WO2019246109A1 - Composés hétérocycliques utiles dans le traitement d'une maladie - Google Patents

Composés hétérocycliques utiles dans le traitement d'une maladie Download PDF

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Publication number
WO2019246109A1
WO2019246109A1 PCT/US2019/037749 US2019037749W WO2019246109A1 WO 2019246109 A1 WO2019246109 A1 WO 2019246109A1 US 2019037749 W US2019037749 W US 2019037749W WO 2019246109 A1 WO2019246109 A1 WO 2019246109A1
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Prior art keywords
pyrazol
biphenyl
fluoro
chloro
carbonyl
Prior art date
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PCT/US2019/037749
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English (en)
Inventor
Graham Beaton
Fabio C. Tucci
Satheesh B. Ravula
Chandravadan R. Shah
Suk Joong Lee
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Epigen Biosciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/010,755 external-priority patent/US10526298B2/en
Priority to US18/015,289 priority Critical patent/US20230286928A1/en
Priority to KR1020217001002A priority patent/KR20210010635A/ko
Priority to SG11202012656WA priority patent/SG11202012656WA/en
Priority to JP2020570145A priority patent/JP7467361B2/ja
Priority to BR112020025927-6A priority patent/BR112020025927A2/pt
Application filed by Epigen Biosciences, Inc. filed Critical Epigen Biosciences, Inc.
Priority to EP19821626.9A priority patent/EP3807254A4/fr
Priority to MX2020014300A priority patent/MX2020014300A/es
Priority to CN201980047732.7A priority patent/CN112424174B/zh
Priority to CA3104465A priority patent/CA3104465A1/fr
Priority to AU2019288275A priority patent/AU2019288275A1/en
Publication of WO2019246109A1 publication Critical patent/WO2019246109A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds having pharmacological activity, to processes for preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and prophylaxis of disease in a subject in need thereof, in particular for human and veterinarian treatments of pain, pruritus, cancer, inflammation and fibrotic diseases.
  • Lysophospholipids affect fundamental cellular functions that include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogensis. Abnormal functions influence many biological processes leading to disease that include, but are not limited to fibrotic disease, inflammation, cancer and peripheral nerve injury.
  • Lysophosphatidic acid (LPA) is a lysophospholipid that has been shown to act through specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine fashion. Antagonists of the LPA receptors find use in the treatment of diseases, disorders or conditions in which LPA plays a role.
  • GPCRs G protein-coupled receptors
  • LPA lysophosphatidic acid
  • those compounds are useful for the treatment of fibrosis of organs (e.g., liver, kidney, lung, heart and the like), liver diseases (e.g. , acute hepatatis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, nonalcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like), cell proliferative disease such as cancers (including but not limited to solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), invasive metastasis of cancer cell, and the like), inflammatory diseases (including but not limited to psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract disease (including but not limited to (irritable bowel syndrome (IBS), inflammatory bowel
  • IBS irritable
  • the compounds of the invention include compounds of Formula I that have the structure:
  • R B is optionally substituted C1-C4 alkyl or has the structure of one of
  • U is substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted Cr C 6 fluoroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C1-C6 heteroalkylene;
  • Ring A has the structure of one of
  • R c is -CN, -F, -Cl, -Br, -I, -OC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 4 fluoroalkyl;
  • R E , R F and R G independently are -H or C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl or R E and
  • R F independently are -H or C 1 -C 4 alkyl or C 1 -C 6 cycloalkyl and one R G is -C 1 -C 4 alkyl and is taken together with the R H pheny moiety of the Ring A R D substituent and the carbon atom to which R G and said phenyl moiety is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle;
  • R H is independently -H, halogen, -CN, -NO 2 , -OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy,
  • compositions, devices, articles of manufacture or methods that "comprise” a component or step are open and they include or read on those compositions or methods plus an additional component(s) or step(s).
  • disclosed compositions, devices, articles of manufacture or methods that "consist of” a component or step are closed and they would not include or read on those compositions or methods having appreciable amounts of an additional component(s) or an additional step(s).
  • use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
  • Bond or "single bond” as used herein means a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • Membered ring as used herein means any cyclic structure.
  • the term “membered” is meant to denote the number of skeletal atoms that constitute the ring.
  • those membered rings include cyclohexyl, pyridinyl, pyranyl and thiopyranyl, which are 6-membered rings and cyclopentyl, pyrrolyl, furanyl, and thienyl, which are 5-membered rings.
