [[4- [2.5 -dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3yl] benzoyl] amino] propanoic acid, (R) -3- (3,4-difluorophenyl) -2 - [[4- [2,5- dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -2 - [[4- [ 1,5-dimethyl-4 - ((R) 1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2 - [[4- [1,5dimethyl-4- ( (R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3 - (4-fluorophenyl) propanoic acid, (R) -3- (4-bromophenyl) -2 - [[4- [1, 5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (4-chlorophenyl) -2 - [[4- [1,5 -dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (3,4-difluorophenyl) -2 - [[4- [1, 5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -2- (4 {5 - [(R) -1 - (2-chlorophenyl ) ethoxycarbonylamino] -4-methylpyrazol-1 -yl} benzoylamino) -3-phenylpropionic acid, (R) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl ] benzylamino} -3 phenylpropionic acid, (R) -3- (2-fluorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] b benzylamino} -3- (4-trifluoromethylphenyl) propionic acid, (R) -3cyclonropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} npropionic acid , (R) -3- (2-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole-5yl] benzylamino} propionic acid, (R) -3- ( 4-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -2- (4- {4- [ (R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3 -methylisoxazol-5-yl} benzylamino) -3-phenylpropionic acid, (R) -2 (4- {4 - [(R) -1- (2 -chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3- (2-fluorophenyl) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzylamino) -3- (4-trifluoromethylphenyl) propionic acid, (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R) -1- (2chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) propionic acid, (R) -2- (4 {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5 -yl} benzylamino) -3-cyclopropylnro pionic acid, 2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3phenylpropionic acid, 2- {4- [3-methyl-4 - (( R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid, (RS) -3 -cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid, (RS) -3-cyclopropyl-2- {4- [3-methyl-4

- 51 038294 ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid, 2- [4- [4- [5- [1- (2chlorofnyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl ] phenyl] phenyl] acetic acid, (R) -1- [4- [4- [1,5dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, (R) -1 - [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, (R) -1 - (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1 -yl} -3-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1 - (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino ] -4fluoropyrazol-1 -yl} -2-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1 - (2-chloro-4 '- {5- [1 - (2chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazole- 1-yl} diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1 -yl} -2-methyldiphenyl- 4-yl) cyclopropanecarboxylic acid, (R) -1- (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1 yl} diphenyl-4-yl) cyclop ropanecarboxylic acid, (R) -1- {4 '- [5- (1-phenylethoxycarbonylαmino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid, (R) -1- {2-fluoro- 4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid, (R) 1- (4- {5- [5- (1-phenylethoxycarbonylamino) pyrazole- 1-yl] -pyridin-2-yl} -phenyl) cyclopropanecarboxylic acid.

122) A method according to embodiments XII is selected from embodiment 31.

123) The method according to embodiments XII is selected from embodiment 32.

124) A method according to embodiments XII is selected from embodiment 33.

125) A method according to embodiments XII is selected from embodiment 34.

126) A method according to embodiments XII is selected from embodiment 35.

127) Method according to Embodiments XII is selected from Embodiment 36.

128) A method according to embodiments XII is selected from embodiment 37.

129) A method according to embodiments XII is selected from embodiment 38.

130) A method according to embodiments XII is selected from embodiment 39.

131) Method according to Embodiments XII is selected from Embodiment 40.

132) A method according to embodiments XII is selected from embodiment 41.

133) A method according to embodiments XII is selected from embodiment 42.

134) A method according to embodiments XII is selected from embodiment 43.

135) A method according to embodiments XII is selected from embodiment 44.

136) A method according to embodiments XII is selected from embodiment 45.

137) A method according to embodiments XII is selected from embodiment 46.

138) A method according to embodiments XII is selected from embodiment 47.

139) A method according to embodiments XII is selected from embodiment 48.

140) A method according to embodiments XII is selected from embodiment 49.

141) A method according to embodiments XII is selected from embodiment 50.

142) A method according to embodiments XII is selected from embodiment 51.

143) A method according to embodiments XII is selected from embodiment 52.

144) A method according to embodiments XII is selected from embodiment 53.

116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (s) of the formula I116-119, where the compound (compounds) of the formula I116-119, where the compound (compounds) of the formula I116-119, g de compound (s) of formula I-

145) A composition according to embodiment 116, wherein the currently used medium is

- 52 038294 is a mast cell membrane stabilizer.

146) The composition of embodiment 116, wherein the currently used agent is a platelet activating factor receptor antagonist.

147) A composition according to embodiment 145, wherein the mast cell membrane stabilizer is cromoglycate, nedocromil, azelastine, bepotastine, epinastine, ketotifen, olopatadine, and rupatadine.

148) The composition according to embodiment 146, wherein the platelet activating factor receptor antagonist is rupatadine, SM-12502, CV-3988, and WEB2170.

1A. A compound where the compound has a structure corresponding to Formula I

A

L — R Formula I

or a pharmaceutically acceptable salt or prodrug thereof, where R ^a is -CO2H, -CO2R ^B , -CN, tetrazolyl, -C (= O) NH2, -C (= O) NHR ^B , -C (= O) NHSO2R ^B or -C (= O) NHCH2CH2SO ₃ H, or isosteric analogue of carboxylic acid groups;

where R ^B represents -H or -C ₁ -C ₄ -alkyl or has one of the following structures:

L ^{1 is} absent or is substituted or unsubstituted C1-C6-αalkylene, substituted or unsubstituted C3-C6 cycloalkylene, C1-C6 fluoroalkylene, substituted or unsubstituted C1-C6 heteroalkylene or -UV-Z-, where -UV- is defined as - OW-, -WO-, -N (RJ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or - C (= O) N (R ^J ) -, where W is substituted or unsubstituted C1-C3 -alkylene or substituted or unsubstituted C3-C6 cycloalkylene, or W is -C (R ^L ) 2-, and where Z is substituted or unsubstituted C ₁ -C ₆ -alkylene, substituted or unsubstituted C ₃ -C ₆ -cycloalkylene or C ₁ -C ₆ -fluoroalkylene, or Z is —C (R ^L ) ₂ -; where n is 0, 1 or 2;

L ^{2 is} absent or is substituted or unsubstituted C ₁ -C ₆ -alkylene, substituted or unsubstituted C ₃ -C ₆ -cycloalkylene, C ₁ -C ₆ -fluoroalkylene, substituted or unsubstituted C1-C6 heteroalkylene, -O-, -S- , -S (= O) -, -S (= O) 2-, -N (R ^J ) -, -C (= O) - or -C (= O) N (R ^J ) -;

Ring A is a 5-6 membered heteroarene selected from one of the following:

where the dotted line indicates the point of attachment of ring A to ring B; where one of R ^C and RD is -H, -CN, -F, -Cl, -Br, -I, -OC1-C4-alkyl, -C1-C4-alkyl, -C3-C6-cycloαalkyl or -CrC4fluoroalkyl and the other R ^C or RD is -N (R ^F ) -C (= O) XCH (R ^G ) -CY, -N (R ^F ) -C (= O) XC (R ^G ) 2-CY, -N (R ^f ) -C (= O) X-CY, -C (= O) -N (R ^f ) -CH (R ^g ) X-CY, -C (= O) -N (R ^f ) -C (R ^g ) ₂ X-CY or -C (= O) XN (R ^f ) -X-CY, where

X is absent or is —O—, —NH— or —CH ₂ -;

RE is —H, —C ₁ -C ₄ -alkyl, or —C ₁ -C ₄ -fluoroalkyl; RF represents -H or C1-C ₄ alkyl; RG is an independently selected RE, or one RG is —C ₁ -C ₄ -alkyl and taken together with the carbon atom to which R ^G is attached and the carbon atom or heteroatom to which CY is attached forms a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and the other RG, if any, is defined for RE;

CY is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₃ -C ₁₀ -cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ -heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein if CY is substituted, then CY is substituted with 1, 2 or 3 independently selected R ^H ;

where each RH is independently selected from -H, halogen, -CN, -NO2, -OH, -OR ^J , -SR ^J , -S (= O) R ^J , -S (= O) ₂ R ^J ,

- 53 038294

-N (R ^j ) S (= O) 2R ^j , -S (= O) 2N (R ^l ) 2, -C (= O) R ^j , OC (= O) R ^j , -CO2R ^j , -OCO2R ^j , -N (R ^l ) 2, -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) 2, -N (R ^j ) C (= O) N (R ^l ) 2, -N (R ^j ) C (= O) R ^j , -N (R ^j ) C (= O) OR ^j , C1-C4-alkyl, C1-C4-fluoroalkyl, G 'G' - „., / S / s.,„ G 'G ”„ „„ D ^J ------ ------------ C1-C4-fluoroalkoxy, C1-C4-alkoxy and C1 -C4 heteroalkyl, where each R ^J is independently substituted or unsubstituted C1-C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C4 alkylene- (substituted or unsubstituted C ₃ -C ₆ -cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene (substituted or unsubstituted heteroaryl);

where each R ^{L is} independently —H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ -alkylene- (substituted or unsubstituted cycloalkyl), -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heterocycloalkyl), -C1- C4 alkylene (substituted or unsubstituted aryl) or -C ₁ -C ₄ -alkylene- (substituted or unsubstituted heteroaryl), or if R ^H is -S (= O) 2N (R ^l ) 2, -N (R ^l ) 2 , -C (= O) N (R ^l ) 2, -OC (= O) N (R ^l ) ₂ or -N (R ^f ) C (= O) N (R ^l ) ₂ , then each R ^L independently is -H or C1-C6-alkyl group, or R ^L are independently a C1-C ₆ alkyl, and wherein, when taken together with the atom N, to which they are attached form a substituted or unsubstituted heterocycle, or when W represents -C (R ^l ) ₂ -, or Z represent is -C (R ^l ) 2-, then each R ^{L is} independently -H, C1-C6 alkyl, or the R ^L groups are independently C1-C ₆ -alkyl and when taken together with the carbon atom to which they are attached to form a carbocycle;

ring B is substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring B is substituted, ring B is substituted with 1, 2 or 3 independently selected R ^H , where R ^{H is} as previously defined;

ring C is absent or is substituted or unsubstituted C3-C10 cycloalkylene, substituted or unsubstituted C ₂ -C ₁₀ heterocycloαalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring C is substituted, ring C is substituted by 1, 2 or 3 independently selected R ^H , where R ^{H is} as previously defined, where if ring B is substituted or unsubstituted arylene, ring C is absent, L ^{2 is} absent, L ¹ is -UV-Z-, where -UV- is -N ( R ^f ) -C (= O) O-, where R ^F is -H, RD is -N (R ^f ) -C (= O) XCH (R ^g ) -CY, where X is -O- , R ^g is -CH ₃ and R ^F is -H and R ^C is -H, -CH3 or -CF3, or if ring B is substituted or unsubstituted arylene and ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene, or ring B is is substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene and ring C is substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C ₁ -C ₆ -alkylene, and R ^C is -H or -CH3, and R ^A is —CO2H or —CO2RB, then ring A has one of the following structures:

and if ring B is C ₂ -C ₁₀ heterocycloalkylene, ring C is substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C1-C6 alkylene, R ^C is —CH3, and R ^a is - CO2H or CO2RB, ring A has one of the following structures:

- 54 038294

2A. The compound of Embodiment 1A, wherein RC is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ alkyl, —C ₁ —C ₄ alkyl, —C ₃ - C ₆ -cycloalkyl or -C ₁ -C ₄ -fluoroalkyl, a R ^D is -N (R ^f ) C (= O) XCH (R ^g ) CY, -N (R ^f ) -C (= O) XC (R ^g ) 2-CY, -N (R ^f ) -C (= O) X-CY, where R ^F and each R ^{G are} independently -H or C1-C ₄ -alkyl.

3A. The compound of Embodiment 2A, wherein Ring A is selected from one of the following:

where R ^d is -N (R ^F ) C (= O) XCH (R ^G ) CY, and R ^C is -H, -CH3 or -CF3, ring B is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene , ring C is missing; L ^{2 is} absent; L ¹ is -UV-Z-, where -UV is -OW-, -WO-, -N (R ^J ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C1-C ₃ -αalkylene; and n is 0, 1 or 2; or ring B and ring C are independently substituted or unsubstituted arylene or substituted or unsubstituted arylene, L ^{2 is} absent, L ¹ is C ₁ -C 6 -alkylene.

realization 2A, where ring A has one of the following

4A. Connection according to structure option:

where ring B is substituted or unsubstituted arylene and ring C is

- 55 038294 is a substituted or unsubstituted arylene or is a substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene, or ring B is a substituted or unsubstituted C3-C10 cycloalkylene and ring C is a substituted or unsubstituted arylene, L ^{2 is} absent, a L ¹ is C ₁ -C ₆ -αalkylene.

5A. The compound of Embodiment 2A wherein L ^{2 is} absent and L ¹ is C1-C6-αalkylene or substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C1-C6 heteroalkylene, or L ² and ring C are absent, and L ¹ is -UV-Z-, where -UV- is defined as -OW-, -WO-, -N (R ^J ) W-, -WN (R ^J ) -, -N (R ^J ) C (= O ) -, -SW-, -S (= O) nW- or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C ₁ -C ₃ -alkylene; and n is 0, 1, or 2.

6A. The compound of Embodiment 5A, wherein L ¹ is -UV-Z-, where -UV is -OW-, -WO-, -N (R ^J ) W-, -WN (R ^J ) - or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C ₁ -C ₃ -alkylene.

7A. The compound of Embodiment 5A wherein L ¹ is -UV-Z-, where -UV is -WO-, -WN (R ^J ) - or -C (= O) N (R ^J ) -, where W is substituted or unsubstituted C ₁ -C ₃ -alkylene, and L ^{2 is} absent.

8A. The compound of Embodiment 7A wherein Z is substituted or unsubstituted C ₁ -C ₆ alkylene.

9A. The compound of Embodiment 7A wherein Z is substituted or unsubstituted C ₁ -C ₆ -alkylene and RA is —CO ₂ H or —CO ₂ R ^B

10A. The compound of Embodiment 7A wherein L ¹ is -UV-Z-, where -UV is -C (= O) N (R ^J ) -, where RJ is -H or -CH3.

11A. The compound of Embodiment 7A, wherein L ¹ is UV-Z—, wherein —UV is —WO—.

12A. The compound of Embodiment 7A, wherein L ¹ is -UV-Z-, where -UV is -WN (R ^J ) -, where RJ is -H or -CH3.

13A. The compound of embodiment 2A wherein L ^{1 is} absent or is substituted or unsubstituted C 1 -C ₄ alkylene or substituted or unsubstituted C ₃ cycloalkylene (ie, cyclopropyldiyl).

14A. The compound of Embodiment 2, wherein L ¹ is —CH ₂ -,

or -C (CH ₃ ) ₂ -.

15A. The compound of Embodiment 2, wherein Ring A has one of the following structures:

where R ^C is -H, -CN, -CH3 or -CF3, RD is -N (R ^F ) C (= O) XCH (R ^G ) CY, -N (R ^f ) C (= O) XC (R ^g ) 2-CY or -N (R ^f ) C (= O) X-CY, a L ¹ is -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or -C (= O) N (R ^J ) -.

16A. The compound of Embodiment 15A wherein RC is —H, —CH3, or —CF ₃ and RD is —N (R ^F ) C (= O) XCH (R ^G ) CY.

17A. The compound of Embodiment 15A wherein RD is —N (R ^f ) C (= O) XCH (R ^g ) CY, wherein —X— is —N (R ^F ) - or —O—; and where R ^G and each RF are independently selected —H or —CH ₃ .

18A. The compound of Embodiment 17A wherein R ^G is -CH3 in the R- or S-configuration and CY is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.

19A. The compound of Embodiment 17A wherein R ^D is —N (R ^F ) C (= O) OCH (R ^G ) —CY, wherein CY is unsubstituted or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two independently selected RJ.

20A. The compound of Embodiment 17A wherein R ^D is —N (R ^F ) C (= O) OCH (CH ₃ ) CY, wherein R ^F is —H and where CY is unsubstituted phenyl.

21A. The compound of Embodiment 17A wherein R ^D is -N (R ^F ) C (= O) OCH (CH3) -CY, wherein R ^F is -H and wherein CY is substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two independently selected RJs, where RJs are halogen atoms.

22A. The compound of Embodiment 21A wherein R ^D is —NH

- 56 038294

C (= O) OCH (CH ₃ ) -CY, where CY is substituted phenyl, where substituted phenyl is phenyl substituted with one RJ, where RJ is —F, —Cl, or —Br.

23A. The compound of Embodiment 21A wherein RD is —NHC (= O) OCH (CH3) CY, wherein CY is substituted phenyl, wherein substituted phenyl is phenyl substituted with one RJ, wherein RJ is —Cl.

24A. The compound of Embodiment 19A wherein RD is —NHC (= O) OCH (CH ₃ ) —CY having the structure

CH ₃ O

[H, Halogen] k. /R

25A. A compound according to 19A, wherein RD is —NH — C (= O) OCH (CH ₃ ) —CY, wherein the methyl group in RD is in the R configuration.

26A. A compound according to any one of Embodiments 5-25, wherein Ring A has the structure

where L ^{2 is} absent and ring B is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene, provided that if ring C is not absent, and L ¹ is C1-C6 alkylene, or ring C is absent, and L ¹ is is -UV-Z, where -UV is -N (R ^f ) -C (= O) O-, and RD has the structure -N (R ^F ) -C (= O) XCH (R ^G ) -CY, - N (R ^f ) C (= O) XC (R ^g ) 2-CY or -N (R ^f ) -C (= O) X-CY, and R ^A is -CO ₂ H, then RC is different from - H, -CH3 and -CF3.

27A. The compound of Embodiment 26A wherein RC is —H, —CH _3, or —CF3 and R ^D is —NH — C (= O) OCH (R ^G ) —CY, where R ^G is —H or - CH3 in the R- or S-configuration, and -CY is substituted or unsubstituted phenyl.

28A. The compound of Embodiment 26A wherein L ² and Ring C are absent, Ring B is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene, and L ¹ is —UV-Z— where —UV— is defined as —WO—, - WN (RJ) - or -C (= O) N (RJ) -.

29A. The compound of Embodiment 26A, wherein L ² and ring C are absent, ring B is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene, and L ¹ is -UV-Z-, where -UV- is defined as -WN (R ^J ) - or -C (= O) N (R ^J ) -, where R ^J is -H or -CH ₃ .

30A. The compound of Embodiment 29A wherein L ¹ is —UV — Z—, where —UV— is —C (═O) NH— and where Z is substituted or unsubstituted C ₁ -C 6 alkylene.

31A. The compound of Embodiment 29A wherein L ¹ is —UV-Z—, where —UV— is —WO—, where W is substituted or unsubstituted C ₁ -C ₃ alkylene, and where Z is substituted or unsubstituted C ₁ -C ₆ -alkylene.

32A. The compound of Embodiment 29A wherein L ¹ is —UV-Z—, where —UV— is —W — NH—, where W is substituted or unsubstituted C ₁ -C ₃ alkylene, and where Z is substituted or unsubstituted C ₁ -C ₆ alkylene.

33A. The compound of Embodiment 26A wherein L ¹ is -UV-Z-, where -UV- is defined as -WO-, -WN (R ^J ) - or -C (= O) N (R ^J ), where R ^J is —H or —CH3, and where Z is substituted or unsubstituted C ₁ -C ₆ alkylene, where alkylene is —CH (CH ₂ cyclopropyl) -, —CH (CH ₂ aryl), or —CH (CH ₂ heteroaryl), where aryl or heteroaryl is substituted or unsubstituted.

34A. The compound of Embodiment 33A wherein L ¹ is -UV-Z-, where -UV- is -C (= O) NH-, -WO-, or -W-NH-, where -W- is -CH ₂ -.

35A. The compound of Embodiment 33A wherein RA is —CO ₂ H or —CO2RB

36A. The compound of Embodiment 33A wherein L ¹ is -UV-Z-, wherein -UV- is -CH2O-, -CH2-NH-, or -C (= O) NH-, wherein Z is substituted or unsubstituted C ₁ -C ₆ -alkylene, where alkylene is —CH (CH ₂ cyclopropyl) -, —CH (CH ₂ aryl), or —CH (CH ₂ heteroaryl), where aryl or heteroaryl is unsubstituted or substituted by 1, 2, or 3 independently selected substituted or unsubstituted C ₁ -C 4 -alkyls or halogen atoms.

37A. The compound of Embodiment 36A, wherein said aryl or heteroaryl substituent or substituents on —CH (CH ₂ aryl) or —CH (CH ₂ heteroaryl), which are substituted or unsubstituted C ₁ -C 4 alkyl or halogen, are selected from the group consisting of from -CH ₃ , -CF ₃ , -F, -Cl

- 57 038294 or -Br.

38A. The compound of Embodiment 33A wherein L ¹ is —UV-Z— and where RA is —CO2H to which Z is attached to form —L ¹ —R ^A (i.e. —UV-Z-RA), where -UV- is defined as -C (= O) NH-, -WO- or -W-NH-, where -W- is -CH ₂ - and Z is CH (CH ₂ aryl), where aryl is substituted or unsubstituted, having one of the following structures:

H

, Cl, CH ₃ , CF ₃ ]

[H, Cl]

39A. The compound of Embodiment 36A wherein the Z substituent is —CH (CH ₂ aryl) in —k'-RA is in the R configuration.

40A. The compound of Embodiment 33A wherein L ¹ is —UV-Z— and where RA is —CO2H to which Z is attached to form —L ¹ —R ^A (i.e. —UV-Z-RA), where -UV is defined as -C (= O) NH-, -WO- or -W-NH-, where -W- is -CH2- and Z is -CH (CH ₂ cyclopropyl) - having the structure

41A. A compound according to embodiments 1A, 2A, 3A, or 4A, wherein the compound has a structure corresponding to Formula V

where A ¹ , A ² and A ³ independently represent -N =, = N-, = CH- or -CH =.

42A. The compound of Embodiment 41A, wherein Ring A has one of the following structures:

where if L ¹ is Q-Cb-alkylene, RD is -N (R ^F ) -C (= O) XCH (R ^G ) -CY, -N (R ^f ) -C (= O) XC (R ^g ) 2-CY, where R ^F is -H, R ^G is -H or -CH3; RA is —CO2H or CO2RB and R ^C is —H or —CH ₃ , ring A has one of the following structures:

43A. The compound of Embodiment 41A, wherein Ring A has one of the following structures:

where ring C is substituted or unsubstituted arylene or heteroarylene, L ¹ is C1-C6 alkylene, RA is —CO2H or CO2RB, RD is —N (R ^F ) —C (= O) XCH (R ^G ) -CY, -N (R ^F ) -C (= O) XC (R ^G ) 2-CY, where R ^F is -H, R ^G is -CH ₃ , and CY is substituted phenyl, and R ^C represents -CN, -F, -Cl, -Br, -I,

-OC ₁ -C ₄ -alkyl, -C ₂ -C ₄ -alkyl, -C ₃ -C ₆ -cycloalkyl or -C ₂ -C ₄ -fluoroalkyl.

- 58 038294

44A. The compound of Embodiment 41A, wherein Ring A has one of the following structures:

where ring C is substituted or unsubstituted arylene or heteroarylene, L ¹ is C1-C6-αalkylene, RA is -CO2H or -CO2R ^B , RD is -N (R ^f ) -C (= O) XCH (R ^g ) CY, -N (R ^f ) -C (= O) XC (R ^g ) 2-CY, where X is -O-, R ^F is -CH3, R ^G is -H or CH3, a CY is substituted phenyl and R ^C is —H, —CN, —F, —Cl, —Br, —I, —OC ₁ —C ₄ alkyl, —C ₁ —C ₄ alkyl, —C ₃ -C ₆ -cycloalkyl or -C 1 -C 4 fluoroalkyl.

