Heterocyclic compounds useful in the treatment of diseases

Abstract

To provide a compound which inhibits the physiological activity of lysophosphatidic acid (LPA) and is useful as a medicine for treating or preventing diseases for which the inhibition of the physiological activity of LPA is useful.SOLUTION: Provided are compounds having the structure of Formula 1 or a pharmaceutically acceptable salt or prodrug thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 16 / 010,755, filed June 18, 2018. The benefit of the specification is claimed, and the entire contents of this provisional patent application are incorporated herein by reference. It is cited.

[0002] STATEMENT OF GOVERNMENT RIGHTS This invention is based on the findings of the National Institutes of Health Government support under grant number DK092005 awarded by the National Institute of Health The United States Government has certain rights in this invention.

[0003] The present invention relates to compounds having pharmacological activity, methods for preparing such compounds, and compounds comprising the same. Pharmaceutical compositions and methods for treating and preventing diseases, particularly pain, in subjects in need thereof , and their use for the human and veterinary treatment of pruritus, cancer, inflammation and fibrosis. [Background technology]

[0004] Lysophospholipids play fundamental roles in cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. Affects cellular function. Abnormal function includes, but is not limited to, fibrosis, inflammation, cancer, and peripheral nerve injury. It affects many biological processes that lead to diseases, including but not limited to lysophosphatidylinositol phosphate phosphate (LPP) and lysophosphatidylinositol phosphate phosphate (LPP). LPA acts in an autocrine and paracrine manner on specific G protein-coupled receptors ( It is a lysophospholipid that has been shown to act via the GPCR (LPA receptor). Antagonists are used to treat diseases, disorders or conditions in which LPA is involved.

[0005] Lysophosphatidic acid receptors are thought to decrease signaling. Drugs that interact with the lipoprotein receptor (LPAR) (i.e., by competitive or non-competitive inhibition) or acting as an inverse agonist) reduces the symptoms of the diseases described herein. The progression or persistence of leukemia is mediated by lysophosphatidic acid receptor subtype 1 (LPA1R). Diseases and conditions mediated in whole or in part by signal transmission are LPA-dependent. It is believed that the LPA-dependent and other conditions and diseases described herein can be treated. There is a need for new agents with therapeutic utility for this purpose. Summary of the Invention [Problem to be solved by the invention]

[0006] It inhibits the physiological activity of lysophosphatidic acid (LPA), thereby Compounds useful as drugs for the treatment or prevention of diseases in which inhibition of the inhibitory activity is useful are disclosed herein. is disclosed in the book. [Means for solving the problem]

[0007] In one embodiment, the compounds are used to treat the fibrosis of organs (e.g., liver, kidney, lung, heart, etc.). fibrosis, liver disease (e.g., acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative disorders) (including non-alcoholic steatohepatitis (NASH), severe liver dysfunction, and abnormalities in hepatic blood flow) Cell proliferative disorders such as cancer (including but not limited to solid tumors, solid tumor metastases, vascular fibrosis) Myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), cancer cells inflammatory diseases (including but not limited to psoriasis, nephropathy, pneumonia, etc.) gastrointestinal disorders (including but not limited to irritable bowel syndrome (IBS), inflammation, Inflammatory bowel disease (IBD), abnormal pancreatic secretion, etc.), kidney disease, urinary tract related diseases (limited to the following) Symptoms include, but are not limited to, symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease, spinal cord Tumors, herniated discs, spinal stenosis, symptoms of diabetes, lower urinary tract disease (including but not limited to the following) urinary tract obstruction), inflammatory diseases of the lower urinary tract, However, this includes dysuria, frequent urination, etc.), pancreatic diseases, and diseases related to abnormal angiogenesis (see below). including but not limited to arterial blockages), scleroderma, brain-related diseases (including but not limited to including cerebral infarction, cerebral hemorrhage, etc.), nervous system diseases (including but not limited to neuropathic pain, , peripheral neuropathy, pruritus, etc.), eye diseases (including but not limited to age-related macular degeneration) AMD, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, green It is useful in the treatment of cataracts (including filtration surgery scars).

[0008] The compounds of the present invention are compounds of Formula I having the following structure: [ka] or a pharmaceutically acceptable salt or prodrug thereof (In the formula, R A -CO2H, -CO2R B , -CN, tetrazolyl, -C(=O)N H2, -C(=O)NHR B , -C(=O)NHSO2R B , or -C(=O)NH CH2CH2SO3H or having the following structure: [ka] R Bis an optionally substituted C1-C4 alkyl or one of the following structures: have [ka] ; L 1 is a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C1-C6 fluoroa alkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C1-C6 heptane It is alkylene; where A1 is -N= or -CH; wherein ring A has one of the following structures: [ka] where R C -CN, -F, -Cl, -Br, -I, -OC1 to C4 alkyl, C 3-C6 cycloalkyl, or C1-C4 fluoroalkyl; And R D -N(R F )-C(=O)XCH(R G )-CY, where X is O and CY is one R H is a phenyl substituted with: [ka] ; R E , R F , and R G are independently —H or C1-C4 alkyl or C3-C 6 cycloalkyl, or R E and R F are independently -H or C1 to C4 alkyl alkyl or C1-C6 cycloalkyl, and one R G is -C1-C4 alkyl , KanAR D R in the substituent H Phenyl moiety and RG and the phenyl moiety is attached together with the carbon atom(s) forming a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. demarcate; R H are independently -H, halogen, -CN, -NO2, -OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 alkoxy (It is Shi).

[0009] Other compounds of the present invention are disclosed in accordance with the numbered embodiments and claims herein. It has the structure shown below. DETAILED DESCRIPTION OF THE INVENTION

[0010] definition As used herein and unless otherwise stated or suggested by context, As used herein, terms have the meanings defined below. By including mutually exclusive elements or alternatives within these definitions and throughout this specification, Therefore, unless specifically prohibited or implied, the terms "a" and "an" refer to one or more. and the term "or" means and / or, where the context permits. Therefore, as used in this specification and the appended claims, the singular forms "a," "an," " and "the" include plural referents unless the context clearly dictates otherwise.

[0011] At various points in this disclosure, for example, in any disclosed embodiment or in the claims "comprise" one or more specific components, elements or steps " compounds, compositions, or methods are referred to. Embodiments of the invention relate to those particular components. those compounds which are, consist of, or consist essentially of elements, components, or steps "comprising," "compositions," or "methods" also specifically include "compositions," "compositions," or "methods." "consist of" and "consist essentially of" The term "(ily of)" is used under U.S. patent law unless specifically stated otherwise. The term "comprised of" has its commonly accepted meaning. Used interchangeably with the term "comprising" and described as synonyms For example, disclosed compositions "comprise" components or steps, The devices, products, or methods are open and may be added to those compositions or methods. In addition, the term "component" may be read as including or including further components or steps. The disclosed compositions, devices, articles of manufacture, or methods "consist of" steps is closed and includes significant additional components or steps It does not include, and cannot be read as including, those compositions or methods. The terms "include", "including", The use of "included" and other forms such as "included" is not exclusive. The section headings used herein are for organizational purposes only and are not intended to be limiting unless otherwise specified. Unless otherwise indicated, mass spectrometry, NMR Conventional methods of HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. I can.

[0012] As used herein, a "bond" or "single bond" refers to a bond between two atoms or If the atoms connected by are considered to be part of a larger substructure, then the two substructures When expressly stated or suggested by context, the present specification When the group described in is a bond, the group referred to is absent, thereby leaving the remaining specified A bond is formed between the groups to be bonded.

[0013] As used herein, "membered ring" means any cyclic structure. The term "atom" is intended to indicate the number of skeletal atoms that constitute the ring. Although not limited to the following, the membered rings include 6-membered rings such as cyclohexyl and pyridyl. and five-membered rings such as cyclopentyl, pyrrolyl, furacil, and pyranyl. Examples include aryl, thienyl, and thienyl.

[0014] As used herein, a "moiety" refers to a specific portion, fragment or molecule of a compound. A chemical moiety is a group that is embedded in or attached to a molecule or compound. is sometimes depicted as a chemical moiety (i.e., a substituent or variable) attached to

[0015] As used herein, "alkyl" refers to any group including normal, secondary, tertiary, or cyclic alkyl groups. configuration, i.e., linear, branched, cyclic configuration or some combination thereof, covalently bonded together. The alkyl substituents for the structure are the groups of carbon atoms bonded together. 3 Through carbon Alkyl groups as used herein are chains of carbon atoms covalently bonded to a structure. The alkyl substituents contain one or more saturated moieties or groups and may further contain unsaturated alkyl moieties or groups. i.e., the substituents may contain one, two, three or more independently selected Typically, such unsaturated alkyl groups have double or triple bonds or combinations thereof. When present, the moiety or group may contain one double bond or one triple bond.

[0016] Unsaturated alkyl moieties or groups include alkenyl, alkynyl, cycloalkyl, and aryl. A saturated alkyl moiety includes a saturated carbon atom (sp 3 ) and non-aromatic, sp 2 or sp carbon atoms. The number of offspring may vary, typically from 1 to about 50, e.g., from about 1 to 30 or from about 1 to 50. 20, and unless otherwise specified, e.g., C 1~8 Alkyl or C1-C8 alkyl means an alkyl moiety containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; C 1~6 Alkyl or C1-C6 contains 1, 2, 3, 4, 5 or 6 carbon atoms It means the alkyl moiety.

[0017] Where alkyl substituents, moieties or groups are recited, the species is not limited to methyl, ethyl, 1-propyl, 1-propyl, 1-propyl- ... 2-propyl (n-propyl), 2-propyl (isopropyl, -CH(CH3)2), 1-propyl butyl (n-butyl), 2-methyl-1-propyl (iso-butyl), -CH2CH(CH3 )2), 2-butyl (sec-butyl, -CH(CH3)CH2CH3), 2-methyl- 2-Propyl (t-butyl, -C(CH3)3), amyl, isoamyl, sec-amyl and other linear, cyclic, and branched alkyl moieties. The alkyl group is a cycloalkyl, alkenyl, alkynyl group, aryl group, arylalkynyl group, The alkyl groups may include the species and groups described below for alkyl groups, alkylaryl groups, and the like.

[0018] Cycloalkyl, as used herein, refers to a single ring consisting only of carbon atoms. The term "cycloalkyl" refers to a monocyclic or polycyclic ring system. Aliphatic, non-aromatic groups are included, where the atoms forming the ring (i.e., the skeletal atoms) are The number of carbon atoms in a cycloalkyl substituent, moiety, or group may vary. Typically, it is 3 to about 50, for example, about 1 to 30 or about 1 to 20, and particularly Unless otherwise stated, e.g., C 3~8 Alkyl or C3-C8 alkyl is 3, 4, 5, means a cycloalkyl substituent, moiety or group containing 6, 7 or 8 carbon atoms, C3 ~6 Alkyl or C3-C6 is cycloalkyl containing 3, 4, 5 or 6 carbon atoms. Cycloalkyl substituents, moieties or groups are typically 3-substituted or 4-substituted cycloalkyl groups. , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, having 19 or 20 carbon atoms and an exocyclic or endocyclic double bond or an endocyclic triple bond or both wherein the endocyclic double or triple bond, or a combination of both, does not form a cyclic conjugated system of 4n+2 electrons; where a bicyclic ring system is one (i.e. i.e., spirocyclic ring systems) or two carbon atoms in common, and tricyclic ring systems may have a total of 2, 3 or may share up to four carbon atoms, typically two or three.

[0019] Unless otherwise stated, cycloalkyl substituents, moieties or groups may also be substituted with alkenyl, alkynyl, The moieties and groups described for alkyl, aryl, arylalkyl, alkylaryl, etc. and may contain one or more other cycloalkyl moieties. Thus, cycloalkyl can be saturated or partially unsaturated. A cycloalkyl group may be fused to a ring, and the point of attachment to the aromatic ring is not at an aromatic ring carbon atom. A cycloalkyl group is a group having 3 to 10 ring atoms. Cycloalkyl substituents, moieties or groups include cyclopropyl, cyclopentyl, This includes butyl, cyclohexyl, adamantyl, or any other cyclic carbon-containing moiety. Cycloalkyl includes cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptyl, and Cycloalkyl groups may be substituted or unsubstituted. Depending on the structure of the group, a cycloalkyl substituent may be a monoradical or a diradical (i.e., Examples include, but are not limited to, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl yl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cyclohexyl cycloalkylenes such as cyclohexan-1,4-diyl, cycloheptan-1,1-diyl, etc. The cycloalkyl may be a Markush group (i.e. When used as a substituent, cycloalkyl is a cycloalkyl group that is not an aromatic carbon. The Markush formula (Ma) is a compound that is connected through a carbon atom contained in the carbocyclic ring system of the aryl group. rkush formula).

[0020] As used herein, an "alkylamine" refers to an -N(alkyl) x H y base, means a moiety or substituent, where x and y are independently the groups x=1, y=1 and x=2; , y=O. Alkylamines are those in which -N(alkyl) x H y containing a group , where x=2 and y=0, and the alkyl groups together with the nitrogen atom to which they are attached to form a cyclic ring system.

[0021] As used herein, "heteroalkylene" refers to one or more heteroalkyl groups of alkyl. The backbone atoms are atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. means a selected alkylene (i.e., alkanediyl) group, moiety, or substituent. Heteroalkylene includes C1-C6 heteroalkylene or C1-C4 heteroalkylene. Exemplary heteroalkylenes include, but are not limited to, -OCH2-, -OC H(CH3)-, -OC(CH3)2-, -OCH2CH2-, -CH2O-, -CH( CH3)O-, C(CH3)2O-, -CH2CH2O-, -CH2OCH2-, -CH 2OCH2CH2-, -CH2CH2OCH2-, -SCH2-, -SCH(CH3)- , -SC(CH3)2-, -SCH2CH2-, -CH2S-, -CH(CH3)S-, -C(CH3)2S-, -CH2CH2S-, -CH2SCH2-, -CH2SCH2C H2-, -CH2CH2SCH2-, -S(=O)2CH2-, -S(=O)2CH(C H3)-, -S(=O)2C(CH3)2-, -S(=O)2CH2CH2-, -CH2 S(=O)2-, -CH(CH3)S(=O)2-, -C(CH3)2S(=O)2-, -CH2CH2S(=O)2-, -CH2S(=O)2CH2-, -CH2S(=O)2 CH2CH2-, CH2CH2S(=O)2CH2-, -NHCH2-, -NHCH(C H3)-, -NHC(CH3)2-, -NHCH2CH2-, -CH2NH-, -CH( CH3)NH-, -C(CH3)2NH-, -CH2CH2NH-, -CH2NHCH2 -, -CH2NHCH2CH2-, -CH2CH2NHCH2-, etc.

[0022] As used herein, "carboxylic acid bioisosters" e)" is a functional group that exhibits physical, biological and / or chemical properties similar to the carboxylic acid moiety , moiety or substituent. Examples include, but are not limited to, carboxylic acid biological Equivalents include the following: [ka]

[0023] As used herein, "alkenyl" refers to an alkyl group having one or more double bond moieties (e.g., For example, -CH=CH-) or 1, 2, 3, 4, 5 or 6 or more, typically 1, It may contain two or three such moieties and may include an aryl moiety or group such as benzene. Unless the alkenyl moiety is a vinyl moiety (e.g., -CH=CH2), the bonded and the like, i.e., linear, branched, cyclic or branched carbon atoms. The term "substituted group," "moiety," or "group" refers to a group having multiple double bonds, including any combination thereof. The alkenyl moiety, group, or substituent is an alkyl group having a cyclic adjacent arrangement of double bonds of 4n+2 electrons. Unless the cyclic conjugated system (i.e., aromatic) of adjacent to a butadienyl carbon atom or a combination thereof (i.e., a 1,3 butadienyl moiety) The double bonds may be spaced apart from one another. The number can vary, typically from 2 to about 50, e.g., from about 2 to 30 or from about 2 to 20. Unless otherwise stated, for example, C 2~8 Alkenyl or C2-8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2 ~6 Alkenyl or C2-6 alkenyl contains 2, 3, 4, 5 or 6 carbon atoms. The alkenyl moiety or group typically has 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 It has carbon atoms.

[0024] Where an alkenyl moiety, group, or substituent is recited, the chemical species may include, by way of example and not limitation, alkyl or cycloalkyl groups as described herein that do not contain one or more double bonds; Alkyl, group, moiety or substituent, methylene (=CH2), methylmethylene (=CH-CH 3), ethyl methylene (=CH-CH2-CH3), =CH-CH2-CH2-CH3, Vinyl (-CH=CH2), allyl, 1-methylvinyl, butenyl, isobutenyl, 3 -methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl hexenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl and at least one di- Any of the other linear, cyclic and branched carbon-containing moieties containing double bonds. When alkenyl is used as a Markush group (i.e., a substituent), it is Unless otherwise specified, the alkenyl moiety or group is substituted through the unsaturated carbon of the double bond. These are linked in a Markush manner.

[0025] As used herein, "alkynyl" refers to an alkyl group having one or more triple bond moieties (including i.e., -C≡C-), e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or two triple bonds, and optionally one, two, three, four, five, six or more double bonds and the remaining bond (if any) is a single bond, and the alkynyl moiety is not ethynyl. As long as the bonded normal, secondary, tertiary or cyclic carbon atoms, i.e., straight-chain, branched Alkenyl means a substituent, moiety, or group that is linear, cyclic, or any combination thereof. The number of carbon atoms in the alkyl moiety or group can vary and is typically from 2 to about 50, e.g. , about 2 to 30 or about 2 to 20, unless otherwise specified, for example, C 2~8 Alkini C2-8 alkynyl is an alkynyl containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The alkynyl moiety is typically an alkynyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 3 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms It has.

[0026] When an alkynyl moiety or group is recited, the chemical species includes, by way of example and not limitation, is an alkyl moiety, group or substituent as described herein having one or more double bonds , ethynyl, propynyl, butynyl, iso-butynyl, 3-methyl-2-butynyl, 1- Pentynyl, cyclopentynyl, 1-methyl-cyclopentynyl, 1-hexynyl, 3- hexynyl, cyclohexynyl and other linear alkyl groups containing at least one triple bond; It includes all carbon-containing moieties, both cyclic and branched. When used as a group (i.e., a substituent), alkynyl refers to the unsaturation of the alkynyl functional group. It is bonded in a Markush fashion via one of the carbon atoms to which it is associated.

[0027] As used herein, "aromatic" refers to a delocalized aromatic ring containing 4n+2π electrons. Aromatic rings are those with 5, 6, 7 or 8 carbon atoms. Aromatic groups can be formed from 8, 9, 10, or 11 or more atoms. Aromatic groups can be optionally substituted. The term "aromatic" refers to aryl carboxylic acids ("aryl", e.g., phenyl) and and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridinium ... The term includes both monocyclic and fused-ring polycyclic (i.e., rings in which adjacent carbon atoms are bonded together). This includes groups sharing a pair of rings.

[0028] As used herein, "aryl" refers to an alkyl group having 1, 2, 3, or 4 to 6 rings, typically Typically, 1 to 3 rings (where the rings consist only of carbon atoms) containing ring heteroatoms. means an aromatic or fused ring system that does not have 4n+2 electrons (Hückel's rule), typically refers to a cyclically conjugated system of 6, 10, or 14 electrons, some of which are exocyclic (cross-conjugated systems (e.g., quinones). The aryl substituent, moiety, or group may further include Typically formed by 5, 6, 7, 8, 9, or 10 or more carbon atoms. The aryl substituent, moiety or group is optionally substituted. Exemplary aryls include phenyl and C6-C such as naphthalenyl and phenanthryl 10 Depending on the structure, Thus, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Exemplary arylenes include, but are not limited to, phenyl-1,2-ene ... phenyl-1,3-ene and phenyl-1,4-ene. When used as a group (i.e., a substituent), aryl refers to the aromatic group of the aryl group. It is bonded in a Markush manner via the carbon to which it is attached.

[0029] As used herein, "arylalkyl" refers to a group in which the aryl moiety is an alkyl moiety. means a substituent, moiety or group attached to a group, i.e., -alkyl-aryl, wherein , alkyl and aryl groups are as described above, for example, —CH 2 —C 6 H 5 or -CH2CH(CH3)-C6H5. Arylalkyl is a Markush group (i.e. When used as an aryl group (i.e., a substituent), the alkyl portion of the arylalkyl is Minutes of sp 3 It is bonded in a Markush manner via the carbon to which it is attached.

[0030] As used herein, "alkylaryl" refers to a group in which an alkyl moiety is substituted with an aryl moiety. means a substituent, moiety or group attached to a group, i.e., -aryl-alkyl, wherein , aryl and alkyl groups are as described above, for example, —C6H4—CH3 or -C6H4-CH2CH(CH3). Alkylaryl is a Markush group (i.e. When used as a substituent, the aryl portion of the alkylaryl is Minutes of sp 2 It is bonded in a Markush manner via the carbon to which it is attached.

[0031] As used herein, "substituted alkyl," "substituted cycloalkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkylaryl," "substituted arylalkyl ", "substituted heterocycle", "substituted aryl" and the like are not limited to alkyl, alkenyl, alkynyl, aliphatic, cyclic ... alkylaryl, arylalkyl heterocycle, aryl, or a substituent or is any other group defined or disclosed herein having a substituent that interrupts the carbon atom chain or Alkenyl and alkynyl groups containing substituents are removed from the double bond. One or more methylene moieties are optionally substituted at the carbon.

[0032] As used herein, "optionally substituted alkyl" and "optionally substituted alkenyl," "optionally substituted alkynyl," "optionally substituted alkylaryl ", "optionally substituted arylalkyl", "optionally substituted heterocycle", "optionally substituted "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted alkyl "Optionally substituted heteroarylalkyl" and the like are alkyl, Alkenyl, alkynyl, alkylaryl, arylalkylheterocycle, aryl, heterocyclic aryl, alkylheteroaryl, heteroarylalkyl, or a hydrogen atom optionally As defined or disclosed herein having substituents that substitute or interrupt the carbon atom chain Such substituents are defined as those described herein. In the case of a phenyl moiety, the arrangement of any two substituents present on the aromatic ring is It can be ortho (o), meta (m), or para (p). The alkyl group is an alkyl or cycloalkyl moiety, typically a linear alkyl group, where 1 One or more hydrogen atoms are substituted with fluorine and at least one other atom other than carbon and fluorine. is replaced by

[0033] Optionally substituted or substituted substituents, moieties or groups include alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, Alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl Sulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl , fluoroalkoxy, and amino (including mono- and di-substituted amino groups), and their protective groups. and one or more substituents replacing the hydrogen atoms thereof, each selected individually and independently from the protected derivatives. Examples include, but are not limited to, optional substituents such as: may be a halide, -CN, -NO2, or LsRs, where each Ls is Independently, bonds: -O-, -C(=O)-, -C(=O)O-, -S-, -S(=O) -, -S(=O)2-, -NH-, -NHC(=O)-, -C(=O)NH-, S(=O )2NH-, -NHS(=O)2, -OC(=O)NH-, -NHC(=O)O-, or -(C1-C6 alkylene)-; each Rs is selected from -H, alkyl, fluoroalkyl alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo The protecting groups that can form protective derivatives of the above substituents are selected from the group consisting of Gr alkyl, ... Optional substituents include halo, Gen, -CN, -NH2, -OH, -N(CH3)2, alkyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl Alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl and selected from the group consisting of alkyl sulfoxides, alkyl sulfones, and aryl sulfones. Halogen, -CN, -NH2, -OH, NH(CH3), -N(CH3)2, -C O2H, -CO2 alkyl, -C(=O)NH2, -C(=O)NH alkyl, -C(= O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S (=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroaromatic alkyl, alkoxy, fluoroalkoxy, -S-alkyl and -S(=0)2 alkyl or halogen, —CN, —NH2, —OH, —NH(CH 3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -O CF3. Typically, optionally substituted, substituted The group, moiety or radical may be one or two of the above groups, or more typically, a group of the above groups. Aliphatic carbon atoms (excluding aromatic carbon atoms, acyclic or cyclic, saturated) are substituted with one of the following: or unsaturated carbon atom) further includes oxo (=O).

[0034] As used herein, "heterocycle" or "heterocyclic" refers to a ring system comprising carbon atoms. One or more of the atoms, typically 1, 2 or 3, but not all, carbon atoms is an atom other than carbon, typically N, O or S, including N, O, S, Se, B, Si, P and wherein two or more heteroatoms are The heteroatoms in may be adjacent to each other or may be separated by one or more carbon atoms, typically They may be separated by 1 to 17 carbon atoms, 1 to 7 atoms, or 1 to 3 atoms. Heterocycles include heteroaromatic rings (also known as heteroaryls) and 1 to 4 heterocyclic rings. Heterocycloalkyl rings (also known as heteroalicyclic groups) containing heteroatoms of wherein each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group is It has 4 to 10 atoms in its ring system, provided that no ring has two adjacent O or S atoms. Contains no atoms.

[0035] Non-aromatic heterocycles, substituents, moieties, or groups (also known as heterocycloalkyls) have at least 3 atoms in their ring system, and aromatic heterocyclic groups have at least 1 atom in their ring system. and benzo-fused ring systems. Examples of heterocyclic rings having one or more atoms include aziridinyl, azetidinyl, thiazolyl, and pyridine. Non-aromatic heterocyclic substituents, moieties or groups include pyrrolidinyl and lysyl. tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinyl tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl nyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, Azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridine pyrinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4 H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, di Thiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl , imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3 Azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocycles include, but are not limited to, pyridinyl, imidazolyl, Pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl nyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl Indolyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, iso Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl , benzofurazanyl, benzo-thiophenyl, benzothiazolyl, benzoxazolyl, Quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl Non-aromatic heterocycles include one or two oxo (=O) moieties. It may be substituted and includes pyrrolidin-2-one.