  • Moiety as used herein means a specific segment, fragment or functional group of a molecule or compound. Chemical moieties are sometimes indicated as chemical entities that are embedded in or appended (i.e., a substituent or variable group) to a molecule or compound.
  • Alkyl as used herein is a collection of carbon atoms that are covalently linked together in normal, secondary, tertiary or cyclic arrangements, i.e., in a linear, branched, cyclic arrangement or some combination thereof.
  • An alkyl substituent to a structure is that chain of carbon atoms that is covalently attached to the structure through a sp 3 carbon of the substituent.
  • alkyl substituents contains one or more saturated moieties or groups and may additionally contain unsaturated alkyl moieties or groups, i.e., the substituent may comprise one, two, three or more independently selected double bonds or triple bonds of a combination thereof, typically one double or one triple bond if such unsaturated alkyl moieties or groups are present.
  • Unsaturated alkyl moieties or groups include moieties or groups as described below for alkenyl, alkynyl, cycloalkyl, and aryl moieties. Saturated alkyl moieties contain saturated carbon atoms (sp 3 ) and no aromatic, sp 2 or sp carbon atoms.
  • the number of carbon atoms in an alkyl moiety or group can vary and typically is 1 to about 50, e.g., about 1-30 or about 1-20, unless otherwise specified, e.g., Ci- 3 alkyl or C1-C8 alkyl means an alkyl moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms and Ci- 6 alkyl or C1-C6 means an alkyl moiety containing 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • species may include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (/so-propyl, -CH(CH3)2), 1-butyl (n-butyl), 2- methyl-1 -propyl (iso- butyl, -CH 2 CH(CH 3 )2), 2-butyl (sec-butyl, -CH(CH 3 )CH 2 CH 3 ), 2- methyl-2-propyl (f-butyl, -C(CH 3 ) 3 ), amyl, isoamyl, sec-amyl and other linear, cyclic and branch chain alkyl moieties.
  • alkyl groups can contain species and groups described below for cycloalkyl, alkenyl, alkynyl groups, aryl groups, arylalkyl groups, alkylaryl groups and the like.
  • Cycloalkyl as used here is a monocyclic, bicyclic or tricyclic ring system composed of only carbon atoms.
  • the term "cycloalkyl” encompasses a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • the number of carbon atoms in an cycloalkyl substituent, moiety or group can vary and typically is 3 to about 50, e.g., about 1-30 or about 1-20, unless otherwise specified, e.g., alkyl or C3-C8 alkyl means an cycloalkyl substituent, moiety or group containing 3, 4, 5, 6, 7 or 8 carbon atoms and C3- 6 alkyl or C3-C6 means an cycloalkyl substituent, moiety or group containing 3, 4, 5 or 6 carbon atoms.
  • Cycloalkyl substituents, moieties or groups will typically have 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms and may contain exo or endo-cyclic double bonds or endo-cyclic triple bonds or a combination of both wherein the endo-cyclic double or triple bonds, or the combination of both, do not form a cyclic conjugated system of 4n + 2 electrons; wherein the bicyclic ring system may share one (i.e., spiro ring system) or two carbon atoms and the tricyclic ring system may share a total of 2, 3 or 4 carbon atoms, typically 2 or 3.
  • cycloalkyl substituents, moieties or groups can contain moieties and groups described for alkenyl, alkynyl, aryl, arylalkyl, alkylaryl and the like and can contain one or more other cycloalkyl moieties.
  • cycloalkyls may be saturated, or partially unsaturated.
  • Cycloalkyls may be fused with an aromatic ring, and the points of attachment to the aromatic ring are at a carbon or carbons of the cycloalkyl substituent, moiety or group that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • Cycloalkyl substituents, moieties or groups include cyclopropyl, cyclopentyl, cyclohexyl, adamantly or other cyclic all carbon containing moieties. Cycloalkyls further include cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptyl and cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted.
  • a cycloalkyl substituent can be a monoradical or a diradical (i.e., an cycloalkylene, such as, but not limited to, cyclopropan- 1 , 1-diyl, cyclobutan-1 , 1-diyl, cyclopentan-1 , 1-diyl, cyclohexan- 1 , 1-diyl, cyclohexan-1 ,4-diyl, cycloheptan-1 , 1-diyl, and the like).