45A. A compound according to embodiments 1A, 2A, or 5A, wherein the compound has a structure according to Formula IV

where ring A has one of the following structures:

where A ¹ represents = N- or = C-; RD is -NR ^F C (= O) OCH (R ^G ) CY; L ¹ is -UV-Z-, where -UV- is defined as -C (= O) N (RJ) -, where RJ is -H or -CH3; R ^F and R ^{g are} independently —H or —CH3; a RA is -CO2H or -CO2RB.

46A. The compound of embodiment 2A, wherein the compound has a structure corresponding to Formula VII

where Ring A is a 5-membered heteroarene having one of the following structures:

where RD is the substituent -N (R ^F ) C (= O) CH (R ^G ) CY in formula VI, where CY is phenyl substituted with one R ^H , and R ^C is -H, -CH3, CF3 or -F; RA is -CO2H or -CO2RB; and R ^F and R ^{G are} independently —H or —CH3; and RH are each independently -H, halogen, -CH3 or -CF _3.

47A. The compound of embodiment 2A, wherein the compound has a structure corresponding to Formula VII

- 59 038294 .j

R

\ ^A

Formula VII where A ¹ is = CH- or having one of the following structures:

= N-; ring A is a 5-membered heteroarene,

where RD is the substituent -N (R ^F ) C (= O) CH (RG) CY in formula VII, where CY is phenyl substituted with one R ^H ; a RC is -H, -CH3, CF3 or -F; RA is -CO2H or -CO2RB; R ^E and R ^{F are} independently —H or C1-C4 alkyl; RG is -H or -CH3; R ^{H are} independently —H, halogen, —CH3, or —CF3; and Z is -c (R ^l ) 2, where one R ^l is -H and the other R ^L is -H or C ₁ -C ₄ -alkyl.

48A. The compound of embodiment 2A, wherein the compound has a structure corresponding to formula VIII

where A ¹ represents = CH- or = N-; where Ring A is a 5-membered heteroarene having one of the following structures:

where RD is the substituent -N (R ^F ) C (= O) CH (RG) CY in formula VII, where CY is phenyl substituted with one R ^H ; RA is -CO2H or -CO2RB; W is -C (R ^l ) ₂ - or

R ^e and R ^{f are} independently —H or C1-C4 alkyl; RG is -H or -CH3; R ^{H are} independently —H, halogen, —CH3, or —CF3; and Z is —C (R ^L ) 2, where one R ^l is —H and the other R ^L is —H or C ₁ -C ₄ alkyl.

49A. The compound of embodiment 2A, wherein the compound has a structure corresponding to formula IX

- 60 038294

where A ¹ represents = CH- or = N-; where Ring A is a 5-membered heteroarene having one of the following structures:

where RD is the substituent -N (R ^F ) C (= O) CH (RG) CY in formula VII, where CY is phenyl substituted with one R ^H ; R ^A represents —CO ₂ H or —CO ₂ R ^B ;

where W represents -C (R ^L ) ₂ - or

R ^e and RF are independently —H or C1-C4 alkyl; RG is -H or -CH3; R ^{H are} independently —H, halogen, —CH3, or —CF3; and Z is —C (R ^L ) 2, where one R ^l is —H and the other R ^L is —H or C ₁ -C ₄ alkyl.

50A. The compound of embodiment 2A, wherein the compound has a structure corresponding to formula IX

where A ¹ represents = CH- or = N-; having one of the following structures:

where ring A is a 5-membered heteroarene,

where RD is the substituent -N (R ^F ) C (= O) CH (RG) CY in formula VII, where CY is phenyl substituted with one R ^H ; RA is -CO2H or -CO2RB; where W represents -C (R ^l ) ₂ - or

R ^e and R ^{f are} independently —H or C1-C4 alkyl; RG is -H or -CH3; R ^{H are} independently —H, halogen, —CH3, or —CF3; and Z is —C (R ^L ) 2, where one R ^l is —H and the other R ^L is —H or C ₁ -C ₄ alkyl.

51A. The connection according to embodiment 2A, where the connection is selected from table. 1.

- 61 038294

52A. The compound of Embodiment 51A, wherein the compound is 1- (4 {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) cyclopropanecarboxylic acid, 2- (4- {4- [ 1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indane-2-carboxylic acid, 2- (S) - (4- {4 - [(R, S) -1- (2 -chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol5-yl} benzoylamino) phenylacetic acid, 2- (R) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] 3-methylisoxazole-5 -yl} benzoylamino) phenylpropanoic acid, 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, 2 (S) - [[4- [3-methyl-4 - ((R) 1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2 - [[4 [2 , 5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3-phenylpropanoic acid, (R) -2 - [[4- [2,5-dimethyl-4 - (( R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, (R) -2 - [[4- [1,5-dimethyl-4 - ((R ) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl) propanoic acid, (R) -3- (4-bromophenyl) -2 [[4- [2,5-dimethyl -4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (4-bromophenyl) -2 - [[4- [1,5-dimethyl- 4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (4-chlorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (4-chlorophenyl) -2 - [[4- [1,5-dimethyl-4- ((R) -1phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid, (R) -3- (3,4-difluorophenyl) -2 - [[4- [2,5-dimethyl-4- ( (R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] npropanoic acid, (R) -3- (3,4-difluorophenyl) -2 - [[4- [1,5-dimethyl-4- ((R) -1-phenylethoxycarbonylamino) pyrazole-3yl] benzoyl] amino] propanoic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylis oxazol-5-yl} benzoylamino) -3-cyclopropylpropionic acid, (R) -2- {4- [3-methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3- phenylpropionic acid, (S) -2- {4- [3-methyl4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3-phenylnropionic acid, (R) 2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-phenylpropionic acid, (R) -2- (4- {4 - [(R) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3- (4-fluorophenyl) propionic acid, (R) -3- (4-chlorophenyl) -2- (4- {4- [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -2- (4- {4 [(R) -1- (2-chlorophenyl ) ethoxycarbonylamino] -3 -methylisoxazol-5 -yl} benzoylamino) -3 - (3,4-difluorophenyl) propionic acid, (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R ) -1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -3- (4-bromophenyl) -2- (4- {4 - [(R) -1- (2chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylam ino) propionic acid, (R) -3 (4-bromophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) -3- (2-fluorophenyl) propionic acid, (R ) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-p-tolylpropionic acid, (R) -2- ( 4- {4 - [(R) -1 (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (4-trifluoromethylphenyl) propionic acid, (R) -2- (4- { 4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) -3- (4-cyanophenyl) propionic acid, (R) -2- (4- {5 - [( R) -1- (2-chlorophenyl) ethoxycarbonylamino] -4-methylpyrazol-1-yl} benzoylamino) -3-phenylpropionic acid, (R) -2- {4- [3-methyl4 - ((R) -1- phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3-phenylnropionic acid, (R) -3 (2-fluorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole- 5-yl] benzylamino} propionic acid, (R) -2- {4- [ 3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3 (4-trifluoromethylphenyl) propionic acid, (R) -3-cyclopropyl-2- {4- [3-methyl -4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} propionic acid, (R) -3- (2-chlorophenyl) -2- {4- [3-methyl4 - ((R) - 1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} npropionic acid, (R) -3- (4-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole- 5-yl] benzylamino} npropionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3phenylpropionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol5-yl} benzylamino) -3- (2-fluorophenyl) propionic acid, (R) - 2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3- (4-trifluoromethylphenyl) propionic acid, (R) 3- ( 2-chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) propionic acid, (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonyl but] -3-methylisoxazole-5yl} benzylamino) -3-cyclopropylpropionic acid, 2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid, (RS) -3-cyclopropyl-2- {4- [3-methyl-4 ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} npropionic acid, (RS) -3-cyclopropyl-2 - {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid, 2- [4- [4- [5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetic acid, (R) -1- [4- [4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, (R) -1- [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid, (R) - 1 - (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4fluoropyrazol-1 -yl} -3-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4' - {5 - [1 - (2-chlorofe

- 62 038294 nyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (2-chloro-4 '- {5- [1- (2 -chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4- fluoropyrazol-1-yl} -2methyldiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} diphenyl- 4-yl) cyclopropanecarboxylic acid, (R) -1- {4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid, (R) -1- { 2-fluoro-4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid, (R) -1- (4- {5- [5- ( 1-phenylethoxycarbonylamino) pyrazol-1-yl] -pyridin-2yl} phenyl) cyclopropanecarboxylic acid.

53A. A compound according to any one of embodiments 1A-52A for the manufacture of a medicament for the treatment of an LPA-dependent disease or condition.

Compounds from table. 1 illustrate, but do not limit the present invention, wherein compounds 57-458 are prepared according to appropriately modified procedures from Preparation Examples 1-458.

Table 1

Compound Name 1 1 - (4- {4- [1 - (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -cyclopropanecarboxylic acid 2 2- (4- {4- [1 - (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -indane-2-carboxylic acid 3 2- (S) - (4- {4 - [(R, S) -1 - (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazol5-yl} -benzoylamino) phenylacetic acid

- 63 038294

4 2- (R) - (4- {4- [(R, S) -1 - (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazol5-yl} -benzoylamino) phenylpropanoic acid 5 2 (R) - [[4- [3-methyl-4 - ((R) -l-phenylethoxcicarbonylamino) isoxazol-5yl] benzoyl] amino] -3-phenylpropanoic acid 6 2 (S) - [[4- [3-methyl-4 - ((R) -l-phhenylethoxcicarbonylamino) isoxazol-5yl] benzoyl] amino] -3-phenylpropanoic acid 7 (7?) - 2- [[4- [2,5-d immethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3-phenylpropanoic acid eight (R) -2- [[4- [1,5-d-immethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3-phenylpropanoic acid nine (R) -2 - [[4- [2,5-dimethyl-4 - ((R) -l-phenylethoxyccarbonylamino) pyrazol-3yl] benzoyl] amino] -3 - (4-fluorophenyl) propanoic acid ten (R) -2- [[4- [1,5-d-immethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3 - (4-fluorophenyl) propanoic acid AND (R) -3 - (4-bromophenyl) -2- [[4- [2,5-dimethyl-4 - ((R) -1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 12 (R) -3 - (4-bromophenyl) -2- [[4- [1,5-dimethyl-4 - ((R) -1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 13 (R) -3 - (4-chlorophenyl) -2- [[4- [2,5-dimethyl-4 - ((R) -1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid fourteen (R) -3 - (4-chlorophenyl) -2- [[4- [1,5-dimethyl-4 - ((R) -1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 15 (R) -3 - (3,4-difluorophenyl) -2- [[4- [2,5-d and methyl-4 - ((R) -1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 16 (R) -3 - (3,4-difluorophenyl) -2- [[4- [1,5-d and methyl-4 - ((R) -1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 17 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycarbonylamino] -3-methyliso-cazol-5yl} -benzoylamino) -3 -cyclopropylpropionic acid eighteen (R) -2- {4- [3-methyl-4 - ((S) -l-phhenylethoxcicarbonylamino) -isocazol-5-yl] benzoylamino} -3-phenylpropionic acid 19 (S) -2- {4- [3-methyl-4 - ((8) -1-phenylethoxycarbonylamino) -isoxazol-5-yl] benzoylamino} -3-phenylpropionic acid twenty (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycarbonylamino] -3-methyliso-cazol-5yl} -benzoylamino) -3-phenylpropionic acid 21 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -ethoxcicarbonylamino] -3-methyliso-cazol-5yl} -benzoylamino) -3- (4-fluorophenyl) -propionic acid 22 (R) -3- (4-chlorophenyl) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycapbonylamino] -3methylisoxazol-5-yl} benzoylamino) -propionic acid 23 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycarbonylamino] -3-methylisocazol-5yl} -benzoylamino) -3- (3,4-difluorophenyl) -propionic acid 24 (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycapbonylamino] -3methylisoxazol-5-yl} benzoylamino) -propionic acid

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25 (K) -3- (4-bromophenyl) -2- (4- {4 - [(K) -1- (2-chlorophenyl) -ethoxycarbonylamino] -3methylisoxazol-5-yl} -benzoylamino) -propionic acid 26 (K) -2- (4- {4 - [(K) -1- (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazole-5yl} -benzoylamino) -3- (2-fluorophenyl) -propionic acid 27 (K) -2- (4- {4 - [(K) -1- (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazole-5yl} -benzoylamino) -3-p-tolylpropionic acid 28 (K) -2- (4- {4 - [(K) -1- (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazole-5yl} -benzoylamino) -3- (4-trifluoromethylphenyl) -propionic acid 29 (K) -2- (4- {4 - [(K) -1- (2-chlorophenyl) -ethoxycarbonylamino] -3-methylisoxazole-5yl} -benzoylamino) -3 - (4-cyanophenyl) -propionic acid thirty (R) -2- (4- {5 - [(R) -1 - (2-chlorophenyl) -ethoxycarbonylamino] -4-methylpyrazol-1 yl} benzoylamino) -3-phenylpropionic acid 31 (R) -2- {4- [3-methyl-4 - ((R) -l-phenylethoxcicaponylamino) -iso-casol-5-yl] benzylamino} -3-phenylpropionic acid 32 (R) -3- (2-phtopφenyl) -2- {4- [3-methyl-4 - ((R) -l-phenylethoxycapbonylamino) isoxazol-5-yl] -benzylamino} -propionic acid 33 (R) -2- {4- [3-methyl-4 - ((R) -l-phenylethoxcicaponylamino) -isoccazol-5-yl] benzylamino} -3 - (4-trifluoromethylphenyl) -propionic acid 34 (R) -3 -cyclopropyl-2- {4- [3 -m6tha-4 - ((R) - 1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -propionic acid 35 (R) -3- (2-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -l-phenylethoxcicaponylamino) isoxazol-5-yl] benzylamino} -propionic acid 36 (R) -3- (4-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -l-phenylethoxycapbonylamino) isoxazol-5-yl] -benzylamino} -propionic acid 37 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycarbonylamino] -3-methyliso-cazol-5yl} -benzylamino) -3-phenylpropionic acid 38 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycarbonylamino] -3-methyliso-cazol-5yl} -benzylamino) -3 - (2-fluorophenyl) -propionic acid 39 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycarbonylamino] -3-methylisocazol-5yl} -benzylamino) -3- (4-trifluoromethylphenyl) -propionic acid 40 (R) -3- (2-chlorophenyl) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoksikaponylamino] -3methylisoxazol-5-yl} -benzylamino) -propionic acid 41 (R) -2- (4- {4 - [(R) -l- (2-chlorophenyl) -etoxycapbonylamino] -3-methyliso-cazol-5yl} -benzylamino) -3 -cyclopropylpropionic acid 42 2- {4- [3-methyl-4 - ((R) -l-phenylethoxcicapbonylamino) -isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid 43 2- {4- [3-methyl-4 - ((R) -l-phenylethoxcicapbonylamino) -isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid 44 (RS) -3 -cyclopropyl-2- {4- [3 -m6tha-4 - ((R) - 1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -propionic acid 45 (RS) -3 - (4-chlorophenyl) -2- {4- [3 -m6tha-4 - ((R) - 1-phenylethoxycarbonyloxy) isoxazol-5-yl] benzyloxy} propionic acid 46 2- [4- [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1 yl] phenyl] phenyl] acetic acid 47 (R) -1 - [4- [4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3 yl] phenyl] phenyl] cyclopropanecarboxylic acid 48 (R) -1 - [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazole-3 -

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yl] phenyl] phenyl] cyclopropanecarboxylic acid 49 (R) -1- (4 '- {5- [1 - (2-chlorophenyl) -ethoxycarbonylamino] -4-fluoropyrazol-1 -yl} -3 fluorodiphenyl-4-yl) -cyclopropanecarboxylic acid 50 (R) -1- (4 '- {5- [1 - (2-chlorophenyl) -ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2fluorodiphenyl-4-yl) -cyclopropanecarboxylic acid 51 (R) -l- (2-chlorop-4 '- {5- [l- (2-chlorophenyl) -etoxycarbonylamino] -4-phtoppyrazol1 -yl} -biphenyl-4-yl) -cyclopropanecarboxylic acid 52 (R) -1- (4 '- {5- [1 - (2-chlorophenyl) -ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2methyldiphenyl-4-yl) -cyclopropanecarboxylic acid 53 (R) -1- (4 '- {5- [1 - (2-chlorophenyl) -ethoxycarbonylamino] -4-fluoropyrazol-1 -yl} diphenyl-4-yl) -cyclopropanecarboxylic acid 54 (R) -l- {4 '- [5- (l-phenylethoxycapbonylamino) -4-triφtomethylpyrazol-l-yl] diphenyl-4-yl} -cyclopropanecarboxylic acid 55 (R) -1 - {2-fluoro-4'- [5 - (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol1-yl] -diphenyl-4-yl} -cyclopropanecarboxylic acid 56 (R) -1 - (4- {5 - [5 - (1-phenylethoxycarbonylamino) -pyrazol-1-yl] pyridin-2-yl} phenyl) -cyclopropanecarboxylic acid 57 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5yl] benzoyl] amino] -3-phenylpropanoic acid 58 3-cyclopropyl-2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5yl] benzoyl] amino] propanoic acid 59 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5yl] benzoyl] amino] -3-phenoxypropanoic acid 60 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5yl] benzoyl] amino] -4-phenylbutanoic acid 61 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3-phenylpropanoic acid 62 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3-cyclopropylpropanoic acid 63 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -4-phenylbutanoic acid 64 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3-phenoxypropanoic acid 65 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -4-phenylbutanoic acid 66 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3-phenoxypropanoic acid 67 3-cyclopropyl-2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 68 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3-phenylpropanoic acid 69 3 - (4-methoxyphenyl) -2- [[4- [3-methyl-4- (1 - phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid 70 3- (4-fluorophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol5-yl] benzoyl] amino] propanoic acid 71 3 - (2,6-d ifluorophenyl) -2- [[4- [3-methyl-4- (1 -

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phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid 72 3 - (3-cyanophenyl) -2- [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole- 5-yl] benzoyl] amino] propanoic acid 73 3- (2-chlorophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol5-yl] benzoyl] amino] propanoic acid 74 3- (4-chlorophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol5-yl] benzoyl] amino] propanoic acid 75 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5yl] benzoyl] amino] -3 - [4- (trifluoromethyl) phenyl] propanoic acid 76 3 - (4-hydroxyphenyl) -2- [[4- [3-methyl-4- (1 - phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid 77 3 - (3,4-difluorophenyl) -2 - [[4- [3-methyl-4- (1 - phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] propanoic acid 78 3- (4-bromophenyl) -2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol5-yl] benzoyl] amino] propanoic acid 79 2 - [[4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazole-5- yl] benzoyl] amino] -3 - [4- (trifluoromethoxy) phenyl] propanoic acid 80 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - (4-methoxyphenyl) propanoic acid 81 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - (4-fluorophenyl) propanoic acid 82 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - (2,6-d ifluorophenyl) propanoic acid 83 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - (3-cyanophenyl) propanoic acid 84 3- (2-chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 85 3- (4-chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 86 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - [4- (trifluoromethyl) phenyl] propanoic acid 87 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - (4-hydroxyphenyl) propanoic acid 88 3- (4-bromophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 89 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3- (3,4-difluorophenyl) propanoic acid 90 2 - [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl] benzoyl] amino] -3 - [4- (trifluoromethoxy) phenyl] propanoic acid 91 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5 yl] benzoyl] amino] -3 - (4-methoxyphenyl) propanoic acid 92 3 - (4-fluorophenyl) -2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3 methylisoxazol-5-yl] benzoyl] amino] propanoic acid 93 3 - (2,6-d ifluorophenyl) -2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3 methylisoxazol-5-yl] benzoyl] amino] propanoic acid

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94 3 - (3-cyanophenyl) -2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3 methylisoxazol-5-yl] benzoyl] amino] propanoic acid 95 3- (2-chlorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 96 3- (4-chlorophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 97 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5 yl] benzoyl] amino] -3 - [4- (trifluoromethyl) phenyl] propanoic acid 98 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5 yl] benzoyl] amino] -3 - (4-hydroxyphenyl) propanoic acid 99 3 - (3,4-difluorophenyl) -2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3 methylisoxazol-5-yl] benzoyl] amino] propanoic acid 100 3- (4-bromophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -3methylisoxazol-5-yl] benzoyl] amino] propanoic acid 101 2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5 yl] benzoyl] amino] -3 - [4- (trifluoromethoxy) phenyl] propanoic acid 102 2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3 - (4-methoxyphenyl) propanoic acid 103 2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3 - (4-fluorophenyl) propanoic acid 104 3 - (2,6-d ifluorophenyl) -2- [[4- [1,5-d imethyl-4- (1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 105 3 - (3-cyanophenyl) -2- [[4 - [1,5-dimethyl-4- (1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 106 3- (2-chlorophenyl) -2 - [[4- [1,5-dimethyl-4- (1- phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 107 3- (4-chlorophenyl) -2 - [[4- [1,5-dimethyl-4- (1- phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 108 2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3 - [4- (trifluoromethyl) phenyl] propanoic acid 109 2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3 - (4-hydroxyphenyl) propanoic acid 110 3 - (3,4-difluorophenyl) -2 - [[4- [1,5-dimethyl-4- (1 - phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 111 3- (4-bromophenyl) -2 - [[4- [1,5-dimethyl-4- (1- phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] propanoic acid 112 2 - [[4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3 yl] benzoyl] amino] -3 - [4- (trifluoromethoxy) phenyl] propanoic acid FROM 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3yl] benzoyl] amino] -3 - (4-methoxyphenyl) propanoic acid 114 2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3yl] benzoyl] amino] -3 - (4-fluorophenyl) propanoic acid

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115 2 - ((4- (4- (1- (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - (2,6-d ifluorophenyl) propanoic acid 116 2 - ((4- (4- (1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - (3-cyanophenyl) propanoic acid 117 3- (2-chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1.5d imethylpyrazol-3-yl] benzoyl] amino] propanoic acid 118 3- (4-chlorophenyl) -2 - [[4- [4- [1- (2-chlorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 119 2 - ((4- (4- (1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - [4- (trifluoromethyl) phenyl] propanoic acid 120 2 - ((4- (4- (1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - (4-hydroxyphenyl) propanoic acid 121 2 - ((4- (4- (1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3- (3,4-difluorophenyl) propanoic acid 122 3 - (4-bromophenyl) -2- [[4- [4- [1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 123 2 - ((4- (4- (1 - (2-chlorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - [4- (trifluoromethoxy) phenyl] propanoic acid 124 2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - (4-methoxyphenyl) propanoic acid 125 3 - (4-fluorophenyl) -2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 126 3 - (2,6-d ifluorophenyl) -2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 127 3 - (3-cyanophenyl) -2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 128 3 - (2-chlorophenyl) -2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 129 3 - (4-chlorophenyl) -2 - [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 130 2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - [4- (trifluoromethyl) phenyl] propanoic acid 131 2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - (4-hydroxyphenyl) propanoic acid 132 3 - (3,4-d ifluorophenyl) -2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 133 3- (4-bromophenyl) -2 - [[4- [4- [1- (2-fluorophenyl) ethoxycarbonylamino] -1,5dimethylpyrazol-3-yl] benzoyl] amino] propanoic acid 134 2- [[4- [4- [1 - (2-fluorophenyl) ethoxycarbonylamino] -1,5-dimethylpyrazol-3 yl] benzoyl] amino] -3 - [4- (trifluoromethoxy) phenyl] propanoic acid 135 2- {p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] benzoylamino} -3-phenylpropionic acid 136 2- (p- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} benzoylamino) -3-phenylpropionic acid 137 3-cyclopropyl-2- {p- (3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] benzoylamino} propionic acid 138 2- (p- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 -