[0036] When a heterocycle is used as a Markush group (i.e., a substituent), the heterocycle is is bonded to the Markush formula to which it is attached via a carbon or heteroatom of the heterocyclic ring, Such arrangements may be used to avoid unstable or unacceptable formates of the corresponding carbon or heteroatom. C-bonded heterocycles are bonded to the molecule through a carbon atom and do not form a -( CH2) n -heterocycle (where n is 1, 2 or 3) or -C<heterocycle (where N-linked heterocycles include moieties such as -N< A bond, sometimes represented as a heterocycle (where N< represents a nitrogen atom in the heterocycle). Therefore, the nitrogen-containing heterocycle is a C-bonded or may be N-linked, such as pyrrol-1-yl (N-linked) or pyrrol-3-yl The pyrrole substituent may be aryl (C-linked), imidazol-1-yl or imidazole imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl Imidazole substituents which can be 5-yl or imidazol-5-yl (all C-linked) Includes:

[0037] As used herein, "heteroaryl" refers to a heteroaryl group consisting of carbon atoms in an aryl ring system. One or more of the atoms, typically 1, 2 or 3, but not all, carbon atoms Heteroatoms are atoms other than carbon, typically including N, O, S, Se, B, Si, and P. to oxygen (-O-), nitrogen (-NX-) or sulfur (-S-) (where X is -H, protected group or C 1~6 and optionally substituted alkyl of the formula wherein the heteroatom is bonded to an adjacent atom in the ring system through a π bond or at the heteroatom. The electrons in the 1-carbon atom are involved in the conjugated system through the lone pair of electrons in the 1-carbon atom, and the 1-carbon atom maintains the cyclic conjugated system. They may be optionally substituted at one or more carbon or heteroatoms, or a combination of both.

[0038] Heterocycles and heteroaryls include, by way of example and not limitation, Paque tte,Leo A.;“Principles of Modern Heteroc yclic Chemistry”(WABenjamin,New York,1 968), especially chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds,A series of Mono "Graphs" (John Wiley & Sons, New York, 1950) (founded in 1949), especially volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. c. 1960, 82:5545-5473, in particular 5566-5573) Examples of heteroaryl include the following: Examples include, but are not limited to, pyridyl, thiazolyl, pyrimidinyl, furanyl, thienyl, pyrrolidinyl, and pyrrolidinyl. pyrazolyl, purinyl, imidazolyl, benzofuranyl, indolyl, isoindolinyl quinolinyl, isoquinolinyl, benzimidazolyl, pyridazinyl, pyrazinyl, benzimidazolyl Benzothiopyran, benzotriazine, isoxazolyl, pyrazolopyrimidinyl, quinoxazone Examples include salinyl, thiadiazolyl, and triazolyl. Examples of rings include, but are not limited to, tetrahydrothiophenyl, tetrahydrophenyl, Drofuranyl, indolenyl, piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, tetra Hydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroquinolinyl Isoquinolinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, imidazoline dinyl, imidazolinyl, pyrazolidinyl, piperazinyl, quinuclidinyl, morpholinyl Examples include oxazolidinyl and oxazolidinyl.

[0039] Other heteroaryls include, by way of example and not limitation, the following moieties: Can be: [ka]

[0040] Monocyclic heteroaryls include, by way of example and not limitation, pyridinyl, iridinyl, cyclohex ... Midazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, aryl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazinyl Heteroaryl includes aryls having 0 to 3 N atoms, 1 to 3 N atoms, or 0 to 3 N atoms. and 0-1 O atoms and 0-1 S atoms. Heteroaryls can be monocyclic or bicyclic. The ring systems of heteroaryl rings are typically and aryls containing 1 to 9 carbons (i.e., C1-C9 heteroaryls). The aryl includes C1-C5 heteroaryl. Examples of heteroaryl include those having 5- or 6-membered ring systems. Bicyclic heteroaryls include C Depending on the structure, heteroaryl groups may be mono- or di-substituted. The radical may be a aryl or diradical (ie, a heteroarylene group).

[0041] As used herein, "heterocycloalkyl" or "heteroalicyclic" refers to At least one carbon of the cycloalkyl chain is selected from the group consisting of nitrogen, oxygen, and sulfur. means a cycloalkyl group, moiety or substituent substituted with a heteroatom. A chloroalkyl may be fused with an aryl or heteroaryl. Also called a non-aromatic heterocycle. Examples of heterocycloalkyl include, but are not limited to: Some examples include: [ka]

[0042] Heterocycloalkyl includes, by way of example and not limitation, oxazolidinone, yl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyr thiazolinyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, Heteroalicyclic includes, but is not limited to, perazinyl, and indolinyl. It further includes all ring forms of carbohydrates, including monosaccharides, disaccharides and oligosaccharides. , heterocycloalkyl is C2-C 10 Heterocycloalkyl, C4-C 10 F Heterocycloalkyl includes 0-2 N atoms, 0-2 O atoms, It may contain 0 to 1 S atoms.

[0043] As used herein, "heteroarylalkyl" refers to a heteroaryl moiety is attached to an alkyl moiety, i.e., -alkyl-heteroaryl Heteroaryl means alkyl, heteroaryl, or heteroaryl groups, where alkyl and heteroaryl groups are as defined above. When arylalkyl is used as a Markush group (i.e., a substituent), The alkyl portion of the arylalkyl is sp 3 It is connected via carbon are combined in a Markush fashion.

[0044] As used herein, "alkylheteroaryl" refers to a heteroaryl moiety is attached to an alkyl moiety, i.e., -heteroaryl-alkyl wherein the heteroaryl and alkyl groups are as defined above. When arylalkyl is used as a Markush group (i.e., a substituent), The heteroaryl portion of the heteroarylalkyl is sp 2 carbon or heteroatom It is connected to the Markush formula to which it is associated via

[0045] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine or means iodine.

[0046] As used herein, a "haloalkyl" refers to a group in which one of its hydrogen atoms or alkyl groups, each of which is substituted with one or more independently selected halide atoms; Haloalkyl means a substituent, moiety, or group. Haloalkyl includes C1-C4 haloalkyl. Exemplary, but non-limiting, C1-C4 haloalkyl include -CH2Cl, CH2Br, - -CH2I, -CHBrCl, -CHCl-CH2Cl and -CHCl-CH2I.

[0047] As used herein, "haloalkylene" refers to an alkyl group in which one or more hydrogen atoms are means an alkylene substituent, moiety, or group substituted with one or more halide atoms The haloalkylene may be C1-C6 haloalkylene or C1-C4 haloalkylene. Examples include:

[0048] As used herein, "fluoroalkyl" refers to a group in which one or more hydrogen atoms are Fluoroalkyl means alkyl substituted with a fluorine atom. and C1-C4 fluoroalkyl. Examples, but not limited to, fluoroalkyl Examples include -CH3F, -CH2F2, and -CF3, and perfluoroalkyl. do.

[0049] As used herein, "fluoroalkylene" refers to a group containing one or more hydrogen atoms. The fluoroalkylene group includes alkylene groups substituted with fluorine atoms. 1 to C6 fluoroalkylene or C1 to C4 fluoroalkylene.

[0050] The term "heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms is other than carbon. atoms, such as alkyl groups selected from oxygen, nitrogen, sulfur, phosphorus, or combinations thereof; In one aspect, heteroalkyl is C1-C6 heteroalkyl.

[0051] As used herein, a "protecting group" refers to a group that protects the functionality of the atom or functional group to which it is attached. means a moiety that prevents or reduces forces from participating in an undesired reaction. In the example, -OR PR In the case of R PR is a protecting group for the oxygen found in hydroxyls On the other hand, -C(O)-OR PR In the case of R PR may be a carboxylic acid protecting group; -SR PR In the case of R PR may be a protecting group for the sulfur in a thiol, and NHR PR or -N(R PR )2-, R PR At least one of the following is first-class or is a nitrogen atom protecting group for secondary amines. Reactive groups may require protection from reactions occurring elsewhere in the molecule. Oxygen, sulfur, or nitrogen Protecting groups for atoms are usually used to prevent undesired reactions with electrophilic compounds, such as acylating agents. Typical protecting groups for atoms or functional groups are described in Greene (1999) ),“Protective groups in organic synthesis is,3 rd ed.”, presented in Wiley Interscience.

[0052] As used herein, an "ester" refers to an ester having the structure -C(O)-O- (i.e., ester functionality), where the carbon atoms of the structure are It is not directly bonded to another heteroatom, but is directly bonded to —H or another carbon atom. The ester may be a carboxylic acid having 1 to 50 carbon atoms, 1 to 20 carbon atoms, or 1 to 8 carbon atoms and 0 to 10 independently selected heteroatoms (e.g., O, S, N, P, Si), typically and wherein the organic moiety is a -C (O)-O- structure, containing an ester moiety such as the organic moiety -C(O)-O- The organic moiety is typically an organic group as described herein, e.g., C 1~20 Alkyl moiety , C 2~20 Alkenyl moiety, C 2~20 Alkynyl moiety, aryl moiety, C 3~8 complex A ring or any of these substituents containing, for example, 1, 2, 3, 4 or more substituents The substituents include any one or more of the following substituents, where each substituent is independently selected: Exemplary, non-limiting substitutions of hydrogen or carbon atoms in these organic groups include substituted alkyl and other are as described above for the substitution moieties of and are independently selected. Typically, substituents that can be used to replace one or more carbon atoms, such as For example, -O- or -C(O)-, or used to replace one or more hydrogen atoms. Exemplary esters include: Examples include, but are not limited to, one or more independently selected acetate esters. Ester, propionate ester, isopropionate ester, isobutyrate ester, butyrate ester ester, valerate ester, isovalerate ester, caproate ester, isocaproate ester esters, hexanoates, heptanoates, octanoates, phenylacetates The ester may be a Markush group (i.e., a substituent group) or a benzoate ester. When used as a substituent, the single-bonded oxygen of the ester functional group is are combined in a Markush fashion.

[0053] As used herein, "acetal," "thioacetal," and "ketal" "thioketal" and the like include a carbon atom to which two of the same or different heteroatoms are attached. means a moiety, group, or substituent consisting of or comprising: In the case of acetals, the carbon is connected to two bonded oxygen atoms, a hydrogen atom, and an S and O atom. In the case of a ketal, the carbon has two bonded oxygen atoms and two wherein the organic moiety is as described herein. and is an alkyl or optionally substituted alkyl group. Thioacetals and thioketa In the case of acetals or ketals, one or both of the oxygen atoms in each acetal or ketal is a sulfur atom. The oxygen or sulfur atoms in the ketals and thioketals are substituted with optionally substituted alkyl groups. Typically, the alkyl moiety is -C(CH3) 2-, -CH(CH3)-, -CH2-, -CH2-CH2-, -C[(C2-C4 Al Kill)2] 1、2、3 - or -[CH(C2-C4 alkyl)] 1、2、3 - and other C is replaced by 1~8 alkyl or branched alkyl structures. Some of these can act as protecting groups for aldehydes or ketones, for example: including, but not limited to, acetals in the case of aldehydes and ketals in the case of ketones; -O-CH2-CH2-CH2-O- or - which forms a spiro ring together with the carbonyl carbon Contains an O-CH2-CH2-O- moiety, which can be removed by chemical synthetic methods or Or it may be eliminated by metabolism in body fluids.

[0054] As used herein, an "ether" refers to one, two, three, four or more - O- means an organic moiety, group or substituent comprising or consisting of a moiety, usually one or two , where the two -O- moieties are not directly adjacent to (i.e., not directly linked to) each other. Typically, the ether has 1 to 50 carbon atoms, 1 to 20 carbon atoms, or 1 to 8 carbon atoms. carbon atoms and 0 to 10 independently selected heteroatoms (e.g., O, S, N, P, S i), typically containing 0 to 2 organic moieties, groups or substituents, containing an organic moiety -O-, where the organic moiety is an alkyl or optionally substituted alkyl group The ether is as described herein for a Markush group (i.e., When used as a substituent, the oxygen of the ether functional group is When an ether is used as a substituent in a Markush group, it is This is sometimes referred to as an "alkoxy" group. Examples of alkoxy include: Examples include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and butoxy. Examples of C1-C4 ether substituents include ethers (excluding ketals). or a substituent, moiety or group containing multiple -OCH2CH2O- moieties in succession (i.e. The polymer further comprises a polyethylene or PEG moiety.

[0055] As used herein, "carbonate" refers to a compound having the structure -OC(=O)-O- ( It refers to a substituent, moiety, or group that contains a carbonate functionality. As used herein, a carbonate group is a group formed via the structure -OC(=O)-O-. 1 to 50 carbon atoms, 1 to 20 carbon atoms, or 1 to 8 carbon atoms and and 0 to 10 independently selected heteroatoms (e.g., O, S, N, P, Si), typically Typically, the organic moiety contains 0 to 2, for example, the organic moiety -OC(=O)-O- consists of it. Carbonate is used as the Markush group (i.e., substituent). When the carbonate functional group is attached, one of the single-bonded oxygen atoms of the carbonate functional group is attached to the are combined in a Markush fashion.

[0056] As used herein, "carbamate" or "urethane" refers to a -OC(= O)N(R PR )-, -OC(=O)N(R PR )2, -OC(=O)NH(optionally -OC(=O)N(optionally substituted alkyl) or -OC(=O)N(optionally substituted alkyl)2- structure means a substituent, moiety, or group containing (i.e., a carbamate functionality), where R P R and optionally substituted alkyl are independently selected; R PRBut independently, -H, E Protecting groups or organic moieties described for esters, alkyls, or optionally substituted alkyls Typically, a carbamate group as used herein is —OC(═O )-NR PR - Approximately 1 to 50 carbon atoms, 1 to 20 carbon atoms, bonded through a structure or 1 to 8 carbon atoms and 0 to 10 independently selected heteroatoms (e.g., O , S, N, P, Si), typically containing 0 to 2 organic moieties, e.g., the organic moiety -O -C(=O)-NR PR - or -OC(=O)-NR PR -containing or containing organic moieties When a carbamate is used as a Markush group (i.e., a substituent), The single bonded oxygen (O-bonded) or nitrogen (N-bonded) of the carbamate functional group , it is bonded to the Markush formula to which it is associated. The bond of the carbamate substituent is clearly as stated (N- or O-attached) or suggested in the context in which this substituent is mentioned. will be done.

[0057] For any substituent group or moiety represented by a given range of carbon atoms, the A range in this context means that any individual number of carbon atoms is recited. Thus, for example, "C1-C4 optionally substituted alkyl", "C2-6 alkenyl optionally substituted References to "C3-C8 optionally substituted alkenyl" and "C3-C8 optionally substituted heterocycle" are as defined herein. There is an optionally substituted alkyl moiety of 1, 2, 3 or 4 carbons, or , alkenyl of 3, 4, 5 or 6 carbons, or 3, 4, 5, 6, 7 or 8 including heterocycles the presence of an optionally substituted alkenyl moiety as defined herein; All such designations expressly disclose all of the individual carbon atom radicals. is clearly intended, and therefore "C1-C4 optionally substituted alkyl" is, e.g. For example, 3-carbon alkyl, 4-carbon substituted alkyl and 4-carbon alkyl (including all positional isomers). The carbon atoms in a given range may be disclosed, explicitly shown, or specified, including, but not limited to, aryl, aryls ... For esters, carbonates and carbamates defined by contains the carbonyl carbon of each functional group. Therefore, the C1 ester is a formate ester. C2 ester refers to an acetate ester. The moieties and groups, as well as any other moieties described herein, typically have labile moieties. and a compound having sufficient chemical stability for one or more of the uses described herein. Exclude unstable moieties unless they are transient species that can be used to create them. Substituents, moieties, or groups that result from the manipulation of the definitions herein to have a pentavalent carbon are: Specifically excluded.

[0058] As used herein, the terms "LPA-dependent," "LPA-mediated," or similar The etiology, progression or persistence of which may be due to, for example but not limited to, lysophosphatidic acid One or more lysophosphatidic acid receptors, including receptor subtypes 1-6 (LPAR) A disease or condition caused in whole or in part by signaling through a subtype LPA-dependent or LPA-mediated diseases and conditions include, but are not limited to: However, fibrosis of organs (e.g., liver, kidney, lung, heart, etc.), liver disease (e.g., acute liver Inflammation, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative disorders, nonalcoholic steatohepatitis (NASH, severe liver dysfunction, abnormal liver blood flow, etc.), cell proliferative disorders (e.g., These include, but are not limited to, solid tumors, solid tumor metastases, angiofibromas, myeloma, multiple myeloma, and cancer. Cancers including leukemia, chronic lymphocytic leukemia (CLL), and invasive metastasis of cancer cells , inflammatory diseases (e.g., psoriasis, nephropathy, pneumonia, etc.), gastrointestinal diseases (e.g., irritable bowel syndrome, (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, etc.), kidney disease, urinary tract related disease ( symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease), spinal tumors, and intervertebral disc lunia, spinal stenosis, symptoms of diabetes, lower urinary tract disease (e.g., lower urinary tract obstruction, etc.) , inflammatory diseases of the lower urinary tract (e.g., dysuria, frequent urination, etc.), pancreatic diseases, and abnormal angiogenesis Related diseases (e.g., arterial occlusion), scleroderma, brain-related diseases (e.g., cerebral infarction, cerebral hemorrhage) etc.), nervous system diseases (e.g., neuropathic pain, peripheral neuropathy, pruritus, etc.), eye diseases (e.g., For example, age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), Examples include cicatricial pemphigoid, glaucoma filtration surgery scars, etc.

[0059] As used herein, an "LPA1R-selective agent" refers to an LPA1R-selective compound. "Compound" and similar terms refer to a compound that binds to lysophosphatidic acid receptors 2-6 in preference to lysophosphatidic acid receptors 2-6. It refers to a drug or compound that interacts with the thymic acid subtype 1 receptor. Priority is determined by experiment. D relative to other known LPARs as measured by This is reflected in the drug's binding affinity to LPA1R, which is 10-fold stronger than that of the agonist.

[0060] As used herein, a "pharmaceutically acceptable formulation" refers to one or more pharmaceutical In addition to a commercially acceptable excipient, the compound contains an active pharmaceutical ingredient, such as a compound represented by formula I-VI. or a composition comprising an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients. refers to a composition prepared from a subject, such as a human or animal, in need thereof. Suitable for administration to a subject. Pharmaceutically acceptable formulations are suitable for administration to humans. In addition, the formulations may contain a biologically active agent for treating or preventing a disease or condition disclosed herein. or the formulation must have a desired activity "for the purpose of treating" a disease or condition. Typically, there must be a prospect of treating a disease or condition. " is a lysophosphatidic acid receptor-mediated condition or disease. More typically, a therapeutic or The disease or condition to be prevented is a lysophosphatidic acid type 1 receptor A pharmaceutically acceptable formulation suitable for administration to an animal is a vector-borne disease or condition. The compounds of Formulas I-XII do not necessarily have to have biological activity to treat or prevent a condition. To evaluate the potential pharmacological or biological activity of a substance, it may be administered to animals. Thus, these formulations can be used to treat the diseases or conditions disclosed herein in an animal in need thereof. or the pharmacological or biological properties of the compounds of formulae I to XII. Suitable for use in in vitro assays only. Compositions containing vehicles, ingredients, or excipients in amounts that are unacceptable in pharmaceutical products , are specifically excluded from the definition of a pharmaceutically acceptable formulation.

[0061] Pharmaceutically acceptable formulations include one, two or more compounds of Formulas I-XII, typically one or two, and one or more pharmaceutically acceptable excipients. More typically, the formulation will contain a single compound of Formula I-XII and one or more pharmaceutical Other formulations may contain one, two or more commercially acceptable excipients. The compounds of formulas I-XII and the lysophosphatidic acid ... One or two drugs currently used to treat steroid type 1 receptor-mediated diseases or conditions comprising or consisting essentially of the above compounds and one or more pharmaceutically acceptable excipients. Typically, these formulations may comprise or consist of a single compound of formula I-XII. , a compound for treating lysophosphatidic acid type 1 receptor-mediated diseases or conditions A single compound and one or more pharmaceutically acceptable excipients currently used to treat The composition may consist essentially of or consist of the agent.

[0062] As used herein, a "solid formulation" refers to at least one A pharmaceutically acceptable carrier comprising a compound of formula I-XII and one or more pharmaceutically acceptable excipients. "Dosage unit" refers to a dosage form suitable for administration of a solid. These include tablets, capsules, caplets, gelcaps, suspensions and typically solid forms. Other dosage units are relevant for parenteral or enteral (oral) administration.

[0063] As used herein, a "liquid formulation" refers to a liquid formulation containing at least one compound of Formulas I-XII. The compound is mixed or contacted with one or more pharmaceutically acceptable excipients, and the excipients At least one of which is in liquid form in the proportions required for a liquid formulation, i.e., Formulas I-X A pharmaceutically acceptable carrier in which the majority of the amount of compound II is dissolved in a non-solid excipient. The dosage unit containing the liquid formulation refers to a formulation that can be tolerated. The parenteral or enteral administration of pharmaceutical preparations to a subject in need thereof includes, for example, sprays, gels, ointments, and typically Other dosage units related to administration are mentioned.

[0064] As used herein, "prevent," "preventing," and similar terms mean The term shall be interpreted in its ordinary and customary sense in the medical arts, and accordingly It is not necessary that each case mentioned be avoided with certainty.

[0065] Numbered Embodiments The following embodiments are illustrative of the present invention and are not intended to limit the present invention in any way. In certain embodiments, the compounds presented herein have one or more stereocenters. and each center independently exists in either the R or S configuration. The compounds include all diastereomeric, enantiomeric, and epimeric forms and the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by stereoselective synthesis and / or chiral chromatography. The separation of stereoisomers can be achieved by methods such as separation of stereoisomers by chromatography column. The methods and formulations include pharmaceutically acceptable salts of compounds having the structures of formulas (I-VI), as well as This includes the use of active metabolites of these compounds that have the same type of activity. In some cases, compounds may exist as tautomers. All tautomers are shown herein. In certain embodiments, the compounds described herein are , and exists as a salt, including a pharmaceutically acceptable salt. The salt form is F - , Cl - , Br- , I - and inorganic addition salts such as sulfates, as well as mesylates, besylates, tosylates, and citrates. In other embodiments, the salts include organic addition salts such as succinate, fumarate, and malonate. Therefore, the compounds described herein exist as quaternary ammonium salts.

[0066] Embodiment 1. A compound of Formula I having the structure: [ka] or a pharmaceutically acceptable salt or prodrug thereof (Wherein, R A is —CO H, —CO R B, —CN, tetrazolyl, —C(═O)N H2, -C(=O)NHRB, C(=O)NHSO2RB, or -C(=O)NHC H2CH2SO3H or having the following structure: [ka] R B is an optionally substituted C1-C4 alkyl or one of the following structures: have [ka] , and; where R B is a substituted or unsubstituted C1-C4 alkyl; L 1 is a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C1-C6 fluoroa alkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C1-C6 heptane It is alkylene; where A1 is -N= or -CH; wherein ring A has one of the following structures: [ka] where R C -CN, -F, -Cl, -Br, -I, -OC1 to C4 alkyl, C 3-C6 cycloalkyl, or C1-C4 fluoroalkyl; And R D is -N(R F )-C(=O)XCH(R G )-CY, where X is O and CY is one R H is a phenyl substituted with: [ka] R E , R F , and R G are independently —H or C1-C4 alkyl or C3-C 6 cycloalkyl, or R E and R F are independently -H or C1 to C4 alkyl alkyl or C1-C6 cycloalkyl, and one R G is -C1-C4 alkyl , KanAR D R in the substituent H Phenyl moiety and R G and the phenyl moiety is attached together with the carbon atom(s) forming a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. demarcate; R H are independently -H, halogen, -CN, -NO2, -OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 alkoxy (It is Shi).

[0067] In one embodiment, R C -CN, -F, -Cl, -Br, -I, -OC 4 alkyl, C1-C4 alkyl, C3-C6 cycloalkyl, or C1-C4 fluoro alkyl, and RD -N(R F )-C(=O)OCH(R G )-CY, where , R F and each R G is independently —H or C1-C4 alkyl.

[0068] In a preferred embodiment, R A is -CO2H, -CONHCN, tetrazolyl, or is -C(=O)NHSO2R B where R B is a substituted or unsubstituted C1-C4 alkyl It's a kill.

[0069] In a particularly preferred embodiment, R A -CO2H, -CONHCN, tetrazolyl , or -C(=O)NHSO2R B where R B is -CH3.

[0070] In one embodiment, L 1 is a substituted or unsubstituted C1-C6 alkylene, C1-C 6 fluoroalkylene, or substituted or unsubstituted C1-C6 heteroalkylene.

[0071] In a particularly preferred embodiment, L 1 teeth [ka] is.

[0072] In one embodiment, the compounds of Formula I are , —CN, —F, —Cl, or C1-C4 fluoroalkyl; C It has.

[0073] In a more preferred embodiment, the compound of formula I has R defined as -F or -Cl. C of Has.

[0074] In certain embodiments, the compound of formula I is —N(R F )C(=O)-OCH(R G )- R defined as CY D where R F is —H or C1-C4 alkyl, and X, C.Y., and R. G is as defined above.

[0075] In a more preferred embodiment, the compound of formula I is -N(R F )C(=O)OCH(R G )-CY defined as R D where R F is -H, and CY and R G is determined first As it was justified.

[0076] In certain embodiments, the compound of formula I is H, C1-C4 alkyl, or C3-C6 silyl. R defined as chloroalkyl F It has.

[0077] In a more preferred embodiment, the compound of formula I has R defined as —H. F It has.

[0078] In certain embodiments of the compound of Formula I, R G are independently —H or C1-C4 alkyl is.

[0079] In a more preferred embodiment, the compound of formula I has R defined as -CH G have .

[0080] In some embodiments of the compound of Formula I, C Y is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein when CY is substituted, CY is 1 , two, or three independently selected R H is replaced by

[0081] In preferred compounds of formula I, R A is -CO2H, and R C is -F or -Cl Yes, R D Ha-NR F C(=O)OCH(R G )-CY and R F , R G , and CY As previously defined.

[0082] In other preferred compounds of formula I, R A is tetrazolyl and R C is -F or - Cl and R D Ha-NR F C(=O)OCH(R G )-CY and R F , R G , and CY is as defined above.