  • an cycloalkylene such as, but not limited to, cyclopropan- 1 , 1-diyl, cyclobutan-1 , 1-diyl, cyclopentan-1 , 1-diyl, cyclohexan- 1 , 1-diyl, cyclohexan-1 ,4-diyl, cycloheptan-1 , 1-diyl, and the like).
  • cycloalkyl When cycloalkyl is used as a Markush group (i.e., a substituent) the cycloalkyl is attached to a Markush formula with which it is associated through a carbon involved in a cyclic carbon ring system carbon of the cycloalkyl group that is not an aromatic carbon.
  • Heteroalkylene as used herein means an alkylene (i.e.
  • alkanediyl group, moiety or substituent in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • Heteroalkylene includes C1 -C6 heteroalkylene or C1 -C4 heteroalkylene.
  • Exemplary heteroalkylenes include, but are not limited to, -OCH2-, -OCH(CH3)-,
  • Carboxylic acid bioisostere as used herein means a functional group, moiety or substituent that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • carboxylic acid bioisosteres include,
  • An alkenyl moiety, group or substituent with multiple double bonds may have the double bonds arranged contiguously (i.e.
  • a 1 ,3 butadienyl moiety or non-contiguously with one or more intervening saturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of double bonds do not form a cyclically conjugated system of 4n + 2 electrons (i.e., aromatic).
  • the number of carbon atoms in an alkenyl group or moiety can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C2-8 alkenyl or C2-8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms and C2-6 alkenyl or C2-6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms.
  • Alkenyl moieties or groups will typically have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • alkenyl When alkenyl is used as a Markush group (i.e. , a substituent) the alkenyl is attached to a Markush formula with which it is associated through an unsaturated carbon of a double bond of the alkenyl moiety or group unless specified otherwise.
  • Alkynyl as used herein means a substituent, moiety or group that comprises one or more triple bond moieties (i.e., -CoC-), e.g., 1 , 2, 3, 4, 5, 6 or more, typically 1 or 2 triple bonds, optionally comprising 1 , 2, 3, 4, 5, 6 or more double bonds, with the remaining bonds (if present) being single bonds and comprising linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched, cyclic or any combination thereof, unless the alkynyl moiety is ethynyl.
  • triple bond moieties i.e., -CoC-
  • the number of carbon atoms in an alkenyl moiety or group can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C2-8 alkynyl or C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Alkynyl groups will typically have 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • species include, by way of example and not limitation, any of the alkyl moieties, groups or substituents described herein that has 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, cyclic and branched chained all carbon containing moieties containing at least one triple bond.
  • alkynyl When an alkynyl is used as a Markush group (i.e., a substituent) the alkynyl is attached to a Markush formula with which it is associated through one of the unsaturated carbons of the alkynyl functional group.
  • Aromatic refers to a planar ring having a delocalized pi-electron system containing 4n+2 pi electrons, where n is a positive integer. Aromatic rings can be formed from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics are optionally substituted.
  • aromatic includes both carboxcylic aryl ("aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (l.e. , rings which share adjacent pairs of carbon atoms) groups.
  • Aryl as used here means an aromatic ring system or a fused ring system with no ring heteroatoms comprising 1 , 2, 3 or 4 to 6 rings, typically 1 to 3 rings, wherein the rings are composed of only carbon atoms; and refers to a cyclically conjugated system of 4n + 2 electrons (Huckel rule), typically 6, 10 or 14 electrons some of which may additionally participate in exocyclic conjugation (cross-conjugated (e.g., quinone).
  • Aryl substituents, moieties or groups are typically formed by five, six, seven, eight, nine, or more than nine, carbon atoms.
  • Aryl substituents, moieties or groups are optionally substituted.
  • Exemplary aryls include C6-C10 aryls such as phenyl and naphthalenyl and phenanthryl.
  • 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.
  • aryl is used as a Markush group (i.e., a substituent) the aryl is attached to a Markush formula with which it is associated through an aromatic carbon of the aryl group.
  • Arylalkyl as used herein means a substituent, moiety or group where an aryl moiety is bonded to an alkyl moiety, i.e., -alkyl-aryl, where alkyl and aryl groups are as described above, e.g., -CH2-C6H5 or -CH 2 CH(CH 3 )-C 6 H 5 .
  • arylalkyl is used as a Markush group (i.e., a substituent) the alkyl moiety of the arylalkyl is attached to a Markush formula with which it is associated through a sp 3 carbon of the alkyl moiety.