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isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid 139 2- [({p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid 140 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid 141 3-cyclopropyl-2 - [({p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} methyl) amino] propionic acid 142 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} phenyl) methyl] amino} -3 -cyclopropylpropionic acid 143 2 - ({and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid 144 2 - [(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5isoxazolyl} phenyl) methoxy] -3-phenylpropionic acid 145 3-cyclopropyl-2- ({p- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} methoxy) propionic acid 146 2 - [(p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid 147 2- {p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] benzoylamino} -3-phenylpropionic acid 148 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5isoxazolyl} benzoylamino) -3-phenylpropionic acid 149 2- {p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5- isoxazolyl] benzoylamino} -3-cyclopropylpropionic acid 150 2- (p- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid 151 2- [({and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid 152 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid 153 2- [({and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] phenyl} methyl) amino] -3-cyclopropylpropionic acid 154 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methyl] amino} -3 -cyclopropylpropionic acid 155 2 - ({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid 156 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methoxy] -3-phenylpropionic acid 157 2 - ({p- [3-cyano-4- (1-phenylethoxycarbonylamino) -5- isoxazolyl] phenyl} methoxy) -3-cyclopropylpropionic acid 158 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid 159 2-benzyl-3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} propionic acid 160 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5 isoxazolyl} -2-pyr idylamino) propionic acid 161 2- (cyclopropylmethyl) -3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} propionic acid

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162 3- (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridylamino) -2- (cyclopropylmethyl) propionic acid 163 2-benzyl-3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} propionic acid 164 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5 isoxazolyl} -2-pyr idyloxy) propionic acid 165 2- (cyclopropylmethyl) -3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 166 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) propionic acid 167 2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3-phenylpropionic acid 168 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridylamino) -3-phenylpropionic acid 169 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridylamino) -3 -cyclopropylpropionic acid 170 2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid 171 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid 172 3-cyclopropyl-2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 173 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -3 -cyclopropylpropionic acid 174 2-benzyl-3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} propionic acid 175 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} -2-pyr idylamino) propionic acid 176 2- (cyclopropylmethyl) -3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} propionic acid 177 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridylamino) -2- (cyclopropylmethyl) propionic acid 178 2-benzyl-3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} propionic acid 179 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} -2-pyr idyloxy) propionic acid 180 2- (cyclopropylmethyl) -3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 181 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) propionic acid 182 2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3-phenylpropionic acid 183 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridylamino) -3-phenylpropionic acid 184 3-cyclopropyl-2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} propionic acid 185 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 -isoxazolyl} -2-

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pyr id ylamino) -3 -cyclopropylpropionic acid 186 2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid 187 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid 188 3-cyclopropyl-2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 189 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridyloxy) -3-cyclopropylpropionic acid 190 2-benzyl-3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} propionic acid 191 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} -2-pyr idylamino) propionic acid 192 3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -2- (cyclopropylmethyl) propionic acid 193 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridylamino) -2- (cyclopropylmethyl) propionic acid 194 2-benzyl-3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} propionic acid 195 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} -2-pyr idyloxy) propionic acid 196 3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -2- (cyclopropylmethyl) propionic acid 197 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) propionic acid 198 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3-phenylpropionic acid 199 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridylamino) -3-phenylpropionic acid 200 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3 -cyclopropylpropionic acid 201 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridylamino) -3 -cyclopropylpropionic acid 202 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid 203 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid 204 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3 -cyclopropylpropionic acid 205 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2pyridyloxy) -3 -cyclopropylpropionic acid 206 2- {and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] benzoylamino} -3-phenylpropionic acid 207 2- (and- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5isoxazolyl} benzoylamino) -3-phenylpropionic acid 208 3-cyclopropyl-2- {and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] benzoylamino} propionic acid

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209 2- (and- {4- [1- (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid 210 2 - [({and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid 211 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid 212 3-cyclopropyl-2 - [({and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methyl) amino] propionic acid 213 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} phenyl) methyl] amino} -3 -cyclopropylpropionic acid 214 2 - ({and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5- isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid 215 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} phenyl) methoxy] -3-phenylpropionic acid 216 3-cyclopropyl-2 - ({and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methoxy) propionic acid 217 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid 218 2- {and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] benzoylamino} -3-phenylpropionic acid 219 2- (and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} benzoylamino) -3-phenylpropionic acid 220 2- {and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] benzoylamino} -3-cyclopropylpropionic acid 221 2- (and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} benzoylamino) -3-cyclopropylpropionic acid 222 2 - [({and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5- isoxazolyl] phenyl} methyl) amino] -3-phenylpropionic acid 223 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methyl] amino} -3-phenylpropionic acid 224 2 - [({and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5- isoxazolyl] phenyl} methyl) amino] -3-cyclopropylpropionic acid 225 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methyl] amino} -3 -cyclopropylpropionic acid 226 2 - ({and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methoxy) -3-phenylpropionic acid 227 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methoxy] -3-phenylpropionic acid 228 2 - ({and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5- isoxazolyl] phenyl} methoxy) -3-cyclopropylpropionic acid 229 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} phenyl) methoxy] -3-cyclopropylpropionic acid 230 2-benzyl-3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2 pyridylamino} propionic acid 231 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5 isoxazolyl} -2-pyr idylamino) propionic acid 232 2- (cyclopropylmethyl) -3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -

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isoxazolyl] -2-pyridylamino} propionic acid 233 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridylamino) -2- (cyclopropylmethyl) propionic acid 234 2-benzyl-3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} propionic acid 235 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5 isoxazolyl} -2-pyr idyloxy) propionic acid 236 2- (cyclopropylmethyl) -3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 237 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) propionic acid 238 2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3-phenylpropionic acid 239 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridylamino) -3-phenylpropionic acid 240 3-cyclopropyl-2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} propionic acid 241 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridylamino) -3 -cyclopropylpropionic acid 242 2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid 243 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid 244 3-cyclopropyl-2- {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 245 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-methyl-5-isoxazolyl} -2pyridyloxy) -3 -cyclopropylpropionic acid 246 2-benzyl-3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} propionic acid 247 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} -2-pyr idylamino) propionic acid 248 2- (cyclopropylmethyl) -3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} propionic acid 249 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridylamino) -2- (cyclopropylmethyl) propionic acid 250 2-benzyl-3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} propionic acid 251 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5 isoxazolyl} -2-pyr idyloxy) propionic acid 252 2- (cyclopropylmethyl) -3 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} propionic acid 253 3- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) propionic acid 254 2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3-phenylpropionic acid 255 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridylamino) -3-phenylpropionic acid

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256 3-cyclopropyl-2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} propionic acid 257 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridylamino) -3 -cyclopropylpropionic acid 258 2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid 259 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid 260 3-cyclopropyl-2- {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy] propionic acid 261 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-fluoro-5-isoxazolyl} -2pyridyloxy) -3-cyclopropylpropionic acid 262 2-benzyl-3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} propionic acid 263 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} -2-pyr idylamino) propionic acid 264 3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -2- (cyclopropylmethyl) propionic acid 265 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridylamino) -2- (cyclopropylmethyl) propionic acid 266 2-benzyl-3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} propionic acid 267 2-benzyl-3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 isoxazolyl} -2-pyridyloxy) propionic acid 268 3 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -2- (cyclopropylmethyl) propionic acid 269 3 - (5 - {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridyloxy) -2- (cyclopropylmethyl) propionic acid 270 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3-phenylpropionic acid 271 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridylamino) -3-phenylpropionic acid 272 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -3 -cyclopropylpropionic acid 273 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridylamino) -3 -cyclopropylpropionic acid 274 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3-phenylpropionic acid 275 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5 -isoxazolyl} -2pyridyloxy) -3-phenylpropionic acid 276 2- {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -3 -cyclopropylpropionic acid 277 2- (5- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -3-cyano-5-isoxazolyl} -2pyridyloxy) -3 -cyclopropylpropionic acid 278 3 - {and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] benzoylamino} -4-phenylbutyric acid 279 4-cyclopropyl-3- {and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-

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isoxazolyl] benzoylamino} butyric acid 280 3 - [({and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methyl) amino] -4-phenylbutyric acid 281 4-cyclopropyl-3 - [({and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5isoxazol yl] phenyl} methyl) amino] butyric acid 282 3 - ({and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methoxy) -4-phenylbutyric acid 283 4-cyclopropyl-3 - ({and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5isoxazolyl] phenyl} methoxy) butyric acid 284 3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridylamino} -4-phenylbutyric acid 285 4-cyclopropyl-3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridylamino} butyric acid 286 3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyloxy} -4-phenylbutyric acid 287 4-cycle opropyl-3 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 isoxazolyl] -2-pyridyloxy} butyric acid 288 2- [4- [4- [4-cyano-5 - (1-phenylethoxycarbonylamino) pyrazol-1 yl] phenyl] phenyl] acetic acid 289 1 [4- [4- [4-cyano-5 - (1-phenylethoxycarbonylamino) pyrazol-1 yl] phenyl] phenyl] cyclopropanecarboxylic acid 290 1 - [4- [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1 yl] phenyl] phenyl] cyclopropanecarboxylic acid 291 2- [4- [4- [4-cyano-5 - (1-phenylethoxycarbonylamino) pyrazol-1 yl] phenyl] phenyl] -2-methylpropanoic acid 292 2- [4- [4- [5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazole-1yl] phenyl] phenyl] -2-methylpropanoic acid 293 1- {4 '- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -4diphenylyl} cyclopropanecarboxylic acid 294 1- (4 '- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 N-pyrazol-1-yl} -4 diphenylyl) cyclopropanecarboxylic acid 295 1 - {3-fluoro-4'- [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1 -yl] -4 diphenylyl} cyclopropanecarboxylic acid 296 1- (4 '- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol-1 -yl} -3 fluoro-4-diphenylyl) cyclopropanecarboxylic acid 297 1 - {2-fluoro-4'- [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1 -yl] -4 diphenylyl} cyclopropanecarboxylic acid 298 1- (4 '- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol-1 -yl} -2fluoro-4-diphenylyl) cyclopropanecarboxylic acid 299 1 - {2-chloro-4 '- [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1 -yl] -4diphenylyl} cyclopropanecarboxylic acid 300 1 - (2-chloro-4'- {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol1-yl} -4-diphenylyl) cyclopropanecarboxylic acid 301 1 - (4- {p- [4-fluoro-5- (1-phenylethoxycarbonylamino) - 1H-pyrazol-1 yl] phenyl} tolyl) cyclopropanecarboxylic acid 302 1 - [4- (p- {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol-1 yl} phenyl) tolyl] cyclopropanecarboxylic acid

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303 1 - (π- {5 - [5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1 -yl] -2pyridyl} phenyl) cyclopropanecarboxylic acid 304 1 - [p- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 N-pyrazol-1-yl} -2pyridyl) phenyl] cyclopropanecarboxylic acid 305 1 - (and- {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] -2pyridyl} phenyl) cyclopropanecarboxylic acid 306 1 - [p- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-methyl-1 H-pyrazol-1 yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid 307 1 - (2-fluoro-4- {5 - [5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] -2pyridyl} phenyl) cyclopropanecarboxylic acid 308 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 N-pyrazol-1-yl} -2pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid 309 1 - (3-fluoro-4- {5 - [5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] -2pyridyl} phenyl) cyclopropanecarboxylic acid 310 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 N-pyrazol-1-yl} -2pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid 311 1 - [p- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-methyl-1 H-pyrazol-1 yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid 312 1 - (2-fluoro-4- {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] 2-pyridyl} phenyl) cyclopropanecarboxylic acid 313 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-methyl-1 H-pyrazol-1 yl} -2-pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid 314 1 - (3-fluoro-4- {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] 2-pyridyl} phenyl) cyclopropanecarboxylic acid 315 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-methyl-1 H-pyrazol-1 yl} -2-pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid 316 1 - (and- {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] -2pyridyl} phenyl) cyclopropanecarboxylic acid 317 1- [p- (5- {5- [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol-1-yl} 2-pyridyl) phenyl] cyclopropanecarboxylic acid 318 1 - (2-fluoro-4- {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] 2-pyridyl} phenyl) cyclopropanecarboxylic acid 319 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol-1 -yl} 2-pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid 320 1 - (3-fluoro-4- {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1 N-pyrazol-1-yl] 2-pyridyl} phenyl) cyclopropanecarboxylic acid 321 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1 H-pyrazol-1 -yl} 2-pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid 322 1 - (and- {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) -1 H-pyrazol-1-yl] -2pyridyl} phenyl) cyclopropanecarboxylic acid 323 1 - [p- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-cyano-1 H-pyrazol-1 yl} -2-pyridyl) phenyl] cyclopropanecarboxylic acid 324 1 - (4- {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) -1 H-pyrazol-1-yl] -2-pyridyl} -2-fluorophenyl) cyclopropanecarboxylic acid 325 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-cyano-1 H-pyrazol-1 yl} -2-pyridyl) -2-fluorophenyl] cyclopropanecarboxylic acid 326 1 - (4- {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) -1 H-pyrazol-1-yl] -2-

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pyridyl} -3-fluorophenyl) cyclopropanecarboxylic acid 327 1 - [4- (5 - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-cyano-1 H-pyrazol-1 yl} -2-pyridyl) -3-fluorophenyl] cyclopropanecarboxylic acid 328 2- {and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - 14 / -pyrazol-3 yl] benzoylamino} -3-phenylpropionic acid 329 3-cyclopropyl-2- {and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - \ Npyrazol-3-yl] benzoylamino} propionic acid 330 2- (and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl- \ Npyrazol-3-yl} benzoylamino) -3-phenylpropionic acid 331 2- (and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl- \ Npyrazol-3-yl} benzoylamino) -3 -cyclopropylpropionic acid 332 2 - [({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - 14 / -pyrazol-3 yl] phenyl} methyl) amino] -3-phenylpropionic acid 333 3-cyclopropyl-2 - [({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) 14 / -pyrazol-3-yl] phenyl} methyl) amino] propionic acid 334 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl- \ Npyrazol-3-yl} phenyl) methyl] amino} -3-phenylpropionic acid 335 2- {[(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl- \ Npyrazol-3-yl} phenyl) methyl] amino} -3 -cyclopropylpropionic acid 336 2 - ({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) -14 / -pyrazole-3yl] phenyl} methoxy) -3-phenylpropionic acid 337 3-cyclopropyl-2 - ({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) 14 / -pyrazol-3-yl] phenyl} methoxy) propionic acid 338 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl- \ Npyrazol-3-yl} phenyl) methoxy] -3-phenylpropionic acid 339 2- [(and- {4- [1 - (o-chlorophenyl) ethoxycarbonylamino] -1 -methyl-5-methyl- \ Npyrazol-3-yl} phenyl) methoxy] -3 -cyclopropylpropionic acid 340 3 - {and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - 14 / -pyrazol-3 yl] benzoylamino} -4-phenylbutyric acid 341 4-cycle opropyl-3 - {p- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - \ Npyrazol-3-yl] benzoylamino} butyric acid 342 3 - [({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - 14 / -pyrazol-3 yl] phenyl} methyl) amino] -4-phenylbutyric acid 343 4-cyclopropyl-3 - [({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) 14 / -pyrazol-3-yl] phenyl} methyl) amino] butyric acid 344 3 - ({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) - 14 / -pyrazol-3 yl] phenyl} methoxy) -4-phenylbutyric acid 345 4-cyclopropyl-3 - ({and- [1-methyl-5-methyl-4- (1-phenylethoxycarbonylamino) 14 / -pyrazol-3-yl] phenyl} methoxy) butyric acid 346 3-phenyl-2 - [[4- [5- (1-phenylethoxycarbonylamino) oxazole-4yl] benzoyl] amino] propanoic acid 347 3-cyclopropyl-2 - [[4- [5- (1-phenylethoxycarbonylamino) oxazole-4yl] benzoyl] amino] propanoic acid 348 4-phenyl-2 - [[4- [5- (1-phenylethoxycarbonylamino) oxazole-4yl] benzoyl] amino] butanoic acid 349 3-phenoxy-2 - [[4- [5- (1-phenylethoxycarbonylamino) oxazole-4yl] benzoyl] amino] propanoic acid

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350 3-phenyl-2 - [({and- [5- (1-phenylethoxycarbonylamino) -1,3-oxazol-4yl] phenyl} methyl) amino] propionic acid 351 3-cyclopropyl-2 - [({and- [5 - (1-phenylethoxycarbonylamino) -1,3-oxazole-4yl] phenyl} methyl) amino] propionic acid 352 3-phenyl-2- ({and- [5- (1-phenylethoxycarbonylamino) -1,3-oxazole-4yl] phenyl} methoxy) propionic acid 353 4-phenyl-3 - ({and- [5- (1-phenylethoxycarbonylamino) -1,3-oxazole-4yl] phenyl} methoxy) butyric acid 354 4-cyclopropyl-3 - ({and- [5- (1-phenylethoxycarbonylamino) -1,3-oxazole-4yl] phenyl} methoxy) butyric acid 355 2 - [[4- [1-methyl-5- (1-phenylethoxycarbonylamino) imidazol-4yl] benzoyl] amino] -3-phenylpropanoic acid 356 3-cyclopropyl-2- [[4- [1-methyl-5 - (1-phenylethoxycarbonylamino) imidazol-4yl] benzoyl] amino] propanoic acid 357 2 - [[4- [1-methyl-5- (1-phenylethoxycarbonylamino) imidazol-4yl] benzoyl] amino] -4-phenylbutanoic acid 358 2 - [[4- [1-methyl-5- (1-phenylethoxycarbonylamino) imidazol-4yl] benzoyl] amino] -3-phenoxypropanoic acid 359 2- [({and- [1-methyl-5 - (1-phenylethoxycarbonylamino) - 1 // - imidazole-4yl] phenyl} methyl) amino] -3-phenylpropionic acid 360 3-cyclopropyl-2 - [({and- [1-methyl-5- (1-phenylethoxycarbonylamino) -1 / 7imidazol-4-yl] phenyl} methyl) amino] propionic acid 361 2 - ({and- [1-methyl-5- (1-phenylethoxycarbonylamino) - 1 // - imidazole-4yl] phenyl} methoxy) -3-phenylpropionic acid 362 3-cyclopropyl-2 - ({and- [1-methyl-5- (1-phenylethoxycarbonylamino) - \ Nimidazol-4-yl] phenyl} methoxy) propionic acid 363 3 - [({p- [1 -methyl-5 - (1-phenylethoxycarbonylamino) - 1 // - imidazol-4yl] phenyl} methyl) amino] -4-phenylbutyric acid 364 4-cyclopropyl-3 - [({and- [1-methyl-5- (1-phenylethoxycarbonylamino) -1 / 7imidazol-4-yl] phenyl} methyl) amino] butyric acid 365 3 - ({and- [1-methyl-5- (1-phenylethoxycarbonylamino) - 1 // - imidazole-4yl] phenyl} methoxy) -4-phenylbutyric acid 366 4-cyclopropyl-3 - ({and- [1-methyl-5- (1-phenylethoxycarbonylamino) - \ Nimidazol-4-yl] phenyl} methoxy) butyric acid 367 2 - [[4- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) pyrazole-4yl] benzoyl] amino] -3-phenylpropanoic acid 368 3-cyclopropyl-2 - [[4- [1,2-dimethyl-3-oxo-5- (1 phenylethoxycarbonylamino) pyrazol-4-yl] benzoyl] amino] propane acid 369 2 - [[4- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) pyrazole-4yl] benzoyl] amino] -4-phenylbutanoic acid 370 2 - [[4- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) pyrazole-4yl] benzoyl] amino] -3-phenoxypropanoic acid 371 2 - [({and- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2 dihydropyrazol-4-yl] phenyl} methyl) amino] -3-phenylpropionic acid 372 3 -cyclopropyl-2 - [({and- [1,2-dimethyl-3-oxo-5- (1 phenylethoxycarbonylamino) -1,2-dihydropyrazole -4yl] phenyl} methyl) amino] propionic acid

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373 2 - ({and- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2 dihydropyrazol-4-yl] phenyl} methoxy) -3-phenylpropionic acid 374 3-cyclopropyl-2 - ({and- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) 1,2-dihydropyrazol-4-yl] phenyl} methoxy) propionic acid 375 3 - [({and- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2 dihydropyrazol-4-yl] phenyl} methyl) amino] -4-phenylbutyric acid 376 4-cyclopropyl-3 - [({and- [1,2-dimethyl-3-oxo-5- (1 phenylethoxycarbonylamino) -1,2-dihydropyrazole -4yl] phenyl} methyl) amino] butyric acid 377 3 - ({and- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) -1,2 dihydropyrazol-4-yl] phenyl} methoxy) -4-phenylbutyric acid 378 4-cyclopropyl-3 - ({and- [1,2-dimethyl-3-oxo-5- (1-phenylethoxycarbonylamino) 1,2-dihydropyrazol-4-yl] phenyl} methoxy) butyric acid 379 3-phenyl-2 - [[4- [5- (1-phenylethoxycarbonylamino) pyrimidin-4yl] benzoyl] amino] propanoic acid 380 3-cyclopropyl-2 - [[4- [5 - (1-phenylethoxycarbonylamino) pyrimidin-4yl] benzoyl] amino] propanoic acid 381 4-phenyl-2 - [[4- [5- (1-phenylethoxycarbonylamino) pyrimidin-4yl] benzoyl] amino] butanoic acid 382 3-phenoxy-2 - [[4- [5- (1-phenylethoxycarbonylamino) pyrimidin-4yl] benzoyl] amino] propanoic acid 383 3-phenyl-2 - [({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methyl) amino] propionic acid 384 3-cyclopropyl-2 - [({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methyl) amino] propionic acid 385 3-phenyl-2 - ({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methoxy) propionic acid 386 3-cyclopropyl-2 - ({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methoxy) propionic acid 387 4-phenyl-3 - [({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methyl) amino] butyric acid 388 4-cyclopropyl-3 - [({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methyl) amino] butyric acid 389 4-phenyl-3 - ({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methoxy) butyric acid 390 4-cyclopropyl-3 - ({and- [5- (1-phenylethoxycarbonylamino) -4pyrimidinyl] phenyl} methoxy) butyric acid 391 2 - [[4- [6-methyl-5- (1-phenylethoxycarbonylamino) pyrimidin-4yl] benzoyl] amino] -3-phenylpropanoic acid 392 3-cyclopropyl-2 - [[4- [6-methyl-5- (1-phenylethoxycarbonylamino) pyrimidin4-yl] benzoyl] amino] propanoic acid 393 2 - [[4- [6-methyl-5- (1-phenylethoxycarbonylamino) pyrimidine-4yl] benzoyl] amino] -4-phenylbutanoic acid 394 2 - [[4- [6-methyl-5- (1-phenylethoxycarbonylamino) pyrimidine-4yl] benzoyl] amino] -3-phenoxypropanoic acid 395 3-phenyl-2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5yl] benzoyl] amino] propanoic acid