[0083] In other preferred compounds of formula I, R A is -C(=O)NHSO2R B and R C is -F or -Cl, and R D Ha-NR F C(=O)OCH(R G )-CY and R B , R F , R G , and CY are as defined above.

[0084] In other preferred compounds of formula I, R A is -CONHCN and R C -F or -Cl, and R D Ha-NRF C(=O)OCH(R G )-CY and R F , R G , and and CY are as defined above.

[0085] Embodiment 2.R A is —COH or CONHCN. .

[0086] Embodiment 3.R A is tetrazolyl.

[0087] Embodiment 4.R A -C(=O)NHSO2R B where R B is -CH3 2. The compound of embodiment 1,

[0088] Embodiment 5.R C is -CN, -F, or -Cl. thing.

[0089] Embodiment 6.R C The compound of embodiments 1-5, wherein is -F or -Cl.

[0090] Embodiment 7.L 1 When present, geminally substituted alkyl, cycloalkyl or a heterocycloalkyl group.

[0091] Embodiment 8.L 1 but [ka] 8. The compound of embodiment 7, wherein

[0092] Embodiment 9.R F The compound of any one of embodiments 1-8, wherein is —H.

[0093] Embodiment 10.R G The compound of any one of embodiments 1 to 9, wherein .

[0094] Embodiment 11. Any one of embodiments 1 to 10, wherein CY is substituted or unsubstituted phenyl. The compound according to any one of claims 1 to 5.

[0095] Embodiment 12.R H -H, halogen, -CN, -NO2, -OH, C1 to C4 Al alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and C1-C4 alkyl The compound of any one of embodiments 1-11, wherein the compound is alkoxy.

[0096] Embodiment 13.R H is -H, halogen, or substituted or unsubstituted C1-C4 alkyl , or substituted C1-C4 alkoxy. The compound according to any one of claims 1 to 4.

[0097] Embodiment 14.R H are independently -H, -Cl, -F, -CH3, -CF3, -OCH 3, or —OCF3.

[0098] Embodiment 15. A compound of Formula II having the following structure: [ka] or a pharmaceutically acceptable salt or prodrug thereof (In the formula, R A -CO2H, -CO2R B , tetrazolyl, -C(=O)NH2, - CONHCN or C(=O)NHSO2R B and; RB is an optionally substituted C1-C4 alkyl L 1 is an optionally substituted C1-C6 alkylene; C1-C6 fluoroalkylene; or or optionally substituted C1-C6 heteroalkylene, or L 1 teeth [ka] or disubstituted dimethylmethane). A 1 is =N- or =CH-; Ring A has the following structure: [ka] R C is -CN, -F, -Cl, or C1-C4 fluoroalkyl; R D -N(R F )-C(=O)XCH(R G )-CY, where X is O , CY is one R H is a phenyl substituted with: [ka] ; R E , R F and R G are independently -H or C1-C4 alkyl or C3-C6 cyclo alkyl, or R E and R F are independently —H or C1-C4 alkyl or C1 ~C6 cycloalkyl, and one R G is -C1-C4 alkyl, and the ring AR D R in the substituent H The phenyl moiety and R G and together with the carbon atom to which said phenyl moiety is attached and other R defines a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. G but , if present, R E as defined for R H -H, halogen, -CN, -NO2, -OH, C1-C4 alkyl, C1-C 4 fluoroalkyl, C1-C4 fluoroalkoxy, and C1-C4 alkoxy ; In particularly preferred compounds of formula II, R A are -CO2H, -CONHCN, -C(= O)NHSO2R B or tetrazolyl, and R B is CH3 and R C -F or -Cl, and R D Ha-NR F C(=O)OCH(R G )-CY and R F , R G , and and CY are as defined above.

[0099] Embodiment 16. A compound of Formula III having the following structure: [ka] or a pharmaceutically acceptable salt or prodrug thereof (In the formula, R A is -COH, -CONHCN, tetrazolyl, or -C(=O)NH SO2R B and; R B is an optionally substituted C1-C4 alkyl L 1 is a substituted C1-C6 alkylene; C1-C6 fluoroalkylene; or optionally substituted C1-C6 heteroalkylene, or L 1 If exists, [ka] , or disubstituted dimethylmethane). A 1 is =N- or =CH-; Ring A has one of the following structures: [ka] R C is -CN, -F, or -Cl; where CY is one R H is phenyl substituted by; R F and R G are independently -H or C1-C4 alkyl or C3-C6 cyclo alkyl or R F are independently -H or C1-C4 alkyl or C1 ~C6 cycloalkyl, and one R G is -C1-C4 alkyl, and the ring AR D Place R of conversion base H The pheny part and R G and the carbon to which said phenyl moiety is attached. Together with the atom, defines a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. death; R H -H, halogen, -CN, -NO2, -OH, C1-C4 alkyl, C1-C 4 fluoroalkyl, C1-C4 fluoroalkoxy, and C1-C4 alkoxy ; In preferred compounds of formula III, R A -CO2H, -CONHCN, -C(=O )NHSO2R B or tetrazolyl, and R B is CH3 and R C is -F or - Cl and R D Ha-NR F C(=O)OCH(R G)-CY and R F is -H , R G is -CH3 and CY is as defined above.

[0100] Embodiment 17. A composition comprising one or more compounds of Formulas I-III and one or more excipients. , a composition consisting essentially of, or consisting of.

[0101] In a preferred embodiment, the composition comprises one compound of Formulas I-III and one or more The excipients may comprise, consist essentially of, or consist of:

[0102] In another preferred embodiment, the composition comprises one compound of formula I-III and one or more Comprising, consisting essentially of, or consisting of a plurality of pharmaceutically acceptable excipients It is a pharmaceutically acceptable formulation.

[0103] Embodiment 18. Binding parent of a compound to lysophosphatidic acid receptor-1 (LPA1R) The compound of formula I to III or a pharmaceutically acceptable salt thereof has a solubility of about 10 μM to 1 pM or less. A salt or prodrug.

[0104] Embodiment 19. A selective lysophosphatidic acid receptor-1 (LPA1R) compound. The compound of embodiments 1-18.

[0105] Embodiment 20. A selective lysophosphatidic acid receptor-1 (LPA1R) compound. A compound of Formula I-III or a pharmaceutically acceptable salt or prodrug thereof.

[0106] Embodiment 21. The compound is a lysophosphatidic acid receptor-1 (LPA1R) compound. , the binding affinity of the LPA1R compound (i.e., K D) is about 1 μM to 1 pM or less, Compounds according to embodiments 1 to 20. In a preferred embodiment, K D is less than 100nM , and more preferably 10 nM or less.

[0107] Embodiment 22. A compound of Table 1.

[0108] Embodiment 23. (R)-1-(4-(5-(5-((1-(2-chlorophenyl) ethoxylate) (4-fluoro-1H-pyrazol-1-yl)pyridine -2-yl)phenyl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(4- Fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid (R)-1-(3-fluoro-4'-(4-fluoro-5-(((1-phenylethoxy) (C)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl] -4-yl)cyclopropane-1-carboxylic acid, (R)-1-(2-fluoro-4'-( 4-Fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazo (1,1'-biphenyl)-4-yl)cyclopropane-1-carbo carboxylic acid, (R)-1-(2-chloro-4'-(4-fluoro-5-(((1-phenylethoxy) (oxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl ]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(4-fluoro -5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl (1,1'-biphenyl)-2-methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carbo carboxylic acid, or (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-carbamoyl) (1,1'-biphenyl)-4-yl-4-fluoro-1H-pyridyl The compound of embodiment 22, wherein the compound is a benzophenone-5-yl)carbamate;

[0109] Embodiment 24. (R)-1-(4-(5-(4-chloro-5-(((1-(2-chloro Phenyl)ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)pyridine- 2-yl)phenyl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(4-chlorophenyl) 1-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole-1 -yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, ( R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino) (1H-pyrazol-1-yl)-3-fluoro-[1,1'-biphenyl]-4- (R)-1-(4'-(4-chloro-5-(( (1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2- Fluoro-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, ( R)-1-(2-chloro-4'-(4-chloro-5-(((1-phenylethoxy)carbamoyl)methyl)- ... (1H-pyrazol-1-yl)amino)-[1,1'-biphenyl]-4-yl (R)-1-(4'-(4-chloro-5-( ((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2 -methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid The compound of embodiment 22,

[0110] Embodiment 25. (R)-1-{4'-[5-(1-phenyl-ethoxycarbonylamino] (4-trifluoromethyl-pyrazol-1-yl)-biphenyl-4-yl}- Chlopropanecarboxylic acid, or (R)-1-{2-fluoro-4'-[5-(1-phenyl (ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]- 23. The compound of embodiment 22, wherein the compound is {biphenyl-4-yl}-cyclopropanecarboxylic acid. thing;

[0111] Embodiment 26. (R)-1-(4'-(4-cyano-5-(((1-phenylethoxy) )carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(5-(((1-( 2-Chlorophenyl)ethoxy)carbonyl)amino)-4-cyano-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid , (R)-2-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl )amino)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2-methylpropanoic acid, or (R)-2-(4'-(4-cyano-5-(( (1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1 1'-biphenyl]-4-yl)-2-methylpropanoic acid. Compounds of;

[0112] Embodiment 27. (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(2 '-Fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)- [1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (4-fluoro-1-(2'-fluoro-4'-(1-(( Methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- (R)-1-(2-chlorophenyl)-1H-pyrazol-5-yl)carbamate (4-chloro-1-(2'-fluoro-4'-(1-(methylsulfonyl) Carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyra (R)-1-phenylethyl (4-chloro-1-(4-azol-5-yl)carbamate '-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl] (R)-1-phenyl)-4-yl)-1H-pyrazol-5-yl)carbamate, (2-chlorophenyl)ethyl (4-fluoro-1-(4'-(1-(methylsulfonyl) -(1,1'-biphenyl)-4-yl)-1H- The compound of embodiment 22, which is a pyrazol-5-yl)carbamate;

[0113] Embodiment 28. (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl )-4-Fluoro-1H-pyrazol-5-yl)carbamate, (R)-1-phenyl Ethyl(1-(4'-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1 ,1'-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl)carba mate, (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetramethylphenyl)methyl)methyl)methyl)methyl (1,1'-biphenyl-4-yl)cyclopropyl-[1,1'-biphenyl]-4-yl-4- 23. The compound of embodiment 22, which is a chloro-1H-pyrazol-5-yl)carbamate. thing;

[0114] Embodiment 29. (R)-1-phenylethyl (4-chloro-1-(4'-(1-(cyano) (1,1'-biphenyl)-4-yl)-1H-biphenyl (R)-1-(2-chlorophenyl)ethyl (4- Chloro-1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl] phenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-( 2-chlorophenyl)ethyl (1-(4'-(1-(cyanocarbamoyl)cyclopropyl) yl)-2'-fluoro-[1,1'-biphenyl]-4-yl)-4-fluoro-1H- The compound of embodiment 22, which is a pyrazol-5-yl)carbamate;

[0115] Embodiment 30. A composition comprising a compound of Table 1 and one or more pharmaceutically acceptable excipients, A pharmaceutically acceptable formulation consisting essentially of or consisting of.

[0116] Embodiment 31. A compound according to embodiment 23 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0117] Embodiment 32. A compound according to embodiment 24 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0118] Embodiment 33. A compound according to embodiment 25 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0119] Embodiment 34. A compound according to embodiment 26 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0120] Embodiment 35. A compound according to embodiment 27 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0121] Embodiment 36. A compound according to embodiment 28 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0122] Embodiment 37. A compound according to embodiment 29 and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of an excipient.

[0123] Embodiment 38. An effective amount of a compound of Formulas I-III is administered to a patient suffering from an LPA-dependent or LPA-mediated disorder. Or a method comprising the step of administering to a subject suffering from a pathological condition.

[0124] Embodiment 39. The LPA-dependent or LPA-mediated disease or condition is a disease accompanied by fibrosis of an organ. 39. The method of embodiment 38, wherein the patient is a patient with

[0125] Embodiment 40. The fibrosis of embodiment 3, wherein the fibrosis is fibrosis of the liver, kidney, lung, heart, eye, etc. 9. The method according to claim 9.

[0126] Embodiment 41. The LPA-dependent or LPA-mediated disease or condition is chronic pain. 39. The method of claim 38.

[0127] Embodiment 42. An embodiment in which the LPA-dependent or LPA-mediated disease or condition is pruritus. 38. The method according to claim 38.

[0128] Embodiment 43. The LPA-mediated disease is cancer (solid tumors, solid tumor metastases, angiofibromas, bone marrow tumors, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), etc.) and Proliferative diseases involving the invasive metastasis of cancer cells, including follicular carcinoma, breast cancer, and triple-negative breast cancer 39. The method of embodiment 38, wherein

[0129] Embodiment 44. The LPA-mediated disease is an inflammatory disease, including psoriasis, nephropathy, pneumonia, etc. 39. The method of embodiment 38.

[0130] Embodiment 45. Embodiment 3, wherein the LPA-mediated disease is a gastrointestinal disease, such as inflammatory bowel disease. 8. The method according to claim 8.

[0131] Embodiment 46. The LPA-mediated disease is age-related macular degeneration (AMD), diabetic retinopathy, Proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scars, uveitis, etc. 39. The method of embodiment 38, wherein the eye disease comprises:

[0132] Embodiment 47. The LPA-mediated disease is acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, biliary tract infection, or the like. stasis pruritus, portal hypertension, aplastic anemia, nonalcoholic steatohepatitis (NASH), hyperlipidemia 39. The method of embodiment 38, wherein the liver disease is a liver disease including severe liver dysfunction, abnormalities in hepatic blood flow, and the like.

[0133] Embodiment 48. The LPA-mediated disease is chronic kidney disease, end-stage renal disease, uremic pruritus, renal 39. The method of embodiment 38, wherein the kidney disease is a kidney disease, including diabetic nephropathy (including diabetic nephropathy).

[0134] Embodiment 49. The LPA-mediated disease is scleroderma, skin scarring, atopic dermatitis, psoriasis, etc. 39. The method of embodiment 38, wherein the skin disease comprises:

[0135] Embodiment 50. The method of any one of embodiments 38 to 49, wherein the subject is a human. .

[0136] Embodiment 51. Any one of embodiments 38 to 50, wherein the compound is selected from Table 1. The method described.

[0137] Embodiment 52. The compound is (R)-1-(4-(5-(5-((1-(2-chlorophenyl) (phenyl)ethoxy)carbonyl)amino)-4-fluoro-1H-pyrazol-1-yl )pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid, (R)-1-(4 -(5-(4-chloro-5-(((1-(2-chlorophenyl)ethoxy)carbonyl) Amino)-1H-pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane (R)-1-(4'-(4-fluoro-5-(((1-phenylene) (1,1'-biphenyl)-1H-pyrazol-1-yl)-[(2-methyl-2-pyrazole ... (R)-1-(4'-(4-chloro-4-yl)cyclopropane-1-carboxylic acid, -5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl (R)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, -1-(4'-(4-cyano-5-(((1-phenylethoxy)carbonyl)amino) -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane 1-(4'-(5-(((1-(2-chlorophenyl) ) ) ) ) (1,1-Trimethyl-4-(2-hydroxy-1H-pyrazol-1-yl)-4-cyano-1H-pyrazol-1-yl)- (R)-1-(3-phenyl)-4-yl)cyclopropane-1-carboxylic acid, Fluoro-4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino )-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopro Pan-1-carboxylic acid, (R)-1-(2-fluoro-4'-(4-fluoro-5-(( (1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(4 '-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyridin (1,1'-biphenyl-4-yl)cyclopropanediol-1-yl propane-1-carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenyl Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2-fluoro-[1 ,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(2 -chloro-4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino) (1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane propane-1-carboxylic acid, (R)-1-(2-chloro-4'-(4-chloro-5-((( 1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(4' -(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pi (1-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl]-4-yl)cyclopro Pan-1-carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenylene (1,1-trimethyl-2-methyl-2-methyl-1H-pyrazol-1-yl)-2-methyl ... '-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(2-chlorophenyl)-4-yl 1-(4'-(1-carbamoylcyclopropyl)-[1,1'-phenyl)ethyl -biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(2'-fluoro) -4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'- Biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1- Phenylethyl (4-fluoro-1-(2'-fluoro-4'-(1-((methylsulfonyl) Nyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H -pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl ( 4-chloro-1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl) )Cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazole-5- (R)-1-phenylethyl (4-chloro-1-(4'-(1-( (Methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4 -yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenoxy) (4-fluoro-1-(4'-(1-((methylsulfonyl)carbamoyl) )Cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazole-5- (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1- (1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4- (R)-1-phenyl)-4-fluoro-1H-pyrazol-5-yl)carbamate Nylethyl(1-(4'-(1-(1H-tetrazol-5-yl)cyclopropyl)- [1,1'-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl) Carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H- Tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)- 4-chloro-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-[1,1 '-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)- 1-(2-chlorophenyl)ethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl) 1,1'-biphenyl-4-yl)cyclopropyl)-1H-pyrazole- 5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4'-( 1-(cyanocarbamoyl)cyclopropyl)-2'-fluoro-[1,1'-biphenyl] (R)-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate -2-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino )-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl )-2-methylpropanoic acid, (R)-2-(4'-(4-cyano-5-(((1-phenyl (Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl] any one of embodiments 78 to 90, wherein the compound is 2-methyl-4-phenyl-2-methylpropanoic acid. The method described in one of the following:

[0138] Embodiment 53. Any of embodiments 38-50, wherein the compound is selected from embodiment 23. or one of the methods described above.

[0139] Embodiment 54. Any of embodiments 38 to 50, wherein the compound is selected from embodiment 24. or one of the methods described above.

[0140] Embodiment 55. Any of embodiments 38-50, wherein the compound is selected from embodiment 25. or one of the methods described above.

[0141] Embodiment 56. Any of embodiments 38 to 50, wherein the compound is selected from embodiment 26. or one of the methods described above.

[0142] Embodiment 57. Any of embodiments 38 to 50, wherein the compound is selected from embodiment 27. or one of the methods described above.

[0143] Embodiment 58. Any of embodiments 38 to 50, wherein the compound is selected from embodiment 28. or one of the methods described above.

[0144] Embodiment 59. Any of embodiments 38-50, wherein the compound is selected from embodiment 29. or one of the methods described above.

[0145] Embodiment 60. One or more compounds of formula (I-III) and LPA-dependent or LPA 1 currently used to treat vector-borne diseases or the diseases or conditions described herein. A composition comprising, consisting essentially of, or consisting of one or more pharmaceutical agents.

[0146] Embodiment 61. One or more compounds of formula (I-III), LPA-dependent or LPA-mediated One or more drugs and one or more pharmaceuticals currently used to treat interstitial diseases pharmaceutically acceptable excipients, consisting essentially of, or consisting of A formulation that can be used.

[0147] Embodiment 62. A subject suffering from an LPA-dependent or LPA-mediated disease or condition is administered a compound of formula (I). Compounds I-III) and compounds currently used to treat LPA-dependent or LPA-mediated diseases The method comprises administering in combination or simultaneously the drugs listed above.

[0148] The one or more additional therapeutically active agents other than the compounds of formula (I-III) may be Ruticosteroids, immunosuppressants, analgesics, anticancer drugs, anti-inflammatory drugs, chemokine receptor antagonists bronchodilator, leukotriene receptor antagonist, leukotriene formation inhibitor agents, platelet-activating factor receptor antagonists, monoacylglycerol kinase inhibitors, Phospholipase A1 inhibitors, phospholipase A2 inhibitors, and lysophospholipase D(l ysoPLD) inhibitor, autotaxin inhibitor, decongestant, mast cell stabilizer, antihistamine Select from antitussives, mucolytics, anticholinergics, antitussives, expectorants, and beta-2 agonists. It is selected.

[0149] In a preferred embodiment, the currently used drug is a lysophosphatidic acid receptor Those listed in the Merck Index that are known to act on signal transduction In another preferred embodiment, the compound of formula (I-III) is selected from Table 1. are selected.

[0150] In another embodiment, a method for treating an LPA-dependent or LPA-mediated disease or condition is provided. The compounds of formula (I-III) can be used to inhibit various signaling pathways leading to LPA synthesis or complementary clinical to produce complementary clinical outcomes Combination treatment with currently available drugs that act on such signaling pathways is described herein. It is included in

[0151] Examples of additional therapeutic agents include, but are not limited to, gossypol, dimethicone, Genasense, polyphenol E, chlorofusin, all trans -retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis-inducing ligand Gand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoin acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, Gerda geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AA G), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD 184352, Taxol (trademark) Taxol™ analogs, such as Taxotere™, U0 126, PD98059, PD184352, PD0325901, ARRY-1428 86, SB239063, SP600 125, BAY 43-9006, Wortmannin , or LY294002, adriamycin, dactinomycin, bleomycin, vin Blastin, cisplatin, acivicin; aclarubicin; acodazole hydrochloride (acod azole hydrochloride); Acronine; Adzelesin; Aldesroi altretamine; ambomycin; amethantrone acetate; aminoglutethimide; Musacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide ;Bisantrene hydrochloride;Bisnafide dimesylate ate); bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; Bleomycin Sulfan; Cactinomycin; Calusterone; Caracemi Carboplatin; Carmustine; Carboplatin hydrochloride Bicin; Carzelesin; Cedefingol; Chlorambucil; Ciroremycin (ciro lemycin); cladribine; crisnatol mesylate; cyclophosphamide; cyta Rabin; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Deaza Guanine; Deazaguanine mesylate; Diaziquone; Doxorubicin; Doxorubicin hydrochloride droloxifene; droloxifene citrate; dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; E Rusamitrucin; Enloplatin; Enpromate; Epipropizin; Epirubicin hydrochloride ;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etopurine; fadrozole hydrochloride Fazarabine; Fenretinide; Floxuridine; Fludarabine phosphate; Fluo Lauracil; Flurocitabine; Foskidone; Fostri Escin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubi hydrochloride Ifosfamide; Iimofosine; Interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a; Interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; Interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometezol Rexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maitan Syn; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melfala Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Ma Mitochromin; Mitogillin; My tomalcin; mitomycin; mitosper r); Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin Syn; Ormaplatin; Oxisuran; Pegaspargase; Periomycin; Pentams pentamustine; peplomycin sulfate; perfosfamide osfamide); pipobroman; piposulfan; piroxantrone hydrochloride; Plicama Isin; Promestane; Porfimer sodium; Porfiromycin; Prednisone Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; Boprin; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtra Zen; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiro Muscin;spiroplatin;streptonigrin;streptozotocin;sulofenur; Tallysomycin; tecogalan sodium; Tegaf Teloxantrone hydrochloride; Temoporfin; Teniposide; Teloxylon; Testol Thompson; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremif Trestrone acetate; Phosphate Triciribine; Trimetrexate; Trimetrexate glucuronate; Triptorelin ;Tubrozole hydrochloride;Uracil mustard;Uredep;Vapreotide;Verteporfin ;Vinblastine sulfate;Vincristine sulfate;Vindesine;Vindesine sulfate;Vinepi sulfate Vinepidine sulfate; Vineglysinate sulfate cinate sulfate); vinleurosine sulfate sulfate); vinorelbine tartrate; vinrosidine sulfate sulfate);vinzolidine sulfate;boro Zol; Zeniplatin; Zinostatin; Zorubicin hydrochloride, Mechlorethamine, Cyclophosph amide, chlorambucil, melphalan, etc.), ethyleneimine, hexamethylmelamine , thiotepa, busulfan), carmustine, lomustine, semustine, streptozotocin ortriazene, dacarbazine, methotrexate, fluticasone Olouracil, floxuridine, cytarabine, mercaptopurine, thioguanine, pen Tostatin, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate Cyprogesterone, estrogen, diethylstilbestrol, ethinyl estradiol tamoxifen), testosterone propionate, fluoxymesterone, fluta amide, leuprolide, cisplatin, carboplatin, mitoxantrone), procarbamate Zin, mitotane, aminoglutethimide, elbrozole, dolastatin 10, isethione Mibobulin, vincristine, NSC-639829, discodermolide, ABT -751, Altrilutin A and Altrilutin C), Spongistatins 1-9, Se hydrochloride Madotine, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone AN-oxide, 16-aza- epothilone B, 21-aminoepothilone B, 21-hydroxyepothilone D, 26-fluoro Epothilone, auristatin PE, sobridotin, cryptophycin 52, vitilevuami Vitilevuamide, Tubulysin A, Canadensol, Centaureysin , Oncocidin Al Fijianolide B, Laulimalide, Nalu Cochin, noscapine, hemiasterlin, vanadocene acetylacetonate (Vanadocene cene acetylacetonate), indanocine, eluterobin (Ele Desmethyleleutherobin robin), desacetyleluterobin, isoeluterobin (lsoeleuth Erytherobin A and Z, carybeoside, carybeolin, halibut Chondrin B, Diazonamide A, Taccalonolide A, Di Ozostatin (Diozostatin), (-)-phenylahisteine, myoseverin B. Resverastatin phosphate sodium te sodium), aprepitant, cannabis, Marinol, dronabinol, erythropoietin Poietin-α, filgrastim, rituximab, natalizumab, cyclophosphamide, Penicillamine, cyclosporine, nitrosoureas, cisplatin, carboplatin, oxaliplatin Saliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogues Protein synthesis inhibitors, dactinomycin, anthracyclines, mitomycin C , Bleomycin, Mithramycin, Atgam® Thymoglobuli ne (registered trademark), OKT3 (registered trademark), basiliximab, daclizumab, cyclosporine Phosphorus, tacrolimus, sirolimus, interferon, opioids, infliximab, Etanercept, adalimumab, golimumab, leflunomide, sulfasalazine, hydrochloride Chloroquine, minocycline, rapamycin, mycophenolate, mycophenolate Mofetil, FTY720, cyclosporine A (CsA) or tacrolimus (FK506 ), Aspirin, Salicylic Acid, Gentisic Acid, Choline Salicylate Magnesium, Salicylic Acid Choline Salicylate, Magnesium Choline Salicylate, Choline Salicylate, Magnesium Salicylate , sodium salicylate, diflunisal, carprofen, fenoprofen, fenop Iropen calcium, flurbiprofen, ibuprofen, ketoprofen, Nabuton (nabutone), ketorolac, ketorolac tromethamine, naproxen, oxap Rosin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meconium Lofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam Sicam, valdecoxib, parecoxib, etoricoxib, lumiracoxib, betamethasone , prednisone, alclometasone, aldosterone, amcinonide, beclomethasone , betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocol Tetoraconolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycortisone Ruticosterone, desonide, desoximetasone, desoxycortone, dexamethasone , diflorasone, diflucortolone, difluprednate, fluchlororone, fludroco Lutisone, fludroxycortide, flumethasone, flunisolide, fluocinolone acetone Nido, fluocinonide, fluocortin, fluocortolone, fluorometholone, flupe Loron, fluprednidene, fluticasone, formocortal, halcinonide, halometazo Hydrocortisone / Cortisol, Hydrocortisone Aceponate, Propionate Butyrate Hydrocortisone, hydrocortisone butyrate, loteprednol, medrysone, meprednisolone Methylprednisolone, methylprednisolone acetonate, methylprednisolone furoate tazone, paramethasone, prednicarbate, prednisone / prednisolone, rimexo ron, tixocortol, triamcinolone, urobetasol, pioglitazone, cloroxazole Fenofibrate, gemfibrozil, folic acid, isbogrel, ozagrel, Ridogrel, dazoxiben, lovastatin, simvastatin, pravastatin, fluvastatin statin, atorvastatin, nisvastatin, and rosuvastatin Tatin, Edaravone, Vitamin C, TROLOX™, Citicoline and Minocycline (2R)-2-propyloctanoic acid, propranolol, nadolol, timolol, Pindolol, labetalol, metoprolol, atenolol, esmolol and Acebutolol, memantine, traxoprodil, tirofiban, lamifiban, and algae Troban, enalapril, cyclandelate, losartan, valsartan, candesartan irbesartan, telmisartan, olmesartan, canagliflozin, dapagliflozin Rosin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin Rosin, Remogliflozin Etabonate, Sotagliflozin, Tofogliflozin, Exe Natide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine , doxylamine, clemastine, dimenhydrinate, pheniramine, chlorphenamine (Chlorpheniramine), dexchlorpheniramine, brompheniramine, triprolide Zinc, cetirizine, cyclizine, chlorcyclizine, hydroxyzine, meclizine, Lora Tadine, desloratadine, promethazine, alimemazine (trimeprazine), cyproheptane Tadine, Azatadine, Ketotifen, Acrivastine, Astemizole, Cetirizine, Micostatin Zolastine, terfenadine, azelastine, epinastine, levocabastine, olopata levocetirizine, fexofenadine, rupatadine, bepotastine), mucolytics , anticholinergic, antitussive, analgesic, expectorant, albuterol, ephedrine, epinephrine Phosphate, formoterol, metaproterenol, terbutaline, budesonide, ciclesonide , dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetone Nido, ipratropium bromide, pseudoephedrine, theophylline, montelukast , pranlukast, tomelukast, zafirlukast, ambu Resentan, bosentan, enrasentan, sitaxsentan , tezosentan, iloprost, treprostinil, pirfenidone, epinephrine, i These include soproterenol, orciprenaline, xanthine, and zileuton .