  • Alkylaryl as used herein means a substituent, moiety or group where an alkyl moiety is bonded to an aryl moiety, i.e., -aryl-alkyl, where aryl and alkyl groups are as described above, e.g., -C6H4-CH3 or -C6H4-CH2CH(CH3).
  • alkylaryl is used as a Markush group (i.e., a substituent) the aryl moiety of the alkylaryl is attached to a Markush formula with which it is associated through a sp 2 carbon of the aryl moiety.
  • Substituted alkyl mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle, aryl or other group or moiety as defined or disclosed herein that has a substituent(s) that replaces a hydrogen atom(s) or a substituent(s) that interrupts a carbon atom chain.
  • Alkenyl and alkynyl groups that comprise a substituent(s) are optionally substituted at a carbon that is one or more methylene moieties removed from the double bond.
  • Optionally substituted alkyl mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle, aryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, or other substituent, moiety or group as defined or disclosed herein that has a substituent(s) that optionally replaces a hydrogen atom(s) or a substituent(s) that interrupts a carbon atom chain.
  • substituents are as described herein.
  • the arrangement of any two substituents present on the aromatic ring can be ortho (o), meta ( m ), or para (p).
  • An optionally substituted fluoroalkyl is an alkyl or cycloalkyl moiety, typically a linear alkyl, wherein one or more hydrogen atoms is replaced by fluorine and at least one other atom other than carbon and fluorine.
  • An optionally substituted or substituted substituent, moiety or group includes those having one or more additional group(s) that replace its hydrogen atom(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • the protecting groups that may form the protective derivatives of the above substituents may be found in sources such as Greene and Wuts, above.
  • Optional substituents include those selected from the group consisting of halogen, -CN, -NH 2 , -OH, -N(CH3) 2 , alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone, those selected from the group consisting of halogen, -CN, -NH 2 , -OH, NH(CH3),
  • an optionally substituted, substituent, moiety or group is substituted with one or two of the preceding groups, or more typically with one of the preceding groups.
  • Heterocycle or“heterocyclic” as used herein means a cycloalkyl or aromatic ring system wherein one or more, typically 1 , 2 or 3, but not all of the carbon atoms comprising the ring system are replaced by a heteroatom which is an atom other than carbon, including, N, O, S, Se, B, Si, P, typically N, O or S wherein two or more heteroatoms may be adjacent to each other or separated by one or more carbon atoms, typically 1-17 carbon atoms, 1-7 atoms or 1-3 atoms.
  • Heterocycles includes heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic, substituents, moieties or groups have at least 3 atoms in their ring system, and aromatic heterocyclic groups have at least 5 atoms in their ring system and include benzo-fused ring systems.
  • Heterocyclics with 3, 4, 5, 6 and 10 atoms include aziridinyl azetidinyl, thiazolyl, pyridyl and quinolinyl, respectively.
  • Nonaromatic heterocyclic substituents, moieties or groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 , 2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-
  • Aromatic heterocyclic includes, by way of example and not limitation, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl.triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzo-thiophenyl, benzothiazolyl, benzoxazolyl, qui
  • heterocycle When heterocycle is used as a Markush group (i.e. , a substituent) the heterocycle is attached to a Markush formula with which it is associated through a carbon or a heteroatom of the heterocycle, where such an attachment does not result in an unstable or disallowed formal oxidation state of that carbon or heteroatom.
  • a heterocycle that is C-linked is bonded to a molecule through a carbon atom include moieties such as -(CH2) n -heterocycle where n is 1 , 2 or 3 or -C ⁇ heterocycle where C ⁇ represents a carbon atom in a heterocycle ring.
  • a heterocycle that is N-linked is a nitrogen containing heterocycle that is bonded a heterocycle ring nitrogen sometimes described as -N ⁇ heterocycle where N ⁇ represents a nitrogen atom in a heterocycle ring.
  • nitrogen-containing heterocycles may be C-linked or N-linked and include pyrrole substituents, which may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked), imidazole substituents, which may be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2- yl, imidazol-4-yl or imidazol-5-yl (all C-linked).
  • Heteroaryl as used herein means an aryl ring system wherein one or more, typically 1 , 2 or 3, but not all of the carbon atoms comprising the aryl ring system are replaced by a heteroatom which is an atom other than carbon, including, N, O, S, Se, B, Si, P, typically, oxygen (-0-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a protecting group or Ci-e optionally substituted alkyl, wherein the heteroatom participates in the conjugated system either through pi-bonding with an adjacent atom in the ring system or through a lone pair of electrons on the heteroatom and may be optionally substituted on one or more carbons or heteroatoms, or a combination of both, in a manner which retains the cyclically conjugated system.