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396 3-cyclopropyl-2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5yl] benzoyl] amino] propanoic acid 397 4-phenyl-2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5yl] benzoyl] amino] butanoic acid 398 3-phenoxy-2 - [[4- [4- (1-phenylethoxycarbonylamino) pyrimidin-5yl] benzoyl] amino] propanoic acid 399 3-phenyl-2 - [[4- [3- (1-phenylethoxycarbonylamino) pyrazine-2yl] benzoyl] amino] propanoic acid 400 3-cyclopropyl-2 - [[4- [3 - (1-phenylethoxycarbonylamino) pyrazine-2yl] benzoyl] amino] propanoic acid 401 4-phenyl-2 - [[4- [3- (1-phenylethoxycarbonylamino) pyrazine-2yl] benzoyl] amino] butanoic acid 402 3-phenoxy-2 - [[4- [3- (1-phenylethoxycarbonylamino) pyrazine-2yl] benzoyl] amino] propanoic acid 403 1 - {and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4piperidinecarboxylic acid 404 (1- {and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4piperidyl) acetic acid 405 1 - (1 - {and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4piperidyl) cyclopropanecarboxylic acid 406 [1 - (1 - {and- [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4piperidyl) cyclopropyl] acetic acid 407 1 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyrid yl} 4-piperidinecarboxylic acid 408 (1 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) acetic acid 409 1 - (1 - {5 - [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid 410 [1- (1- {5- [3-methyl-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) cyclopropyl] acetic acid 411 1 - {and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4piperidinecarboxylic acid 412 (1 - {and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4piperidyl) acetic acid 413 1 - (1 - {and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4piperidyl) cyclopropanecarboxylic acid 414 [1 - (1 - {and- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4piperidyl) cyclopropyl] acetic acid 415 1 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyrid yl} 4-piperidinecarboxylic acid 416 (1 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyridyl} 4-piperidyl) acetic acid 417 1 - (1 - {5 - [3-fluoro-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid 418 [1 - (1 - {5- [3-fluoro-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] -2pyridyl} -4-piperidyl) cyclopropyl] acetic acid 419 1- {and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4-

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piperidinecarboxylic acid 420 (1- {and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} -4piperidyl) acetic acid 421 1 - (1 - {and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4piperidyl) cyclopropanecarboxylic acid 422 [1 - (1 - {and- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] phenyl} -4piperidyl) cyclopropyl] acetic acid 423 1 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2-pyrid yl} 4-piperidinecarboxylic acid 424 (1 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) acetic acid 425 1 - (1 - {5 - [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid 426 [1- (1- {5- [3-cyano-4- (1-phenylethoxycarbonylamino) -5 -isoxazolyl] -2pyridyl} -4-piperidyl) cyclopropyl] acetic acid 427 1- {and- [5- (1-phenylethoxycarbonylamino) -1 Η- p irazol-1-yl] phenyl} -4piperidinecarboxylic acid 428 (1 - {and- [5- (1-phenylethoxycarbonylamino) -1 // - pyrazol-1 -yl] phenyl} -4piperidyl) acetic acid 429 1 - (1 - {and- [5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} -4piperidyl) cyclopropanecarboxylic acid 430 [1 - (1 - {and- [5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 -yl] phenyl} -4piperidyl) cyclopropyl] acetic acid 431 1- {5- [5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2-pyridyl} -4piperidinecarboxylic acid 432 (1- {5- [5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2-pyridyl} -4piperidyl) acetic acid 433 1 - (1 - {5 - [5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2-pyridyl} -4piperidyl) cyclopropanecarboxylic acid 434 [1 - (1 - {5 - [5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1 -yl] -2-pyridyl} -4piperidyl) cyclopropyl] acetic acid 435 1 {and- [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} -4piperidinecarboxylic acid 436 (1- {and- [4-methyl-5- (1-phenylethoxycarbonylamino) -177-pyrazol-1-yl] phenyl} -4piperidyl) acetic acid 437 1 - (1 - {and- [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} 4-piperidyl) cyclopropanecarboxylic acid 438 [1 - (1 - {and- [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 yl] phenyl} -4-piperidyl) cyclopropyl] acetic acid 439 1 - {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidinecarboxylic acid 440 (1 - {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidyl) acetic acid 441 1 - (1 - {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid 442 [1 - (1 - {5 - [4-methyl-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 -yl] -2pyridyl} -4-piperidyl) cyclopropyl] acetic acid

- 82 038294

443 1 - {"- [4-fluoro-5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} -4piperidinecarboxylic acid 444 (1 - {and- [4-fluoro-5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} -4piperidyl) acetic acid 445 1 - (1 - {and- [4-fluoro-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} 4-piperidyl) cyclopropanecarboxylic acid 446 [1 - (1 - {and- [4-fluoro-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} 4-piperidyl) cyclopropyl] acetic acid 447 1 - {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidinecarboxylic acid 448 (1 - {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidyl) acetic acid 449 1 - (1 - {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid 450 [1 - (1 - {5 - [4-fluoro-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 -yl] -2pyridyl} -4-piperidyl) cyclopropyl] acetic acid 451 1 - {and- [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} -4piperidinecarboxylic acid 452 (1 - {and- [4-cyano-5- (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} -4piperidyl) acetic acid 453 1 - (1 - {and- [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] phenyl} 4-piperidyl) cyclopropanecarboxylic acid 454 [1 - (1 - {and- [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 yl] phenyl} -4-piperidyl) cyclopropyl] acetic acid 455 1 - {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidinecarboxylic acid 456 (1 - {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 -yl] -2pyridyl} -4-piperidyl) acetic acid 457 1 - (1 - {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1-yl] -2pyridyl} -4-piperidyl) cyclopropanecarboxylic acid 458 [1 - (1 - {5 - [4-cyano-5 - (1-phenylethoxycarbonylamino) - 177-pyrazol-1 -yl] -2pyridyl} -4-piperidyl) cyclopropyl] acetic acid

Examples of

HPLC methods.

HPLC curves for synthesized examples of compounds were recorded using an HPLC system consisting of Shimadzu HPLC pumps, a degasser and a UV detector equipped with an Agilent 1100 series autosampler.Mass detector (APCI) PE Sciex API 150 EX was used to record the mass spectra data. ... HPLC / mass spectrometry recorder curves were obtained using one of three chromatographic methods:

Method 1. Column Zorbax C18, size 4.6 mm x 7.5 cm; Solvent A: 0.05% TFA in water, Solvent B: 0.05% TFA in acetonitrile; flow rate - 0.7 ml / min; gradient: 5% B to 100% B in 9 minutes, held at 100% B for 4 minutes and 100% B to 5% B in 0.5 minutes; UV detector - channel 1 = 220 nm, channel 2 = 254 nm.

Method 2. Column Zorbax C18, size 4.6 mm x 7.5 cm; Solvent A: 0.05% TFA in water, Solvent B: 0.05% TFA in acetonitrile; flow rate - 0.7 ml / min; gradient: 5% B to 100% B in 5 minutes, held at 100% B for 2 minutes and from 100% B to 5% B in 0.5 minutes; UV detector - channel 1 = 220 nm, channel 2 = 254 nm.

Method 3. Column SunFire ™ (Waters) C18, size 2.1 mm x 50 mm; Solvent A: 0.05% TFA in water, Solvent B: 0.05% TFA in acetonitrile; flow rate - 0.8 ml / min; gradient: 10% B to 90% B in 2.4 min held at 90% B for 1.25 min and 90% B to 10% B in 0.25 min held at 10% B for 1 ,5 minutes; UV detector - channel 1 = 220 nm, channel 2 = 254 nm.

Example 1. 1- (4- {4- [1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) cyclopropanecarboxylic acid.

Step 1. Tert-butyl ester of 2- (4-carboxymethylbenzoyl) -3-oxo-butyric acid.

To a suspension of magnesium chloride (8.48 g, 89.0 mmol) in dichloromethane (88 ml), which was cooled to 0 ° C, was added tert-butyl acetoacetate (15.1 ml, 89.0 mmol). Pyridine (13.8 mL, 171 mmol) was added to the mixture and stirring was continued for an additional 15 minutes. Then, methyl ester of 4- (chlorocarbonyl) benzoic acid (17.0 g, 85.6 mmol) in dichloromethane (88 ml) was added dropwise to the reaction mixture. This mixture was stirred at 0 ° C for 90 minutes and then at room temperature for 90 minutes. At this stage, the mixture was treated with 0.2M hydrochloric acid solution (10 ml). The organic layer was diluted with dichloromethane (70 ml), washed with 0.2 M hydrochloric acid solution (30

- 83 038294 ml), separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. A yellow oil was obtained which was used directly in the next step (17.1 g, 68%). Method 2, Rt 5.4 min MS (ESI) mass / charge 321.2 [M + H +].

Step 2. 5- (4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid tert-butyl ester;

5- (4-methylcarboxyphenyl) -3-methylisoxazol-4-ylcarboxylic acid tert-butyl ester.

A mixture of 2- (4-carboxymethylbenzoyl) -3-oxo-butyric acid tert-butyl ester [example 1, step 1] (7.45 g, 23.2 mmol), hydroxylamine hydrochloride (5.17 g, 74.4 mmol) , ethanol (46.5 ml) and water (32.2 ml) was heated at 60-62 ° C for 2 hours. At this stage, the reaction mixture was allowed to cool and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. A crude product was obtained which was originally purified by chromatography on silica gel using hexane / ethyl acetate 9/1 as eluent to give 5- (4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid tert-butyl ester (4 , 69 g, 64%). Method 2, Rt 6.14 min MS (ESI) mass / charge 318.2 [M + H +].

Step 3. 5- (4-Methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid. 5- (4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid tert-butyl ester [example 1, step 2] (6.35 g, 20 mmol) was dissolved in dichloromethane (100 ml) and trifluoroacetic acid was added to these components. acid (50 ml). The mixture was stirred for 2 hours at room temperature while the volatiles were removed. The product (5.2 g, 99%) was used as is in step 4. Method 2, Rt 4.08 min MS (ESI) mass / charge 262 [M + H +].

Step 4. Methyl ester of 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid.

5- (4-Methylcarboxyphenyl) -3-methylisoxazol-4-ylcarboxylic acid [example 1, step 3] (3.91 g, 15.0 mmol) was suspended in toluene (120 ml) and diisopropylethylamine (3, 13 ml, 18.0 mmol). To the resulting solution was added diphenylphosphorylazide (3.56 ml, 16.5 mmol) and the mixture was heated to 90 ° C. After 15 minutes, 1- (2-chlorophenyl) ethanol (2.98 mL, 22.5 mmol) was added slowly and heating was continued for 4 hours. The reaction mixture was allowed to cool overnight. This mixture was diluted with toluene, transferred to a separatory funnel, and extracted with water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the crude product (8.34 g). The crude product was purified by chromatography on silica gel eluting with a gradient of 30 to 40% ethyl acetate in hexanes to afford the purified product (3.59 g, 58%) as three fractions. Method 2, Rt 5.70 min MS (ESI) mass / charge 415.4 [M + H +].

Step 5. 1- (4- {4- [1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid.

Methyl ester of 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoic acid [example 1, step 4] (1.5 g, 3.62 mmol) was dissolved in THF / water mixture (1/1: 20 ml) and treated with LiOH (5.1 ml 1M aqueous solution) .The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 2, transferred to a separatory funnel, diluted with water and extracted with dichloromethane The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the product (0.8 g, 55%) Method 2, Rt 4.77 min mS (ESI) w / w 401 , 3 [M + H +].

Step 6. Methyl ester of 1-aminocyclopropanecarboxylic acid 1-aminocyclopropanecarboxylic acid (202 mg, 2 mmol) in methanol (4 ml) was cooled to -10 ° C and thionyl chloride (581 μl, 8 mmol) was added dropwise to these components. The mixture was allowed to warm and then heated under reflux for 2 hours. The solvents were evaporated and the residue was redissolved in boiling alcohol. To the cooled solution was added diethyl ether until the cloud point, and then the mixture was artificially cooled for 2 days. The resulting precipitate gave the product (223 mg, 67%) which was used in step 7.

Step 7. Methyl ester of 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) cyclopropanecarboxylic acid.

To 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 1, step 5] (49.8 mg, 0.12 mmol) was added 1 β-hydroxybenzotriazole (18 mg, 0.13 mmol), N- (3-dimethylaminopropyl) ethylcarbodiimide (EDCI: 25 mg, 0.13 mmol), dichloromethane (2 ml), diisopropylethylamine (52 μl, 0.30 mmol) and methyl ester 1-aminocyclopropanecarboxylic acid [example 1, step 6] (20 mg, 0.13 mmol) and this mixture was stirred overnight.At this step, the mixture was diluted with ethyl acetate (20 ml) and washed with saturated sodium bicarbonate solution (10 ml), solution citric acid (5 ml) and water The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product (101 mg) The residue was purified by preparative TLC eluting with 40% v / v ethyl acetate and hexane. extraction of the purified material as a band gave the product (55 mg, 92%) Method 2, Rt 4.76 min MS (ESI)

- 84 038294 mass / charge 498.4 [M + H +].

Step 8. 1- (4- {4- [1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) cyclopropanecarboxylic acid.

Methyl ester of 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) cyclopropanecarboxylic acid [example 1, step 7] (55 mg, 0.11 mmol) was dissolved in a mixture of THF / water 1: 1 and treated with lithium hydroxide (8 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 2 days. At this stage, the pH was brought to 2 with hydrochloric acid and the mixture was extracted with ethyl acetate (3 x 20 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the crude product (190 mg). The residue was purified by preparative TLC, eluting with 45% v / v. a mixture of acetone and dichloromethane. After extraction of the purified material, the product was obtained as a band (22 mg, 41%). Method 2, Rt 4.30 min MS (ESI) mass / charge 484.6 [M + H +].

Example 2. 2- (4- {4- [1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indane-2-carboxylic acid.

Step 1. Methyl ester of 2-amino-2-indanecarboxylic acid.

Methyl ester of 2-amino-2-indanecarboxylic acid was prepared according to a procedure similar to that described for step 6 of example 1 from 2-amino-2-indanecarboxylic acid hydrochloride (214 mg, 1 mmol) which was used directly. Yield: 155 mg (68%).

Step 2. Methyl ester of 2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indan-2-carboxylic acid.

Methyl ester of 2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoylamino) indane-2-carboxylic acid was prepared according to a procedure similar to that described for step 7 of example 1, from 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 1, step 5] (49.8 mg, 0.12 mmol) and methyl complex ester of 2-amino-2-indanecarboxylic acid [example 2, step 1] Yield: 55 mg (81%) Method 2, Rt 5.49 min MS (ESI) mass / charge 574.6 [M + H +].

Step 3. 2- (4- {4- [1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indane-2-carboxylic acid.

2- (4- {4- [1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indan-2carboxylic acid was prepared according to a procedure similar to that described for step 8 of example 1 from the methyl ester 2- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) indane-2-carboxylic acid [example 2, step 7] (55 mg, 0.11 mmol ). Yield: 6 mg (11%). Method 2, Rt 5.00 min MS (ESI) mass / charge 560.3 [M + H +].

Example 3. 2- (S) - (4- {4 - [(R, S) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid.

Step 1. L-phenylglycine methyl ester was prepared according to a procedure similar to that described for step 6 of Example 1 from L-phenylglycine (756 mg, 5 mmol) which was used directly. Yield: 480 mg (58%).

Step 2. Methyl ester of 2- (S) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid.

Methyl ester of 2- (S) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid was prepared according to a procedure similar to described for step 7 of example 1, from 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 1, step 5] (58.1 mg, 0.14 mmol) and L-phenylglycine methyl ester [Example 3, step 1] which was used without purification Yield: 60 mg (76%) Method 2, Rt 5.41 min MS (ESI) w / w 548 , 6 [M + H +].

Step 3. 2- (S) - (4- {4 - [(R, S) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid.

2- (S) - (4- {4 - [(R, S) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid was prepared according to a procedure similar to that described for step 8 of example 1, from methyl ester of 2- (S) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylacetic acid [ example 3, step 2] (60 mg, 0.11 mmol). Yield: 4 mg (11%). Method 2, Rt 4.90 min MS (ESI) mass / charge 534.4 [M + H +].

Example 4 2- (R) - (4- {4 - [(R, S) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid.

Step 1. D-phenylalanine methyl ester.

D-phenylalanine methyl ester was prepared according to a procedure similar to that described for step 6 of Example 1 from D-phenylalanine (1.12 g, 7 mmol). Yield: 650 mg (53%).

Step 2. Methyl ester of 2- (R) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylα-amino] -3methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid.

Methyl ester of 2- (R) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid was prepared according to a procedure similar to opi

- 85,038294 sledge for stage 7 of example 1, from 1- (4- {4- [1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzoic acid [example 1, stage 5] (58.1 mg , 0.14 mmol) and methyl ester D-phenylalanine [example 4, step 1] to obtain the product (40 mg, 49%), which was used directly Method 2, Rt 5.6 min MS (ESI) mass / charge 562, 2 [M + H +].

Step 3. 2- (R) - (4- {4 - [(R, S) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid.

2- (R) - (4- {4 - [(R, S) -1- (2-Chlorophenyl) ethoxycarbonylα-amino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid was prepared according to a procedure similar to that described for step 8 of example 1, from methyl ester of 2- (R) - (4- {4 - [(R, S) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) phenylpropanoic acid [ example 4, step 2] (40 mg, 0.07 mmol). Yield: 8 mg (21%). Method 2, Rt 4.94 min mS (ESI) mass / charge 548.5 [M + H +].

Example 5. 2 (R) - [[4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] 3-phenylpropanoic acid.

Step 1. Methyl ester of 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazol-5-yl] benzoic acid.

Methyl ester 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazole-5yl] benzoic acid was prepared according to a procedure similar to that described for step 4 of example 1, from 5 ( 4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid [example 1, step 3] (1.55 g, 5.9 mmol) and 1- (R) - (+) - phenylethanol. Yield: 1.18 g (52%).

Step 2. 2 (R) - [[4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazol-5-yl] benzoic acid.

2 (R) - [[4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoic acid was prepared according to a procedure similar to that described for step 5 of example 1 from the methyl ester 2 (R) [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoic acid [example 5, step 1] (1.5 g, 3.62 mmol) ... Yield: 1.04 g (91%). Method 3, Rt 2.72 min MS (ESI) mass / charge 367.3 [M + H +].

Step 3. Methyl ester of 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid.

Methyl ester of 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5yl] benzoyl] amino] -3-phenylpropanoic acid was prepared according to a procedure similar to that described for step 7 of example 1, from 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoic acid [example 5, step 2] (64.7 mg , 0.18 mmol) and methyl ester of D-phenylalanine [example 4, step 1]. Yield: 100 mg (92%). Method 3, Rt 3.04 min MS (ESI) mass / charge 528.3 [M + H +].

Step 4. 2 (R) - [[4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazol-5-yl] benzoyl] amino] -3phenylpropanoic acid (sodium salt).

2 (R) - [[4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid was prepared according to a procedure similar to that described for step 8 example 1, from methyl ester 2 (R) - [[4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazol-5-yl] benzoyl] amino] -3-phenylpropanoic acid [example 5 , stage 3] (100 mg, 0.19 mmol). The crude material (21 mg) was dissolved in methanol and treated with 1N. sodium hydroxide (40 μl) before drying to obtain the product as its sodium salt (22 mg, 22%). Method 3, Rt 3.04 min MS (ESI) mass / charge 514.3 [M + H +].

Example 6 2 (S) - [[4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoyl] amino] 3-phenylpropanoic acid.

The title compound was prepared according to a procedure similar to that described for example 5, from 5 (4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid [example 1, step 3] (64.7 mg, 0.18 mmol) and methyl ester L-phenylalanine to give the product as its sodium salt (18 mg, 18%). Method 3 Rt 3.05 min MS (ESI) mass / charge 514.3 [M + H +].

Example 7 (R) -2 - [[4- [2,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylα-amino) pyrazol-3-yl] benzoyl] amino] -3-phenylpropanoic acid.

Step 1.tert-butyl ester of 5- (4-methoxycarbonylphenyl) -1,3-dimethyl-1H-pyrazole-4carboxylic acid and tert-butyl ester of 3- (4-methoxycarbonylphenyl) -1,5-dimethyl-1Hpyrazole- 4-carboxylic acid.

Methyl ester of 4- (2-tert-butoxycarbonyl-3-oxobutyryl) benzoic acid [example 1, step 1] (76.0 g, 208.8 mmol of crude material at 100% purity) was dissolved in ethanol (2.2 l). Methylhydrazine (9.72 g, 210.9 mmol) was added dropwise to the above solution with stirring at room temperature. The reaction mixture was stirred for another 3 hours at RT after the addition was complete. Completion of the reaction was confirmed by LC / MS. The solvent was removed in vacuo. The residue was dissolved in EtOAc (700 ml) and washed with water (2 x 500 ml). The organics were dried over Na ₂ SO ₄ , filtered and evaporated. A mixture of products was obtained in the form of an oil, which was used in the next step without further purification. Crude yield: 72.6 g. Method 3, Rt 3.12 min MS (ESI) mass / charge 331.0 [M + H +].

Step 2. 5- (4-Methoxycarbonylphenyl) -1,3-dimethyl-1H-pyrazole-4-carboxylic acid and 3- (4methoxycarbonylphenyl) -1,5-dimethyl-1H-pyrazole-4-carboxylic acid.

- 86 038294

A mixture of 5- (4-methoxycarbonylphenyl) -1,3-dimethyl-1H-pyrazole-4carboxylic acid tert-butyl ester and 3- (4-methoxycarbonylphenyl) -1,5-dimethyl-1Hpyrazole-4- tert-butyl ester carboxylic acid [example 7, step 1] (5.00 g, 15.13 mmol) was dissolved in CH ₂ Cl ₂ (120.0 ml) and trifluoroacetic acid (40.0 ml) was added and the reaction mixture was stirred for 3 h at room temperature. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (50.0 ml). This was then extracted with saturated aqueous Na ₂ CO ₃ solution (40 ml). The separated aqueous layer was washed with ethyl acetate (2 x 20 ml). It was then treated with 1M HCl to pH 2. It was then extracted with ethyl acetate (2x35 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give a white solid acid mixture (3.0 g, 72%). TLC on silica gel plate (15% acetone in DCM): two fluorescent spots corresponding to the two isomers with Rf. 0.2 and Rf. 0.125. Method 3, Rt 2.94 min MS (ESI) mass / charge 275.0 [M + H +];

Step 3. Methyl ester of 4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-pyrazol-3-yl] benzoic acid and methyl ester of 4- [1,5-dimethyl- 4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoic acid.

A mixture of isomeric acids [example 7, step 2] (6.0 g, 21.88 mmol) was suspended in anhydrous toluene (180.0 ml) under nitrogen atmosphere with stirring. Then diisopropylethylamine (3.39 g, 26.24 mmol) was added. A clear solution was obtained, to which was added diphenylphosphoryl azide (7.22 g, 26.24 mmol). The reaction mixture was heated to 95 ° C. Then (R) - (+) - 1-phenylethyl alcohol (4.008 g, 32.8 mmol) was added dropwise at 95 ° C over a period of 40 minutes. The reaction mixture was then heated for an additional 5 h at 95 ° C, followed by stirring at room temperature overnight. The next day it was diluted with EtOAc (300 ml), washed with saturated aqueous Na2CO3 (200.0 ml) and water (2 x 500 ml), dried (Na2SO4), filtered and concentrated to give crude oily carbamate (12.5 G). The crude product was purified by column chromatography (SiO ₂ ), initial elution with DCM (250 ml) and subsequent gradient elution with acetone: DCM (2% acetone in DCM to 10% acetone in DCM). Two pure isomers were obtained. Received a fast moving isomer (1.667 g, 19.4%) and a slow moving isomer (2.132 g, 24.77%) [> 95% purity by HPLC]. A fraction was obtained containing a mixture of isomers (0.812 g, 9.4%). A) Slow moving spot: method 3, Rt 2.78 min MS (ESI) mass / charge 394.2 [M + H +]; previously defined as (R) -4 [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) -1H-πyrazol-3-yl] benzoic acid methyl ester. B) Fast moving spot. Method 3 Rt 2.80 min MS (ESI) mass / charge 394.4 [M + H +]; previously defined as (R) -4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-π-pyrazole-3yl] benzoic acid methyl ester.

Step 4. 4- [2,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-pyrazol-3-yl] benzoic acid.