[0152] Embodiment 63. The method of embodiments 60-62, wherein the subject is a human.

[0153] Embodiment 64. Any of embodiments 60-62, wherein the compound of Formula I-III is selected from Table 1. The method described.

[0154] Embodiment 65. The compound of Formulas I-III is (R)-1-(4-(5-(5-(((1- (2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1H-pyrazo (phenyl-1-yl)pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid, R)-1-(4-(5-(4-chloro-5-(((1-(2-chlorophenyl)ethoxy )carbonyl)amino)-1H-pyrazol-1-yl)pyridin-2-yl)phenyl ) cyclopropane-1-carboxylic acid, (R)-1-(4'-(4-fluoro-5-((( 1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(4' -(4-chloro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyra (1,1'-biphenyl-4-yl)cyclopropane-1-ol carboxylic acid, (R)-1-(4'-(4-cyano-5-(((1-phenylethoxy)carboxamide) Nyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl )Cyclopropane-1-carboxylic acid, (R)-1-(4'-(5-(((1-(2-chloro (phenyl)ethoxy)carbonyl)amino)-4-cyano-1H-pyrazol-1-yl (R)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, -1-(3-fluoro-4'-(4-fluoro-5-(((1-phenylethoxy)carbamoyl) (1H-pyrazol-1-yl)amino)-[1,1'-biphenyl]-4-yl (R)-1-(2-fluoro-4'-(4-fluoro-1-methyl-2-methyl-4-oxo-1-methyl-4 ... Oro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole-1 -yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, ( R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino) (1H-pyrazol-1-yl)-3-fluoro-[1,1'-biphenyl]-4- (R)-1-(4'-(4-chloro-5-(( (1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2- Fluoro-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, ( R)-1-(2-chloro-4'-(4-fluoro-5-(((1-phenylethoxy) (carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- (R)-1-(2-chloro-4'-(4-chloro-yl)cyclopropane-1-carboxylic acid, b-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole-1- (R yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, )-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amine (1H-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl]-4-yl (R)-1-(4'-(4-chloro-5-((( 1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2-methyl (R) ethyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid -1-(2-chlorophenyl)ethyl(1-(4'-(1-carbamoylcyclopropyl )-[1,1'-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-( 2'-Fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl) -[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate , (R)-1-phenylethyl (4-fluoro-1-(2'-fluoro-4'-(1-( (Methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4 -yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenoxy) (4-chloro-1-(2'-fluoro-4'-(1-((methylsulfonyl) )carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-biphenyl (R)-1-phenylethyl (4-chloro-1-( 4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl] phenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-( 2-chlorophenyl)ethyl (4-fluoro-1-(4'-(1-((methylsulfonyl )carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-biphenyl (R)-1-(2-chlorophenyl)ethyl (1- (4'-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl] (phenyl)-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate, R)-1-phenylethyl (1-(4'-(1-(1H-tetrazol-5-yl)cyclohexyl) (1,1'-biphenyl)-4-yl)-4-chloro-1H-pyrazole -5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4'- (1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl] -4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate, (R)-1- Phenylethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl)cyclopropyl) (1,1'-biphenyl)-4-yl-1H-pyrazol-5-yl)carbamate (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(4'-(1-( Cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H -pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl ( 1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-2'-fluoro-[1, 1'-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carba Mate, (R)-2-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbamate (1,1'-biphenyl)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl] (R)-2-(4'-(4-cyano-5-( ((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[ 1,1'-biphenyl]-4-yl)-2-methylpropanoic acid , the method according to embodiments 60 to 62;

[0155] Embodiment 66. The compound of Formulas I-III is selected from embodiment 23. The method according to claim 63.

[0156] Embodiment 67. Embodiment 60, wherein the compound of Formulas I-III is selected from embodiment 24. The method according to claim 63.

[0157] Embodiment 68. Embodiment 60, wherein the compound of Formulas I-III is selected from embodiment 25. The method according to claim 63.

[0158] Embodiment 69. Embodiment 60, wherein the compound of Formulas I-III is selected from embodiment 26. The method according to claim 63.

[0159] Embodiment 70. The compound of Formulas I-III is selected from embodiment 27. The method according to claim 63.

[0160] Embodiment 71. The compound of Formulas I-III is selected from embodiment 28. The method according to claim 63.

[0161] Embodiment 72. The compound of Formulas I-III is selected from embodiment 29. The method according to claim 63.

[0162] Embodiment 73. The method of embodiment 60, wherein the currently used agent is a mast cell stabilizer. The composition described above.

[0163] Embodiment 74. The currently used drug is a platelet-activating factor receptor antagonist. 61. The composition of embodiment 60.

[0164] Embodiment 75. The mast cell stabilizer is cromoglycate, nedocromil, azelastine, bepotastine, epinastine, ketotifen, olopatadine and rupatadine. 74. The composition of claim 73.

[0165] Embodiment 76. The platelet-activating factor receptor antagonist is rupatadine, SM-125 02, CV-3988, and WEB 2170.

[0166] Embodiment 1A. Formula I [ka] or a pharmaceutically acceptable salt or prodrug thereof. (In the formula, R A is -COH, -CONHCN, tetrazolyl, or -C(=O)NHS O2R Band; where R B is a substituted or unsubstituted C1-C4 alkyl; L 1 is a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C1-C6 fluoroa alkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C1-C6 heptane It is alkylene; where A1 is -N= or -CH; wherein ring A has one of the following structures: [ka] where R C -CN, -F, -Cl, -Br, -I, -OC1 to C4 alkyl, C 3-C6 cycloalkyl, or C1-C4 fluoroalkyl; And R D is -N(R F )-C(=O)XCH(R G )-CY, where X is O and CY is one R H is a phenyl substituted with: [ka] ; R E , R F , and R G are independently —H or C1-C4 alkyl or C3-C 6 cycloalkyl, or R E and R F are independently -H or C1 to C4 alkyl alkyl or C1-C6 cycloalkyl, and one R G is -C1-C4 alkyl , KanAR D R in the substituent H Phenyl moiety and R G and the phenyl moiety is attached together with the carbon atom(s) forming a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. demarcate; R H are independently -H, halogen, -CN, -NO2, -OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 alkoxy (It is Shi).

[0167] In one embodiment, R C -CN, -F, -Cl, -Br, -I, -OC 4 alkyl, C1-C4 alkyl, C3-C6 cycloalkyl, or C1-C4 fluoro alkyl, and R D is -N(R F )-C(=O)OCH(R G )-CY, where So, R F and each R G is independently —H or C1-C4 alkyl.

[0168] In a preferred embodiment, R A is -CO2H, -CONHCN, tetrazolyl, or is -C(=O)NHSO2R B where R B is a substituted or unsubstituted C1-C4 alkyl It's a kill.

[0169] In a particularly preferred embodiment, R A -CO2H, -CONHCN, tetrazolyl , or -C(=O)NHSO2R B where R B is -CH3.

[0170] In one embodiment, L 1 is a substituted or unsubstituted C1-C6 alkylene, C1-C 6 fluoroalkylene, or substituted or unsubstituted C1-C6 heteroalkylene.

[0171] In a particularly preferred embodiment, L 1 teeth [ka] is.

[0172] In certain embodiments, the compound of formula I is -CN, -F, -Cl, or C1-C4 fulvic acid. R defined as fluoroalkyl C It has.

[0173] In a more preferred embodiment, the compound of formula I has R defined as -F or -Cl. C of Has.

[0174] In certain embodiments, the compound of formula I is —N(R F )C(=O)-OCH(R G )- R defined as CY D where R F is —H or C1-C4 alkyl, and X, C.Y., and R. G is as defined above.

[0175] In a more preferred embodiment, the compound of formula I is -N(R F )C(=O)OCH(R G )-CY defined as R D where R F is -H, and CY and R G is determined first As it was justified.

[0176] In certain embodiments, the compound of formula I is H, C1-C4 alkyl, or C3-C6 silyl. R defined as chloroalkyl F It has.

[0177] In a more preferred embodiment, the compound of formula I has R defined as —H. FIt has.

[0178] In certain embodiments of the compound of Formula I, R G are independently —H or C1-C4 alkyl is.

[0179] In a more preferred embodiment, the compound of formula I has R defined as -CH G have .

[0180] In some embodiments of the compound of Formula I, C Y is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein when CY is substituted, CY is 1 , two, or three independently selected R H is replaced by

[0181] In preferred compounds of formula I, R A is -CO2H, and R C is -F or -Cl Yes, R D Ha-NR F C(=O)OCH(R G )-CY and R F , R G , and CY As previously defined.

[0182] In other preferred compounds of formula I, R A is tetrazolyl and R C is -F or - Cl and R D Ha-NR F C(=O)OCH(R G )-CY and R F , R G , and CY is as defined above.

[0183] In other preferred compounds of formula I, R A is -C(=O)NHSO2R B and R C is -F or -Cl, and R D Ha-NR F C(=O)OCH(R G )-CY and R B , R F , R G , and CY are as defined above.

[0184] In other preferred compounds of formula I, R A is -CONHCN and R C -F or -Cl, and R D Ha-NR F C(=O)OCH(R G )-CY and R F , R G , and and CY are as defined above.

[0185] Embodiment 2A. R A -CO2H, tetrazolyl [ka] , -C(=O)NH2, or -C(=O)NHSO2R B and; L 1 But -CH2-, [ka] or disubstituted dimethylmethane; ring [ka] Among them, R H is -H, halogen, or -CH3; ring [ka] Among them, A 1 is CH or N, and R H is -H; Ring A [ka] having the structure R C is -F, -Cl, -CN, or -CF3; R F is -H; R G is -CH3 in the R configuration; and CY ring [ka] Among them, R H A compound according to embodiment 1A, wherein is -H or halogen.

[0186] Embodiment 3A. R A is -CO2H; L 1 but [ka] and; ring [ka] Among them, R H is -H; ring [ka] Among them, A 1 is N and R H is -H; R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 2A, wherein is -Cl.

[0187] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 1, (R)-1-(4-(5-(5-((1-(2-chlorophenyl) (I)ethoxy)carbonyl)amino)-4-fluoro-1H-pyrazol-1-yl)pyrazole Lysin-2-yl)phenyl)cyclopropane-1-carboxylic acid. [ka]

[0188] Embodiment 4A. R A is -CO2H; L 1 but [ka] and; ring [ka] Among them, R H is -H; ring [ka] Among them, A 1 is N and R H is -H; R C is -Cl; and CY ring [ka] Among them, R HA compound according to embodiment 2A, wherein is -Cl.

[0189] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 2, (R)-1-(4-(5-(4-chloro-5-(((1-(2- Chlorophenyl)ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)pyridine It is (2-phenyl-2-inyl)phenyl)cyclopropane-1-carboxylic acid. [ka]

[0190] Embodiment 5A. ring [ka] Among them, A 1 is CH and R H A compound according to embodiment 2A, wherein is -H.

[0191] Embodiment 6A. R A is -CO2H; and L 1 but [ka] The compound of embodiment 5A, wherein:

[0192] Embodiment 7A. ring [ka] Among them, R H A compound according to embodiment 6A, wherein is -H.

[0193] Embodiment 8A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 7A, wherein is -H.

[0194] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 3, (R)-1-(4'-(4-fluoro-5-(((1-phenyl Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl [4-(4-methyl-4-yl)cyclopropane-1-carboxylic acid]. [ka]

[0195] Embodiment 9A. R C is -Cl; and ring [ka] Among them, R H A compound according to embodiment 7A, wherein is -H.

[0196] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 4, (R)-1-(4'-(4-chloro-5-(((1-phenylene) (1,1'-biphenyl)-1H-pyrazol-1-yl)-[(2-methyl-2-pyrazole ... It is [4-(4-yl)cyclopropane-1-carboxylic acid]. [ka]

[0197] Embodiment 10A. R C is -CN; and ring [ka] Among them, R H A compound according to embodiment 7A, wherein is -H.

[0198] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 5, (R)-1-(4'-(4-cyano-5-(((1-phenylene) (1,1'-biphenyl)-1H-pyrazol-1-yl)-[(2-methyl-2-pyrazole ... It is [4-(4-yl)cyclopropane-1-carboxylic acid]. [ka]

[0199] Embodiment 11A. R C is -CN; and ring [ka] Among them, R H A compound according to embodiment 7A, wherein is -Cl.

[0200] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 6, (R)-1-(4'-(5-(((1-(2-chlorophenyl) Ethoxy)carbonyl)amino)-4-cyano-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid. [ka]

[0201] Embodiment 12A. ring [ka] Among them, R H A compound according to embodiment 6A, wherein is -F.

[0202] Embodiment 13A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 12A, wherein is -H.

[0203] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A suitable molecule is compound 7, (R)-1-(3-fluoro-4'-(4-fluoro-5-(( (1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, and compound 8, ( R)-1-(2-fluoro-4'-(4-fluoro-5-(((1-phenylethoxy) Carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4 -yl)cyclopropane-1-carboxylic acid. [ka]

[0204] Embodiment 14A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 12A, wherein is -H.

[0205] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 9, (R)-1-(4'-(4-chloro-5-(((1-phenylene) (trimethyl)carbonyl)amino)-1H-pyrazol-1-yl)-3-fluoro-[1, 1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, and compound 10, R )-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino )-1H-pyrazol-1-yl)-2-fluoro-[1,1'-biphenyl]-4-yl cyclopropane-1-carboxylic acid. [ka]

[0206] Embodiment 15A. ring [ka] Among them, R H A compound according to embodiment 6A, wherein is -Cl.

[0207] Embodiment 16A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 15A, wherein is -H.

[0208] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 11, (R)-1-(2-chloro-4'-(4-fluoro-5-(( (1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid. [ka]

[0209] Embodiment 17A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 15A, wherein is -H.

[0210] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 12, (R)-1-(2-chloro-4'-(4-chloro-5-((( 1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid. [ka]

[0211] Embodiment 18A. ring [ka] Among them, R H A compound according to embodiment 6A, wherein is -CH3.

[0212] Embodiment 19A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 18A, wherein is -H.

[0213] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 13, (R)-1-(4'-(4-fluoro-5-(((1-phenyl) (ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2-methyl-[1 ,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid. [ka]

[0214] Embodiment 20A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 18A, wherein is -H.

[0215] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 14, (R)-1-(4'-(4-chloro-5-(((1-phenyl Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2-methyl-[1, 1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid. [ka]

[0216] Embodiment 21A. R A is -C(=O)NH2; L 1 but [ka] and; ring [ka] Among them, R H is -H; R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 5A, wherein is -Cl.

[0217] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 15, (R)-1-(2-chlorophenyl)ethyl (1-(4'-( 1-Carbamoylcyclopropyl)-[1,1'-biphenyl]-4-yl)-4-fluoro It is a 1H-pyrazol-5-yl)carbamate. [ka]

[0218] Embodiment 22A. R A -C(=O)NHSO2R B where R B is -CH3; and L 1 but [ka] The compound of embodiment 5A, wherein:

[0219] Embodiment 23A. ring [ka] Among them, R H A compound according to embodiment 22A, wherein is -F.

[0220] Embodiment 24A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 23A, wherein is -Cl.

[0221] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 16, (R)-1-(2-chlorophenyl)ethyl(4-fluoro- 1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl) (pyr)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carba It's my mate. [ka]

[0222] Embodiment 25A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 23A, wherein is -H.

[0223] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 17, (R)-1-phenylethyl (4-fluoro-1-(2'-fluoro- Fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1, 1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate. [ka]

[0224] Embodiment 26A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 23A, wherein is -Cl.

[0225] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 18, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1 -(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl (1,1'-biphenyl)-4-yl-1H-pyrazol-5-yl)carbamate It is a route. [ka]

[0226] Embodiment 27A. ring [ka] Among them, R H A compound according to embodiment 22A, wherein is -H.

[0227] Embodiment 28A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 27A, wherein is -H.

[0228] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 27, (R)-1-phenylethyl (4-chloro-1-(4'-(1 -((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl] 1H-pyrazol-5-yl)carbamate. [ka]

[0229] Embodiment 29A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 27A, wherein is -Cl.

[0230] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 20, (R)-1-(2-chlorophenyl)ethyl(4-fluoro- 1-(4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1 '-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate. [ka]

[0231] Embodiment 30A. R A Tetrazolyl [ka] and; L 1 but [ka] and ring [ka] Among them, R H A compound according to embodiment 5A, wherein is -H.

[0232] Embodiment 31A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 30A, wherein is -Cl.

[0233] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 21, (R)-1-(2-chlorophenyl)ethyl (1-(4'-( 1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]- 4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate. [ka]

[0234] Embodiment 32A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 30A, wherein is -H.

[0235] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 22, (R)-1-phenylethyl (1-(4'-(1-(1H-tetradecanoic acid) Trazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-4 -chloro-1H-pyrazol-5-yl)carbamate. [ka]

[0236] Embodiment 33A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 30A, wherein is -Cl.

[0237] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 23, (R)-1-(2-chlorophenyl)ethyl (1-(4'-( 1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]- 4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate. [ka]

[0238] Embodiment 34A. R A is CONHCN L 1 but [ka] and ring [ka] Among them, R H A compound according to embodiment 5A, wherein is -H.

[0239] Embodiment 35A. R C is -Cl; and CY ring [ka] Among them, R HA compound according to embodiment 34A, wherein is -H.

[0240] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 24(R)-1-phenylethyl (4-chloro-1-(4'-(1- (Cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate. [ka]

[0241] Embodiment 36A. R C is -Cl; and CY ring [ka] Among them, R H A compound according to embodiment 33A, wherein is -Cl.

[0242] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 25, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1 -(4'-(1-(cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl] 1H-pyrazol-5-yl)carbamate. [ka]

[0243] Embodiment 37A. R A is CONHCN L 1 but [ka] and ring [ka] Among them, R H A compound according to embodiment 5A, wherein is -F.

[0244] Embodiment 38A. R C is -F; and CY ring [ka] Among them, R H A compound according to embodiment 37A, wherein is -Cl.

[0245] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 26, (R)-1-(2-chlorophenyl)ethyl (1-(4'-( 1-(cyanocarbamoyl)cyclopropyl)-2'-fluoro-[1,1'-biphenyl] The compound is 4-fluoro-1H-pyrazol-5-yl)carbamate. [ka]

[0246] Embodiment 39A. R A is -CO2H; L 1 Dimethylmethane [ka] and; ring [ka] Among them, R H is -H; ring [ka] Among them, A 1 is CH and R H is -H; And R C The compound of embodiment 2A, wherein is -CN.

[0247] Embodiment 40A. CY ring [ka] Among them, R HA compound according to embodiment 39A, wherein is -Cl.

[0248] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 27, (R)-2-(4'-(5-(((1-(2-chlorophenyl )ethoxy)carbonyl)amino)-4-cyano-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2-methylpropanoic acid. [ka]

[0249] Embodiment 41A. CY ring [ka] Among them, R H A compound according to embodiment 39A, wherein is -H.

[0250] In this embodiment, R H But individually, [ka] ,ring [ka] , and CY ring [ka] It is understood that the carbon atom may be located at any available carbon atom within the structure. A typical molecule is compound 28, (R)-2-(4'-(4-cyano-5-(((1-phenyl Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl Nyl-4-yl)-2-methylpropanoic acid. [ka]

[0251] Embodiment 42A.R G The compound of embodiment 1A, wherein is in the R or S configuration.

[0252] Embodiment 43A. A compound according to embodiment 2A selected from Table 1.

[0253] Embodiment 44A. (R)-1-(4-(5-(5-(((1-(2-chlorophenyl) Ethoxy)carbonyl)amino)-4-fluoro-1H-pyrazol-1-yl)pyridin (R)-1-(4-(5-phenyl-2-yl)phenyl)cyclopropane-1-carboxylic acid, (4-chloro-5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino) -1H-pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane-1- Carboxylic acid, (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy) Carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4 -yl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(4-chloro-5-( ((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[ 1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-( 4'-(4-cyano-5-(((1-phenylethoxy)carbonyl)amino)-1H- Pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1- Carboxylic acid, (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy) Carbonyl)amino)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl] (R)-1-(3-fluoro-phenyl)-4-yl)cyclopropane-1-carboxylic acid, 4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid, (R)-1-(2-fluoro-4'-(4-fluoro-5-(((1-fluoro (phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'- (R)-1-(4'-(biphenyl)-4-yl)cyclopropane-1-carboxylic acid -Chloro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole -1-yl)-3-fluoro-[1,1'-biphenyl]-4-yl)cyclopropane- 1-carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy) )carbonyl)amino)-1H-pyrazol-1-yl)-2-fluoro-[1,1'- Biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(2-chloro -4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane- 1-carboxylic acid, (R)-1-(2-chloro-4'-(4-chloro-5-(((1-phenyl) (1,1'-biphenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenylethoxy] (R)-1-(4'-(4-phenyl)-4-yl)cyclopropane-1-carboxylic acid Fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole -1-yl)-2-methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy) Carbonyl)amino)-1H-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl] (R)-1-(2-chlorophenyl)-4-yl)cyclopropane-1-carboxylic acid 1-(4'-(1-carbamoylcyclopropyl)-[1,1'-biphenyl]ethyl (R )-1-(2-chlorophenyl)ethyl(4-fluoro-1-(2'-fluoro-4'- (1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl (R)-1-phenyl Ethyl (4-fluoro-1-(2'-fluoro-4'-(1-((methylsulfonyl)carbonyl) (Rubamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazo (R)-1-(2-chlorophenyl)ethyl(4-chloro-5-yl)carbamate 1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclohexyl)methyl)-4'-(methylsulfon ... Propyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl) Carbamate, (R)-1-phenylethyl (4-chloro-1-(4'-(1-((methyl Sulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl) -1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethoxy 4-fluoro-1-(4'-(1-((methylsulfonyl)carbamoyl)cyclo[ ... Propyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl) Carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H- Tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)- 4-Fluoro-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl 1-(4'-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1 '-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrazolium) (5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-chloro (R)-1-phenylethyl (4-chloro-1H-pyrazol-5-yl)carbamate 1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-( ... (R)-1-(2-phenyl)-4-yl)-1H-pyrazol-5-yl)carbamate -chlorophenyl)ethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl) (chloropropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl ) carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(chlorophenyl) (Anocarbamoyl)cyclopropyl)-2'-fluoro-[1,1'-biphenyl]-4 -yl)-4-fluoro-1H-pyrazol-5-yl)carbamate, (R)-2-( 4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4- Cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2- Methylpropanoic acid, (R)-2-(4'-(4-cyano-5-(((1-phenylethoxy) (C)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl] The compound according to embodiment 43A, wherein the compound is 2-methyl-4-yl-2-methylpropanoic acid.

[0254] Embodiment 45A. For the preparation of a medicament for treating an LPA-dependent disease or condition, The compound of any one of Forms 1A to 44A.