  • Heterocycles and heteroaryls include, by way of example and not limitation, heterocycles and heteroaryls described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1 , 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960, 82:5545-5473 particularly 5566-5573).
  • heteroaryls include by way of example and not limitation pyridyl, thiazolyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, purinyl, imidazolyl, benzofuranyl, indolyl, isoindoyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyridazinyl, pyrazinyl, benzothiopyran, benzotriazine, isoxazolyl, pyrazolopyrimidinyl, quinoxalinyl, thiadiazolyl, triazolyl and the like.
  • Heterocycles that are not heteroaryls include, by way of example and not limitation, tetrahydrothiophenyl, tetrahydrofuranyl, indolenyl, piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, piperazinyl, quinuclidinyl, morpholinyl, oxazolidinyl and the like.
  • heteroaryls include, by way of example and not limitation, the following moieties:
  • Monocyclic heteroaryls include, by way of example and not limitation, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Heteroaryls include those substituents, moieties or groups containing 0-3 N atoms, 1-3 N atoms or 0-3 N atoms, 0-1 O atoms and 0-1 S atoms.
  • a heteroaryl may be monocyclic or bicyclic.
  • the ring system of a heteroaryls ring typically contains 1-9 carbons (i.e. , Ci-Cg heteroaryl).
  • Monocyclic heteroaryls include C1 -C5 heteroaryls.
  • Monocyclic heteroaryls include those having 5-membered or 6-membered ring systems.
  • Bicyclic heteroaryls include C6-C9 heteroaryls.
  • a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
  • Heterocycloalkyl or“heteroalicyclic” as used herein means a cycloalkyl group, moiety or substituent wherein at least on carbon of the cycloalkyl chain is replaces with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocycloalkyl may be fused with an aryl or heteroaryl.
  • Heterocycloalkyls also referred to as non-aromatic heterocycles, include by way of example and not limitation:
  • Heterocycloalkyl includes, by way of example and not limitation, oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl.
  • Heteroalicyclics further includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.
  • a heterocycloalkyl is a C2-C10 heterocycloalkyl and includes C4-C10 heterocycloalkyl.
  • a heterocycloalkyl may contain 0-2 N atoms, 0-2 O atoms or 0-1 S atoms.
  • Heteroarylalkyl as used herein means a substituent, moiety or group where a heteroaryl moiety is bonded to an alkyl moiety, i.e., -alkyl-heteroaryl, where alkyl and heteroaryl groups are as described above.
  • heteroarylalkyl is used as a Markush group (i.e. , a substituent) the alkyl moiety of the heteroarylalkyl is attached to a Markush formula with which it is associated through a sp 3 carbon of the alkyl moiety.
  • Alkylheteroaryl as used herein means a substituent, moiety or group where a heteroaryl moiety is bonded to an alkyl moiety, i.e., -heteroaryl-alkyl, where heteroaryl and alkyl groups are as described above.
  • heteroarylalkyl is used as a Markush group (i.e., a substituent) the heteroaryl moiety of the heteroarylalkyl is attached to a Markush formula with which it is associated through a sp 2 carbon or heteroatom of the alkyl moiety.
  • Halogen or“halo” as used herein means fluorine, chlorine, bromine or iodine.
  • Haloalkyl as used herein means an alkyl substituent moiety or group in which one or more of its hydrogen atoms are replaced by one or more independently selected halide atoms.
  • Haloalkyl includes C1-C4 haloalkyl.
  • Example but non-limiting C1-C4 haloalkyls are -CH 2 CI, CH 2 Br, -CH 2 I, -CHBrCI, -CHCI-CH 2 CI and -CHCI-CH2I.
  • Haloalkylene as used herein means an alkylene substituent, moiety or group in which one or more hydrogen atoms are replaced by one or more halide atoms.
  • Haloalkylene includes Ci-Ce haloalkylenes or C1-C4 haloalkylenes.
  • Fluoroalkyl as used herein means an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. Fluoroalkyl includes C1-C 6 and C1-C4 fluoroalkyls. Example but non-limiting fluoroalkyls include -CH 3 F, -CH2F2 and -CF 3 and perfluroalkyls.
  • Fluoroalkylene as used herein means an alkylene in which one or more hydrogen atoms are replaced by a fluorine atom. Fluoroalkylene includes C1-C6 fluoroalkylenes or C1-C4 fluoroalkylenes.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a heteroalkyl is a C1-C6 heteroalkyl.