4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-pyrazole-3yl] benzoic acid methyl ester [Example 7, step 3B] (240 mg, 0.61 mmol) was dissolved in a mixture of THF / water (2/1 v / v, 2.25 ml) and treated with LiOH (1.2 ml of 1M aqueous solution, 2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified to pH 2, diluted with water and extracted with EtOAc (2 x 40 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the product (180 mg, 78%). Method 3, Rt 2.81 min mS (ESI) mass / charge 380.2 [M + H +].

Step 5. (R) -2- {4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2Hpyrazol-3-yl] benzoylamino} -3-phenylpropionic acid methyl ester.

1 β-hydroxybenzotriazole (43 mg, 0.32 mmol), EDCI (67 mg, 0.34 mmol), dimethylformamide (2 ml), diisopropylethylamine (184 μl, 1.06 mmol) and D-phenylalanine methyl ester [example 4, step 1] (86 mg, 0.39 mmol) and the mixture was stirred overnight. At this stage, the mixture was diluted with ethyl acetate (20 ml) and washed with 1N. sodium hydroxide solution (10 ml) and water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the crude product (193 mg), which was purified by silica gel chromatography eluting with an ethyl acetate / dichloromethane gradient to give the title compound (95 mg, 68%). HPLC was> 95% pure. Method 3, Rt 2.91 min MS (ESI) mass / charge 541.3 [M + H +].

Step 6. (R) -2 - [[4- [2,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] 3-phenylpropanoic acid.

(R) -2- {4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-pyrazol-3-yl] benzoylamino} -3-phenylpropionic acid methyl ester [example 7, step 5] (95 mg, 0.176 mmol) was dissolved in a mixture of THF / water 2: 1 (2.25 ml) and treated with 1M lithium hydroxide solution (2 ml). The resulting mixture was stirred at room temperature overnight. The pH of the aqueous layer was adjusted to 2 with hydrochloric acid and the mixture was extracted with ethyl acetate (3 x 20 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the crude product

- 87 038294 (112 mg). The crude material was purified by chromatography on silica gel eluting with a dichloromethane / acetone gradient. (90 mg, 97%). Method 3, Rt 2.90 min MS (ESl) mass / charge 527.5 [M + H +].

Example 8 (R) -2 - [[4- [1,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3-phenylpropanoic acid.

Step 1. 4- [1,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoic acid.

4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazole-3yl] benzoic acid methyl ester [example 7, step 3A] (240 mg, 0.61 mmol) was dissolved in a mixture of THF / water (2/1 v / v, 2.25 ml) and treated with LiOH (1.2 ml of 1M aqueous solution, 2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified to pH 2, transferred to a separatory funnel, diluted with water and extracted with EtOAc (2 x 40 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the product (205 mg, 89%). The HPLC was 97% pure. Method 3, Rt 2.43 min MS (ESI) mass / charge 380.2 [M + H +].

Step 2. (R) -2- {4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1Hpyrazol-3-yl] benzoylamino} -3-phenylpropionic acid methyl ester.

1 β-hydroxybenzotriazole (43 mg, 0.32 mmol), EDCI (67 mg, 0.34 mmol), dimethylformamide (2 ml), diisopropylethylamine (184 μl, 1.06 mmol) and D-phenylalanine methyl ester [example 4, step 1] (86 mg, 0.39 mmol) and the mixture was stirred overnight. At this stage, the mixture was diluted with ethyl acetate (20 ml) and washed with 1N. sodium hydroxide solution (10 ml) and water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the crude product (150 mg), which was purified by silica gel chromatography eluting with an ethyl acetate / dichloromethane gradient to give the product (75 mg, 53%). The HPLC was> 97% pure. Method 3, Rt 3.05 min MS (ESI) mass / charge 541.2 [M + H +].

Step 3. (R) -2 - [[4- [1,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] 3-phenylpropanoic acid.

(R) -2- {4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoylamino} -3-phenylpropionic acid methyl ester [example 8, step 2] (75 mg, 0.139 mmol) was dissolved in a mixture of THF / water 2: 1 (1.5 ml) and treated with 1M lithium hydroxide solution (0.28 ml). The resulting mixture was stirred at room temperature overnight. The pH of the aqueous layer was adjusted to 2 with hydrochloric acid and the mixture was extracted with ethyl acetate (3 x 20 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the product [> 95% pure by HPLC] (60 mg, 82%). Method 3, Rt 2.69 min MS (ESI) mass / charge 527.5 [M + H +].

Example 9. (R) -2 - [[4- [2,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3 - (4-fluorophenyl) propane acid.

Step 1. (R) -2-amino-3- (4-fluorophenyl) propionic acid methyl ester hydrochloride.

(R) -2-amino-3- (4-fluorophenyl) propionic acid methyl ester hydrochloride was prepared according to a procedure similar to that described for step 6 of Example 1 from D-4-fluorophenylalanine (1 g, 5.46 mmol). Yield: 900 mg (71%). Method 3, Rt 0.54 min MS (ESI) mass / charge 198.3 [M + H +].

Step 2. Methyl ester (R) -2- {4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2Hpyrazol-3-yl] benzoylamino} -3 - (4-fluorophenyl) propionic acid.

(R) -2- {4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-pyrazol-3-yl] benzoylamino} -3- (4-fluorophenyl) propionic methyl ester acids were obtained according to a procedure similar to that described for step 5 of example 7, from (R) -4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) -2H-pyrazole-3yl] benzoic acid [example 7, step 4 ] (50 mg, 0.132 mmol) and (R) -2-amino-3- (4-fluorophenyl) propionic acid methyl ester hydrochloride [example 9, step 1]. Yield: 59 mg (80%).

Step 3. (R) -2 - [[4- [2,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] 3- (4-fluorophenyl) propanoic acid ...

(R) -2 - [[4- [2,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4fluorophenyl) propanoic acid was prepared according to the procedure, similar to that described for step 6 of example 7, from methyl ester (R) -2- {4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2Hpyrazol-3-yl] benzoylamino} - 3- (4-fluorophenyl) propionic acid [example 9, step 2] (59 mg, 0.11 mmol) to give 55 mg of product (87%). Method 3, Rt 2.73 min MS (ESI) mass / charge 545.4 [M + H +].

Example 10 (R) -2 - [[4- [1,5-Dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol-3-yl] benzoyl] amino] -3- (4-fluorophenyl) propane acid. The title compound was prepared according to a procedure similar to that described for example 8, from 4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazole-3yl] benzoic acid [example 8, step 1] ( 50 mg, 0.132 mmol) and (R) -2-amino-3- (4-fluorophenyl) propionic acid methyl ester hydrochloride [example 9, step 1]. Yield: 55 mg (87%). Method 3, Rt 2.69 min MS (ESI) mass / charge 545.4 [M + H +].

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Example 11 (K) -3- (4-Bromophenyl) -2 - [[4- [2,5-dimethyl-4 - ((K) -1-phenylethoxycarbonylamino) pyrazol3-yl] benzoyl] amino] propanoic acid.

Step 1. (R) -2-amino-3- (4-bromophenyl) propionic acid methyl ester hydrochloride.

The title compound was prepared using a procedure similar to that described for step 6 of example 1 from D-4-bromophenylalanine (1 g, 4.1 mmol). Yield: 550 mg (46%). Method 3, Rt 1.70 min MS (ESI) mass / charge 258.1 [M + H +].

Step 2. (R) -3- (4-Bromophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazole-3yl] benzoyl] amino] propanoic acid.

The title compound was prepared according to a procedure similar to that described for example 9 (steps 2 and 3), from 4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -2H-pyrαzol-3-yl] benzoic acid [example 7, step 4] and (R) -2-amino-3- (4-bromophenyl) propionic acid methyl ester hydrochloride [example 11, step 1]. Yield: 30 mg (65%). Method 3, Rt 3.03 min MS (ESI) mass / charge 607.4 [M + H +].

Example 12 (R) -3- (4-Bromophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol3-yl] benzoyl] amino] propanoic acid.

The title compound was prepared according to a procedure similar to that described for example 8, from 4 [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoic acid [example 8, step 1] (50 mg, 0.132 mmol) and 3- (4-bromophenyl) propionic acid methyl ester hydrochloride [example 11, step 1]. Yield: 60 mg (80%). Method 3, Rt 3.02 min MS (ESI) mass / charge 619.2 [M + H +].

Example 13 (R) -3- (4-Chlorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol3-yl] benzoyl] amino] propanoic acid.

Step 1. (R) -2-amino-3- (4-chlorophenyl) propionic acid methyl ester hydrochloride.

(R) -2-α-amino-3- (4-chlorophenyl) propionic acid methyl ester hydrochloride was prepared using a procedure similar to that described for step 6 of Example 1 from D-4-chlorophenylalanine (1 g, 5 mmol). Yield: 940 mg (75%). Method 3, Rt 0.03 min MS (ESI) mass / charge 214.0 [M + H +].

Step 2. (R, R) -3- (4-Chlorophenyl) -2 - [[4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazole-3yl] benzoyl] amino] propanoic acid.

The title compound was prepared according to a procedure similar to that described for example 9 (steps 2 and 3), from (R) -4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) -2H-pyrαzol-3-yl] benzoic acid [example 7, step 4] and (R) -2-amino-3- (4-chlorophenyl) propionic acid methyl ester hydrochloride [example 13, step 1]. Yield: 40 mg (55%). Method 3, Rt 2.80 min MS (ESI) mass / charge 561.3 [M + H +].

Example 14 (R) -3- (4-Chlorophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) pyrazol3-yl] benzoyl] amino] propanoic acid.

The title compound was prepared according to a procedure similar to that described for example 8, from 4 [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoic acid [example 8, step 1] and (R) -2-amino-3- (4-chlorophenyl) propionic acid methyl ester hydrochloride [example 8, step 1]. Yield: 40 mg (54%). Method 3, Rt 3.00 min MS (ESI) mass / charge 561.3 [M + H +].

Example 15 (R) -3- (3,4-Difluorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylαmino) pyrazol-3-yl] benzoyl] amino ] propanoic acid.

Step 1. (R) -2-amino-3- (3,4-difluorophenyl) propionic acid methyl ester hydrochloride.

(R) -2-amino-3- (3,4-difluorophenyl) propionic acid methyl ester hydrochloride was prepared using a procedure similar to that described for step 6 of Example 1 from D-3,4-difluorophenylalanine (1 g, 4 , 97 mmol). Yield: 1.04 g (83%). Method 3, Rt 0.16 min MS (ESI) mass / charge 216.0 [M + H +].

Step 2. (R) -3- (3,4-Difluorophenyl) -2 - [[4- [2,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylαmino) pyrazol3-yl] benzoyl] amino] propane acid.

The title compound was prepared according to a procedure similar to that described for example 9 (steps 2 and 3), from (R) -4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) -2H-pyrαzol-3-yl] benzoic acid [example 7, step 4] (50 mg, 0.132 mmol) and (R) -2-amino-3- (3,4difluorophenyl) propionic acid methyl ester hydrochloride [example 15, step 1]. Yield: 30 mg (61%). Method 3, Rt 2.96 min MS (ESI) mass / charge 563.4 [M + H +].

Example 16 (R) -3- (3,4-Difluorophenyl) -2 - [[4- [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylαmino) pyrazol-3-yl] benzoyl] amino ] propanoic acid.

The title compound was prepared according to a procedure similar to that described for example 8, from 4 [1,5-dimethyl-4 - ((R) -1-phenylethoxycarbonylamino) -1H-pyrazol-3-yl] benzoic acid [example 8, step 1] (50 mg, 0.132 mmol) and (R) -2-α-amino-3- (3,4-difluorophenyl) propionic acid methyl ester hydrochloride [example 15, step 1]. Yield: 20 mg (56%). Method 3, Rt 2.71 min MS (ESI) mass / charge 563.3 [M + H +].

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Example 17 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-cyclopropylpropionic acid.

Step 1. (R) -2-amino-3-cyclo-propyl-propionic acid methyl ester hydrochloride.

(R) -2-amino-3-cyclopropylpropionic acid methyl ester hydrochloride was prepared using a procedure similar to that described for step 6 of Example 1 from (R) -2-amino-3cyclopropylpropionic acid and used directly. Yield: 350 mg (100%).

Step 2. Methyl ester of 4- {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid.

Was prepared analogously to step 1 of example 5 using 5- (4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid [example 1, step 3] (3.47 g, 13.28 mmol) and (R) -1- ( 2-chlorophenyl) ethanol. Yield = 1.81 g (4.36 mmol, 25%). HPLC (254 nm). Method 3, Rt 3.31 min MS (ESI) mass / charge 415.5 [M + H +].

Step 3. 4- {4- [1 - ((R-2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid.

Was prepared analogously to step 2 of example 5 using methyl ester 4- {4- [1 - ((R) -2chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 2] (1.81 d, 4.46 mmol). Yield = 1.70 g (4.25 mmol, 95%). HPLC (254 nm). Method 3, Rt 3.01 min MS (ESI) mass / charge 401.2 [M + H +].

Step 4. (R) -2- (4- {4- [1 - ((R) -2-Chlorophenyl) ethoxycarbonylα-amino] -3-methylisoxazol-5-yl} benzoylamino) -3-cyclopropylpropionic acid.

The title compound was prepared according to a procedure similar to that described for example 5, from 4 {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 50 mg, 0.13 mmol) and (R) -2-amino-3-cyclopropylpropionic acid methyl ester hydrochloride [example 17, step 1]. Yield: 22 mg (34%). Method 3, Rt 3.27 min MS (ESI) mass / charge 512.5 [M + H +].

Example 18 (R) -2- {4- [3-Methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} 3-phenylpropionic acid. Step 1. 4- [3-methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazole-5yl] benzoic acid.

4- [3-Methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxαzol-5-yl] benzoic acid was prepared analogously to example 17 [step 3] from 5- (4-methoxycarbonylphenyl) -3-methylisoxazole-4-carboxylic acid acid [example 1, step 3] (1 g, 3.3 mmol) and (S) -1- (2-chlorophenyl) ethanol. Yield = 800 mg (2.19 mmol, 60%). HPLC (254 nm). Method 3, Rt 2.67 min MS (ESI) mass / charge 367.4 [M + H +].

Step 2. (S, R) -2- {4- [3-Methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} -3phenylpropionic acid.

The title compound was prepared according to a procedure similar to that described for example 5, from (S) 4- [3-methyl-4- (1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoic acid [example 18, step 2] (61 mg, 0 , 12 mmol) and D-phenylalanine methyl ester hydrochloride. Yield = 30 mg (0.06 mmol, 49%). HPLC (254 nm). Method 3, Rt 3.05 min MS (ESI) mass / charge 514.5 [M + H +].

Example 19 (S) -2- {4- [3-Methyl-4 - ((S) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzoylamino} 3-phenylpropionic acid.

The title compound was prepared according to a procedure similar to that described for example 18, from 4 [3-methyl-4 - ((S) -1-phenylethoxycarbonylα-amino) isoxazol-5-yl] benzoic acid [example 18, step 2] (61 mg, 0 , 12 mmol) and L-phenylalanine methyl ester hydrochloride. Yield = 22 mg (0.04 mmol, 36%). HPLC (254 nm). Method 3, Rt 2.87 min MS (ESI) mass / charge 514.5 [M + H +].

Example 20 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-phenylpropionic acid.

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-phenylalanine methyl ester. Yield = 65 mg (0.12 mmol, 77%). HPLC (254 nm). Method 3, Rt 2.93 min MS (ESI) mass / charge 566.3 [M + H +].

Example 21 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylα-amino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (4-fluorophenyl) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-4-fluorophenylalanine methyl ester. Yield = 65 mg (0.12 mmol, 77%). HPLC (254 nm). Method 3, Rt 2.93 min mS (ESI) mass / charge 566.3 [M + H +].

Example 22 (R) -3- (4-Chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-4-chlorophenylalanine methyl ester. Yield = 64 mg (0.11 mmol, 74%). HPLC (254 nm). Method 3 Rt 3.11 min MS (ESI) mass / charge 583.4 [M + H +].

Example 23 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (3,4-difluorophenyl) propionic acid.

- 90 038294

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-3,4-difluorophenylalanine methyl ester hydrochloride. Yield = 41 mg (0.07 mmol, 47%). HPLC (254 nm). Method 3 Rt 2.96 min MS (ESI) mass / charge 584.1 [M + H +].

Example 24 (R) -3- (2-Chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4- [1 - ((R) -2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-2-chlorophenylalanine methyl ester hydrochloride. Yield = 41 mg (0.07 mmol, 47%). HPLC (254 nm). Method 3 Rt 3.06 min MS (ESI) mass / charge 584.2 [M + H +].

Example 25 (R) -3 - (4-Bromophenyl) -2- (4- {4 - [(K) -1 - (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-4-bromophenylalanine methyl ester hydrochloride. Yield = 65 mg (0.10 mmol, 35%). HPLC (254 nm). Method 3, Rt 3.28 min MS (ESI) mass / charge 626.3, 628.4 [M + H +].

Example 26 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (2-fluorophenyl) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-2-fluorophenylalanine methyl ester hydrochloride. Yield = 70 mg (0.12 mmol, 52%). HPLC (254 nm). Method 3, Rt 3.12 min MS (ESI) mass / charge 566.5, 567.8 [M + H +].

Example 27 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3-p-tolylpropionic acid.

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4 - [(R) -1- (4-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-4-methylphenylalanine methyl ester hydrochloride. Yield = 37 mg (0.07 mmol, 43%). HPLC (254 nm). Method 3, Rt 3.13 min MS (ESI) mass / charge 562.3 [M + H +].

Example 28 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3 - (4-trifluoromethylphenyl) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4 - [(R) -1- (4-bromophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-4-trifluoromethylphenylalanine methyl ester hydrochloride. Yield = 40 mg (0.06 mmol, 44%). HPLC (254 nm). Method 3, Rt 3.00 min MS (ESI) mass / charge 616.2 [M + H +].

Example 29 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoylamino) -3- (4-cyanophenyl) propionic acid ...

The title compound was prepared according to a procedure similar to that described for example 17, from 4 {4 - [(R) -1- (4-bromophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzoic acid [example 17, step 3] ( 60 mg, 0.15 mmol) and D-4-cyanophenylalanine methyl ester hydrochloride. Yield = 17 mg (0.03 mmol, 20%). HPLC (254 nm). Method 3, Rt 2.93 min MS (ESI) mass / charge 573.2 [M + H +].

Example 30 (R) -2- (4- {5 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -4-methylpyrazol-1-yl} benzoylamino) -3-phenylpropionic acid.

Step 1. Ethyl ester of 2- (4-cyanophenyl) -4-methyl-2H-pyrazole-3-carboxylic acid.

A solution of trichloroacetyl chloride (12.92 ml, 115.8 mmol) in dichloromethane (30 ml) was cooled to -10 ° C under nitrogen atmosphere. A solution of ethyl propenyl ether (12.82 ml, 115.8 mmol) and pyridine (9.36 ml, 115.8 mmol) was added dropwise at a rate necessary to maintain the internal temperature at -10 ° C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 24 hours. The mixture was filtered and the solids were washed with dichloromethane (50 ml). The filtrates were evaporated to dryness in vacuo to give an oil (31.71 g). This material was dissolved in ethanol (400 ml) and treated with 4-cyanophenylhydrazine hydrochloride (24.81 g, 139 mmol). The resulting mixture was heated under reflux for 3 hours and then cooled to room temperature. Volatiles were evaporated in vacuo, the residue was dissolved in EtOAc (1L) and washed with 1N HCl. aqueous HCl solution (2 x 300 ml). The organic layer was separated, washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow solid (27.8 g). It was triturated with EtOAc (130 ml) and the remaining solids (not containing the product) were removed by filtration. The filtrates were concentrated to a volume of 50 ml and the precipitated solids (not containing the product) were filtered off. The filtrates were concentrated and purified by chromatography on silica gel eluting with a hexanes / acetone gradient from 100/0 to 88/12. The collected fractions, which contained a mixture of the two isomeric products, were concentrated to dryness and triturated with methanol to give the desired [2- (4-cyanophenyl) -4methyl-2H-π-pyrazole-3-carboxylic acid ethyl ester] isomer as a yellow solid (3 , 77 g, 14.8 mmol, 13%).

- 91 038294

HPLC (254 nm). Method 3, Rt 2.93 min MS (ESI) mass / charge 256.3 [M + H +]. 1H NMR (500 MHz, CDCl ₃ ) δ 7.73 (d, J = 8.5 Hz, 2H); 7.58 (s, 1H); 7.52 (d, J = 8.5 Hz, 2H); 4.27 (q, J = 7.1 Hz, 2H); 2.35 (s, 3H); 1.26 (t, J = 7.1 Hz, 3H).

Step 2. 2- (4-Cyanophenyl) -4-methyl-2H-pyrazole-3-carboxylic acid.

A stirred solution of ethyl ester of 2- (4-cyanophenyl) -4-methyl-2H-pyrazole-3carboxylic acid [example 30, step 1] (500 mg, 1.96 mmol) in THF (10 ml) was treated with 1N. aqueous LiOH solution (10 ml) and the resulting mixture was stirred at room temperature for 6 hours, after which approximately 60% conversion to product was detected by HPLC / MS analysis. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with 1N. aqueous NaOH solution (100 ml). The organic layer contained unreacted starting material. The aqueous layer was acidified to pH 1 with 1N. aqueous HCl solution and the resulting suspension was extracted with ethyl acetate (100 ml). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the pure product as a white solid (289 mg, 1.27 mmol, 65%). HPLC (254 nm). Method 3, Rt 2.56 min mS (ESI) mass / charge 228.3 [M + H +].

Step 3. (R) -1- (2-Chlorophenyl) [2- (4-cyanophenyl) -4-methyl-2H-pyrαzol-3-yl] carbamic acid ethyl ester.

2- (4-Cyanophenyl) -4-methyl-2H-pyrazole-3-carboxylic acid [example 30, step 2] (218 mg, 0.96 mmol) was suspended in toluene (10 ml) and treated with diisopropylethylamine (200 μl, 1.16 mmol). The resulting solution was treated with diphenylphosphoryl azide (230 μl, 1.06 mmol) and heated to 65 ° C. (R) -1- (2-chlorophenyl) ethanol (227 mg, 1.44 mmol) was added to the reaction mixture and the temperature was raised to 105 ° C over 30 minutes, during which time vigorous gas evolution was observed. The reaction mixture was brought to 65 ° C and stirred at this temperature for 4 hours. The reaction was considered complete by HPLC / MS. After cooling, the volatiles were removed in vacuo and the crude residue was purified by chromatography on silica gel eluting with a hexanes / ethyl acetate gradient. The product was isolated as a white solid (120 mg, 0.31 mmol, 33%). HPLC (254 nm). Method 3, Rt 3.84 min MS (ESI) mass / charge 381.2 [M + H +].

Step 4. 4- {5 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylα-amino] -4-methylpyrazol-1-yl} benzoic acid.

A solution containing 1- (2-chlorophenyl) ethyl ester (R) - [2- (4-cyanophenyl) -4-methyl-2H-pyrazol-3-yl] carbamic acid (120 mg, 0.32 mmol) and THF ( 1.5 ml), treated with 1N. aqueous LiOH solution (1.5 ml) and the resulting mixture was stirred at room temperature for 36 h, followed by heating to 45 ° C for 24 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with 1N. aqueous NaOH solution (50 ml). The aqueous layer was acidified to pH 1 with 1N. aqueous HCl solution and the resulting suspension was extracted with ethyl acetate (50 ml). The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the pure product as a white solid. Yield = 62 mg (0.16 mmol, 49%). HPLC (254 nm). Method 3, Rt 3.14 min MS (ESI) mass / charge 399.2 [M + H +].

Step 3. (R) -2- (4- {5 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -4methylpyrazol-1-yl} benzoylamino) -3-phenylpropionic acid methyl ester.