[0255] The compounds in Table 1 are illustrative of the present invention but are not limiting, and additional compounds may be Prepared according to the appropriately modified procedures of the Examples for the preparation of Compounds 1-28.

[0256] [Table 1]

[0257] [Table 2] [Example]

[0258] HPLC method HPLC traces of the synthesized examples were obtained using an Agilent 1100 Series Autosampler. An Agilent HPLC pump, degasser, and UV detector were used. Recorded using PLC. MS detector (APCI) PE Sciex API 150 EX was installed to record mass spectral data. HPLC / mass traces were obtained using one of the methods.

[0259] Method 1: Column Zorbax C18, size 4.6 mm x 7.5 cm; Solvent A: 0 in water 0.05% TFA, Solvent B: 0.05% TFA in acetonitrile; Flow rate - 0.7 mL / Gradient: 5% B to 100% B in 9 minutes, hold at 100% B for 4 minutes, and and 100% B to 5% B in 0.5 min; UV detector - channel 1 = 220 nm, Nel2 = 254 nm.

[0260] Method 2: Column Zorbax C18, size 4.6 mm x 7.5 cm; Solvent A: 0 in water 0.05% TFA, Solvent B: 0.05% TFA in acetonitrile; Flow rate - 0.7 mL / Gradient: 5% B to 100% B in 5 minutes, hold at 100% B for 2 minutes, and and 100% B to 5% B in 0.5 min; UV detector - channel 1 = 220 nm, Nel2 = 254 nm.

[0261] Method 3: 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, then 1.25 min. Hold at 90% B for 0.25 minutes, then change from 90% B to 10% B for 1.5 minutes. Stand and hold at 10% B; UV detector - channel 1 = 220 nm, channel 2 = 254 nm m.

[0262] Method 4: Column Zorbax C18, size 4.6 mm x 50 mm, 5 μ particle size; solvent A Solvent B: acetonitrile; Solvent B: 0.1% HCOOH in water; Flow rate: 1.5 mL / min; Gradient 10-95% A in 2.5 minutes.

[0263] Example 1: (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy )carbonyl)amino)-4-fluoro-1H-pyrazol-1-yl)pyridine-2- (I)phenyl)cyclopropane-1-carboxylic acid [Compound 1] Step 1: Ethyl 2-(6-chloro-3-pyridyl)-2H-pyrazole-3-carboxylate rate Ethyl pyruvate (3.89 mL, 35.0 mmol) and dimethylformamide ethyl acetal (9.30 mL, 70.0 mmol) and para-toluenesulfonic acid (1 A mixture of 100 mg of HCl was stirred at room temperature overnight and then heated to 80° C. for 2 hours. The mixture was cooled to rt and concentrated to dryness in vacuo. The 3-butenoate was dissolved in ethanol (90 mL) and (6-chloro-3-pyridyl) Hydrazine hydrochloride (7.5 g, 35.0 mmol) and concentrated hydrochloric acid (250 μL) The resulting mixture was heated to 88°C overnight, then cooled to room temperature and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with a hexane / ethyl acetate gradient. The two regioisomers were separated - the desired isomer A [ethyl 2- (6-chloro-3-pyridyl)-2H-pyrazole-3-carboxylate] was first The undesired regioisomer B [ethyl 1-(6-chloro-3-pyridyl) -1H-pyrazole-3-carboxylate] was isolated as the more polar compound. The desired product was obtained as a yellow oil that solidified on standing. Isomer A, Yield = 216 mg (2%). Method 3, Rt 2.68 min. MS (ESI) m / z 251.9[M+H + ]. 1 H NMR (CDCl3) δ 8.50 (d, J= 2.0Hz,1H);7.78(dd,J1=6.8Hz,J2=2.0Hz,1H); 7.75(d,J=1.6Hz,1H);7.43(d,J=6.8Hz,1H);7. 08(d,J=1.6Hz,1H);4.28(q,J=5.6Hz,2H);1.31 ,(t,J=5.6Hz,3H). Isomer B, yield = 150 mg (1.7%). Method 3, Rt 2.70 minutes. MS(ESI ) m / z 251.9[M+H + ]. 1 H NMR (CDCl3) δ 8.77 (d, J=2.4Hz,1H);8.15(dd,J1=7.2Hz,J2=2.4Hz,1H );7.96(d,J=2.0Hz,1H);7.46(d,J=6.8Hz,1H); 7.04(d,J=2.0Hz,1H);4.45(q,J=5.6Hz,2H);1. 43,(t,J=5.6Hz,3H).

[0264] Step 2: 2-(6-chloro-3-pyridyl)-2H-pyrazole-3-carboxylic acid Ethyl 2-(6-chloro-3-pyridyl)-2H-pyrazole-3-carboxylate [Example 1, Step 1] (205 mg, 0.814 mmol) in THF (4 mL) The resulting mixture was treated with 4 mL of aqueous LiOH (M) and stirred vigorously at room temperature for 16 h. LCMS showed complete conversion to the product. The reaction mixture was transferred to a separatory funnel and diluted with 0. Treat with 1N aqueous HCl to bring the pH to about 1. The product was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to give the product as a white solid. Yield = 190 mg (quantitative). Method 3, Rt 1.71 min (broad). MS (ESI) m / z 224.5[M+H + ].

[0265] Step 3: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- (6-chloro-3-pyridyl)-2H-pyrazole 2-(6-chloro-3-pyridyl)-2H-pyrazole-3-carboxylic acid [Example 1, Step 2] (190 mg, 0.82 mmol) was suspended in dichloromethane (4 mL) and the catalyst The reaction mixture was treated with a small amount of N,N-dimethylformamide (2 drops) at room temperature. / Cooled to 0°C in a water bath. Add oxalyl chloride (143 μL, 1.64 mmol) dropwise. The resulting mixture was stirred at 0°C for 15 minutes and at room temperature for 2 hours. and subjected to LCMS analysis, which showed complete conversion to the corresponding acid chloride. The volatiles were removed under reduced pressure to give the crude acid chloride as a white solid. The solid was suspended in ethyl acetate (4 mL) and heated with vigorous magnetic stirring at room temperature in NaN3 (1 After 1 hour, an aliquot was treated with a solution of 0.07 mg (1.64 mmol) of HCl in 4 mL of water. When dissolved in methanol and subjected to LCMS analysis, it was found to be completely converted to the corresponding acyl azide. The organic layer was separated, dried over anhydrous MgSO4, filtered, and evaporated under vacuum at room temperature. Evaporation with toluene gave the crude acyl azide as a white solid. 4 mL) and heated to 95°C for 30 minutes with stirring, and gas evolution was observed. (R)-1-(o-chlorophenyl)-1-ethanol (157 mg, 1.0 mmol) l) was added and the resulting mixture was heated to 65°C overnight. The reaction mixture was cooled to room temperature and The crude residue was purified by silica gel column eluting with a hexane / ethyl acetate gradient. The pure product was obtained as a colorless oil. Yield = 308mg (quantitative). Method 3, Rt 2.97 minutes. MS(ESI) m / z 377. 2[M+H + ].

[0266] Step 4: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- (6-chloro-3-pyridyl)-4-fluoro-2H-pyrazole Selectfluor® (236 mg, 0.67 mmol) was dissolved in acetonitrile 3-[(R)-1-(o-chlorophenyl)-2-methyl-2-propanol] in tolyl (2.7 mL) and glacial acetic acid (270 μL) [phenyl]ethoxycarbonylamino]-2-(6-chloro-3-pyridyl)-2H-pyra A stirred solution of stizole [Example 1, Step 3] (100 mg, 0.27 mmol) The resulting mixture was stirred overnight and then The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 and The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated. Preparative thin-layer chromatography was performed eluting with a 4:1 (volume ratio) mixture of hexane / ethyl acetate. Purification by column chromatography (TLC) gave the pure product as a colorless film. =42mg(40%). Method 3, Rt 3.04 minutes. MS(ESI) m / z 395. 3[M+H + ].

[0267] Step 5: (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy) Carbonyl)amino)-4-fluoro-1H-pyrazol-1-yl)pyridin-2-yl (phenyl)phenyl)cyclopropane-1-carboxylic acid 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(6- (chloro-3-pyridyl)-4-fluoro-2H-pyrazole [Example 1, Step 4] (42 mg, 0.107 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 m L), 2M Na2CO3 aqueous solution (360 μL), and 4-[(1-methoxycarbonyl )Cyclopropyl]phenylboronic acid pinacol ester (48 mg, 0.161 mmol) l) The stirring mixture was degassed under N2 for 10 minutes; The resulting mixture was treated with Pd[PhP] (6 mg, 0.005 mmol). The reaction mixture was heated to 5°C and stirred at that temperature for 16 hours. The reaction mixture was cooled to room temperature and the product was extracted with acetic acid. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and filtered. After concentration in vacuo, the crude product was directly dissolved in THF (1 mL) and 1M LiO The resulting mixture was stirred at room temperature for 16 hours. The pH was adjusted to 1. The reaction mixture was treated with 1M aqueous HCl to obtain the product. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and filtered. After concentration in air, the residue was eluted with a 50:50 (v / v) mixture of hexane / ethyl acetate. The product was purified by preparative thin layer chromatography on silica gel. Yield: 19 mg (34 %). Method 3, Rt 2.98 minutes. MS(ESI) m / z 521.5[M+H + ].

[0268] Example 2: (R)-1-(4-(5-(4-chloro-5-(((1-(2-chlorophenyl) (I)ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)pyridin-2-yl (phenyl)cyclopropane-1-carboxylic acid [Compound 2] Step 1: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-4- Chloro-2-(6-chloro-3-pyridyl)-2H-pyrazole 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(6- chloro-3-pyridyl)-2H-pyrazole [Example 1, Step 3] (158 mg, 0.4 A solution of N-chlorobenzoate (2 mmol) in acetonitrile (2.1 mL) was stirred at room temperature. The resulting mixture was treated with succinimide (64 mg, 0.48 mmol). The resulting mixture was cooled to room temperature and heated for 1 hour. Preparative thin-layer chromatography eluting with a 4:1 (volume ratio) mixture of hexane and ethyl acetate. The desired product was isolated as a white solid with an Rf of 0.2. Yield = 13 mg (8%). Method 3, Rt 3.09 minutes. MS(ESI) m / z 411 .4[M+H + ].

[0269] Step 2: (R)-1-(4-(5-(4-chloro-5-(((1-(2-chlorophenyl )Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)pyridin-2-yl )phenyl)cyclopropane-1-carboxylic acid 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-4-chloro -2-(6-chloro-3-pyridyl)-2H-pyrazole [Example 2, Step 1] (13m g, 0.032 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL ), 2M Na2CO3 aqueous solution (300 μL), and methyl 1-[p-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropane A stirred mixture of carboxylate (15 mg, 0.048 mmol) was added under N2 for 10 min. The mixture was degassed and treated with Pd[Ph3P]4 (4 mg, 0.0032 mmol). The mixture was heated to 85° C. and stirred at that temperature for 8 hours. The reaction mixture was cooled to room temperature and the product The residue was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and After concentration in vacuo, the crude product was directly dissolved in THF (1 mL) and diluted to 1 M It was treated with aqueous LiOH (1 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with 1M aqueous HCl to bring the pH to 1. The product was extracted with acetic acid. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and filtered. After concentration in vacuo, the residue was diluted with a 50:50 (v / v) mixture of hexane and ethyl acetate. The mixture was purified by preparative thin layer chromatography on silica gel eluting with hexane. Yield=1.7 mg(10%). Method 3, Rt 3.07 minutes. MS(ESI) m / z 537.1[M +H + ].

[0270] Example 3: (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)-2-methyl-2-methyl-4 ...2-methyl-4 (carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- (I)cyclopropane-1-carboxylic acid [Compound 3] Step 1: Ethyl-2-acetyl-3-(dimethylamino)acrylate Ethyl acetoacetate (200.0 g, 1.54 mol) and dimethylformamide di A mixture of methyl acetal (219.7 g, 1.84 mol) was stirred at room temperature for 16 hours. The reaction was monitored by thin layer chromatography (30% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure to give 290.0 g of crude product, which was purified further. Carried on to next step without further purification. Method 4, Rt 1.584 min. MS(ESI) m / z 186 .00-187.00[M+H + ]. 1 H NMR(DMSO-d6)δ 7.60(s,1H);4.13(q,2H); 3.34-2.90(br,6H);2.14(s,3H);1.24(t,3H).

[0271] Step 2: Ethyl 1-(p-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylate Boxylate Ethyl-2-acetyl-3-(dimethylamino)acrylate [Example 3, Step 1] ( A solution of 290.0 g (1.57 mol) of 4-bromophenytoin in ethanol (4.35 L) was To the resulting mixture was added hydrazine hydrochloride (315.0 g, 1.41 mol) at room temperature. The reaction was refluxed for 3 hours. The progress of the reaction was monitored by thin layer chromatography (hexane The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was then Recrystallization from 10% diethyl ether in water gave 174.0 g of the title compound. The resulting product was a yellow solid. The mother liquor was concentrated to dryness and washed with 10% diethyl ether in hexane. Recrystallization from HCl gave another 116.0 g of product. Total yield = 290.0 g (60% yield). ). Method 4, Rt 2.954 minutes. MS(ESI) m / z 309.00-310.0 0[M+H+ ]. 1 H NMR(DMSO-d6)δ 8.03(s,1H);7.78(d,2H); 7.53(d,2H);4.26(m,2H);3.34(s,3H);1.30(m, 3H).

[0272] Step 3: 1-(p-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid Ethyl 1-(p-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylate Dissolve the ester [Example 3, Step 2] (200.0 g, 0.65 mol) in ethanol (1.4 L) ) solution, an aqueous solution of KOH (72.45 g, 1.29 mol) dissolved in water (1 L) was added. The resulting mixture was refluxed for 3 hours. The reaction was monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure to give the compound The corresponding potassium salt was formed, which was dissolved in water and washed with diethyl ether. The mixture was neutralized with aqueous NHCl and extracted with ethyl acetate. The organic layer was washed with water and brine. Then, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 172.0 g The product was obtained as an off-white solid (yield=95%). Method 4, Rt 2.341 min. M S(ESI) m / z 280.8-280.9[M+H + ]. 1 H NMR(DMSO-d6)δ 12.48(s,1H);7.99(s,1H) ;7.77(d,2H);7.53(d,2H);3.36(s,3H).

[0273] Step 4: 1-(p-bromophenyl)-5-methyl-1H-pyrazole 1-(p-Bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [Implementation Example 3, Step 3] (300.0 g, 1.07 mol) was placed in a 3-liter round-bottom flask. The mixture was stirred at 260°C (bath temperature 280-300°C) for 10 hours. The reaction mixture was monitored by HPLC (10% methanol in chloroform). Diluted with ether, washed with 10% sodium carbonate, water, and brine, then with sodium sulfate. The organic layer was concentrated under reduced pressure to give 200.0 g of product. Obtained as a brown liquid (Yield - 79%). Method 4, Rt 2.739 min. MS(ESI) m / z 237.0-239.9 [M+H + ].

[0274] Step 5: 2-(p-Bromophenyl)-2H-pyrazole-3-carboxylic acid 1-(p-Bromophenyl)-5-methyl-1H-pyrazole [Example 3, Step 4] A solution of 200.0 g (0.84 mol) of tert-butanol (2 L) was added to 1 L of water. The solution was treated with an aqueous solution of dissolved KOH (141.7 g, 2.53 mol) at room temperature, followed by treatment with KMnO4 (266.6 g, 1.69 mol). Reflux for 3 hours, then continue heating for 10 hours, adding the same amount of KMnO4 at intervals of 1 hour. The reaction was monitored by thin layer chromatography (1 in chloroform). 0% methanol). The reaction mixture was filtered through a pad of Celite and washed with hot water. The aqueous solution was washed with diethyl ether, then neutralized with 6N HCl solution and ethyl acetate was added. The organic layer was washed with water, brine, then dried over sodium sulfate and filtered. Filtration and concentration under reduced pressure gave 120.0 g of product as a pale yellow solid (yield = 53%). Method 4, Rt 2.210 minutes. MS(ESI) m / z 269.00[M+ H + ]. 1 H NMR(DMSO-d6)δ 13.40(s,1H);7.79(s,1H) ;7.66(d,2H);7.43(d,2H);7.03(s,1H).

[0275] Step 6: 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl) (phenyl)-2H-pyrazole 2-(p-Bromophenyl)-2H-pyrazole-3-carboxamide in toluene (64 mL) A suspension of benzoic acid [Example 3, Step 5] (1.69 g, 6.36 mmol) was added to triethyl ether. Amine (1.07 mL, 7.63 mmol), (R)-1-phenyl-1-ethanol ( 1.16 g, 9.54 mmol), and diphenylphosphoryl azide (1.94 g, 7. The reaction was monitored by LCMS. The resulting solution was heated to 90° C. for 6 h. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude residue was purified by silica gel chromatography eluting with a hexane / ethyl acetate gradient. The product was obtained as a yellow oil that solidified on standing. Yield = 839 ml g(34%). Method 3, Rt 3.05 minutes. MS(ESI) m / z 388.0[M+ H + ].

[0276] Step 7: 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl) (phenyl)-4-fluoro-2H-pyrazole 3-[(R)-1-phenyl]-2-(2-(2-(4 ... [Ethoxycarbonylamino]-2-(p-bromophenyl)-2H-pyrazole [Implementation Example 3, Step 6] Add a stirred solution of (385 mg, 1.0 mmol) of Select fluor® (354 mg, 1.0 mmol), and the resulting mixture was Stirred at room temperature overnight. LCMS showed 90% conversion to product. ctfluor® (70 mg) was added and the reaction was stirred at room temperature for an additional 10 hours. LCMS indicates the reaction is complete. The reaction mixture is concentrated in vacuo to give a crude residue. The organic layer was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated aqueous NaHCO3, and brine. The organics were dried over anhydrous MgSO4, filtered and evaporated. The membrane was purified by silica gel chromatography eluting with a hexane / ethyl acetate gradient. Yield = 278 mg (69%). Method 3, Rt 3.36 min. MS(ESI) m / z 404-.1-406.0[M+H + ].

[0277] Step 8: (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbamate) (1H-pyrazol-1-yl)amino)-[1,1'-biphenyl]-4-yl (I)cyclopropane-1-carboxylic acid 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-fluoro-2H-pyrazole [Example 3, Step 7] (55 mg, 0.136 mm ol), a 2:1 (volume ratio) mixture of toluene and ethanol (1.4 mL), and 2M N a2CO3 aqueous solution (450 μL) and 4-[(1-methoxycarbonyl)cyclopropyl ] a stirred mixture of phenylboronic acid pinacol ester (54 mg, 0.180 mmol) The solution was degassed under N2 for 10 min and added to Pd[Ph3P]4 (8 mg, 0.0068 mmol). The resulting mixture was heated to 85°C and stirred at that temperature for 16 hours. The mixture was cooled to room temperature and the product was extracted with ethyl acetate. The organic layer was washed with water and brine. After drying over anhydrous MgSO4 and filtering, the crude product was concentrated in vacuo and dissolved in THF (1 mL ) and treated with 1M aqueous LiOH (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The pH was adjusted to 1 with 1M aqueous HCl. The product was extracted with ethyl acetate, and the organic layer was washed with water and brine, and After concentration in vacuo, the residue was diluted with 95:5 (volume ratio) dichloromethane and 1,2-dichloromethane. Preparative thin-layer chromatography on silica gel eluting with methyl ethane / methanol mixtures Purified from Method 3. Yield = 28 mg (43%). Rt 3.25 min. MS (ESI) m / z 486.2[M+H + ].

[0278] Example 4: (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbamate) (1H-pyrazol-1-yl)amino)-[1,1'-biphenyl]-4-yl Cyclopropane-1-carboxylic acid [Compound 4] Step 1: 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl) (phenyl)-4-chloro-2H-pyrazole N-Chlorosuccinimide (97 mg, 0.73 mmol) was dissolved in acetonitrile (3. 7 mL) in 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromo (281 mg, 0.73 mmol)-2H-pyrazole [Example 3, Step 6] The resulting mixture was heated to 80°C for 5 hours, after which the reaction The reaction mixture was cooled to room temperature and concentrated in vacuo to give a 4% yield of 100% methyl 2-hydroxybenzoate. The product was directly separated by silica gel column chromatography eluting with a hexane / ethyl acetate gradient. The product was obtained as a yellow oil that solidified on standing. Yield = 277 mg ( 91%). Method 3, Rt 3.24 minutes. MS(ESI) m / z 422.1[M+H + ].

[0279] Step 2: Methyl 1-(4'-{5-[(R)-1-phenylethoxycarbonylamino] -4-chloro-1H-pyrazol-1-yl}-4-biphenylyl)cyclopropane chlor Boxylate 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (43 mg, 0.103 mmol) l) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL) and 2M NaCl O3 aqueous solution (343 μL) and methyl 1-[p-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (4 A stirred mixture of Pd[Ph3 The resulting mixture was heated to 85°C. The reaction mixture was cooled to room temperature and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. After condensation, the residue was chromatographed on silica gel eluting with a hexane / ethyl acetate gradient. Purified by HPLC. Yield = 45 mg (85%). Method 3, Rt 3.34 min. MS(E SI) m / z 516.1 [M+H + ].

[0280] Step 3: (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbo Nyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl )Cyclopropane-1-carboxylic acid Methyl 1-(4'-{5-[(R)-1-phenylethoxycarbonylamino]-4- Chloro-1H-pyrazol-1-yl}-4-biphenylyl)cyclopropanecarboxy Dissolve 45 mg of methylpropional [Example 4, Step 2] (0.087 mmol) in 1 mL of THF. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was treated with 1M aqueous HCl to bring the pH to 1. The product was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous MgSO4, and After concentration in vacuo, the residue was diluted with 95:5 (volume ratio) dichloromethane / Purification was performed by preparative thin layer chromatography on silica gel eluting with a mixture of methanol. Yield = 23 mg (53%). Method 3, Rt 3.11 min. MS(ESI) m / z 502.3[M+H + ].

[0281] Example 5: (R)-1-(4'-(4-cyano-5-(((1-phenylethoxy)carbamate) (1H-pyrazol-1-yl)amino)-[1,1'-biphenyl]-4-yl Cyclopropane-1-carboxylic acid [Compound 5] Step 1: 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl) (phenyl)-2H-pyrazole-4-carbonitrile 5-Amino-1-(4-bromophenyl)-1H-pyrazoline in THF (4.8 mL) benzoyl-4-carbonitrile (262 mg, 1.0 mmol) and triphosgene (436 mg The stirred suspension containing triethylamine (730 μL, 5.26 mmol) was added to the flask. The resulting mixture was heated to 90°C for 30 minutes. and then treated with (R)-1-phenylethanol (160 μL, 1.3 mmol). The reaction was heated to 105°C for 3 hours, after which time TLC (5% aldehyde in toluene) showed Monitoring with acetone indicated that one major product was formed. The reaction was heated to room temperature. The mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in a 95:5 (volume ratio) mixture of toluene and acetone, respectively. The product was purified directly by preparative thin layer chromatography eluting with a 200 mL hexanes (2 mL) mixture. Yield = 153 mg (37%). Method 3, Rt 3.53 min. MS (ES I) m / z 411.5-413.6 [M+H + ].

[0282] Step 2: Methyl 1-[p-(4,4,5,5-tetramethyl-1,3,2-dioxaboro] (2-yl)phenyl]cyclopropanecarboxylate 1-(p-Bromophenyl)cyclopropanecarboxylic acid (1.22 g, 5.0 mmol) ) was dissolved in methanol (20 mL) and cooled to -20°C using ice water (2 parts) and salt (1 part). The mixture was cooled to °C. To this solution, thionyl chloride (1.45 mL, 20.0 mmol) was added dropwise. After the addition was complete, the reaction was stirred for 15 minutes at -20°C and then allowed to stand for 2 hours. The reaction was concentrated in vacuo and the residue was stirred for 1 hour at rt. The mixture was partitioned between dichloromethane and saturated aqueous Na2CO3. The organic layer was dried over anhydrous MgSO4. The mixture was filtered and evaporated to give methyl 1-(p-bromophenyl)cyclopropanecarboxylate. This material was reacted with 1,4-dioxo-2-methylpropanol to give the silane (1.08 g, 4.2 mmol, 84%). Dissolve bis(pinacolato)diboron (3.19 g, 12.1 mmHg) in 20 mL of ammonium hydroxide. ol), KOAc (1.24 g, 12.6 mmol) and [1,1'-bis(diphenyl Complexes of [phosphino]ferrocenedichloropalladium(II) with dichloromethane (32 The resulting mixture was heated to 100°C overnight and then The mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with methanol. A portion of the crude material was separated by preparative chromatography on a thin layer of silica gel, eluting with hexane. Purified by chromatography. The product is a white solid. Yield = 270 mg. Method 3, Rt 3.08 minutes. MS(ESI) m / z 303.4[M+H + ].

[0283] Step 3: Methyl 1-(4'-{5-[(R)-1-phenylethoxycarbonylamino] -4-cyano-1H-pyrazol-1-yl}-4-biphenylyl)cyclopropanecarboxamide Boxylate 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-2H-pyrazole-4-carbonitrile [Example 5, Step 1] (58 mg, 0.14 mmol), 1,4-dioxane (2 mL), and 2 M aqueous Na2CO3 (315 μL) L) and methyl 1-[p-(4,4,5,5-tetramethyl-1,3,2-dioxaboro (2-phenyl)cyclopropanecarboxylate [Example 5, Step 2] (5 A stirred mixture of Pd[PhP ]4 (23 mg, 0.02 mmol). The resulting mixture was heated to 95 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of CELITE, and washed with methanol. The filtrate was concentrated in vacuo and the crude residue was extracted with 70% hexane and 70% ethyl acetate. It was directly purified by preparative thin-layer chromatography eluting with a 1:30 (volume ratio) mixture. . Yield = 18 mg (26%). Method 3, Rt 3.13 minutes. MS(ESI) m / z 5 07.6[M+H + ].