  • Protecting group means a moiety that prevents or reduces the ability of the atom or functional group to which it is linked from participating in unwanted reactions.
  • Non-limiting examples are for -OR PR , wherein R PR is a protecting group for the oxygen atom found in a hydroxyl, while for -C(0)-OR PR , R PR may be a carboxylic acid protecting group; for -SR PR , R PR may be a protecting group for sulfur in thiols and for -NHR PR or -N(R PR )2-, at least one of R PR is a nitrogen atom protecting group for primary or secondary amines. Hydroxyl, amine, ketones and other reactive groups may require protection against reactions taking place elsewhere in the molecule.
  • the protecting groups for oxygen, sulfur or nitrogen atoms are usually used to prevent unwanted reactions with electrophilic compounds, such as acylating agents.
  • Typical protecting groups for atoms or functional groups are given in Greene (1999),“Protective groups in organic synthesis, 3 rd ed.”, Wiley Interscience.
  • Ester as used herein means a substituent, moiety or group that contains a -C(0)-0- structure (i.e. , ester functional group) wherein the carbon atom of the structure is not directly connected to another heteroatom and is directly connected to -H or another carbon atom.
  • esters comprise or consist of an organic moiety containing 1-50 carbon atoms, 1-20 carbon atoms or 1-8 carbon atoms and 0 to 10 independently selected heteroatoms (e.g., O, S, N, P, Si), typically 0-2 where the organic moiety is bonded through the -C(0)-0- structure and include ester moieties such as organic moiety-C(0)-0-.
  • the organic moiety usually comprises one or more of any of the organic groups described herein, e.g., C1-20 alkyl moieties, C2-20 alkenyl moieties, C2-20 alkynyl moieties, aryl moieties, C3-8 heterocycles or substituted derivatives of any of these, e.g., comprising 1 , 2, 3, 4 or more substituents, where each substituent is independently chosen.
  • Exemplary, non-limiting substitutions for hydrogen or carbon atoms in these organic groups are as described above for substituted alkyl and other substituted moieties and are independently chosen.
  • esters include by way of example and not limitation, one or more independently selected acetate, propionate, isopropionate, isobutyrate, butyrate, valerate, isovalerate, caproate, isocaproate, hexanoate, heptanoate, octanoate, phenylacetate esters or benzoate esters.
  • ester is used as a Markush group (i.e., a substituent) the single bonded oxygen of the ester functional group is attached to a Markush formula with which it is associated.
  • Acetal”,“thioacetal”, “ketal”, “thioketal” and the like as used herein means a moiety, group or substituent comprising or consisting of a carbon to which is bonded two of the same or different heteroatoms wherein the heteroatoms are independently selected S and O.
  • the carbon has two bonded oxygen atoms, a hydrogen atom and an organic moiety.
  • the carbon has two bonded oxygen atoms and two independently selected organic moieties where the organic moiety is as described herein alkyl or optionally substituted alkyl group.
  • thioacetals and thioketals one or both of the oxygen atoms in acetal or ketal, respectively, is replaced by sulfur.
  • the oxygen or sulfur atoms in ketals and thioketals are sometimes linked by an optionally substituted alkyl moiety.
  • the alkyl moiety is an optionally substituted C1-8 alkyl or branched alkyl structure such as -C(CH3)2-, -CH(CH3)-, -CH2-, -CH2-CH2-, -C[(C2-C4 alkyl)2]i , 2 , 3- or -[CH(C2-C4 alkyl)]i , 2 , 3-.
  • moieties can serve as protecting groups for an aldehyde or ketone include, by way of example and not limitation, acetals for aldehydes and ketals for ketones and contain -O-CH2-CH2-CH2-O- or -O-CH2-CH2-O- moieties that form a spiro ring with the carbonyl carbon, and can be removed by chemical synthesis methods or by metabolism in cells or biological fluids.
  • Ether as used herein means an organic moiety, group or substituent that comprises or consists of 1 , 2, 3, 4 or more -O- moieties, usually 1 or 2, wherein no two -O- moieties are immediately adjacent (i.e. , directly attached) to each other.
  • ethers comprise an organic moiety containing 1-50 carbon atoms, 1-20 carbon atoms or 1-8 carbon atoms and 0 to 10 independently selected heteroatoms (e.g., O, S, N, P, Si), typically 0-2.