4- {5 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylα-amino] -4-methylpyrazol-1-yl} benzoic acid (62 mg, 0.16 mmol) was dissolved in DMF (1.4 ml) and treated diisopropylethylamine (112 μL, 0.62 mmol) under nitrogen. EDCI (40 mg, 0.20 mmol) and HOBt (26 mg, 0.19 mmol) were added and the resulting mixture was stirred for 30 min. D-phenylalanine methyl ester hydrochloride (50 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 ml) and transferred to a separatory funnel. The organic matter was washed with 1N. aqueous HCl and brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude residue was purified by preparative TLC on plates (1000 μm), eluting with a 7: 3 v / v hexanes / ethyl acetate mixture. The product was obtained as a white solid. Yield = 35 mg (0.06 mmol, 39%). HPLC (254 nm). Method 3, Rt 3.28 min MS (ESI) mass / charge 561.3, 563.3 [M + H +].

Step 4. (R) -2- (4- {5 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -4-methylpyr-azol-1-yl} benzoyl-amino) -3-phenylpropionic acid.

A solution containing methyl ester of (R) -2- (4- {5 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -4-methylpyrazol-1-yl} benzoylamino) -3-phenylpropionic acid (35 mg, 0.06 mmol) and THF (1 ml), were treated with 1N. aqueous LiOH solution (125 μl) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and acidified to pH 1 with 1N. aqueous HCl solution. The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the pure product as a white solid. Yield = 20 mg (0.04 mmol, 61%). HPLC (254 nm). Method 3, Rt 3.19 min MS (ESI) mass / charge 547.6, 550.6 [M + H +].

Example 31 (R) -2- {4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} 3-phenylpropionic acid.

Step 1. 5- (4-chloromethylphenyl) -3-methylisoxazole-4-carboxylic acid tert-butyl ester

- 92 038294 slots.

A stirred suspension of MgCl ₂ (2.97 g, 31.2 mmol) in dichloromethane (30 ml) under nitrogen was treated dropwise with tert-butyl acetoacetate (5.17 ml, 31.2 mmol) and the resulting mixture was cooled to 0 ° C. The mixture was stirred at this temperature for 15 min and then worked up by adding pyridine dropwise (4.85 ml, 60.0 mmol). After 15 min, a solution of 4- (chloromethyl) benzoyl chloride (5.67 g, 30.0 mmol) in dichloromethane (30 ml) was added dropwise. The resulting mixture was kept at 0 ° C for 1 hour and then at room temperature for an additional hour. The reaction mixture was quenched by the careful addition of water (100 ml) and the mixture was transferred to a separatory funnel. The organic layer was washed with 1N. aqueous HCl solution (2x100 ml), then dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude residue was dissolved in ethanol (60 ml) and treated with a solution of NH ₂ OH-HCl (6.67 g, 96.0 mmol) in water (13 ml). This mixture was heated to 60 ° C for 2 hours and at room temperature overnight. The resulting thick white precipitate was filtered, rinsed with ethanol, and dried in air. The mother liquor was concentrated and cooled to 0 ° C to obtain a second batch of solid, which was filtered and air dried. Total yield = 5.82 g (19.0 mmol, 63%). HPLC (254 nm). Method 3, Rt 3.49 min mS (ESI) mass / charge 308.4 [M + H +].

Step 2. 5- (4-Chloromethylphenyl) -3-methylisoxazole-4-carboxylic acid.

5- (4-Chloromethylphenyl) -3-methylisoxazole-4-carboxylic acid tert-butyl ester (4.61 g, 15.0 mmol) was dissolved in dichloromethane (7.5 ml) and treated with trifluoroacetic acid (7.5 ml ). The resulting mixture was stirred at room temperature for 18 hours at which time the reaction was considered complete by HPLC / MS. The volatiles were removed in vacuo to give the crude product as a white solid (3.8 g, 15.0 mmol, quantitative yield) which was used as is in the next step.

Step 3. (R) -1-Phenylethyl [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid ester.

5- (4-Chloromethylphenyl) -3-methylisoxazole-4-carboxylic acid (3.0 g, 12.0 mmol) was suspended in toluene (120 ml) and treated with triethylamine (2.02 ml, 14.4 mmol). The resulting solution was treated with diphenylphosphoryl azide (2.85 ml, 13.2 mmol) and heated to 65 ° C. (R) -1- (phenyl) ethanol (1.9 g, 15.6 mmol) was added to the reaction mixture and the temperature was raised to 105 ° C over 30 minutes, during which time vigorous gas evolution was observed. The reaction mixture was brought to 65 ° C and stirred at this temperature for 4 hours. The reaction was considered complete by HPLC / MS. After cooling, the volatiles were removed in vacuo and the crude residue was purified by chromatography on silica gel eluting with a hexanes / ethyl acetate gradient. The product was isolated as a white solid (3.16 g, 8.52 mmol, 71%). HPLC (254 nm). Method 3, Rt 3.02 min MS (ESI) mass / charge 371.2 [M + H +].

Step 4. (R) -2- {4- [3-methyl-4 - ((R-1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3-phenylpropionic acid methyl ester).

A solution containing (R) -1-phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid (74 mg, 0.2 mmol), DMF (2 ml) and triethylamine (224 μl, 1.6 mmol), treated with D-phenylalanine methyl ester hydrochloride (173 mg, 0.80 mmol) and heated to 80 ° C for 3 hours. The reaction was considered complete by HPLC / MS. The reaction mixture was cooled, partitioned between EtOAc and water, and transferred to a separatory funnel. The organic layer was washed with water and brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude yellow oily residue was purified by chromatography on silica gel eluting with a hexanes / EtOAc gradient. The product was obtained as a colorless film (77 mg, 0.15 mmol, 75%). HPLC (254 nm). Method 3, Rt 2.67 min MS (ESI) mass / charge 514.4 [M + H +].

Step 5. (R) -2- {4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3-phenylpropionic acid.

A solution containing (R) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzylamino} -3-phenylpropionic acid methyl ester (77 mg, 0, 15 mmol) and THF (1.5 ml) were treated with 1N. aqueous LiOH solution (1.5 ml) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and acidified to pH ~ 5 1N. aqueous HCl solution. The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give the pure product as a white solid (9 mg, 0.018 mmol, 12%). HPLC (254 nm). Method 3, Rt 2.74 min MS (ESI) mass / charge 500.5 [M + H +].

Example 32 (R) -3- (2-Fluorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole-5yl] benzylamino} propionic acid.

The title compound was prepared analogously to example 31 using (R) -1-phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 31, step 3] (100 mg, 0.27 mmol) and D-2-fluorophenylalanine methyl ester hydrochloride. Output = 10

- 93 038294 mg (0.02 mmol, 7%). HPLC (254 nm). Method 3, Rt 2.64 min MS (ESI) mass / charge 518.4 [M + H +].

Example 33 (R) -2- {4- [3-Methyl-4 - ((R) -1-phenulemoxicαcarbonylαmino) isoxαzol-5-yl] benzylαmino} 3 - (4-trifluoromethylphenyl) propionic acid.

The title compound was prepared analogously to example 31 using (R) -1-phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 31, step 3] (100 mg, 0.27 mmol) and D-4-trifluoromethylphenylalanine methyl ester hydrochloride. Yield = 18 mg (0.03 mmol, 11%). HPLC (254 nm). Method 3, Rt 3.10 min MS (ESI) mass / charge 568.5 [M + H +].

Example 34 (R) -3-Cyclonropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazole-5yl] benzylamino} propionic acid.

The title compound was prepared analogously to example 31 using (R) -1-phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 31, step 3] (100 mg, 0.27 mmol) and (R) -2-amino-3-cyclo-propylnropionic acid methyl ester hydrochloride [example 17, step 1]. Yield = 13 mg (0.03 mmol, 35%). HPLC (254 nm). Method 3, Rt 2.82 min MS (ESI) mass / charge 464.5 [M + H +].

Example 35 (R) -3- (2-Chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5yl] benzylamino} propionic acid.

The title compound was prepared analogously to example 31 using (R) -1-phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 31, step 3] (100 mg, 0.27 mmol) and D-2-chlorophenylalanine methyl ester hydrochloride. Yield = 38 mg (0.07 mmol, 27%). HPLC (254 nm). Method 3, Rt 3.05 min MS (ESI) mass / charge 534.2 [M + H +].

Example 36 (R) -3- (4-Chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole-5yl] benzylamino} propionic acid.

The title compound was prepared analogously to example 31 using (R) -1-phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 31, step 3] (100 mg, 0.27 mmol) and D-4-chlorophenylalanine methyl ester hydrochloride. Yield = 8 mg (0.01 mmol, 5%). HPLC (254 nm). Method 3, Rt 3.13 min MS (ESI) mass / charge 534.4 [M + H +].

Example 37 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3-phenylpropionic acid.

Step 1. (R) -1- (2-Chlorophenyl) [5- (4-chloromethylphenyl) -3-methylisoxazole-4yl] carbamic acid ethyl ester.

(R) -1- (2-Chlorophenyl) ethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid was prepared analogously to steps 1-3 of Example 31 from 5- (4-chloromethylphenyl) - 3-methylisoxazole-4-carboxylic acid [example 31, step 2] (1.95 g, 7.75 mmol) and (R) -1- (2-chlorophenyl) ethanol (1.82 g, 11.62 mmol) ... Yield = 1.33 mg (3.28 mmol, 42%). HPLC (254 nm). Method 3, Rt 3.31 min MS (ESI) mass / charge 405.3 [M + H +].

Step 2. (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylα-amino] -3methylisoxazol-5-yl} benzylamino) -3-phenylpropionic acid methyl ester.

(R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3-phenylpropionic acid methyl ester was prepared analogously to step 4 of example 31 from (R) -1- (2-chlorophenyl) [5- (4-chloromethylphenyl) -3-methylisoxazole-4yl] carbamic acid ethyl ester [Example 37, step 1] (101 mg, 0.25 mmol) and D-phenylalanine methyl ester hydrochloride. Yield = 45 mg (0.08 mmol, 33%). HPLC (254 nm). Method 3, Rt 2.90 min MS (ESI) mass / charge 548.5 [M + H +].

Step 3. (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylα-amino] -3-methylisoxazol-5-yl} benzylα-amino) -3-phenylpropionic acid.

Prepared analogously to step 5 of example J using the following reagents and quantities: (R) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazole-5yl} benzylamino methyl ester ) -3-phenylpropionic acid [example 37, step 2] (45 mg, 0.08 mmol). Yield = 6 mg (0.01 mmol, 14%). HPLC (254 nm). Method 3, Rt 2.69 min MS (ESI) mass / charge 534.3 [M + H +].

Example 38 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3 - (2-fluorophenyl) propionic acid ...

The title compound was prepared analogously to example 31 using (R) -1- (2-chlorophenyl) ethyl ester [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 37, step 1] (101 mg, 0.25 mmol) and D-2-fluorophenylalanine methyl ester hydrochloride. Yield = 30 mg (0.05 mmol, 22%). HPLC (254 nm). Method 3, Rt 2.57 min MS (ESI) mass / charge 552.3 [M + H +].

Example 39 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3- (4-trifluoromethylphenyl) propionic acid ...

The title compound was prepared analogously to example 31 using (R) -1- (2-chlorophenyl) ethyl ester [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 37, step 1] (101 mg, 0.25 mmol) and D-4-trifluorome methyl ester hydrochloride

- 94 038294 tylphenylalanine. Yield = 38 mg (0.06 mmol, 25%). HPLC (254 nm). Method 3, Rt 3.06 min MS (ESI) mass / charge 602.6 [M + H +].

Example 40 (R) -3- (2-Chlorophenyl) -2- (4- {4 - [(R) -1- (2-chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) propionic acid ...

The title compound was prepared analogously to example 31 using (R) -1- (2chlorophenyl) ethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 37, step 1] (101 mg, 0.25 mmol) and D-2chlorophenylalanine methyl ester hydrochloride. Yield = 8 mg (0.01 mmol, 5%). HPLC (254 nm). Method 3, Rt 2.78 min MS (ESI) mass / charge 569.3 [M + H +].

Example 41 (R) -2- (4- {4 - [(R) -1- (2-Chlorophenyl) ethoxycarbonylamino] -3-methylisoxazol-5-yl} benzylamino) -3-cyclopropylpropionic acid.

The title compound was prepared analogously to example 31 using (R) -1- (2-chlorophenyl) ethyl ester [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 37, step 1] (101 mg, 0.25 mmol) and (R) -2-amino-3-cyclopropylpropionic acid methyl ester hydrochloride [example 17, step 1]. Yield = 8 mg (0.01 mmol, 3%). HPLC (254 nm). Method 3, Rt 2.80 min MS (ESI) mass / charge 498.4 [M + H +].

Example 42 2- {4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid.

Step 1. {n- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) -5-isoxazolyl] phenyl} methyl acetate.

(R) -1-Phenylethyl ester of [5- (4-chloromethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [Example 31, step 3] (1 g, 2.8 mmol) was mixed with potassium acetate (2 g, 14 mmol) and sodium iodide (0.5 g, 2.8 mmol) and to these components was added N, N-dimethylacetamide (20 ml). The mixture was sonicated and then heated to 80 ° C for 1.5 hours. The mixture was cooled to room temperature and partitioned between saturated sodium chloride solution and ethyl acetate. The organic layer was washed additionally with water 4 times and then with saturated sodium chloride solution before being dried over magnesium sulfate. The filtered solution was evaporated to give a solid which was used directly. Yield: 0.94 g (2.4 mmol, 87%). HPLC (254 nm). Method 3, Rt 2.89 min MS (ESI) mass / charge 395.3 [M + H +].

Step 2. (R) -1-Phenylethyl [5- (4-hydroxymethylphenyl) -3-methylisoxazole-4yl] carbamic acid ester.

In THF (20 ml) and methanol (20 ml) was dissolved {n- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) -5isoxazolyl] phenyl} methyl acetate [Example 42, step 1] (0.94 g , 2.4 mmol) and potassium carbonate (981 mg, 7.1 mmol) was added to these components. The resulting mixture was allowed to stir for 1.5 hours at room temperature, at which time LC / MS indicated the formation of one product [HPLC (254 nm). Method 3, Rt 2.93 min MS (ESI) mass / charge 353.2 [M + H +]. The solvents were evaporated and the residue was partitioned between saturated sodium chloride solution and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a residue, which was chromatographed on a gradient of 0-50% ethyl acetate in hexanes to give the product. Yield: 0.63 g (1.79 mmol, 74%).

Step 3. Methyl 2-diazophenylpropanoate.

D-phenylalanine methyl ester hydrochloride (2 g, 9.3 mmol) was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a residue which was used directly. D-phenylalanine methyl ester (836 mg, 4.7 mmol) was dissolved in chloroform (20 ml) and acetic acid (0.055 ml, 0.94 mmol) was added. The solution was heated to reflux with slow dropwise addition of isoamyl nitrite (0.76 mL, 5.6 mmol), which was completed until the solvent refluxed. The mixture was heated under reflux for an additional 30 min to give a yellow solution, which was cooled to 0 ° C. The organic solution was washed with 1N. sulfuric acid (25 ml), water (20 ml), saturated sodium bicarbonate solution (25 ml), water (25 ml) and 1N. sulfuric acid (25 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated to give a residue, which was chromatographed on a gradient of 0-5% ethyl acetate in hexanes to give the product. Yield: 0.65 g (3.4 mmol, 72%).

Step 4. Methyl ester of 2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazole-5yl] benzyloxy} -3-phenylpropionic acid.

(R) -1-Phenylethyl [5- (4-hydroxymethylphenyl) -3-methylisoxazol-4-yl] carbamic acid ester [Example 42, step 2] (100 mg, 0.28 mmol) and methyl 2-diazophenylpropanoate [example 42, step 3] (61 mg, 0.39 mmol) was suspended in benzene (3 ml) in a screw cap vial. To these components was added dyrodium tetraacetate (1 mg, 0.002 mmol). After 10 minutes at room temperature, the vial was heated to 90 ° C for 1 hour. The mixture was cooled to room temperature and the mixture was chromatographed on a gradient of 0-20% ethyl acetate in hexanes to afford the product. Yield = 52 mg (0.1 mmol, 36%). HPlC (254 nm). Method 3, Rt 3.56 min MS (ESI) mass / charge 515.5 [M + H +].

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Step 5. 2- {4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid.

Methyl ester of 2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5yl] benzyloxy} -3-phenylpropionic acid (52 mg, 0.10 mmol) was dissolved in THF / water 2/1 rev / rev (4.5 ml) and the mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution. The aqueous layer was acidified to pH ~ 3 with 6N. HCl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was coevaporated with diethyl ether to give the pure product as a white solid (22 mg, 0.043 mmol, 44%). HPLC (254 nm). Method 3, Rt 3.03 min MS (ESI) mass / charge 501.5 [M + H +].

Example 43 2- {4- [3-Methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} -3-phenylpropionic acid.

The compound from example 43 was prepared analogously to example 42 from (R) -1-phenylethyl ester of [5- (4-hydroxymethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 42, step 2] (100 mg, 0, 28 mmol) dissolved in 15% THF in benzene (1.15 ml) using methyl 2 diazophenyl propanoate, which was synthesized from L-phenylalanine methyl ester hydrochloride (2 g, 9.3 mmol). Yield: 20 mg (0.04 mmol, 14%). HPLC (254 nm). Method 3, Rt 2.96 min MS (ESI) mass / charge 501.6 [M + H +].

Example 44 (RS) -3-Cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazole-5yl] benzyloxy} propionic acid.

Step 1. Methyl ester of D, L-2-αminocyclopropylpropanoic acid.

Prepared analogously to step 6 of example 1 from D, L-2-aminocyclopropylpropanoic acid (500 mg, 3.87 mmol). The crude residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a residue which was used directly. Yield: 295 mg (2.06 mmol, 53%).

Step 2. R, S-Methyl-2-diazocyclopropylpropanoate.

Prepared analogously to Step 3 of Example 42 from D, L-2-αminocyclopropylpropanoic acid methyl ester (295 mg, 2.06 mmol) and used directly. Yield: 200 mg (1.29 mmol, 62%).

Step 3. (RS) -3-cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid methyl ester.

Prepared analogously to step 4 of example 42 from (R) -1-phenylethyl ester of [5- (4-hydroxymethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 42, step 2] (90 mg, 0.25 mmol), dissolved in 15% THF in benzene (1 ml) and R, S-methyl-2-diazocyclopropylpropanoate [example 44, step 2] (118 mg, 0.75 mmol). Yield: 50 mg (0.1 mmol, 40%). HPLC (254 nm). Method 3, Rt 2.99 min MS (ESI) mass / charge 479.1 [M + H +].

Step 4. (RS) -3-Cyclopropyl-2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonylα-amino) isoxazole-5yl] benzyloxy} propionic acid.

Was prepared analogously to step 5 of example 42 from methyl ester (RS) -3-cyclopropyl-2- {4 [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid [example 44, step 3] (50 mg, 0.1 mmol). Yield: 21 mg (0.1 mmol, 40%). HPLC (254 nm). Method 3, Rt 3.06 min mS (ESI) mass / charge 465 [M + H +].

Example 45 (RS) -3- (4-Chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonyloxy) isoxazole-5yl] benzyloxy} propionic acid.

Step 1. Methyl ester of D, L-2-αmino-3 (4-chlorophenyl) propanoic acid.

Prepared analogously to step 6 of example 1 from D, L-2-αmino-3 (4-chlorophenyl) propanoic acid (600 mg, 3 mmol). The crude residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a residue which was used directly. Yield: 698 mg (3.3 mmol, 100%).

Step 2. R, S-Methyl-2-diazo-3 (4-chlorophenyl) propαnoate.

Prepared analogously to step 3 of example 42 from methyl ester of D, L-2-αmino-3 (4chlorophenyl) propanoic acid [example 45, step 1] (698 mg, 3.3 mmol) and used directly. Yield: 275 mg (1.33 mmol, 40%).

Step 3. (RS) -3- (4-chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonyloxy) isoxazol-5-yl] benzyloxy} propionic acid methyl ester.

Prepared analogously to step 4 of example 42 from (R) -1-phenylethyl ester of [5- (4-hydroxymethylphenyl) -3-methylisoxazol-4-yl] carbamic acid [example 42, step 2] (90 mg, 0.25 mmol), dissolved in 15% THF in benzene (1 ml) and R, S-methyl-2-diazo-3 (4-chlorophenyl) propanoate [example 45, step 2] (200 mg, 0.89 mmol). Yield: 55 mg (0.1 mmol, 40%). HPLC (254 nm). Method 3, Rt 3.49 min MS (ESI) mass / charge 549.6 [M + H +].

Step 4. (RS) -3- (4-Chlorophenyl) -2- {4- [3-methyl-4 - ((R) -1-phenylethoxycarbonyloxy) isoxazole-5yl] benzyloxy} propionic acid.

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Was prepared analogously to step 5 of example 42 from methyl ester (RS) -3-cyclopropyl-2- {4 [3-methyl-4 - ((R) -1-phenylethoxycarbonylamino) isoxazol-5-yl] benzyloxy} propionic acid [example 44, step 3] (55 mg, 0.1 mmol). Yield: 20 mg (0.04 mmol, 37%). HPLC (254 nm). Method 3, Rt 3.26 min mS (ESI) mass / charge 535 [M + H +].

Example 46 2- [4- [4- [5- [1- (2-Chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetic acid.

Step 1. 5-Amino-1- (4-bromophenyl) pyrazole-4-carbonitrile.

(4-bromophenyl) hydrazine hydrochloride (2.24 g, 10 mmol) was suspended in ethanol (20 ml) and treated with triethylamine (1.53 ml, 11 mmol). The resulting solution was then treated with malononitrile (1.22 g, 10 mmol) added in portions. After observing a slight exothermic effect, the reaction mixture was heated to reflux temperature for 1 hour. The reaction mixture was cooled to room temperature; the solids were collected by vacuum filtration and rinsed with cold ethanol. The solids were air dried. Yield = 0.93 g, 3.5 mmol (35%). HPLC (254 nm): Method 2, Rt 5.82 min MS (ESI) mass / charge 265 [M + H +]; 263 [M + H +]; 184 [(M-Br) + H ⁺ ].

Step 2. 1- (2-Chlorophenyl) ethyl-N- [2- (4-bromophenyl) -4-cyanopyrazol-3-yl] carbamate.

A solution of 5-amino-1- (4-bromophenyl) pyrazole-4-carbonitrile [example 46, step 1] (26 mg, 0.1 mmol) in CH ₂ Cl ₂ (1 ml) was treated with triethylamine (28 μl, 0, 2 mmol), and then phosgene (100 μl of 20% v / v solution in toluene, calculated amount 0.2 mmol). The resulting solution was stirred at room temperature for 30 minutes. (±) -1- (2-chlorophenyl) ethanol (23 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove volatiles and the residue was purified by chromatography on silica gel eluting with 4: 1 v / v hexanes / ethyl acetate. The product was obtained in the form of a colorless film. Yield = 27 mg (0.06 mmol, 61%). HPLC (254 nm). Method 1, Rt 6.31 min MS (ESI) mass / charge 447 [M + H +]; 445 [M + H +]. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90 (s, 1H); 7.57 (d, J = 8.8 Hz, 2H); 7.377.35 (m, 1H); 7.32 (d, J = 8.8 Hz, 2H); 7.27 (m, 3H); 6.70 (br, 1H); 6.14 (q, J = 6.5 Hz, 1H); 1.54 (d, J = 6.5 Hz, 3H).

Step 3. Ethyl 2- [4- [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetate.