[0284] Step 4: (R)-1-(4'-(4-cyano-5-(((1-phenylethoxy)carbo Nyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl )Cyclopropane-1-carboxylic acid Methyl 1-(4'-{5-[(R)-1-phenylethoxycarbonylamino]-4- Cyano-1H-pyrazol-1-yl}-4-biphenylyl)cyclopropanecarboxy Dissolve 18 mg of methylpropional [Example 5, Step 3] (0.03 mmol) in 1 mL of THF. and treated with 1M aqueous LiOH (1 mL), and the resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography (30% acetic acid in hexane). The reaction was treated with 1M aqueous HCl (3 mL) and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude residue was Each was subjected to preparative thin-layer chromatography eluting with a 70:30 (volume ratio) mixture of toluene and acetone. The product was obtained as a white solid. Yield = 10 mg (7 1%). Method 3, Rt 2.77 minutes. MS(ESI) m / z 493.6[M+H + ] .

[0285] Example 6: (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)- (carbonyl)amino)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl Nyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 6] Step 1: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- (p-Bromophenyl)-2H-pyrazole-4-carbonitrile 5-Amino-1-(4-bromophenyl)-1H-pyrazoline in THF (4.8 mL) benzoyl-4-carbonitrile (262 mg, 1.0 mmol) and triphosgene (436 mg The stirred suspension containing triethylamine (730 μL, 5.26 mmol) was added to the flask. The resulting mixture was heated to 90°C for 30 minutes. Then, (R)-1-(2-chlorophenyl)ethanol (172 μL, 1.3 The reaction was heated to 105° C. for 3 hours, after which time TLC ( Monitoring with 5% acetone in toluene showed that one major product was formed. The reaction was cooled to room temperature and concentrated in vacuo. The residue was extracted with 9 mL of toluene and acetone, respectively. Direct purification was performed by preparative thin-layer chromatography eluting with a 5:5 (volume ratio) mixture The product was obtained as a solid. Yield = 153 mg (37%). Method 3, Rt 2.94 Minutes. MS(ESI) m / z 445.5-447.5[M+H + ].

[0286] Step 2: Methyl 1-(4'-{5-[(R)-1-(o-chlorophenyl)ethoxy]methyl 4-(4-cyano-1H-pyrazol-1-yl)-4-biphenylyl)cyclohexyl Isopropanecarboxylate 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-2H-pyrazole-4-carbonitrile [Example 6, Step 1] (51 mg, 0.14 mmol), 1,4-dioxane (2 mL), and 2 M aqueous Na2CO3 Solution (315 μL) and methyl 1-[p-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate [Example 5 , step 2] (51 mg, 0.17 mmol) was degassed under N2 for 10 min, The resulting mixture was treated with Pd[PhP] (23 mg, 0.02 mmol). The reaction mixture was heated to 5°C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of CELITE. The filtrate was concentrated in vacuo, and the crude residue was purified by hexane and acetic acid, respectively. The eluate was analyzed by preparative thin-layer chromatography eluting with a 70:30 (volume ratio) mixture of ethyl acetate and ethyl acetate. Direct purification. Yield = 25 mg (33%). Method 3, Rt 3.20 min. MS (ESI ) m / z 541.3[M+H + ].

[0287] Step 3: (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbamate) (1,1'-biphenyl)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl] [4-(4-yl)cyclopropane-1-carboxylic acid] Methyl 1-(4'-{5-[(R)-1-(o-chlorophenyl)ethoxycarbonyl Amino]-4-cyano-1H-pyrazol-1-yl}-4-biphenylyl)cyclopro Pancarboxylate [Example 6, Step 2] (25 mg, 0.03 mmol) was dissolved in THF ( The resulting mixture was dissolved in 1 mL of 1M LiOH (1 mL) and treated with 1 M aqueous LiOH (1 mL). The reaction was stirred overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (Hexa The reaction was treated with 1M aqueous HCl (3 mL) to give the product. The extract was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The residue was eluted with a 70:30 (volume ratio) mixture of toluene and acetone, respectively. Purification was carried out by preparative thin layer chromatography. The product was obtained as a white solid. Yield =12mg(76%). Method 3, Rt 2.88 minutes. MS(ESI) m / z 527. 5[M+H + ].

[0288] Example 7: (R)-1-(3-fluoro-4'-(4-fluoro-5-(((1-phenyl) (Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl] Phenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 7] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-fluoro-2H-pyrazole [Example 3, Step 7] (55 mg, 0.136 mm ol), a 2:1 (volume ratio) mixture of toluene and ethanol (1.4 mL), and 2M N a2CO3 aqueous solution (450 μL) and 4-(1-carboxycyclopropyl)-3-fluoro Mixture of phenylboronic acid pinacol ester (55 mg, 0.180 mmol) with stirring. The mixture was degassed under N2 for 10 min and Pd[Ph3P]4 (8 mg, 0.0068 mmol) The resulting mixture was heated to 85°C and stirred at that temperature for 16 hours. The mixture was cooled to room temperature and treated with 1M aqueous HCl to bring the pH to 1. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and After concentration in vacuo, the crude product was extracted with 95:5 (volume ratio) dichloromethane / methanol. Purification was performed by preparative thin-layer chromatography on silica gel eluting with a mixture of ethanol. . Yield = 7 mg (10%). Method 3, Rt 3.26 minutes. MS(ESI) m / z 50 4.2[M+H + ].

[0289] Example 8 -(R)-1-(2-fluoro-4'-(4-fluoro-5-(((1-phenyl) (Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl] Phenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 8] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-fluoro-2H-pyrazole [Example 3, Step 7] (55 mg, 0.136 mm ol), a 2:1 (volume ratio) mixture of toluene and ethanol (1.4 mL), and 2M N a2CO3 aqueous solution (450 μL) and 4-(1-carboxycyclopropyl)-2-fluoro Mixture of phenylboronic acid pinacol ester (55 mg, 0.180 mmol) with stirring. The mixture was degassed under N2 for 10 min and Pd[Ph3P]4 (8 mg, 0.0068 mmol) The resulting mixture was heated to 85°C and stirred at that temperature for 16 hours. The mixture was cooled to room temperature and treated with 1M aqueous HCl to bring the pH to 1. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and After concentration in vacuo, the crude product was extracted with 95:5 (volume ratio) dichloromethane / methanol. Purification was performed by preparative thin-layer chromatography on silica gel eluting with a mixture of ethanol. . Yield = 19 mg (28%). Method 3, Rt 3.27 minutes. MS(ESI) m / z 5 04.2[M+H + ].

[0290] Example 9: (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbamate) (1H-pyrazol-1-yl)-3-fluoro-[1,1'-biphenyl] Nyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 9] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (43 mg, 0.103 mmol) l) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL) and 2M NaCl O3 aqueous solution (343 μL) and 1-[2-fluoro-4-(4,4,5,5-tetramethyl phenyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid ( A stirred mixture of Pd[Ph] (41 mg, 0.134 mmol) was degassed under N2 for 10 min and The resulting mixture was heated to 85° C. The reaction mixture was cooled to room temperature and poured into a 1M aqueous HCl solution. The solution was carefully treated to bring the pH to about 1. Ethyl acetate (1 mL) was added and the resulting mixture was After vigorously stirring for 5 minutes, the organic layer was separated and diluted with 95:1 of dichloromethane and methanol, respectively. The product was directly purified by preparative thin layer chromatography eluting with a 5 (volume ratio) mixture. Amount = 17mg (32%). Method 3, Rt 3.33 minutes. MS(ESI) m / z 520 .2[M+H + ].

[0291] Example 10: (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy))caprylate) (carbonyl)amino)-1H-pyrazol-1-yl)-2-fluoro-[1,1'-biphenyl] Phenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 10] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (43 mg, 0.103 mmol) l) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL) and 2M NaCl O3 aqueous solution (343 μL) and 1-[3-fluoro-4-(4,4,5,5-tetramethyl phenyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid ( A stirred mixture of Pd[Ph] (41 mg, 0.134 mmol) was degassed under N2 for 10 min and The resulting mixture was heated to 85° C. The reaction mixture was cooled to room temperature and poured into a 1M aqueous HCl solution. The solution was carefully treated to bring the pH to about 1. Ethyl acetate (1 mL) was added and the resulting mixture was After vigorously stirring for 5 minutes, the organic layer was separated and diluted with 95:1 of dichloromethane and methanol, respectively. The product was directly purified by preparative thin layer chromatography eluting with a 5 (volume ratio) mixture. Amount=9mg(17%). Method 3, Rt 3.14 minutes. MS(ESI) m / z 520. 3[M+H + ].

[0292] Example 11: (R)-1-(2-chloro-4'-(4-fluoro-5-(((1-phenyl) (Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl] Phenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 11] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-fluoro-2H-pyrazole [Example 3, Step 7] (55 mg, 0.136 mm ol), a 2:1 (volume ratio) mixture of toluene and ethanol (1.4 mL), and 2M N a2CO3 aqueous solution (450 μL) and 1-[3-chloro-4-(dihydroxyboranyl) [phenyl]cyclopropane-1-carboxylic acid (43 mg, 0.180 mmol) The mixture was degassed under N for 10 min and Pd[PhP] (8 mg, 0.0068 mmol) was added. The resulting mixture was heated to 85°C and stirred at that temperature for 16 hours. The mixture was cooled to room temperature and treated with 1M aqueous HCl to bring the pH to 1. The residue was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and After concentration in vacuo, the crude product was extracted with 95:5 (volume ratio) dichloromethane / Purification was performed by preparative thin layer chromatography on silica gel eluting with a mixture of methanol. Yield = 13 mg (19%). Method 3, Rt 3.31 min. MS(ESI) m / z 520.3 [M+H + ].

[0293] Example 12: (R)-1-(2-chloro-4'-(4-chloro-5-(((1-phenyl Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl Nyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 12] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (43 mg, 0.103 mmol) l) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL) and 2M NaCl O3 aqueous solution (343 μL) and 1-[3-chloro-4-(dihydroxyboranyl)phenyl] A stirred mixture of [[(2-chloro-1-methylcyclopropane-1-carboxylic acid] (32 mg, 0.134 mmol) , degassed under N2 for 10 min, and then treated with Pd[Ph3P]4 (6 mg, 0.052 mmol). The resulting mixture was heated to 85°C and stirred at that temperature overnight. The mixture was cooled to rt and carefully treated with 1 M aqueous HCl to bring the solution pH to approximately 1. Chiller (1 mL) was added and the resulting mixture was stirred vigorously for 5 min. The organic layer was separated and The column was subjected to preparative thin-layer chromatography while eluting with a 95:5 (volume ratio) mixture of dichloromethane and methanol. Directly purified by chromatography. Yield = 21 mg (38%). Method 3, Rt 3.2 0 min. MS(ESI) m / z 536.1 [M+H + ].

[0294] Example 13: (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy) Carbonyl)amino)-1H-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl] Phenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 13] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-fluoro-2H-pyrazole [Example 3, Step 7] (55 mg, 0.136 mm ol), a 2:1 (volume ratio) mixture of toluene and ethanol (1.4 mL), and 2M N a2CO3 aqueous solution (450 μL) and 1-[4-(dihydroxyboranyl)-3-methyl phenyl]cyclopropane-1-carboxylic acid (30 mg, 0.180 mmol) The mixture was degassed under N for 10 min and Pd[PhP] (8 mg, 0.0068 mmol) was added. The resulting mixture was heated to 85°C and stirred at that temperature for 16 hours. The mixture was cooled to room temperature and treated with 1M aqueous HCl to bring the pH to 1. The residue was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and After concentration in vacuo, the crude product was extracted with 95:5 (volume ratio) dichloromethane / Purification was performed by preparative thin layer chromatography on silica gel eluting with a mixture of methanol. Yield = 12 mg (18%). Method 3, Rt 3.13 min. MS(ESI) m / z 500.4[M+H + ].

[0295] Example 14: (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy))caprylate) (carbonyl)amino)-1H-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl] Nyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 14] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (43 mg, 0.103 mmol) l) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL) and 2M NaCl O3 aqueous solution (343 μL) and 1-[4-(dihydroxyboranyl)-3-methylphenyl] A stirred mixture of [[[(2-chloro-1-methylcyclopropane-1-carboxylic acid]]cyclopropane-1-carboxylic acid (29 mg, 0.134 mmol) , degassed under N2 for 10 min, and then treated with Pd[Ph3P]4 (6 mg, 0.052 mmol). The resulting mixture was heated to 85°C and stirred at that temperature overnight. The mixture was cooled to rt and carefully treated with 1 M aqueous HCl to bring the solution pH to approximately 1. Chiller (1 mL) was added and the resulting mixture was stirred vigorously for 5 min. The organic layer was separated and The column was subjected to preparative thin-layer chromatography while eluting with a 95:5 (volume ratio) mixture of dichloromethane and methanol. Directly purified by chromatography. Yield = 23 mg (43%). Method 3, Rt 3.1 8 min. MS(ESI) m / z 516.3 [M+H + ].

[0296] Example 15: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-carbamoyl)methyl)- (1,1'-biphenyl)-4-yl)-4-fluoro-1H- Pyrazol-5-yl)carbamate [Compound 15] Step 1: 1-(p-bromophenyl)cyclopropanecarboxamide 1-(p-Bromophenyl)cyclopropanecarbonitrile in ethanol (5 mL) A stirred solution of (500 mg, 2.25 mmol) was added to 1 M aqueous KOH (0.3 mL) and The resulting mixture was heated to 85° C. for 2 h. The reaction was cooled to room temperature, quenched with water, and the product was extracted with ethyl acetate. The crude product was washed with water, dried over anhydrous MgSO4, filtered and evaporated. which was used directly in the next step without further purification. Yield = 0.44 g (8 1%).

[0297] Step 2: 1-[p-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl]cyclopropanecarboxamide 1-(p-bromophenyl)cyclopropanecarboxamide [Example 15, Step 1] ( 430 mg, 1.8 mmol) was dissolved in 1,4-dioxane (5 mL) and KOAc( 210 mg, 2.1 mmol) and bis(pinacolato)diboron (545 mg, 2.1 mmol) The resulting mixture was degassed under N2 for 5 minutes and treated with [1,1'-bis(diphenyl ether)]. Phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (73 mg, 0.08 mmol) and heated to 95° C. for 4 h. The reaction was cooled The mixture was filtered through a pad of Celite and rinsed with ethyl acetate. The filtrate was diluted with water and brine. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was obtained as a dark oil (0.99 g). This material was purified without further purification. was used in the next step.

[0298] Step 3: Ethyl (E)-4-(dimethylamino)-2-oxo-but-3-enoate Ethyl pyruvate (5 g, 43.1 mmol) was dissolved in CH2Cl2 (86 mL). and treated with dimethylformamide dimethyl acetal (5.73 mL, 43.1 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product was carried on directly to the next step. Used. Yield = 7.4g.

[0299] Step 4: Ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate 4-Bromophenylhydrazine hydrochloride (2.0 g, 8.95 mmol) was dissolved in MeOH ( 18 mL) and the crude ethyl (E)-4-(dimethylamino)-2-oxo- was treated with thiazolinone-3-enoate [Example 15, Step 3] (1.54 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 6 hours. The volatiles were removed under reduced pressure and the residue was A 95:5 mixture of hexane / ethyl acetate ( The product was purified by chromatography on silica gel, eluting with 2,000 ml of hexane (v / v). Two isomeric products, namely, ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate, The carboxylate was obtained as an orange solid (0.82 g, 2.78 mmol, 31%) and and ethyl 1-(4-bromophenyl)pyrazole-3-carboxylate were obtained as red solids ( Isolated as 0.44 g, 1.49 mmol, 17%). Ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate: HPLC (25 4nm): Method 2 Rt 5.22 minutes. MS(ESI)m / z 297[M+H + ]; 294.8[M+H + ];252[(M-EtO)+H + ];250[(M-EtO)+ H + ]. 1 H NMR(500MHz, CDCl3)δ 7.69(d,J=1.9Hz, 1H) ;7.58(d,J=8.7Hz, 2H);7.32(d,J=8.7Hz, 2H);7 .03(d,J=1.9Hz, 1H);4.26(q,J=7.1Hz, 2H);1.2 8 (t, J = 7.1 Hz, 3 H). Ethyl 1-(4-bromophenyl)pyrazole-3-carboxylate: 1 H NMR (500MHz, CDCl3)δ 7.91(d,J=2.4Hz, 1H);7.65( d,J=7.2Hz, 2H);7.60(d,J=7.2Hz, 2H);7.00(d, J=2.4Hz, 1H);4.44(q,J=7.0Hz, 2H);1.43(t,J= 7.0Hz, 3H).

[0300] Step 5: 2-(4-bromo-phenyl)-4-fluoro-2H-pyrazole-3-carbohydrate Phosphonic acid ethyl ester Ethyl 2-(4-bromophenyl)pyrazole-3-carboxylate [Example 15, Step 4] (1.08 g, 3.68 mmol) was dissolved in acetonitrile (12 mL). The resulting mixture was treated with glacial acetic acid (4.6 mL). -4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro oroborate) (Selectfluor®, 3.91 g, 11.04 mmol) l) was added in one portion and the resulting mixture was heated to 105°C for 18 hours. The mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was directly loaded onto a silica gel column. The mixture was filled with hexane / ethyl acetate at 95:5, increasing in polarity to 9:1 with time. The product was purified by elution with a mixture (v / v) of The starting material was isolated as 0.31 mmol, 36%) and recovered as 0.93 mmol (272 mg, 0.93 mmol). mol, 25%). 2-(4-Bromo-phenyl)-4-fluoro-2H-pyrazole- 3-Carboxylic acid ethyl ester: HPLC (254 nm): Method 3 Rt 2.9 7 minutes. MS(ESI)m / z 313.1[M+H + ]. 1 H NMR(500MHz, CDCl3)δ 7.60(s,1H);7.58(d, J=9Hz, 2H);7.29(d,J=9Hz,2H);4.30(q,J=7.1H z, 2H);1.28(t,J=7.1Hz, 3H).

[0301] Step 6: 2-(4-bromo-phenyl)-4-fluoro-2H-pyrazole-3-carbohydrate Phosphoric acid 2-(4-Bromo-phenyl)-4-fluoro-2H-pyrazoline in THF (13 mL) 410 mg, 1.31 m A stirred solution of 1000 mol) was treated with a 1N aqueous solution of LiOH (13 mL), and the resulting mixture The mixture was stirred at room temperature overnight. The reaction was found to be complete by thin layer chromatography and HPLC / MS. The reaction mixture was diluted with ethyl acetate and 1N aqueous HCl (100 mL v The organic layer was separated, and the aqueous layer was diluted with ethyl acetate (30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. Upon concentration at 4°C, the pure product was obtained as a white solid (347 mg, 1.22 mmol, 93% ) HPLC (254 nm): Method 3 Rt 2.82 min. MS (ES I) m / z 285.1 [M+H + ].

[0302] Step 7: (R)-[2-(4-bromo-phenyl)-4-fluoro-2H-pyrazole- 3-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester 2-(4-Bromo-phenyl)-4-fluoro-2H-pyrazole-3-carboxylic acid [ Example 15, Step 6] (347 mg, 1.22 mmol) was suspended in toluene (12 mL). The resulting solution was stirred and treated with triethylamine (205 μL, 1.46 mmol). was treated with diphenylphosphoryl azide (316 μL, 1.46 mmol) and heated to 65° C. (R)-1-(2-chlorophenyl)-ethanol (230 mg, 1.46 mmHg) ol) was added to the reaction mixture and the temperature was increased to 105°C over 30 minutes, during which time Vigorous gas evolution was observed. The reaction was brought to 65°C and stirred at that temperature for 4 hours. The reaction was deemed complete by C / MS. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by silica gel chromatography eluting with a hexane / ethyl acetate gradient. The product was purified by HPLC as a white solid (452 ​​mg, 1.03 mmol, 85%). %). HPLC (254 nm): Method 3 Rt 3.16 min. MS (E SI) m / z 440.1 [M+H + ].

[0303] Step 8: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-carbamoyl) Cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-fluoro-1H-pyra (5-isole)carbamate (R)-[2-(4-bromophenyl)-4-fluoro-2H-pyrazol-3-yl] [Example 15, step 1]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester 7] (200 mg, 0.45 mmol) and 1-[p-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide [Example 15, Step 2] (196 mg, 0.68 mmol) in acetonitrile (3 mL) and treated with 2M aqueous Na2CO3 (1.5 mL). , degassed under N2 for 10 min, and then treated with Pd[Ph3P]4 (8 mg, 0.006 mmol). and heated to 80° C. for 6 hours, after which the reaction was deemed complete by LCMS. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was washed with water and brine. The organic layer was washed with brine and anhydrous Na2S The product was eluted with a hexane / ethyl acetate gradient. The pure product was obtained as a tan solid. Obtained. Yield = 28 mg (12%). Method 3, Rt 3.07 min. MS(ESI) m / z 518.4[M+H + ].

[0304] Example 16: (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(2'- Fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1 ,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate [compound Item 16] Step 1: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- (p-Bromophenyl)-2H-pyrazole 2 in dichloromethane (1880 mL) and N,N-dimethylformamide (1 mL) -(p-Bromophenyl)-2H-pyrazole-3-carboxylic acid [Example 3, Step 5] A mechanically stirred suspension of 100g of ethanol (376mmol) was cooled to 0°C under a nitrogen atmosphere. Oxalyl chloride (65.6 mL, 752 mmol) was added via a dropping funnel over approximately 30 minutes. The resulting suspension was allowed to warm to room temperature and then heated to reflux. After 2 hours of reflux, L CMS showed complete conversion to the acid chloride. The reaction mixture was cooled to room temperature and the volatiles were removed. The acid chloride was obtained as a light brown solid. This material was dissolved in acetic acid. ethyl acetate (940 mL) and NaN3 (48. After stirring at room temperature for 1 hour, LCMS showed The organic layer was separated, dried over anhydrous MgSO4, and filtered. The mixture was filtered and evaporated under vacuum at room temperature to give the acyl azide as a light brown solid. The product was dissolved in toluene (1880 mL) with mechanical stirring. The reaction was heated to 100°C. Upon heating at RT for 1 h, N2 evolution was observed. After MeOH quenching, the isocyanate The conversion to the intermediate was monitored by LCMS. )-1-ethanol (64.77 g, 413.6 mmol) was added dropwise, and the resulting mixture was The reaction was stirred overnight at 5° C. The reaction was cooled and concentrated to dryness in vacuo. The crude product was a viscous amber solid. This oil was dissolved in iPrO (500 mL) and stirred for 1 h at room temperature. The viscous light brown precipitate was filtered, rinsed with iPrO and air dried. The mother liquor was concentrated to dryness, and the resulting oily residue was treated with iPrO(20 The solid was redissolved in 100 mL of HCl (0.0 mL) and stirred at room temperature overnight. The solid was filtered, rinsed with iPrO, and air-dried. 10 g (6%) was obtained. Overall yield = 107 g (67%). Method 3, Rt 3.18 minutes. MS(ESI) m / z 422.1[M+H + ].

[0305] Step 2: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- (p-Bromophenyl)-4-fluoro-2H-pyrazole 3-[(R)-1-(o -chlorophenyl)ethoxycarbonylamino]-2-(p-bromophenyl)-2H- A stirred solution of pyrazole [Example 16, Step 1] (50 g, 119 mmol) Treated with Selectfluor® (105.4 g, 297.5 mmol) The resulting mixture was heated to 50° C. After 1.5 h, LCMS showed complete conversion to product. The reaction mixture was cooled and concentrated in vacuo. The crude residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and filtered. The viscous amber oil was dissolved in iPrO (300 mL) and stirred at room temperature. The precipitate was filtered under vacuum and air dried to give 40 g (77%) of pure product. Method 3, Rt 3.38 min. MS(ESI) m / z 439.8 [M+H + ] .

[0306] Step 3: 1-(4-bromo-3-fluorophenyl)-N-(methylsulfonyl)cyclo Propane-1-carboxamide 1-(4-bromo-3-fluorophenyl)cyclopropanecarboxylic acid (5.18 g, 20.0 mmol) was suspended in dichloromethane (100 mL) and a catalytic amount of N,N-dimethylformamide was added. The reaction mixture was cooled to 0° C. in an ice / water bath. After cooling, oxalyl chloride (3.49 mL, 40.0 mmol) was added dropwise and the resulting mixture The mixture was stirred at 0° C. for 15 minutes and at room temperature for 30 minutes, and then heated to reflux for 1.5 hours. When dissolved in methanol and subjected to LCMS analysis, it was found to be completely converted to the corresponding acid chloride. Volatiles were removed under reduced pressure to give the crude acid chloride as a white solid. A portion of the acid chloride (833 mg, 3.0 mmol) was dissolved in toluene. Dissolved in toluene and added triethylamine (2.1 mL, 15.0 mmol) and methyl sulfonyl alcohol. The resulting mixture was refluxed for 2 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The organic layer was dried over anhydrous MgSO4 and washed with 1N aqueous HCl and brine. Filtered and evaporated. The crude solid was triturated with diethyl ether and filtered. The product was obtained as a light brown solid. Yield = 439 mg (44%). Method 3, Rt 2 .60 minutes. MS(ESI) m / z 338.4[M+H + ].

[0307] Step 4: 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-diol) (2-oxaborolan-2-yl)phenyl)-N-(methylsulfonyl)cyclopropane-1- Carboxamide 1-(4-bromo-3-fluorophenyl)-N-(methylsulfonyl)cyclopropane 1-methyl-1-carboxamide [Example 16, Step 3] (437 mg, 1.30 mmol) 4-dioxane (13 mL) and potassium acetate (287 mg, 2.93 mmol). l) and pinacoldiborane (826 mg, 3.25 mmol). The mixture was degassed under N2 for 10 min. [1,1'-bis(diphenylphosphino)phenanthroline] [locene]dichloropalladium(II) complex with dichloromethane (53 mg, 0.065 (mmol) was added and the resulting mixture was heated to 95°C for 16 hours. After cooling, the reaction mixture was The crude residue was filtered through a pad of ELITE, rinsed with ethyl acetate, and concentrated. Silica gel chromatography, eluting with a 1:1 (by volume) mixture of ethanol and ethyl acetate. After trituration from diethyl ether, the product was purified by HPLC. Obtained as a solid. Yield = 273 mg (55%). Method 3, Rt 2.80 min. MS( ESI) m / z 384.5 [M+H + ].