  • An ether moiety, group or substituent includes organic moiety-O- wherein the organic moiety is as described herein for alkyl or optionally substituted alkyl group.
  • ether When ether is used as a Markush group (i.e., a substituent) the oxygen of the ether functional group is attached to a Markush formula with which it is associated.
  • ether When ether is a used as substituent in a Markush group it is sometimes designated as an "alkoxy" group.
  • Alkoxy includes C1-C4 ether substituents such as, by way of example and not limitation, methoxy, ethoxy, propoxy, iso-propoxy and butoxy.
  • Ether further includes those substituents, moieties or groups that contain one (excluding ketal) or more -OCH2CH2O-, moieties in sequence (i.e., polyethylene or PEG moieties).
  • a Markush group i.e., a substituent
  • one of the singly bonded oxygen atoms of the carbonate functional group is attached to a Markush formula with which it is associated.
  • heteroatoms e.g., O, S, N, P, Si
  • carbamate When carbamate is used as a Markush group (i.e., a substituent) the singly bonded oxygen (O-linked) or nitrogen (N-linked) of the carbamate functional group is attached to a Markush formula with which it is associated.
  • the linkage of the carbamate substituent is either explicitly stated (N- or O- linked) or implicit in the context to which this substituent is referred.
  • a C1 ester refers to a formate ester and a C2 ester refers to an acetate ester.
  • LPA-dependent means a disease or condition whose etiology, progression or persistence is effected by in whole or in part by signaling through one or more lysophosphatidic acid receptor subtypes, including by way of example and not limitation lysophosphatidic acid receptor subtypes 1-6 (LPARs).
  • LPARs lysophosphatidic acid receptor subtypes 1-6
  • LPA-dependent or LPA-mediated diseases and conditions include but not limited to fibrosis of organs (e.g., liver, kidney, lung, heart and the like), liver diseases (e.g., acute hepatatis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, nonalcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like), cell proliferative disease (e.g., cancers, including but not limited to solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), invasive metastasis of cancer cell, and the like), inflammatory disease (e.g., psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract disease (e.g., irritable bowel syndrome (I
  • LPA1 R selective agents means agents or compounds that interact with the lysophosphatidic acid subtype 1 receptor in preference to the lysophosphatidic acid receptor 2-6. Typically, that preference is manifested by 10-fold stronger binding affinity of the agent to LPA1 R in comparison to other known LPARs as measured by experimentally determined K D values.
  • “Pharmaceutically acceptable formulation” as used herein means a composition comprising an active pharmaceutical ingredient, such as a compound having the formula of l-VI in addition to one or more pharmaceutically acceptable excipients or refers to a composition prepared from an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients, wherein the composition is suitable for administration to a subject, such as a human or an animal, in need thereof.
  • an active pharmaceutical ingredient such as a compound having the formula of l-VI in addition to one or more pharmaceutically acceptable excipients or refers to a composition prepared from an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients, wherein the composition is suitable for administration to a subject, such as a human or an animal, in need thereof.
  • the formulation must have biological activity for treating or preventing a disease or condition disclosed herein or an expectation must exist that the formulation would have a desired activity towards an“intent to treat” disease or condition.
  • the“intent to treat” disease or condition is a lysophosphatidic acid receptor-mediated condition or disease. More typically the disease or condition to be treated or prevented is a lysophosphatidic acid lysophosphatidic acid type 1 receptor-mediated disease or condition.
  • a pharmaceutically acceptable formulation that is suitable for administration to an animal does not necessarily require a biological activity for treating or preventing a disease or condition, and may be administered to the animal in order to evaluate a potential pharmacological or biological activity of a Formula l-XII compound. Those formulations must therefore be suitable for treating or preventing a disease or condition disclosed herein in an animal in need thereof or is suitable for evaluating a pharmacological or biological activity of a Formula l-XII compound.
  • Compositions that are suitable only for use in vitro assays or which contain a vehicle, component or excipient in an amount not permitted in a drug product are specifically excluded from the definition of a pharmaceutically acceptable formulation.
  • the pharmaceutically acceptable formulation may be comprised of, or be prepared from, one, two or more Formula l-XII compounds, typically one or two, and one or more pharmaceutically acceptable excipients. More typically, the formulations will consist essentially of or consist of a single Formula l-XII compound and one or more pharmaceutically acceptable excipients. Other formulations may be comprised of, consist essentially of, or consist of one, two or more Formula l-XII compounds and one two or more compounds in current use for treating lysophosphatidic acid lysophosphatidic acid type 1 receptor-mediated disease or condition disclosed herein and one or more pharmaceutically acceptable excipients.