In a pressure vessel, 1- (2-chlorophenyl) ethyl-N- [2- (4-bromophenyl) -4-cyanopyrazol-3-yl] carbamate [Example 46, step 2] (80 mg, 0.18 mmol) was dissolved in a mixture of toluene and ethanol 2: 1 vol./about. (2 ml) and treated with Na ₂ CO ₃ (0.6 ml of a 2N aqueous solution) and [4- (2-ethoxy-2-oxoethyl) phenyl] boronic acid (75 mg, 0.36 mmol). The resulting mixture was degassed under Ar for 15 min, then treated with Pd [Ph ₃ P] ₄ (8 mg, 0.007 mmol). The vessel was closed with a lid and immersed in an oil bath at 80 ° C with vigorous stirring with a magnetic stirrer. The reaction was considered complete after 14 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and brine. The combined aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 4: 1 v / v hexanes / ethyl acetate mixture. The product was obtained as a white solid. Yield = 82 mg (0.16 mmol, 89%). HPLC (254 nm). Method 1 Rt 6.94 min MS (ESI) mass / charge 529.3 [M + H +]; 485.1 [(M-EtO) + H ⁺ ].

Step 4. 2- [4- [4- [5- [1- (2-Chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetic acid.

Ethyl 2- [4- [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetate [Example 46, step 3] (45 mg, 0.085 mmol ) was dissolved in THF (1 ml) and treated with LiOH (1 ml of 1M aqueous solution). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was transferred to a separatory funnel, diluted with water and extracted with ethyl acetate. The organic layer was decanted and the aqueous layer was brought to pH 2 with 0.1N. HCl solution. The product was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the pure product as a white solid. Yield = 42 mg (0.085 mmol, quantitative). HPLC (254 nm): Method 1, Rt 6.99 min MS (ESI) mass / charge 501.3 [M + H +]; 457.2 [(M-CO2H) + H ⁺ ]. 1H NMR (500 MHz, DMSO46) δ 12.39 (br, 1H); 10.42 (br, 1H); 8.31 (s, 1H); 7.82 (d, J = 8.6 Hz, 2H); 7.67 (d, J = 8.3 Hz, 2H); 7.56 (d, J = 8.6 Hz, 2H); 7.43 (d, J = 7.7 Hz, 1H); 7.39 (d, J = 8.3 Hz, 2H); 7.33-7.29 (m, 3H); 5.94 (q, J = 6.5 Hz, 1H); 3.64 (s, 2H); 1.44 (br, 3H).

Example 47 (R) -1- [4- [4- [1,5-Dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid.

Step 1. Ethyl ester of 2- (4-bromobenzoyl) -3-oxo-butyric acid.

To a suspension of magnesium chloride (1.49 g, 15.6 mmol) in dichloromethane (15 ml), which was cooled to 0 ° C, was added ethyl acetoacetate (1.97 ml, 15.6 mmol). Pyridine (2.43 mL, 30 mmol) was added to the mixture and stirring was continued for an additional 15 minutes. Then, to the reaction mixture was added

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4-bromobenzoyl chloride (3.29 g, 15 mmol) in dichloromethane (15 ml). This mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 1 hour. At this stage, the mixture was treated with 6N. hydrochloric acid solution (20 ml). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a colorless oil, which was used directly in the next step.

Step 2. Ethyl ester of 3- (4-bromophenyl) -1,5-dimethyl-1H-pyrazole-4-carboxylic acid and ethyl ester of 5- (4-bromophenyl) -1,3-dimethyl-1H-pyrazole- 4-carboxylic acid.

Ethyl ester of 2- (4-bromobenzoyl) -3-oxo-butyric acid [example 47, step 1] (4.7 g, 15 mmol), methylhydrazine (0.79 ml, 15.1 mmol), p-toluenesulfonic acid ( 0.15 g) was mixed with ethanol (150 ml) and this mixture was heated to 78 ° C for 2 hours. At this stage, the reaction mixture was allowed to cool and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. A crude product was obtained which was initially purified by chromatography on silica gel with hexane / ethyl acetate 95/5 as eluent and then with hexane / ethyl acetate 88/12 to give ethyl 3- (4-bromophenyl) - 1,5-dimethyl-1H-pyrazole-4-carboxylic acid (600 mg, 12%) and 5- (4-bromophenyl) -1,3-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (190 mg, 4%) ...

Step 3. 3- (4-Bromophenyl) -1,5-dimethyl-1H-pyrazole-4-carboxylic acid.

A mixture of ethyl ester of 3- (4-bromophenyl) -1,5-dimethyl-1H-pyrazole-4-carboxylic acid [example 47, step 2] (600 mg, 1.85 mmol), 1N. a solution of sodium hydroxide (18.5 ml) and dioxane (18.5 ml) was stirred at 100 ° C for 3 hours. After cooling, the mixture was acidified to pH 3-4 with 3N. hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a solid (422 mg, 77%).

Step 4. (R) -1- (Phenyl) ethyl-N- [2- (4-bromophenyl) -1,5-dimethyl-1H-pyrazol-3-yl] carbamate.

Suspension of 3- (4-bromophenyl) -1,5-dimethyl-1H-pyrazole-4-carboxylic acid [example 47, step 3] (50 mg, 0.17 mmol) in toluene (1 ml) and triethylamine (17 mg , 0.17 mmol) was treated with diphenylphosphoryl azide (44 μl, 0.20 mmol) and the mixture was stirred at 45 ° C for 3 h and then at 95 ° C with gas evolution. After 30 min, (R) - (+) - 1-phenylethanol (25 mg, 0.20 mmol) was added. Heating was continued for an additional 1 hour before the mixture was allowed to cool. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and the solution was washed with 0.1M potassium carbonate solution and then with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the product (64 mg, 91%), which was used directly in the next step. HPLC (254 nm). Method 3, Rt 3.10 min MS (ESI) mass / charge 416.2, 414.4 [M + H +].

Step 5. Methyl ester of 2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) phenyl] cyclopropanecarboxylic acid.

Methyl 1- (4-bromophenyl) cyclopropanecarboxylate (1 g, 3.92 mmol), potassium acetate (461 mg, 4.7 mmol) and bis (pinacolato) dibor (1.19 g, 4.70 mmol) were mixed in dioxane (10 ml) and degassed for 10 min in an argon flow. [1, T-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (32 mg) was added and the mixture was heated at 95 ° C for 2 hours. At this stage, the mixture was allowed to cool and the mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. A crude product was obtained which was purified by chromatography on silica gel using hexane / ethyl acetate 95/5 as eluent to give the product as a white solid (1.02 g, 86%).

Step 6. (R) -1- [4- [4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid methyl ester.

In a pressure vessel, (R) -1- (phenyl) ethyl-N- [2- (4-bromophenyl) -1,5-dimethyl-1H-pyrazole-3yl] carbamate [Example 47, step 4) (64 mg, 0.16 mmol) was dissolved in a 2: 1 v / v mixture of toluene and ethanol. (2 ml) and treated with Na ₂ CO ₃ (0.5 ml of a 2N aqueous solution) and methyl ester 2- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl) phenyl] cyclopropanecarboxylic acid [example 47, step 5] (52 mg, 0.17 mmol). The resulting mixture was degassed under argon for 15 min and then treated with tetrakis (triphenylphosphine) palladium (0) (1 mg, 0.006 mmol). The vessel was closed with a lid and immersed in an oil bath at 80 ° C with vigorous stirring with a magnetic stirrer overnight. This reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and brine. The combined aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. This material was purified by preparative TLC eluting with hexane / ethyl acetate 1/1 v / v to give the product as a yellow film (10 mg, 13%).

Step 7. (R) -1- [4- [4- [2,5-Dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid.

(R) -1- [4- [4- [1,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazole-3) methyl ester

- 98 038294 yl] phenyl] phenyl] cyclopropanecarboxylic acid [example 47, step 6] (10 mg, 0.02 mmol) was dissolved in THF (1 ml) and treated with LiOH (1 ml of 2M aqueous solution). The resulting mixture was stirred overnight and then heated under reflux for 5 hours. The reaction mixture was cooled and transferred to a separatory funnel, diluted with water and extracted with ethyl acetate. The organic layer was decanted and the aqueous layer was brought to pH 1 with 0.1N. HCl solution and then the product was extracted with ethyl acetate. This organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. A residue was obtained which was triturated with dimethoxyethane. The solids were filtered off and the filtrate was evaporated to dryness to give a residue which was purified by preparative TLC eluting with 2/1 v / v ethyl acetate / hexane. The product was obtained as a white solid (3 mg, 28%). HPLC (254 nm). Method 3, Rt 3.12 min MS (ESI) mass / charge 496.6 [M + H +].

Example 48 (R) -1- [4- [4- [2,5-Dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid.

Step 1. 5- (4-Bromophenyl) -1,3-dimethyl-1H-pyrazole-4-carboxylic acid.

A mixture of 5- (4-bromophenyl) -1,3-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester [example 47, step 2] (190 mg, 0.59 mmol), 1N. a solution of sodium hydroxide (5.9 ml) and dioxane (5.9 ml) was stirred at 100 ° C for 1 hour. After cooling, the mixture was acidified to pH 3-4 with 3N. hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the product as a solid (170 mg, 98%).

Step 2. (R) -1- (Phenyl) ethyl-N- [5- (4-bromophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] carbamate.

5- (4-Bromophenyl) -1,3-dimethyl-1H-pyrazole-4-carboxylic acid [example 48, step 1] (50 mg, 0.17 mmol) was used to prepare (R) -1- (phenyl) ethyl N- [5- (4-bromophenyl) -1,3-dimethyl-1H-pyrazole-4yl] carbamate according to the procedure described for step 4 of Example 47 to give the product (64 mg, 91%) which was used on next step. HPLC (254 nm). Method 3, Rt 3.03 min MS (ESI) mass / charge 416.5 [M + H +].

Step 3. (R) -1- [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid methyl ester.

In a pressure vessel, (R) -1- (phenyl) ethyl-N- [5- (4-bromophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] carbamate [Example 48, step 2) (64 mg, 0.16 mmol) was used to obtain the product as an oil (32 mg, 41%) using a procedure similar to that described for step 6 of Example 47.

Step 4. (R) -1- [4- [4- [2,5-Dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3-yl] phenyl] phenyl] cyclopropanecarboxylic acid.

(R) -1- [4- [4- [2,5-dimethyl-4- (1-phenylethoxycarbonylamino) pyrazol-3yl] phenyl] phenyl] cyclopropanecarboxylic acid methyl ester [example 48 step 3] (32 mg, 0.06 mmol) was dissolved in THF (3 ml) and treated with LiOH (3 ml of 2M aqueous solution). The resulting mixture was stirred overnight and then heated under reflux for 5 hours. The reaction mixture was cooled and transferred to a separatory funnel, diluted with water and extracted with ethyl acetate. The organic layer was decanted and the aqueous layer was brought to pH 1 with 0.1N. HCl solution and then the product was extracted with ethyl acetate. This organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. A residue was obtained which was triturated with dimethoxyethane. The solids were filtered off and the filtrate was evaporated to dryness to give a residue which was purified by preparative TLC eluting with 2/1 v / v ethyl acetate / hexane. The product was obtained as a white solid (10 mg, 32%). HPLC (254 nm). Method 3, Rt 2.92 min MS (ESI) mass / charge 496.6 [M + H +].

Example 49 (R) -1- (4 '- {5- [1- (2-Chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -3-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid.

Step 1. Ethyl- (E) -4- (dimethylamino) -2-oxobut-3-enoate.

Ethyl pyruvate (5 g, 43.1 mmol) was dissolved in CH ₂ Cl ₂ (86 ml) and treated with dimethylformamide dimethyl acetal (5.73 ml, 43.1 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The crude product was used as is in the next step. Yield = 7.4 g.

Step 2. Ethyl 2- (4-bromophenyl) pyrazole-3-carboxylate.

4-bromophenylhydrazine hydrochloride (2.0 g, 8.95 mmol) was dissolved in MeOH (18 ml) and treated with crude ethyl (E) -4- (dimethylamino) -2-oxobutam-3-enoate [example 3, step 1 ] (1.54 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 6 hours. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel eluting with 95: 5 v / v hexanes / ethyl acetate, increasing in polarity over time to 9: 1. Two isomeric products were isolated: ethyl 2- (4-bromophenyl) pyrazole-3-carboxylate as an orange solid (0.82 g, 2.78 mmol, 31%) and ethyl 1- (4-bromophenyl) pyrazole- 3-carboxylate as a red solid (0.44 g, 1.49 mmol, 17%).

Ethyl 2- (4-bromophenyl) pyrazole-3-carboxylate: HPLC (254 nm). Method 2 Rt 5.22 min MS (ESI) mass / charge 297 [M + H +]; 294.8 [M + H +]; 252 [(M-EtO) + H ⁺ ]; 250 [(M-EtO) + H +]. ¹ H NMR (500 MHz, CDCl ₃ ) δ

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7.69 (d, J = 1.9 Hz, 1H); 7.58 (d, J = 8.7 Hz, 2H); 7.32 (d, J = 8.7 Hz, 2H); 7.03 (d, J = 1.9 Hz, 1H); 4.26 (q J = 7.1 Hz, 2H); 1.28 (t, J = 7.1 Hz, 3H).

Ethyl 1- (4-bromophenyl) pyrazole-3-carboxylate: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.91 (d, J = 2.4 Hz, 1H); 7.65 (d, J = 7.2 Hz, 2H); 7.60 (d, J = 7.2 Hz, 2H); 7.00 (d, J = 2.4 Hz, 1H); 4.44 (q, J = 7.0 Hz, 2H); 1.43 (t, J = 7.0 Hz, 3H).

Step 3. Ethyl ester of 2- (4-bromophenyl) -4-fluoro-2H-pyrazole-3-carboxylic acid.

Ethyl 2- (4-bromophenyl) pyrazole-3-carboxylate (1.08 g, 3.68 mmol) was dissolved in acetonitrile (12 ml) and the resulting mixture was treated with glacial acetic acid (4.6 ml). To this solution was added bis (tetrafluoroborate) 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane in one portion. (Selectfluor®, 3.91 g, 11.04 mmol) and the resulting mixture was heated to 105 ° C for 18 hours. The mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude residue was loaded directly onto a silica gel column and purified by elution with hexanes / ethyl acetate 95: 5 v / v, increasing the polarity over time to 9: 1. The product was isolated as a white solid (410 mg, 1.31 mmol, 36%) and the starting material was recovered (272 mg, 0.93 mmol, 25%). For 2- (4-bromophenyl) -4-fluoro-2H-pyrazole-3-carboxylic acid ethyl ester: HPLC (254 nm). Method 3, Rt 2.97 min MS (ESI) mass / charge 313.1 [M + H +]. 1H NMR (500 MHz, CDCl ₃ ) δ 7.60 (s, 1H); 7.58 (d, J = 9 Hz, 2H); 7.29 (d, J = 9 Hz, 2H); 4.30 (q, J = 7.1 Hz, 2H); 1.28 (t, J = 7.1 Hz, 3H).

Step 4. 2- (4-Bromophenyl) -4-fluoro-2H-pyrazole-3-carboxylic acid.

A stirred solution of 2- (4-bromophenyl) -4-fluoro-2H-pyrazole-3carboxylic acid ethyl ester (410 mg, 1.31 mmol) in THF (13 ml) was treated with 1N HCI. aqueous LiOH solution (13 ml) and the resulting mixture was stirred at room temperature overnight. The reaction was considered complete by TLC and HPLC / MS. The reaction mixture was distributed between ethyl acetate and 1N. aqueous HCl solution (100 ml v / v) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the pure product as a white solid (347 mg, 1.22 mmol, 93%). HPLC (254 nm). Method 3, Rt 2.82 min mS (ESI) mass / charge 285.1 [M + H +].

Step 5. (R) - [2- (4-bromophenyl) -4-fluoro-2H-pyrazole-3yl] carbamic acid 1- (2-Chlorophenyl) ethyl ester.

2- (4-Bromophenyl) -4-fluoro-2H-pyrazole-3-carboxylic acid (347 mg, 1.22 mmol) was suspended in toluene (12 ml) and treated with triethylamine (205 μl, 1.46 mmol). The resulting solution was treated with diphenylphosphoryl azide (316 μl, 1.46 mmol) and heated to 65 ° C. To the reaction mixture was added (R) -1- (2-chlorophenyl) ethanol (230 mg, 1.46 mmol) and the temperature was raised to 105 ° C over 30 minutes, during which time vigorous gas evolution was observed. The reaction mixture was brought to 65 ° C and stirred at this temperature for 4 hours. The reaction was considered complete by HPLC / MS. After cooling, the volatiles were removed in vacuo and the crude residue was purified by chromatography on silica gel eluting with a hexanes / ethyl acetate gradient. The product was isolated as a white solid (452 mg, 1.03 mmol, 85%). HPLC (254 nm). Method 3, Rt 3.16 min MS (ESI) mass / charge 440.1 [M + H +].

Step 6. (R) -1- (4 '- {5- [1- (2-Chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -3-fluorodiphenyl4-yl) cyclopropanecarboxylic acid.

Stirred suspension of 1- (2-chlorophenyl) ethyl ester (R) - [2- (4-bromophenyl) -4fluoro-2H-pyrazol-3-yl] carbamic acid (88 mg, 0.2 mmol), toluene / ethanol 2: 1 v / v (2 ml), 2M aqueous solution of Na ₂ CO ₃ (670 μl) and 1- (4-boron-2-fluorophenyl) cyclopropane-1-carboxylic acid (45 mg, 0.2 mmol) were degassed in a nitrogen atmosphere for 10 min and treated with Pd [Ph ₃ P] ₄ (12 mg, 0.01 mmol). The resulting mixture was immersed in an oil bath with stirring at 90 ° C for 12 h. The reaction mixture was cooled, transferred to a separatory funnel and diluted with ethyl acetate (50 ml). The mixture was carefully treated with 1N. aqueous HCl solution (20 ml). The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by preparative TLC on plates (1000 μm), eluting with hexanes / ethyl acetate 1: 1 v / v. The product was obtained as a tan solid. Yield = 35 mg (35%). HPLC (254 nm). Method 3, Rt 3.11 min MS (ESI) mass / charge 538.3 [M + H +].

Example 50 (R) -1- (4 '- {5- [1 - (2-Chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid.

The title compound was prepared analogously to example 49 using 1- (2-chlorophenyl) ethyl ester (R) - [2- (4-bromophenyl) -4-fluoro-2H-pyrazol-3-yl] carbamic acid (example 49, step 5 (88 mg, 0.2 mmol)) and 1- [4- (dihydroxyboranyl) -3-fluorophenyl] cyclopropane-1-carboxylic acid. Yield: 40 mg (37%) as a light yellow solid. HPLC (254 nm). Method 3, Rt 3.14 min MS (ESI) mass / charge 538.3 [M + H +].

Example 51 (R) -1- (2-Chloro-4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -di

- 100 038294 phenyl-4-yl) cyclopropanecarboxylic acid.

The title compound was prepared analogously to example 49 using 1- (2-chlorophenyl) ethyl ester (R) - [2- (4-bromophenyl) -4-fluoro-2H-pyrazol-3-yl] carbamic acid (example 49, step 5 (88 mg, 0.2 mmol)) and 1- [3-chloro-4- (dihydroxyboranyl) phenyl] cyclopropane-1-carboxylic acid. Yield: 24 mg (22%) as a light yellow solid. HPLC (254 nm). Method 3, Rt 3.40 min MS (ESI) mass / charge 554.4 [M + H +].

Example 52 (R) -1- (4 '- {5- [1 - (2-Chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-methyldiphenyl-4-yl) cyclopropanecarboxylic acid.

The title compound was prepared analogously to example 49 using 1- (2-chlorophenyl) ethyl ester (R) - [2- (4-bromophenyl) -4-fluoro-2H-pyrazol-3-yl] carbamic acid (example 49, step 5 (88 mg, 0.2 mmol)) and 1- [4- (dihydroxyboranyl) -3-methylphenyl] cyclopropane-1-carboxylic acid. Yield: 36 mg (34%) as a light yellow solid. HPLC (254 nm). Method 3, Rt 3.19 min MS (ESI) mass / charge 534.3 [M + H +].

Example 53 (R) -1- (4 '- {5- [1 - (2-Chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} diphenyl-4yl) cyclopropanecarboxylic acid.

The title compound was prepared analogously to example 49 using 1- (2-chlorophenyl) ethyl ester (R) - [2- (4-bromophenyl) -4-fluoro-2H-pyrazol-3-yl] carbamic acid (example 49, step 5 (88 mg, 0.2 mmol)) and 4- (1-carboxycyclopropyl) phenylboronic acid pinacol ester. Yield: 9 mg (9%) as a white solid. HPLC (254 nm). Method 3, Rt 3.20 min MS (ESI) mass / charge 520.0 [M + H +].

Example 54 (R) -1- {4 '- [5- (1-Phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4yl} cyclopropanecarboxylic acid.

Step 1. Ethyl ester of 2- (4-bromophenyl) -4-iodo-2H-pyrazole-3-carboxylic acid.

Ethyl 2- (4-bromophenyl) pyrazole-3-carboxylate (example 49, step 2, 294 mg, 1.0 mmol) was dissolved in methanol (3 ml) and treated dropwise with iodine monochloride (115 μl, 2.3 mmol ). The resulting mixture was heated to 50 ° C for 3 hours. Another aliquot of iodine monochloride (120 μl) was added and heating continued for an additional 3 hours. The reaction was considered complete by HPLC / MS. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 ml) and transferred to a separatory funnel. The organic layer was washed sequentially with 1N. aqueous Na ₂ S ₂ O ₃ (30 ml) and brine (30 ml). The organic layer was separated, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product [2- (4-bromophenyl) -4-iodo-2H-π-pyrazole-3-carboxylic acid ethyl ester] was obtained as a pale yellow solid (420 mg, quantitative) and was used as is in the next step. HPLC (254 nm). Method 3, Rt 3.33 min MS (ESI) mass / charge 421.0, 423.0 [M + H +].

Step 2. Ethyl ester of 2- (4-bromophenyl) -4-trifluoromethyl-2H-pyrazole-3-carboxylic acid.

Ethyl ester of 2- (4-bromophenyl) -4-iodo-2H-pyrazole-3-carboxylic acid (420 mg, 1.0 mmol) was dissolved in DMF (4 ml) and the resulting solution was degassed with nitrogen for 10 min. (1,10-Phenanthroline) (trifluoromethyl) copper (I) (Trifluoromethylator ™, 520 mg, 1.5 mmol) was added in one portion under an inert atmosphere and the resulting mixture was stirred at 50 ° C for 18 hours. The reaction mixture was cooled to room temperature and filtered through a celite pad and rinsed thoroughly with ethyl acetate. The filtrates were washed with 1N. aqueous HCl, brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude product 2- (4-bromophenyl) -4-trifluoromethyl-2H-pyrazole-3-carboxylic acid ethyl ester was used as is in the next step (291 mg, 0.80 mmol, 80%). HPLC (254 nm). Method 3, Rt 3.23 min MS (ESI) mass / charge 365.2 [M + H +].

Step 3. 2- (4-Bromophenyl) -4-trifluoromethyl-2H-pyrazole-3-carboxylic acid.

Ethyl ester of 2- (4-bromophenyl) -4-trifluoromethyl-2H-pyrazole-3-carboxylic acid (291 mg, 0.80 mmol) in THF (8 ml) was treated with 1N HCI. aqueous LiOH (8 ml) and the resulting mixture was stirred at room temperature for 3 hours. The reaction was considered complete by TLC and HPLC / MS. The reaction mixture was distributed between ethyl acetate and 1N. aqueous HCl solution (100 ml v / v) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the pure product as a white solid (268 mg, 0.80 mmol, quantitative yield). HPLC (254 nm). Method 3, Rt 2.97 min MS (ESI) mass / charge 335.2 [M + H +].

Step 4. (R) - [2- (4-bromophenyl) -4-trifluoromethyl-2H-pyrαzol-3yl] carbamic acid 1-Phenylethyl ester.