[0308] Step 5: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-4- Fluoro-2-{2'-fluoro-4'-[1-(methylsulfonylamino)carbonyl Cyclopropyl]-4-biphenylyl}-2H-pyrazole 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-4-fluoro-2H-pyrazole [Example 16, Step 2] (44 mg , 0.10 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL). , 2M Na2CO3 aqueous solution (333 μL) and 1-(3-fluoro-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(methyl (ethylsulfonyl)cyclopropane-1-carboxamide [Example 16, Step 4] (57m g, 0.15 mmol) was degassed under N2 for 10 min and Pd[Ph3P]4 (6 mg, 0.005 mmol). The resulting mixture was heated to 85° C. The mixture was stirred at room temperature for 6 hours, cooled to room temperature, extracted with ethyl acetate (50 mL), and The organic layer was washed with 1N aqueous HCl and brine, dried over anhydrous MgSO4, and filtered. The crude product was dissolved in acetone and dichloromethane in a 90:10 (volume ratio) mixture. The mixture was purified by preparative thin layer chromatography eluting with a mixture of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 3 3%). Method 3, Rt 3.24 minutes. MS(ESI) m / z 615.2[M+H + ] .

[0309] Example 17: (R)-1-phenylethyl (4-fluoro-1-(2'-fluoro-4' -(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl Nyl)-4-yl)-1H-pyrazol-5-yl)carbamate [Compound 17] 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-fluoro-2H-pyrazole [Example 3, Step 7] (37 mg, 0.092 mm ol), a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL), and 2M Na2 CO3 aqueous solution (333 μL) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl- (methylsulfonyl)-1,3,2-dioxaborolan-2-yl)phenyl ) Cyclopropane-1-carboxamide [Example 16, Step 4] (57 mg, 0.15 m A stirred mixture of Pd[Ph3P]4 (6 mg, 0. The resulting mixture was heated to 85°C and stirred at that temperature for 6 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 mL), and diluted with 1N aqueous HCl. The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude product was eluted with a 90:10 (volume ratio) mixture of acetone and dichloromethane, respectively. The product was purified by preparative thin layer chromatography. Yield: 6 mg (11%). Method 3 , Rt 3.34 minutes. MS(ESI) m / z 581.4[M+H + ].

[0310] Example 18: (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(2'-phenyl)-2-methyl-2-propanol Fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1, 1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate [compound 18] Step 1: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- (p-Bromophenyl)-4-chloro-2H-pyrazole N-chlorosuccinimide (155 mg, 1.16 mmol) was dissolved in acetonitrile (6 mL) in 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2 -(p-Bromophenyl)-2H-pyrazole [Example 16, Step 1] (486 mg, 1 The resulting mixture was heated to 80°C for 4 hours. After which the reaction was deemed complete by LCMS. The reaction mixture was cooled to room temperature and evaporated in vacuo. and chromatographed on a silica gel column eluting with a hexane / ethyl acetate gradient. The product was obtained as a yellow oil that solidified on standing. Yield = 328 mg (62%). Method 3, Rt 3.27 minutes. MS(ESI) m / z 455. 8[M+H + ].

[0311] Step 2: (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(2'-fluorophenyl)methyl) 4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1' -biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-4-chloro-2H-pyrazole [Example 18, Step 1] (45 mg, 0.10 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (1 mL), 2M Na2CO3 aqueous solution (333 μL) and 1-(3-fluoro-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(methyl (phenylsulfonyl)cyclopropane-1-carboxamide [Example 16, Step 4] (57 mg A stirred mixture of Pd[PhP]( The resulting mixture was heated to 85°C. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL). The organic layer was washed with aqueous NHCl and brine, dried over anhydrous MgSO4, and filtered. The crude product was diluted with acetone and dichloromethane in a volume ratio of 90:10, respectively, and evaporated. The mixture was purified by preparative thin layer chromatography eluting with 100 ml of hexane. Yield = 4.8 mg ( 8%). Method 3, Rt 3.11 minutes. MS(ESI) m / z 631.7[M+H + ] .

[0312] Example 19: (R)-1-phenylethyl (4-chloro-1-(4'-(1-(methyl Sulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl) -1H-pyrazol-5-yl)carbamate [Compound 19] Step 1: 1-(4-bromophenyl)-N-(methylsulfonyl)cyclopropane-1- Carboxamide 1-(p-Bromophenyl)cyclopropanecarboxylic acid (2.41 g, 10.0 mmol) l) was suspended in dichloromethane (50 mL) and a catalytic amount of N,N-dimethylformamide was added. The reaction mixture was cooled to 0°C in an ice / water bath. Xalyl (1.75 mL, 20.0 mmol) was added dropwise, and the resulting mixture was stirred at 0° C. for 15 min. The mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1.5 hours. Upon elution and LCMS analysis, it showed complete conversion to the corresponding acid chloride. Volatiles were removed under reduced pressure to give the crude acid chloride as a white solid, which was immediately The acid chloride (2.60 g, 10.0 mmol) was dissolved in toluene (25 mL). The solution was dissolved in triethylamine (7.01 mL, 50.0 mmol) and methylsulfonamide The resulting mixture was heated at reflux for 2 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and 1 The organic layer was washed with aqueous NHCl and brine, dried over anhydrous MgSO4, and filtered. The crude solid was triturated with diisopropyl ether and filtered. The product was obtained as a tan solid. Yield = 997 mg (31%). Method 3, Rt 2.74 minutes. MS(ESI) m / z 318.3-319.8[M+H + ].

[0313] Step 2: N-(methylsulfonyl)-1-(4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamide 1-(4-Bromophenyl)-N-(methylsulfonyl)cyclopropane-1-carbo oxamide [Example 19, Step 1] (997 mg, 3.13 mmol) was added to 1,4-dioxazol-2-one. The mixture was dissolved in ethanol (30 mL) and added potassium acetate (690 mg, 7.04 mmol) and pinaco The resulting mixture was treated with diborane (1.99 g, 7.83 mmol). The mixture was degassed under vacuum for 10 minutes. Palladium(II) complex with dichloromethane (128 mg, 0.157 mmol) The resulting mixture was heated to 95°C for 16 hours. After cooling, the reaction mixture was The crude residue was filtered through a pad, rinsed with ethyl acetate, and concentrated. The product was purified by silica gel chromatography eluting with a gradient of diethyl ether. After trituration from ether, the product was obtained as a white solid. Yield=1.0 0g(88%). Method 3, Rt 2.95 minutes. MS(ESI) m / z 366.0[M +H + ].

[0314] Step 3: (R)-1-phenylethyl (4-chloro-1-(4'-(1-methylsulfonyl) (phenyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (210 mg, 0.5 mmol ), a 2:1 (volume ratio) mixture of toluene and ethanol (5 mL), and 2 M NaCO 3 aqueous solution (1.67 mL) and N-(methylsulfonyl)-1-(4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane 1-carboxamide [Example 19, Step 2] (219 mg, 0.6 mmol) The mixture was degassed under N for 10 min and Pd[PhP] (29 mg, 0.025 mmol) was added. The resulting mixture was heated to 85°C and stirred at that temperature for 16 hours. The mixture was cooled to room temperature, extracted with ethyl acetate (50 mL), and washed with 1N aqueous HCl and The organic layer was dried over anhydrous MgSO4, filtered and evaporated. Purified by silica gel chromatography eluting with a gradient of hexane and ethyl acetate The product was obtained as a white solid. Yield = 140 mg (48%). Method 3, Rt 3.36 minutes. MS(ESI) m / z 579.4[M+H + ].

[0315] Example 20: (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(4'- (1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl [4-yl]-1H-pyrazol-5-yl)carbamate [Compound 20] 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-4-fluoro-2H-pyrazole [Example 15, Step 5] (219m g, 0.5 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (5 mL). , 2M Na2CO3 aqueous solution (1.67 mL) and N-(methylsulfonyl)-1-(4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl (I)cyclopropane-1-carboxamide [Example 19, Step 2] (219 mg, 0.6 The stirred mixture of Pd[PhP] (29 mg, The resulting mixture was heated to 85°C and heated at that temperature for 16 The reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 mL), and diluted with 1N H The organic layer was washed with aqueous Cl and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was chromatographed on silica gel eluting with a gradient of hexane and ethyl acetate. The product was obtained as a white solid. Yield = 110 mg (37 %). Method 3, Rt 3.21 minutes. MS(ESI) m / z 597.4[M+H + ].

[0316] Example 21: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H- Tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)- 4-Fluoro-1H-pyrazol-5-yl)carbamate [Compound 21] Step 1: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2- [4'-(1-cyanocyclopropyl)-4-biphenylyl]-4-fluoro-2H-biphenyl Razor 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-4-fluoro-2H-pyrazole [Example 15, Step 5] (438m g, 1.0 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (10 mL). , 2M Na2CO3 aqueous solution (3.3 mL), and 4-(1-cyanocyclopropyl)fluoride. A stirred mixture of phenylboronic acid (243 mg, 1.3 mmol) was degassed under N for 10 min. and treated with Pd[Ph3P]4 (58 mg, 0.05 mmol). The mixture was heated to 85° C. and heated at that temperature for 3 hours. The reaction mixture was cooled to room temperature and (50 mL) and washed with 1N aqueous HCl and brine. The organic layer was extracted with anhydrous Mg The crude product was dissolved in a gradient of hexane and ethyl acetate. The product was purified by silica gel chromatography while separating the residue. Yield: 403 mg (81%) . Method 3, Rt 3.20 minutes. MS(ESI) m / z 501.7[M+H + ].

[0317] Step 2: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrachlorophenyl)methyl)-4-methylphenyl)-2-methyl-2-methyl-1-(4'-(1-(1H-tetrachlorophenyl)methyl)-4-methylphenyl)-2-methyl-1-(4'-(1-(1H-tetrachlorophenyl)methyl ... (1,1'-biphenyl-4-yl)cyclopropyl-[1,1'-biphenyl]-4-yl-4- Fluoro-1H-pyrazol-5-yl)carbamate 3-[(R)-1-(o-chlorophenyl)ethoxycarbonyl]propanol in toluene (10 mL) Nylamino]-2-{6-[p-(1-cyanocyclopropyl)phenyl]-3-pyridin {4-fluoro-2H-pyrazole [Example 21, Step 1] (50 mg, 0.10 m A stirred solution containing 0.5g of dibutyltin(IV) oxide (27mg, 0.5mol) was added to the solution. 10 mmol) and trimethylsilyl azide (36 μL, 0.27 mmol) The resulting mixture was heated to 100° C. for 16 hours, then cooled to room temperature and concentrated in vacuo. The crude products were dissolved in a 95:5 (volume ratio) mixture of dichloromethane and methanol. The product was purified by preparative thin layer chromatography while separating the product. Yield: 17 mg (31%). Law 3, Rt 3.29 minutes. MS(ESI) m / z 544.5[M+H + ].

[0318] Example 22: (R)-1-phenylethyl (1-(4'-(1-(1H-tetrazole- 5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-chloro-1 H-pyrazol-5-yl)carbamate [Compound 22] Step 1: 3-[(R)-1-phenylethoxycarbonylamino]-4-chloro-2-[ 4'-(1-cyanocyclopropyl)-4-biphenylyl]-2H-pyrazole 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-4-chloro-2H-pyrazole [Example 4, Step 1] (210 mg, 0.5 mmol ), a 2:1 (volume ratio) mixture of toluene and ethanol (5 mL), and 2 M NaCO 3 aqueous solution (1.7 mL) and 4-(1-cyanocyclopropyl)phenylboronic acid (11 A stirred mixture of Pd[PhP] (2 mg, 0.6 mmol) was degassed under N2 for 10 min and Pd[PhP] The resulting mixture was heated to 85° C. and treated with 4 (29 mg, 0.025 mmol). The mixture was heated at that temperature for 3 hours, cooled to room temperature, and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous MgSO4 and washed with 1N aqueous HCl and brine. The crude product was purified by filtration and evaporation using a silica gel column eluting with a gradient of hexane and ethyl acetate. The product was obtained as a white solid. Yield = 17. 3mg (72%). Method 3, Rt 3.36 minutes. MS(ESI) m / z 483.5[ M+H + ].

[0319] Step 2: (R)-1-phenylethyl (1-(4'-(1-(1H-tetrazole-5- yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-chloro-1H- Pyrazol-5-yl)carbamate 3-[(R)-1-phenylethoxycarbonylamino]-4 in toluene (1 mL) -chloro-2-[4'-(1-cyanocyclopropyl)-4-biphenylyl]-2H-biphenyl A stirred mixture containing benzophenone [Example 22, Step 1] (101 mg, 0.21 mmol) The resulting solution was diluted with dibutyltin(IV) oxide (58 mg, 0.23 mmol) and trimethyltin(IV) oxide. The resulting mixture was treated with 100 mL of methylsilyl azide (75 μL, 0.57 mmol). The mixture was heated to 0°C for 16 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic layer was evaporated, treated with 1N aqueous HCl, and washed with brine. The crude product was extracted with water and acetonitrile + 0.1% TFA. Purification was performed by C-18 reverse phase chromatography with gradient elution. Yield = 39 mg ( 35%). Method 3, Rt 3.07 minutes. MS(ESI) m / z 526.1[M+H + ].

[0320] Example 23: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H- Tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)- 4-Chloro-1H-pyrazol-5-yl)carbamate [Compound 23] Step 1: 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-4- Chloro-2-[4'-(1-cyanocyclopropyl)-4-biphenylyl]-2H-pyra Zoll 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-4-chloro-2H-pyrazole [Example 18, Step 1] (227 mg , 0.5 mmol) and a 2:1 (volume ratio) mixture of toluene and ethanol (5 mL), 2M Na2CO3 aqueous solution (1.7 mL) and 4-(1-cyanocyclopropyl)phenyl A stirred mixture of boronic acid (112 mg, 0.6 mmol) was degassed under N for 10 min. The resulting mixture was treated with Pd[PhP] (29 mg, 0.025 mmol). The reaction mixture was heated to 85°C and heated at that temperature for 3 hours. The reaction mixture was cooled to room temperature and The organic layer was extracted with 50 mL of HCl and washed with 1N aqueous HCl and brine. The crude product was eluted with a gradient of hexane and ethyl acetate. The product was obtained as a white solid. Yield = 189 mg (73%). Method 3, Rt 3.48 min. MS(ESI) m / z 517.3[M+H + ].

[0321] Step 2: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrachlorophenyl)methyl)-4-methylphenyl)-2-methyl-2-methyl-1-(4'-(1-(1H-tetrachlorophenyl)methyl)-4-methylphenyl)-2-methyl-1-(4'-(1-(1H-tetrachlorophenyl)methyl ... (1,1'-biphenyl-4-yl)cyclopropyl-[1,1'-biphenyl]-4-yl-4- Chloro-1H-pyrazol-5-yl)carbamate 3-[(R)-1-(o-chlorophenyl)ethoxycarbonyl] 4-chloro-2-[4'-(1-cyanocyclopropyl)-4-biphenyl [2H-pyrazole]-2H-pyrazole [Example 23, Step 1] (108 mg, 0.21 mmol) The stirred solution was treated with dibutyltin(IV) oxide (58 mg, 0.23 mmol) ) and trimethylsilyl azide (75 μL, 0.57 mmol). The mixture was heated to 100° C. for 16 h, then cooled to room temperature and concentrated in vacuo. The organic layer was dissolved in ethyl acetate, treated with 1N aqueous HCl, and washed with brine. The crude product was dried over anhydrous MgSO4, filtered and evaporated. The product was purified by C-18 reverse phase chromatography eluting with a gradient of 0.1% TFA. Amount = 36 mg (31%). Method 3, Rt 3.18 minutes. MS(ESI) m / z 560 .1[M+H + ].

[0322] Example 24: (R)-1-phenylethyl (4-chloro-1-(4'-(1-cyano) (Rubamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazo (5-hydroxybenzoyl)carbamate [Compound 24] (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl) Amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclohexyl Isopropane-1-carboxylic acid [Example 4] (200 mg, 0.40 mmol) was added to pyridine The resulting solution was coevaporated twice with ethanol (10 mL) and dissolved in DMF (4.5 mL). The solution was treated with pyridine (300 μL, 3.75 mmol), followed by trifluoride. Pentafluorophenyl diacetate (125 μL, 0.71 mmol) was added dropwise. After 2 hours, LCMS analysis showed complete conversion to the corresponding pentafluorophenyl ester. The reaction mixture was diluted with ethyl acetate (30 mL) and treated with saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was taken up in DMF (4 mL) and diluted with sodium hydrogen cyanamide (77 mg, 1. The reaction was treated with 2 mmol) at room temperature overnight. The next morning, the reaction was diluted with ethyl acetate (30 mL). The organic layer was separated, washed with brine, and The products were dried over MgSO4, filtered and evaporated. by preparative thin-layer chromatography eluting with a 90:10 (volume ratio) mixture of ethanol. Purified. Yield = 36 mg (32%). Method 3, Rt 2.84 min. MS(ESI) m / z 526.5[M+H + ].

[0323] Example 25: (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(4'-( 1-(cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl) -1H-pyrazol-5-yl)carbamate [Compound 25] Step 1: 1-(4-bromophenyl)-N-cyanocyclopropane-1-carboxamide 1-(p-Bromophenyl)cyclopropanecarboxylic acid (2.41 g, 10.0 mmol) l) was suspended in dichloromethane (34 mL) and a catalytic amount of N,N-dimethylformamide was added. The reaction mixture was cooled to 0°C in an ice / water bath. Xalyl (1.75 mL, 20.0 mmol) was added dropwise, and the resulting mixture was stirred at 0° C. for 15 min. The mixture was stirred at room temperature for 30 minutes and then heated to reflux for 2 hours. LCMS analysis showed complete conversion to the corresponding acid chloride. The reactants were removed under reduced pressure to give the crude acid chloride as a white solid, which was used immediately. Acid chloride (2.60 g, 10.0 mmol) was dissolved in DMF (30 mL). Take 10 mL of this solution (3.3 mmol) and add sodium hydrogen cyanamide (640 mg, 10.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with 1N aqueous HCl and brine. It was dried over anhydrous MgSO4, filtered and evaporated. The crude solid product was carried on without further purification. Used in the next step. The product was obtained as a solid. Yield = 650 mg (74%). 3, Rt 2.68 minutes. MS(ESI) m / z 267.3[M+H + ].

[0324] Step 2: N-cyano-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa)methyl) Saborolan-2-yl)phenyl)cyclopropane-1-carboxamide 1-(4-Bromophenyl)-N-cyanocyclopropane-1-carboxamide [Implementation Example 25, Step 1] (650 mg, 2.44 mmol) in 1,4-dioxane (12 mL) Dissolve bis(pinacolato)diboron (1.94 g, 7.33 mmol), KOAc (720 mg, 7.33 mmol) and [1,1'-bis(diphenylphosphino)phenanthroline] [locene]dichloropalladium(II) complex with dichloromethane (193 mg, 0.32 The resulting mixture was heated to 100° C. overnight and then cooled to room temperature. The mixture was filtered through a pad of Celite and rinsed with methanol. The filtrate was concentrated in vacuo. The crude material was purified by silica gel elution with a 1:1 (v / v) mixture of hexane and ethyl acetate. Purification was achieved by preparative thin layer chromatography on gel. The product is a white solid. Yield = 400 mg (53%). Method 3, Rt 2.86 min. MS( ESI) m / z 313.6 [M+H + ].

[0325] Step 3: (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(4'-(1- (Cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p- bromophenyl)-4-chloro-2H-pyrazole [Example 18, Step 1] (127 mg , 0.28 mmol), 1,4-dioxane (3 mL), and a 2 M aqueous solution of Na2CO3 (630 μL) and N-cyano-1-(4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamide [Actual Example 25, Step 2] A stirred suspension of (106 mg, 0.34 mmol) was added under nitrogen The mixture was degassed under reduced pressure for 10 min and treated with Pd[PhP] (46 mg, 0.04 mmol). The resulting mixture was immersed in an oil bath at 95°C for 12 hours with stirring. The reaction was cooled and The mixture was transferred to a separatory funnel and diluted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, and The crude residue was diluted with 9:1 (volume ratio) dichloromethane and concentrated in vacuo. Purification was performed on preparative TLC plates (1000 μm) eluting with a 1000 μm / methanol mixture. The product was obtained as a white solid. Yield = 18 mg (12%). HPLC (254n m): Method 3, Rt 3.15 minutes. MS(ESI) m / z 560.5[M+H + ].

[0326] Example 26: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(cyano) (Carbamoyl)cyclopropyl)-2'-fluoro-[1,1'-biphenyl]-4-yl (4-fluoro-1H-pyrazol-5-yl)carbamate [Compound 26] Step 1: (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbamate) (1-bornyl)amino)-4-fluoro-1H-pyrazol-1-yl)-2-fluoro-[1 ,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid (R)-[2-(4-bromophenyl)-4-fluoro-2H-pyrazol-3-yl] [Example 15, step 1]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester 5] (88 mg, 0.2 mmol) and 2:1 (volume ratio) toluene / ethanol (2 mL ), 2M aqueous Na2CO3 (670 μL), and 1-[4-(dihydroxyboranyl )-3-fluorophenyl]cyclopropane-1-carboxylic acid (45 mg, 0.20 mm A stirred suspension of Pd[Ph3P]4 (12m mol) was degassed under nitrogen for 10 min and The resulting mixture was stirred at 90°C for 12 hours. 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 (20 mL). The organic layer was separated. The crude residue was extracted with HCl, washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. , preparative TLC plates (1 The product was obtained as a white solid. Yield = 40 mg ( 37%). HPLC (254nm): Method 3, Rt 3.14 min. MS(ESI)m / z 538.3[M+H + ].

[0327] Step 2: (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(cyanocalciferol)-1-yl)methyl ... (bamoyl)cyclopropyl)-2'-fluoro-[1,1'-biphenyl]-4-yl) -4-fluoro-1H-pyrazol-5-yl)carbamate (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl )amino)-4-fluoro-1H-pyrazol-1-yl)-2-fluoro-[1,1' -biphenyl]-4-yl)cyclopropane-1-carboxylic acid [Example 26, Step 1] ( 107 mg, 0.2 mmol), THF (1 mL), and N-hydroxysuccinimide A stirred mixture containing N,N'-dicyclohexylcarbohydrate (23 mg, 0.2 mmol) was added to The resulting mixture was stirred for 3 hours. The mixture was stirred, and the separated solid was then filtered off, and the filtrate solution was dissolved in sodium hydrogen cyanamide in water (1 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with 0.1 N aqueous HCl. The organic layer was separated, washed with brine, and dried over anhydrous MgSO4. The crude product was extracted with 90% dichloromethane and 90% methanol. The product was purified by preparative thin layer chromatography eluting with a 1:10 (volume ratio) mixture. Amount = 36 mg (32%). Method 3, Rt 3.13 minutes. MS(ESI) m / z 561 .9[M+H + ].

[0328] Example 27: (R)-2-(4'-(5-(((1-(2-chlorophenyl)ethoxy) Carbonyl)amino)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl] [phenyl]-4-yl)-2-methylpropanoic acid [Compound 27] 2-(p-Bromophenyl)-2-methylpropionic acid (6 mL) in ethanol (3 mL) 6 mg, 0.27 mmol), tetrahydroxydiboron (109 mg, 1.22 mmol) l), a mixture containing KOAc (26 mg, 1.22 mmol) was degassed under N2 and then This mixture was treated with XPhosPdG3 (6 mg, 0.007 mmol) at rt. The reaction was heated to 80° C. with magnetic stirring for 2 hours and then cooled to room temperature. , successively, 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]- 2-(p-Bromophenyl)-2H-pyrazole-4-carbonitrile [Example 6, step 1] (54 mg, 0.12 mmol), 2 M K2CO3 aqueous solution (270 μL), and X The resulting mixture was treated with PhosPdG3 (2 mg, 0.0023). The reaction was degassed for 5 min and then heated to 80° C. for 16 h. The reaction was cooled to room temperature and added to CELITE The mixture was filtered through a pad of ethanol and rinsed with ethanol. The filtrate was concentrated in vacuo and the residue was Preparative thin-layer chromatography was performed eluting with toluene and acetone in a volume ratio of 70:30. The product was obtained as a white solid (12 mg, 19%). Method 3 , Rt 3.23 minutes. MS(ESI) m / z 529.5[M+H + ].

[0329] Example 28-(R)-2-(4'-(4-cyano-5-(((1-phenylethoxy)carbonyl) (carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- (yl)-2-methylpropanoic acid [Compound 28] Step 1: Methyl 2-methyl-2-[p-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)phenyl]propionate 2-(p-Bromophenyl)-2-methylpropionic acid (1.22 g, 5.0 mmol) ) was dissolved in methanol (20 mL) and cooled to -20°C using ice water (2 parts) and salt (1 part). The mixture was cooled to °C. To this solution, thionyl chloride (1.45 mL, 20.0 mmol) was added dropwise. After the addition was complete, the reaction was stirred for 15 minutes at -20°C and then allowed to stand at room temperature for 2 hours. The reaction was concentrated in vacuo and the residue was treated with dichloromethane. The organic layer was dried over anhydrous MgSO4 and partitioned between methane and saturated aqueous Na2CO3. Filtration and evaporation gave methyl 2-(p-bromophenyl)-2-methylpropionate This material was dissolved in 1,4-dioxane (20 mL), bis(pinacolato)diboron (2.69 g, 10.1 mmol), K OAc (1.03 g, 10.5 mmol), and [1,1'-bis(diphenylphosphine (II) Ferrocene dichloropalladium(II) complex with dichloromethane (328 mg, The resulting mixture was heated to 100° C. overnight and then cooled to room temperature. The mixture was cooled to rt and filtered through a pad of CELITE, rinsing with methanol. The filtrate was concentrated in vacuo. A portion of the crude material was purified by preparative chromatography on a thin layer of silica gel (thi The product was purified by NK layer chromatography. The product was a white solid. Yield =153mg. Method 3, Rt 3.37 minutes. MS(ESI) m / z 305.8[M+ H + ].

[0330] Step 2: Methyl 2-(4'-{5-[(R)-1-phenylethoxycarbonylamino] -4-cyano-1H-pyrazol-1-yl}-4-biphenylyl)-2-methylprop Onate 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl )-2H-pyrazole-4-carbonitrile [Example 5, Step 1] (58 mg, 0.14 mmol), 1,4-dioxane (2 mL), and 2 M aqueous Na2CO3 (315 μL) L) and methyl 2-methyl-2-[p-(4,4,5,5-tetramethyl-1,3,2- (Dioxaborolan-2-yl)phenyl]propionate [Example 24, Step 1] (51 The stirred mixture (mg, 0.17 mmol) was degassed under N2 for 10 min and Pd[Ph3P] The resulting mixture was heated to 95 °C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of Celite and purified with methanol. The filtrate was concentrated in vacuo and the crude residue was extracted with 70:1 mixture of hexane and ethyl acetate, respectively. It was directly purified by preparative thin layer chromatography eluting with a 30 (volume ratio) mixture. Yield = 20 mg (28%). Method 3, Rt 3.17 minutes. MS(ESI) m / z 50 9.3[M+H + ].

[0331] Step 3: (R)-2-(4'-(4-cyano-5-(((1-phenylethoxy)carbo Nyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl )-2-Methylpropanoic acid Methyl 2-(4'-{5-[(R)-1-phenylethoxycarbonylamino]-4- Cyano-1H-pyrazol-1-yl}-4-biphenylyl)-2-methylpropionate [Example 28, Step 1] (18 mg, 0.03 mmol) was dissolved in THF (1 mL). The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography (30% ethanol in hexane). The reaction was treated with 1M aqueous HCl (5 mL) and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude residue was Each was subjected to preparative thin-layer chromatography eluting with a 70:30 (volume ratio) mixture of toluene and acetone. The product was obtained as a white solid. Yield = 15 mg (quantitative). target). Method 3, Rt 2.93 minutes. MS(ESI) m / z 495.8[M+H + ].

[0332] The compounds in Table 1 and their derivatives were prepared according to the procedure outlined for compounds 1-28. The heterocyclic amine or ester required to assemble the corresponding carbamate is prepared by The esters were prepared based on the methods described in references 1-19.

[0333] Specific pyrazole substitutions were determined following the construction of the appropriate arylpyrazole (8, Scheme 1). Prepared by direct fluorination, chlorination, or Trifluoromethylation can be carried out by further cleaving compounds of the invention according to the procedures described in Examples 1-28. This affords the aryl bromide (9), a suitable intermediate for further modifications. [ka]

[0334] Alternatively, the core pyrazole (8) can be prepared according to the procedure depicted in Scheme 2: [ka]

[0335] R C If the need for cyano is important, the corresponding core cyanopyrazole (9) , is prepared according to the steps described in Scheme 3: [ka]

[0336] Example 29. Receptor binding assay The binding affinities of compounds of Formulas I-III were determined using a protocol similar to that described in reference 17. In this protocol, tritium-labeled lysophosphatidylinositol (LPA1R) was isolated from CHO cells expressing LPA1R. zinc acid ([ 3 The assay was determined based on the ability of the platelets to transfer ATP ([H]-LPA). In this study, CHO cells expressing human LPA1R [Cerep] were 3 H]-LPA Increasing concentrations of test compounds were added to each well and incubated at room temperature for 9 min. At this point, the plate was washed and the radioactivity in the wells was counted. The cells were incubated in the presence of 10 μM unlabeled LPA. 3 Results of control and treated with [H]-LPA Specific ligand binding to the receptor was determined in the presence of excess unlabeled ligand. The binding was defined as the difference between the total binding measured in the presence of the test compound and the nonspecific binding. Percentage of control specific binding ((measured specific binding / control specific binding) x 100 ) and as percent inhibition of control specific binding (100-((measured specific binding Results were expressed as IC / specific binding of control × 100. 50 Values ​​(specific results of control The concentration (concentration resulting in half-maximal inhibition of the total) and Hill coefficient (nH) were calculated by curve fitting of the Hill equation (Hi ll equation curve fitting)(Y=D+[(AD) / (1 +(C / C50)nH)], where Y = specific binding and D = minimum specific binding , A = maximum specific binding, C = compound concentration, C50 = IC50, and n H = slope factor, using the mean replicate value ) was determined by nonlinear regression analysis of the competition curves generated by Cer The analysis was performed using software developed by ep (Hill software) and Wind The commercially available software SigmaPlot® 4.0 (author) for ows® This was confirmed by comparison with data generated by SPSS Inc. (Copyright 1997, SPSS Inc.). The inhibition constant (Ki) was calculated using the Cheng-Prusoff equation (Ki = IC50 / (1 + (L / KD))). where L = concentration of radioligand in the assay and KD = radioligand binding to the receptor. The Kd was calculated using the Scatchard plot. It has been decided.

[0337] Example 30. Calcium flux assay LPA-stimulated Ca 2+ Flux inhibition using a 96-well plate format The efficacy of the compounds was evaluated using FLIPR technology in the rats. Assays used The buffer solution contained 20 mM HEPES and 2.5 mM probenecid at pH 7.4. Hanks Balanced Salt Solution (HBSS) was supplemented with adjusted ed Salt Solution)(HBSS)(Millipore, GPCR P LPA1R-expressing cells (Millipore) were used. Plates were prepared 24 hours prior to assay of the test substance. 2+ Ion flux Fluo-based No Wash Ca 2+ The fluorescence of the dye was evaluated. The agonist data were calculated based on the LPA concentration sufficient to produce 80% efficacy [EC 80 ] The percentage of inhibition was calculated as a function of the concentration of the compounds of formulas I-VI. For dose-response, the inhibition data were used to calculate the IC of the compound. 50 Calculate Ta.

[0338] Agonist assays were performed using FLIPR TETRA The fluorescence-based After establishing the line, test compounds, vehicle controls, and control agonists were administered to the assay plate. The agonist assay lasted a total of 180 seconds, which was used to The ability of each compound to activate each GPCR was assessed. Agonist assays were completed. Once the assay plate is in place, TETRA Remove from the container and incubate at 25°C for 7 minutes. After the incubation period, the assay plate was incubated in a FLIPR TETR A and the antagonist assay was initiated.

[0339] Antagonist Assay: EC determined during agonist assay after establishment of fluorescence baseline 80 The effectiveness value All pre-incubated sample compound wells were then diluted with EC 80 Concentration control jaw The cells were challenged with agonists. Antagonist assays were performed using the same assay plates. Please use FLIPR TETRA The experiment was carried out in an instrument in which nine vehicle controls and E C 80 A control agonist of 1000 mg / mL was added to the appropriate wells. The time was 180 seconds and was used to assess the ability of each compound to inhibit each GPCR being assayed. strength was evaluated.

[0340] Data Processing: All assay plate data were subjected to appropriate baseline correction. After applying the positive, export the maximum fluorescence value and process the data to calculate the activation percentage. (Emax relative to control agonist and vehicle control values), percentage inhibition (EC 80 and vehicle control values), and further statistics (i.e., Z', replicate data The percentage change between the values ​​was calculated to assess the quality of each plate. If the data were rejected, further experiments were performed. All dose-response curves were plotted in Graph Created using Pad Prism. Sigmoidal Dose Response Curve fitting was performed using the formula "Low Slope Response (Variable Slope)" where the lower parameter The bottom parameter is fixed to "0". If a consistent curve was not generated by the concentrations assayed, the efficacy value could be better predicted. To achieve this, the top parameter was fixed at 100.

[0341] Representative compounds prepared according to the synthetic methods disclosed herein include antagonists. The activity data are shown in Table 2.

[0342] [Table 3]

[0343] Unless otherwise stated, the compounds tested were LPA1R Ca 2+ Flux Functional Assay In B, IC less than 50 μM 50 A=less than 0.3 μM; B=0 .3 μM or more and less than 1 μM; C = more than 1 μM and less than 50 μM; D = 50 μM or more.

[0344] References Menozzi G, Mosti L, Schenone P, Donnoli D, Schiariti F, Marmo E. (1990). 1 - phenyl - 1H - p yrazole derivatives with anti - inflammator y, analgesic and antipyretic activities. F armaco 45(2):167 - 86. Pinto DJ, Orwat MJ, Wang S, Fevig JM, Quan M L, Amparo E, Cacciola J, Rossi KA, Alexander RS, Smallwood AM, Luettgen JM, Liang L, Aun gst BJ, Wright MR, Knabb RM, Wong PC, Wexler RR, Lam PY(2001). Discovery of 1 - [3 - (amin omethyl)phenyl] - N - 3 - fluoro - 2’ - (methylsul fonyl)-[1,1’ - biphenyl] - 4 - yl] - 3 - (trifluor omethyl)-1H - pyrazole - 5 - carboxamide(DPC42 3), a highly potent, selective, and orally bioavailable inhibitor of blood coagulat ion factor Xa. J Med Chem 44(4):566 - 78. 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Lahm GP,Selby TP(2004).Substituted hereafter ocyclic phthalic acid diamide arthropods cides.Federal Regulatory Authority Regulations 2004 / 63738 A1 Protocol. Guerrini G,Ciciani G,Cambi G,Bruni F,Sel this S,Besnard F,Montali M,Martini C,Ghe lardini C,Galeotti N,Costanzo A(2007).No vel 3-iodo-8-ethoxypyrazolo[5,1-c][1,2,4 ]benzotriazine 5-oxide as promising lead for the design of alpha5-inverse agonist us eful tools for therapy of mnemonic information e.Bioorg Med Chem 15(7):2573-86. Guerrini G,Ciciani G,Bruni F,Celery S,G uarino C,Melanie F,Montali M,Daniel S,Ma rtini C,Ghelardini C,Norcini M,Ciattini S,Costanzo A(2010).New fluoro derivative s of the pyrazolo[5,1-c][1,2,4]benzotria zine 5-oxide system:evaluation of fluori ne binding properties in the benzodiazep ine site on γ-aminobutyrric acid type A( GABA(A))receptor.Design,synthesis,biolog ical,and molecular modeling investigatio n.J Med Chem 53(21):7532-48. Banks RE,Mohialdin-Khaffaf SN,Lal GS,Sha rif I,Syvret RG(1992).1-Alkyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane salts:a novel family of electrophilic fluorinati ng agents.J.Chem.Soc.,Chem.Commun 8,595- 596. Morimoto H,Tsubogo T,Litvinas ND,Hartwig JF(2011).A broadly applicable copper re agent for trifluoromethylations and perf luoroalkylations of aryl iodides and bro mides.Angew Chem Int Ed Engl 50(16):3793 -8. Menozzi G,Mosti L,Schenone P(1987).React ion of 2‐dimethylaminomethylene‐1,3‐dion es with dinucleophiles.VI.Synthesis of e thyl or methyl 1,5‐disubstituted 1H‐pyra zole‐4‐carboxylates.Journal of Heterocyc lic Chemistry,24,6,1669-1675. Luconi L,Rossin A,Motta A,Tuci G,Giambas tiani G(2013).Group IV organometallic co mpounds based on dianionic “pincer” liga nds:synthesis,characterization,and catal ytic activity in intramolecular hydroami nation reactions.Chemistry 19(15):4906-2 1. Stoermer M(1907).Justus Liebigs Annalen der Chemie,vol.352p.333. Claisen R(1894).Justus Liebigs Annalen d er Chemie,vol.278p.295. Peretto I,Radaelli S,Parini C,Zandi M,Ra veglia LF,Dondio G,Fontanella L,Misiano P,Bigogno C,Rizzi A,Riccardi B,Biscaioli M,Marchetti S,Puccini P,Catinella S,Ron delli I,Cenacchi V,Bolzoni PT,Caruso P,V illetti G,Facchinetti F,Del Giudice E,Mo retto N,Imbimbo BP(2005).Synthesis and b iological activity of flurbiprofen analo gues as selective inhibitors of beta-amy loid(1)(-)(42)secretion.J Med Chem 48(18 ):5705-20. Huang A,Moretto A,Janz K,Lowe M,Bedard P W,Tam S,Di L,Clerin V,Sushkova N,Tcherny chev B,Tsao DH,Keith JC,Shaw GD,Schaub R G,Wang Q,Kaila N(2010).Discovery of 2-[1 -(4-chlorophenyl)cyclopropyl]-3-hydroxy- 8-(trifluoromethyl)quinoline-4-carboxyli c acid(PSI-421),a P-selectin inhibitor w ith improved pharmacokinetic properties and oral efficacy in models of vascular injury.J Med Chem 53(16):6003-17. 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Claims

1. Formula I 【Chemistry 1】 (In the formula, R Ａ is -CO ２ H, tetrazolyl, —C(═O)NH ２ , -C(=O)NHR Ｂ , -CONHCN, -C(=O)NHSO ２ R Ｂ , or —C(═O)NHCH ２ C H ２ SO ３ H, or a carboxylic acid equivalent; R Ｂ is an optionally substituted C １ ~C ４ alkyl or one of the following structures: Yes 【Chemistry 2】 ； L １ is an optionally substituted C １ ~C ６ Alkylene; C １ ~C ６ Fluoroalkylene; or optionally substituted C １ ~C ６ heteroalkylene, or L １ is present Combined, -CH ２ -、 【Transformation 3】 or a disubstituted dimethylmethane; A １ is N or C; Ring A has one of the following structures: 【Chemistry 4】 ； R Ｃ is -CN, -F, -Cl, -Br, -I, -OC １ ~C ４ Alkyl, C ３ ~C ６ S Chloroalkyl, or C １ ~C ４ is fluoroalkyl; R Ｄ is -N(R Ｆ )-C(=O)XCH(R Ｇ )-CY, where X is O , CY is one R Ｈ is phenyl substituted with: 【Transformation 5】 ； R Ｅ , R Ｆ , and R Ｇ are independently —H or C １ ~C ４ Alkyl or C ３ ~C ６ cycloalkyl or R Ｅ and R Ｆ are independently —H or C １ ~C ４ Archi Ru or C １ ~C ６ cycloalkyl, and one R Ｇ Ha-C １ ~C ４ It is an alkyl , the ring A R Ｄ The R of the substituent Ｈ The phenyl moiety and R Ｇ and the phenyl moiety is bonded Together with the carbon atoms surrounding the ring, a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted polycyclic ring may be formed. Defines a ring and other R Ｇ If present, R Ｅ as defined with respect to Each R Ｈ are independently —H, halogen, C １ ~C ４ alkyl) or a pharmaceutically acceptable salt or prodrug thereof.

2. R Ａ But -CO ２ H, tetrazolyl 【Transformation 6】 , —C(═O)NH ２ , -CONHCN, or -C(=O)NHSO ２ R Ｂ and L １ But -CH ２ -, 【Transformation 7】 or a disubstituted dimethylmethane; ring 【Transformation 8】 Among them, R Ｈ is —H, halogen, or —CH ３ and ring 【Chemistry 9】 Among them, A １ is C or N, and R Ｈ is —H; Ring A is 【Chemistry 10】 having the structure R Ｃ is —F, —Cl, or —CN; R Ｆ is —H; R Ｇ is in the R configuration ３ and CY ring 【Chemistry 11】 Among them, R Ｈ The compound of claim 1 , wherein is —H or a halogen.

3. R Ａ Ga-CO ２ H; L １ but 【Chemistry 12】 and ring 【Chemistry 13】 Among them, R Ｈ is —H; ring 【Chemistry 14】 Among them, A １ is N and R Ｈ is —H; R Ｃ is —F or —Cl; and CY ring 【Chemistry 15】 Among them, R Ｈ The compound of claim 2, wherein is -Cl.

4. (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy)carbo nyl)amino)-4-fluoro-1H-pyrazol-1-yl)pyridin-2-yl)fluoro (R)-1-(4-(5-(4-chloro- 5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-1H-pyrazo (phenyl-1-yl)pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid The compound according to claim 3 .

5. R Ａ Ga-CO ２ H, L １ but, 【Chemistry 16】 or dimethylmethane 【Chemistry 17】 and R Ｃ is —F or —CN, and ring [Chemistry 18] Among them, A １ is C and R Ｈ The compound of claim 2, wherein is —H.

6. (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl ) amino)-4-fluoro-1H-pyrazol-1-yl)-[1,1'-biphenyl] (R)-1-(4'-(4-cyano-5-yl)cyclopropane-1-carboxylic acid, -(((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl) -[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1 -(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)- 4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyano Chloropropane-1-carboxylic acid, (R)-1-(2-fluoro-4'-(4-fluoro- 5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl )-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)- 1-(2-chloro-4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl (1,1'-biphenyl)amino)-4-fluoro-1H-pyrazol-1-yl)-[1,1'-biphenyl ]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(2-chloro-4'-( 4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazo (1,1'-biphenyl)-4-yl)cyclopropane-1-carbo carboxylic acid, (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl) (nyl)amino)-1H-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl ]-4-yl)cyclopropane-1-carboxylic acid, (R)-2-(4'-(5-(((1 -(2-chlorophenyl)ethoxy)carbonyl)amino)-4-cyano-1H-pyrazo (1,1'-biphenyl)-4-yl)-2-methylpropanoic acid, is (R)-2-(4'-(4-cyano-5-(((1-phenylethoxy)carbonyl) Amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2 6. The compound of claim 5, wherein the compound is methylpropanoic acid.

7. R Ａ Ga-CO ２ H; and L １ but 【Chemistry 19】 and R Ｃ is —Cl; and ring 【Chemistry 20】 Among them, A １ is C and R Ｈ The compound of claim 2, wherein is —H.

8. (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl) Amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclohexyl (R)-1-(4'-(4-chloro-5-(((1-phenyl) (1H-pyrazol-1-yl)carbonyl)amino)-1H-pyrazol-1-yl)-3-fluoro- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, 1-(4'- {5-[(R)-1-phenylethoxycarbonylamino]-4-chloro-1H-pyrazoline {R-1-yl}-2-fluoro-4-biphenylyl)cyclopropanecarboxylic acid, )-1-(2-chloro-4'-(4-chloro-5-(((1-phenylethoxy)carbo (1,1'-biphenyl)-4-yl ) cyclopropane-1-carboxylic acid, or 1-[4-(p-{5-[(R)-1-phenyl (4-chloro-1H-pyrazol-1-yl)phenyl) 8. The compound of claim 7, wherein the compound is cyclopropanecarboxylic acid.

9. R Ａ -C(=O)NH ２ and L １ but 【Chemistry 21】 and R Ｃ is -F; and ring 【Chemistry 22】 Among them, A １ is C and R Ｈ The compound of claim 2, wherein is —H.

10. (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-carbamoylcyclo Propyl)-[1,1'-biphenyl]-4-yl)-4-fluoro-1H-pyrazole 10. The compound of claim 9, wherein the compound is a hydroxybenzoate (5-yl)carbamate.

11. R Ａ -C(=O)NHSO ２ R Ｂ where R Ｂ Ga-CH ３ and L １ but 【Chemistry 23】 and R Ｃ is —F or —Cl, and ring 【Chemistry 24】 Among them, A １ is C and R Ｈ The compound of claim 2, wherein is —H.

12. (R)-1-(2-chlorophenyl)ethyl(4-fluoro-1-(2'-fluoro- 4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl] (R)-1-phenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, phenylethyl (4-fluoro-1-(2'-fluoro-4'-(1-((methylsulfonyl (1,1'-biphenyl)-4-yl)-1H-(cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-(1,1'-biphenyl)-4-yl pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4 -chloro-1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl) Cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl (R)-1-phenylethyl (4-chloro-1-(4'-(1-(( Methylsulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4- (R)-1-(2-chlorophenyl)-1H-pyrazol-5-yl)carbamate, phenyl)ethyl (4-fluoro-1-(4'-(1-((methylsulfonyl)carbamoyl (1,1'-biphenyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazole-5 12. The compound of claim 11, wherein the compound is a (C-yl)carbamate.

13. R Ａ Tetrazolyl 【Chemistry 25】 and L １ but 【Chemistry 26】 and R Ｃ is —F or —Cl; and ring 【Chemistry 27】 Among them, A １ is C and R Ｈ The compound of claim 2, wherein is —H.

14. (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrazole) (1,1'-biphenyl)-4-yl)-4-fluoro 1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (1-( 4'-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenanthroline (nyl)-4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate, or ( R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrazole- 5-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-chloro-1 14. The compound of claim 13, which is a 5-H-pyrazol-5-yl)carbamate.

15. R Ａ is -CONHCN, L １ but 【Chemistry 28】 and R Ｃ is —F or —Cl; and ring 【Chemistry 29】 Among them, A １ is C and R Ｈ The compound of claim 2, wherein is —H.

16. (R)-1-phenylethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl) ) cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazole-5- (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-( 4'-(1-(cyanocarbamoyl)cyclopropyl)-[1,1'-biphenyl]-4 -yl)-1H-pyrazol-5-yl)carbamate, or (R)-1-(2-chloro phenyl)ethyl(1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-2' -fluoro-[1,1'-biphenyl]-4-yl)-4-fluoro-1H-pyrazole 16. The compound of claim 15, wherein the compound is a hydroxybenzoate (-5-yl)carbamate.

17. (R)-1-phenylethyl (4-chloro-1-(4'-(1-((methylsulfonyl )carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-1H-biphenyl 13. The compound according to claim 2 or 12, which is a benzophenone-5-yl carbamate.

18. R Ｇ The compound of claim 1 , wherein is in the R or S configuration.

19. A compound according to claim 1; and pharmaceutically acceptable excipients 10. A pharmaceutical composition comprising:

20. Lysophosphatidic acid-dependent disease or condition in a subject in need of treatment 1. A method for treating a phosphate-dependent disease or condition, comprising administering to said subject a therapeutically effective amount of 1. A method comprising administering a compound of claim 1.

21. The lysophosphatidic acid-dependent disease or condition is diabetic nephropathy or non-alcoholic fatty liver disease.

80. The method of claim 79, which is fatty liver disease (NASH).

22. (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy)carbo nyl)amino)-4-fluoro-1H-pyrazol-1-yl)pyridin-2-yl)fluoro (R)-1-(4-(5-(4-chloro-5-phenyl)cyclopropane-1-carboxylic acid, -(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-1H-pyrazo (R-1-yl)pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid, )-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino) (1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane propane-1-carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenyl Ethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphen (R)-1-(4'-(4-cyclohexyl)-4-yl)cyclopropane-1-carboxylic acid, ... 5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole-1- (R yl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, )-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino) (no)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl (R)-1-(3-fluoro-4'-(4-fluoro)cyclopropane-1-carboxylic acid, O-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole-1 -yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, ( R)-1-(2-fluoro-4'-(4-fluoro-5-(((1-phenylethoxy) Carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4 -yl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(4-chloro-5-( ((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-3 -fluoro-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)a (amino)-1H-pyrazol-1-yl)-2-fluoro-[1,1'-biphenyl]-4 (R)-1-(2-chloro-4'-(4-fluoro-2-methyl-2-phenyl)-2-propanecarboxylic acid, (R)-1-(2-chloro-4'-(4-fluoro-2-methyl-2-phenyl)-2-phenyl ... Fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazole- 1-yl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, (R)-1-(2-chloro-4'-(4-chloro-5-(((1-phenylethoxy)carbonyl) (carbonyl)amino)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- (R)-1-(4'-(4-fluoro-5-( ((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl)-2 -methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid, ( R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amine (I)-1H-pyrazol-1-yl)-2-methyl-[1,1'-biphenyl]-4-yl (R)-1-(2-chlorophenyl)ethyl(1-chlorophenyl)cyclopropane-1-carboxylic acid, -(4'-(1-carbamoylcyclopropyl)-[1,1'-biphenyl]-4-yl )-4-fluoro-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chloro- 4-fluoro-1-(2'-fluoro-4'-(1-((methyl sulfonyl)carbamoyl)cyclopropyl)-[1,1'-biphenyl]-4-yl) -1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl(4-fluroyl)carbamate 1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclohexyl) (1,1'-biphenyl)-4-yl)-1H-pyrazol-5-yl) Carbamate, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(2'- Fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1 ,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R )-1-phenylethyl(4-chloro-1-(4'-(1-((methylsulfonyl) carbamate) (1,1'-biphenyl)-4-yl)-1H-pyrazoline (R)-1-(2-chlorophenyl)ethyl (4-fluorophenyl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-fluorophenyl)carbamate 1-(4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1 ,1'-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R )-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrazole-5 -yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-fluoro-1 H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (1-(4'- (1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1'-biphenyl] (R)-1-(4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate, (2-chlorophenyl)ethyl (1-(4'-(1-(1H-tetrazol-5-yl) Cyclopropyl)-[1,1'-biphenyl]-4-yl)-4-chloro-1H-pyrazo 3-[(R)-1-phenylethoxycarbonylamino]carbamate, ]-4-chloro-2-{4'-[1-(cyanoamino)carbonylcyclopropyl]-4 -biphenylyl}-2H-pyrazole, 3-[(R)-1-(o-chlorophenyl)ethoxy] 4-chloro-2-{4'-[1-(cyanoamino)carbonyl cyclopropyl]-4-biphenylyl}-2H-pyrazole, 3-[(R)-1-(o- chlorophenyl)ethoxycarbonylamino]-2-{4'-[1-(cyanoamino)carbonyl carbonylcyclopropyl]-2'-fluoro-4-biphenylyl}-4-fluoro-2H -pyrazole, (R)-2-(4'-(5-(((1-(2-chlorophenyl)ethoxy )carbonyl)amino)-4-cyano-1H-pyrazol-1-yl)-[1,1'-biphenyl] (R)-2-(4'-(4-cyano- 5-(((1-phenylethoxy)carbonyl)amino)-1H-pyrazol-1-yl )-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid Compounds that are used.

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