2- (4-Bromophenyl) -4-trifluoromethyl-2H-pyrazole-3-carboxylic acid (268 mg, 0.80 mmol) was suspended in toluene (8 ml) and treated with triethylamine (135 μl, 0.97 mmol). The resulting solution was treated with diphenylphosphoryl azide (209 μl, 0.97 mmol) and heated to 65 ° C. (R) -1- (phenyl) ethanol (118 mg, 0.97 mmol) was added to the reaction mixture and the temperature was raised to 105 ° C in

- 101 038294 for 30 minutes, during which intense gas evolution was observed. The reaction mixture was brought to 65 ° C and stirred at this temperature for 4 hours. The reaction was considered complete by HPLC / MS. After cooling, the volatiles were removed in vacuo and the crude residue was purified by chromatography on silica gel eluting with a hexanes / ethyl acetate gradient. The product was isolated as a white solid (195 mg, 0.43 mmol, 54%). HPLC (254 nm). Method 3, Rt 3.23 min MS (ESI) mass / charge 454.0, 456.1 [M + H +].

Step 5. (R) -1- {4 '- [5- (1-Phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4yl} cyclopropanecarboxylic acid.

Stirred suspension of (R) - [2- (4-bromophenyl) -4trifluoromethyl-2H-pyrazol-3-yl] carbamic acid 1-phenylethyl ester (98 mg, 0.22 mmol), toluene / ethanol 2: 1 vol. /about. (2.2 ml), 2M aqueous Na2CO3 solution (720 μl) and pinacol ester of 4- (1-carboxycyclopropyl) phenylboronic acid (124 mg, 0.43 mmol) were degassed under nitrogen for 10 min and treated with Pd [Ph ₃ P] ₄ (12 mg, 0.01 mmol). The resulting mixture was immersed in an oil bath with stirring at 95 ° C for 3 h. The reaction mixture was cooled, transferred to a separatory funnel and diluted with ethyl acetate (50 ml). The mixture was carefully treated with 1N. aqueous HCl solution (20 ml). The organic layer was separated, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude residue was purified by preparative TLC on plates (1000 μm), eluting with hexanes / ethyl acetate 1: 1 v / v. The product was obtained as a tan solid. Yield = 6.8 mg (6%). HPLC (254 nm). Method 3, Rt 3.21 min MS (ESI) mass / charge 536.3 [M + H +].

Example 55 (R) -1- {2-Fluoro-4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid.

The title compound was prepared analogously to example 54 using 1-phenylethyl ester (R) - [2- (4-bromophenyl) -4-trifluoromethyl-2H-pyrazol-3-yl] carbamic acid (example 54, step 4 (98 mg, 0.22 mmol)) and 1- [4- (dihydroxyboranyl) -3-fluorophenyl] cyclopropane-1-carboxylic acid. Yield: 7 mg (6%) as a white solid. HPLC (254 nm). Method 3, Rt 3.11 min MS (ESI) mass / charge 554.4 [M + H +].

Example 56 (R) -1- (4- {5- [5- (1-Phenylethoxycarbonylamino) pyrazol-1-yl] pyridin-2-yl} phenyl) cyclopropanecarboxylic acid.

Step 1. Ethyl ester of 2- (6-chloropyridin-3-yl) -2H-pyrazole-3-carboxylic acid.

Ethyl ester of 2- (6-chloropyridin-3-yl) -2H-pyrazole-3-carboxylic acid was prepared analogously to step 2 of Example 49 using (6-chloropyridin-3-yl) hydrazine hydrochloride (9.89 g, 48, 68 mmol; prepared according to WO 2005/92856 A1) and ethyl (E) -4- (dimethylamino) -2-oxobut-3-enoate (7.82 g, 45.68 mmol, example 49, step 1). Yield = 1.35 g (5.38 mmol, 12%). HPLC (254 nm). Method 3, Rt 2.87 min MS (ESI) mass / charge 252.2 [M + H +]. 1H NMR (500 MHz, CDCl ₃ ) δ 8.50 (d, J = 3.0 Hz, 1H); 7.77 (dd, J1 = 3.0Hz, J2 = 8.5Hz, 1H); 7.74 (d, J = 2.0 Hz, 1H); 7.43 (d, J = 8.5 Hz, 1H); 7.08 (d, J = 2.0 Hz, 1H); 4.28 (q, J = 7.5 Hz, 2H); 1.30 (t, J = 7.5 Hz, 3H).

Step 2. Hydrochloric salt of 2- (6-chloropyridin-3-yl) -2H-pyrazole-3-carboxylic acid.

Stirred solution of 2- (6-chloropyridin-3-yl) -2H-pyrazole-3-carboxylic acid ethyl ester [Example 56, step 1] (1.35 g, 5.4 mmol) in THF / water 8: 2 v / v (35 ml) was treated with 1N. aqueous LiOH (6.5 ml) and the resulting mixture was stirred at room temperature for 3 hours. The reaction was considered complete by TLC and HPLC / MS. The reaction mixture was diluted with water (100 ml) and washed with dichloromethane (60 ml). The aqueous layer was acidified with 1N. aqueous HCl solution to pH 2, resulting in a white suspension. The solids were filtered off, rinsed with water and air dried to give the title compound as a white solid. Yield = 0.90 g (3.46 mmol, 64%). HPLC (254 nm). Method 3, Rt 2.65 min MS (ESI) mass / charge 224.3 [M + H +].

Step 3. (R) - [2- (6-chloropyridin-3-yl) -2H-pyrazol-3-yl] carbamic acid 1-Phenylethyl ester.

2- (6-chloropyridin-3-yl) -2H-pyrazole-3-carboxylic acid hydrochloride salt [example 56, step 2] (0.90 g, 4.03 mmol) was suspended in toluene (27 ml) and treated with diisopropylethylamine (1.28 ml, 8.86 mmol). The resulting solution was treated with diphenylphosphoryl azide (855 μl, 4.83 mmol) and heated to 65 ° C. (R) -1- (phenyl) ethanol (600 μL, 6.03 mmol) was added to the reaction mixture and the temperature was raised to 105 ° C over 30 minutes, during which time vigorous gas evolution was observed. The reaction mixture was brought to 65 ° C and stirred at this temperature for 4 hours. The reaction was considered complete by HPLC / MS. After cooling, the volatiles were removed in vacuo and the crude residue was purified by chromatography on silica gel eluting with a hexanes / ethyl acetate gradient. The product was isolated as a white solid. Yield = 0.60 g (1.75 mmol, 44%). HPLC (254 nm). Method 3, Rt 3.05 min MS (ESI) mass / charge 343.2 [M + H +].

Step 4. (R) -1- (4- {5- [4-methyl-5- (1-phenylethoxycarbonylamino) pyrazol1-yl] pyridin-2-yl} phenyl) cyclopropanecarboxylic acid methyl ester.

Stirred suspension of 1-phenylethyl ester (R) - [2- (6-chloropyridin-3-yl) -2H

- 102 038294 pyrazol-3-yl] carbamic acid [example 56, step 3] (240 mg, 0.70 mmol) in a mixture of toluene / ethanol 2: 1 v / v. (7 ml), 2M aqueous Na ₂ CO ₃ solution (1.5 ml) and methyl ester 1- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] cyclopropanecarboxylic acid (260 mg, 0.84 mmol) was degassed under nitrogen for 10 min and treated with Pd [Ph ₃ P] ₄ (42 mg, 0.036 mmol). The resulting mixture was immersed in an oil bath with stirring at 90 ° C for 15 h. The reaction mixture was cooled, transferred to a separatory funnel and diluted with ethyl acetate (50 ml). The mixture was carefully treated with 1N. aqueous HCl solution (20 ml). The organic layer was separated, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with a 0-30% hexanes / ethyl acetate gradient with increasing polarity. The product was obtained as a tan solid. Yield = 136 mg (0.28 mmol, 40%). HPLC (254 nm). Method 3, Rt 2.93 min MS (ESI) mass / charge 483.4 [M + H +].

Step 6. (R) -1- (4- {5- [5- (1-Phenylethoxycarbonylamino) pyrazol-1-yl] pyridin-2-yl} phenyl) cyclopropanecarboxylic acid.

A solution of (R) -1- (4- {5- [4-methyl-5- (1-phenylethoxycarbonylamino) nyrazol-1-yl] pyridin-2-yl} phenyl) cyclopropanecarboxylic acid methyl ester (136 mg, 0, 28 mmol) in a THF / water mixture 2: 1 v / v. (3 ml) was treated with 1N. aqueous LiOH solution (420 μl) and stirred at ambient temperature for 16 hours, the Reaction mixture was brought to pH 1 by adding 1N. aqueous HCl solution. The mixture was extracted with EtOAc and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was obtained as an off-white solid, prepared analogously to Step 6 of Example M1 using the following reagents and amounts: methyl ester (R) -1- (4- {5- [5- (1-phenylethoxycarbonylamino) pyrazole-1yl] pyridine- 2-yl} phenyl) cyclopropanecarboxylic acid (136 mg, 0.28 mmol), THF / water 2: 1 v / v. (3 ml), 1N. an aqueous solution of LiOH (420 μl). Yield = 15 mg (0.032 mmol, 11%). HPLC (254 nm). Method 3, Rt 2.93 min MS (ESI) mass / charge 483.3 [M + H +].

Compounds 57-458 from the table. 1 and their derivatives were prepared according to the procedures outlined for compounds 1-56. The heterocyclic amines or esters required for the assembly of the corresponding carbamates were prepared based on the methods described in Literatures 1-24.

Certain substituted isoxazoles are obtained after the formation of the corresponding arylisoxazole (3, Scheme 1). Direct fluorination or bromination and cyanation give aryl bromide (4) or acid (5) after palladium-catalyzed carbonylation.

Scheme 1

5

Acid (5, Scheme 2) can be directly coupled with amines to give amide intermediates (6), which can be converted to carbamate products (7) after acid hydrolysis, Curtius rearrangement, and deprotection with acid. Scheme 2

Acid (5) can be reduced to alcohol (8) and / or converted to its chloride (9) according to Scheme 3. Alcohols can be converted to their ether analogs (10) by rhodium-catalyzed insertion of diazo intermediates ₂ N ⁺ -zR ^B , or amines (11) can be obtained from chlorides (IX).

- 103 038294

Scheme 3

Alternatively, bromides (4) can be directly coupled with alcohols or amines (UV-ZR ^B ), provided U is —OH or —NH2, via heat or metal-catalyzed halogen substitution according to Scheme 4. All key intermediates (10 -12) can be further modified to give the end products described in Scheme 1 by acid hydrolysis, Curtius rearrangement and subsequent deprotection with acid.

Scheme 4

Example 57. Assays of binding to receptors.

The binding affinity of compounds of formula I-XII was determined based on their ability to displace tritiated lysophosphatidic acid ([ ³ H] -LPA) from CHO cells expressing LPA1R according to a protocol similar to that described in Literature 17. In 96-well format, CHO cells expressing human LPA1R [Cerep] were treated with [ ³ H] -LPA (2 nM). Increasing concentrations of test compounds were added to each well and incubated at room temperature for 90 minutes. At this stage, the plates were washed and the radioactivity in the wells was calculated. The results were compared to a control where cells were treated with [ ³ H] -LPA in the presence of 10 µm unlabeled LPA. Specific binding of a ligand to receptors was defined as the difference between total binding and non-specific binding, determined in the presence of an excess of unlabeled ligand. Results were expressed as a percentage of control specific binding ((measured specific binding / control specific binding) x 100) and as percentage inhibition of control specific binding (100 - ((measured specific binding / control specific binding) x 100)) obtained in presence of test compounds. The IC ₅₀ (concentration causing half-maximal inhibition of the control specific binding) and Hill's coefficient (nH) were determined by non-linear regression analysis of the competitive displacement curve plotted from the means for replicates using Hill's equation fit

Y = D + [(A - D) / (1 + (C / C50) nH)], where Y is specific binding, D is minimum specific binding, A is maximum specific binding, C is compound concentration, C50 is IC50 and nH is the slope. This analysis was performed using the software developed at Cerep (Hill software) and the results were confirmed by comparison with data obtained using the commercial software SigmaPlot® 4.0 for Windows® (© 1997 developed by SPSS Inc.). The inhibition constant (Ki) was calculated using the Cheng-Prusoff equation

Ki = IC50 / (1+ (L / KD)), where L is the concentration of the radioligand in the assay, and KD is the affinity of the radioligand for the receptor. The Scatchard plot was used to determine Kd.

Example 58. Analysis of calcium ion flux.

- 104 038294

Inhibition of LPA-stimulated Ca ²⁺ flux was used to assess the activity of compounds using FLIPR technology in 96-well plate format. The assay buffer used was Hanks Modified Balanced Salt Solution (HBSS), where HBSS was supplemented with 20 mM HEPES and 2.5 mM probenecid at pH 7.4 (Millipore, GPCR Profiler®). Cells expressing LPA1R (Millipore) were plated and prepared 24 hours prior to analysis of the test samples. The Ca ²⁺ ion flux was evaluated based on the fluorescence of a fluorescent Ca ⁺ leave-in dye. Antagonist data were obtained from plates with LPA concentrations sufficient to obtain 80% efficacy [EC ₈₀ ]. Percent inhibition was calculated from the decrease in efficacy as a function of the concentration of compounds of formula I-VI. The inhibition data was used to calculate the IC _{50 of the} compounds to determine the dose-response effect.

Agonist analysis was performed on a FLIPR ^{tetra instrument} , where the test (s) compound (s), control inert substances and a reference agonist were added to the assay plate after establishing the baseline fluorescence level. The agonist assay lasted for a total of 180 seconds and was used to assess the ability of each compound to activate each GPCR assay. After completion of the agonist assay, the assay plate was removed from the FLIPR and incubated at 25 ° C for 7 minutes. At the end of the incubation period, the assay plate was placed back in the FLIPR ^tetra and antagonist assay started.

Analysis of antagonists. Using the EC _{80 activity values determined during the agonist assay, a reference agonist at an EC 80} concentration was injected into all wells with pre-incubated samples of compounds after the baseline fluorescence level was established. Antagonist assays were performed using the same assay plate as used for agonist assays. The analysis of antagonists was performed on a FLIPR ^{tetra instrument} , where 9 control inert substances and a reference agonist at a concentration of EC ₈₀ were added to the corresponding wells. The antagonist assay lasted for a total of 180 seconds and was used to assess the ability of each compound to block each GPCR assay.

Data processing. All data from assay plates were subjected to appropriate corrections to baseline. After baseline corrections were applied, maximum fluorescence values were exported and data processed to calculate percent activation (versus Emax for reference agonist and values for inert control), percent inhibition (versus EC ₈₀ and values for inert control), and additional statistics (i.e., Z'-factor, percent variation in data values among different replicates) to assess the quality of data from each plate. If the data from the assay plates were rejected, then additional experiments were performed. All dose response curves were constructed using GraphPad Prism. Curve fitting was performed using a sigmoidal dose-response curve equation (variable slope), where the lower parameter was set to 0. If necessary, the upper parameter was set to 100 to better predict the activity values if a solid curve was not plotted from the analyzed concentrations.

Data on the antagonistic activity of exemplary compounds obtained according to the methods of synthesis disclosed in this document are presented in table. 2.

Table 2. In Vitro Biological Data for Illustrative Compounds of Formulas I-XII

Example number LPA1R antagonistic activity Example number LPA1R antagonistic activity Example number LPA1R antagonistic activity 1 WITH twenty A 37 A 2 WITH 21 A 38 A 3 D 22 A 39 A 4 V 23 A 40 A 5 A 24 A 41 A 6 D 25 A 42 A 7 D 26 A 43 V eight D 27 A 44 A nine D 28 A 45 A ten D 29 WITH 46 WITH

- 105 038294

eleven D thirty D 47 V 12 D thirty C 48 C 13 D 31 A 49 A fourteen D 31 A 50 A 15 D 32 A 51 A 16 D 33 A 52 A 17 A 34 A 53 A eighteen D 35 A 54 V 19 D 36 A 55 V 56 A

Unless otherwise indicated, test compounds in the LPA1R-mediated ^{Ca 2+} _{flux functional assay had an IC 50 of} less than 50 μM.

Unless otherwise indicated, test compounds in the LPA1R-mediated ^{Ca 2+} _{flux functional assay had an IC 50 of} less than 50 μM. A - less than 0.3 μM; B - more than 0.3 μM and less than 1 μM; C - more than 1 μM and less than 50 μM; D - more than 50 μM.

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US2009 / 36450 Al, 2009.

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Claims (18)

CLAIM 1. A compound where the compound has the structure of formula I or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered heteroarene selected from one of the following: where the dotted line indicates the point of attachment of ring A to ring B; ring B is - 107 038294 where A ¹ , A ² and A ³ independently represent -N =, = N-, = CH- or -CH =; ring C is substituted or unsubstituted C ₆ -C ₁₀ -aρylene, substituted or unsubstituted C ₃ -C ₁₀ -cycloalkylene, whereby if ring C is substituted, ring C is substituted with 1, 2 or 3 independently selected R ^H , where R ^{H is} defined below where R ^a is —CO ₂ H; L ¹ is C ₁ -C ₆ alkylene, C ₃ -C ₆ cycloalkylene, C ₁ -C ₆ heteroalkylene, which is an alkylene group having up to 6 skeletal atoms, containing up to 5 carbons and 1-2 heteroatoms selected from oxygen and nitrogen, L ^{2 is} absent; where R ^C is -F, -Cl, -Br, -I, -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl or -CN, and R ^d is -N (R ^F ) C ( = O) XCH (R ^G ) CY, -N (R ^F ) C (= O) XC (R ^G ) 2-CY, where X is -O-; RE is —H, —C ₁ -C ₄ alkyl; RF is —H or C ₁ -C ₄ alkyl; R ^g is independently selected R ^E ; CY is substituted or unsubstituted C ₆ -C ₁₀ aryl, where if CY is substituted, then CY is substituted with 1, 2 or 3 independently selected R ^H , where each RH is independently selected from —H, halogen, —OH, —ORJ, -SRJ, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C ₁ -C ₄ -alkoxy, where RJ is selected from -H or C ₁ -C ₆ -alkyl. 2. The compound according to claim 1, where R ^D represents -N (R ^F ) C (= O) XCH (R ^G ) CY, -N (R ^F ) C (= O) XC (R ^G ) 2CY, where R ^g represent -H or C1-C ₄ -alkyl. 3. A compound according to claim 2, wherein ring B is and where ring A has the structure and ring C is substituted or unsubstituted C ₆ -C ₁₀ arylene or substituted or unsubstituted C ₃ -C ₁₀ cycloalkylene. 4. A compound according to claim 2, wherein L ¹ is C ₁ -C ₄ alkylene or C ₃ cycloalkylene. 5. A compound according to claim 2, wherein L ¹ is —CH ₂ -, or —C (CH ₃ ) ₂ -. 6. A compound according to claim 5, wherein R ^C is —F, —CN, or —CF ₃ and R ^D is —N (R ^F ) C (= O) XCH (R ^G ) CY. 7. The compound according to claim 6, where -X- represents -NH- or -O-; and where R ^G and each RF are independently selected —H or —CH ₃ . 8. A compound according to claim 7, wherein R ^G is —CH ₃ in the R- or S-configuration, and CY is substituted or unsubstituted phenyl, where if CY is substituted, then CY is substituted with 1, 2 or 3 independently selected R ^H. 9. The compound according to claim 8, where RF represents -H; X represents -O-; and R ^D has the structure CH _O O if o Ν '> ⁿ [H, Halogen] 10. The compound according to claim 9, where RF represents-H; X represents -O-; and R ^G is in R configuration. 11. A compound according to claim 1 or 2, wherein ring A is a 5-membered heteroarene having the structure - 108 038294 where R ^d represents -N (R ^F ) C (= O) XCH (R ^G ) CY; X represents -O-; CY is phenyl substituted with one RH; ring C is substituted or unsubstituted C ₆ -arylene, wherein if ring C is substituted, ring C is substituted with 1 RH; R ^a represents -CO2H; where L ¹ represents -CH2-, or C (CH ₃ ) ₂ ; R ^e represents -H or C ₁ -C ₄ -alkyl; RG is -H or -CH3; and RH is —H, halogen, —CH3, or —CF3. 12. A compound according to claim 2, wherein the compound is 2- [4- [4- [5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] acetic acid, ( R) -1- (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -3-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- ( 4 '{5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-fluorodiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (2-chloro-4'- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1 - (4 '- {5- [1 - (2- chlorophenyl) ethoxycarbonylamino] -4fluoropyrazol-1 -yl} -2-methyldiphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1- (4 '- {5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazole -1 -yl} diphenyl-4-yl) cyclopropanecarboxylic acid, (R) -1 {4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl-4-yl} cyclopropanecarboxylic acid, ( R) -1- {2-fluoro-4 '- [5- (1-phenylethoxycarbonylamino) -4-trifluoromethylpyrazol-1-yl] diphenyl4-yl} cyclopropanecarboxylic acid, 1- [4- [4- [4- cyano-5- (1-phenylethoxycarbonylamino) pyrazole-1yl] phenyl] phenyl] cyclopropanecarboxylic acid, 1- [4- [4- [5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4 cyanopyrazol-1 -yl] phenyl] phenyl] cyclopropanecarboxylic acid, 2- [4- [4- [4-cyano-5- (1-phenylethoxycarbonylamino) pyrazol-1-yl] phenyl] phenyl] -2-methylpropanoic acid, 2- [4- [4- [ 5- [1 - (2-chlorophenyl) ethoxycarbonylamino] -4-cyanopyrazol-1-yl] phenyl] phenyl] -2-methylpropanoic acid, 1- {4 '- [4fluoro-5- (1-phenylethoxycarbonylamino) -1H- pyrazol-1-yl] -4-diphenylyl} cyclopropanecarboxylic acid, 1- {3-fluoro-4 '- [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1 -yl] -4-diphenylyl} cyclopropanecarboxylic acid, 1- {2-fluoro-4 '- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -4-diphenylyl} cyclopropanecarboxylic acid, 1 - (4' - {5 - [1 - (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-Spirazol-1 -yl} -2-fluoro-4-diphenylyl) cyclopropanecarboxylic acid, 1- {2-chloro-4 '- [4-fluoro-5 - (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -4-diphenylyl} cyclopropanecarboxylic acid, 1- (4 '- (4fluoro-5 - (((1-phenylethoxy) carbonyl) amino) -1H-pyrazol-1-yl) -2-methyl- [1,1'-biphenyl] -4-yl) cyclopropan1 -carboxylic acid, 1- [p- (5- {5- [1- (o-chlorophenyl) ethoxycarbonylamino] -4-fluoro-1H-pyrazol-1-yl} -2pyridyl) phenyl] cyclopropanecarboxylic acid. 13. A compound according to claim 12, wherein the compound is (R) -1- (4 '- {5- [1- (2-chlorophenyl) ethoxycarbonylamino] -4-fluoropyrazol-1-yl} -2-fluorodiphenyl-4 -yl) cyclopropanecarboxylic acid. 14. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a lysophosphatidic acid-dependent disease or condition. 15. A medicament for treating a subject with a lysophosphatidic acid-dependent disease or condition, comprising a compound according to claim 1. 16. Use according to claim 14, wherein the lysophosphatidic acid-dependent disease or condition is diabetic nephropathy or non-alcoholic steatohepatitis (NASH). 17. The medicament of claim 15, wherein the lysophosphatidic acid-dependent disease or condition is diabetic nephropathy or non-alcoholic steatohepatitis (NASH). 18. A compound according to claim 12, wherein the compound is 1- {4 '- [4-fluoro-5- (1-phenylethoxycarbonylamino) -1H-pyrazol-1-yl] -4-diphenylyl} cyclopropanecarboxylic acid.