  • those formulations will consist essentially of or consist of a single Formula l-XII compound, a single compound in current use for treating a lysophosphatidic acid lysophosphatidic acid type 1 receptor-mediated disease or condition and one or more pharmaceutically acceptable excipients.
  • Solid formulation refers to a pharmaceutically acceptable formulation comprising at least one Formula l-XII compound and one or more pharmaceutically acceptable excipients in solid form(s) wherein the formulation is in a unit dosage form suitable for administration of a solid.
  • the dosage units include tablets, capsules, caplets, gelcaps, suspensions and other dosage units typically associated with parenteral or enteral (oral) administration of a solid.
  • Liquid formulation refers to a pharmaceutically acceptable formulation wherein at least one Formula l-XII compound has been admixed or contacted with one or more pharmaceutically acceptable excipients, wherein at least one of the excipients is in liquid form in proportions required for a liquid formulation, i.e., such that a majority of the mass amount of the Formula l-XII compound(s) is dissolved into the non-solid excipient.
  • Dosage units containing a liquid formulation include syrups, gels, ointments and other dosage units typically associated with parenteral or enteral administration of a pharmaceutical formulation to a subject in need thereof in liquid form.
  • the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • the methods and formulations described herein include the use of pharmaceutically acceptable salts of compounds having the structure of Formulas (l-VI), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers.
  • the compounds described herein will exist as salts, including pharmaceutically acceptable salts.
  • the salt forms include inorganic addition salts such as F Cl , Br, I and sulfate salts and organic addition salts such as mesylate, besylate, tosylate, citrate, succinate, fumarate and malonate.
  • the compounds described herein exist as quaternary ammonium salts.
  • R B is optionally substituted C1-C4 alkyl or has the structure of one of
  • R B is substituted or unsubstituted C1-C4 alkyl
  • L 1 is substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted Cr C 6 fluoroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted C1-C6 heteroalkylene;
  • Ring A has the structure of one of
  • R c is -CN, -F, -Cl, -Br, -I, -OC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 4 fluoroalkyl;
  • R E , R F and R G independently are -H or C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl or R E and R F independently are -H or C 1 -C 4 alkyl or C 1 -C 6 cycloalkyl and one R G is -C 1 -C 4 alkyl and is taken together with the R H pheny moiety of the Ring A R D substituent and the carbon atom to which R G and said phenyl moiety is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle;
  • R H is independently -H, halogen, -CN, -NO 2 , -OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy,
  • R F and each R G independently are -H or C 1 -C 4 alkyl.
  • R A is -CO2H, -CONHCN, tetrazolyl, or
  • U is substituted or unsubstituted C1-C6 alkylene, C1-C6 fluoroalkylene, or substituted or unsubstituted C1-C6 heteroalkylene.
  • Formula I compounds have R c defined as -CN, -F, -Cl, or C 1 -C 4 fluoroalkyl.
  • Formula I compounds have R c defined as -F, or -Cl.
  • Formula I compounds have R F defined as H, C 1 -C 4 alkyl or C3-C6 cycloalkyl.
  • Formula I compounds have R F defined as -H.
  • R G is independently -H or C 1 -C 4 alkyl.
  • Formula I compounds have R G defined as -CH 3 .
  • CY is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 independently selected R H .
  • R F , R G , and CY are as previously defined.
  • R A is tetrazolyl
  • R c is -F
  • R F , R G , and CY are as previously defined.
  • R B is -F or -Cl
  • R B , R F , R G , and CY are as previously defined.
  • R A is -CONHCN
  • R c is -F
  • R F , R G , and CY are as previously defined.
  • Embodiment 2 The compound of Embodiment 1 wherein R A is -CO2H or CONHCN.
  • Embodiment 3 The compound of Embodiment 1 wherein R A is tetrazolyl.
  • Embodiment 5 The compound of Embodiment 1-4 wherein R c is -CN, -F, or -Cl.
  • Embodiment 6 The compound of Embodiment 1-5 wherein R c is -F or -Cl.
  • Embodiment 7 The compound of Embodiment 1-6 wherein L 1 , when present, is a geminally substituted alkyl, cycloalkyl or heterocycloalkyl group,
  • Embodiment 8 The compound of Embodiments 7 wherein L 1 is [117] Embodiment 9. The compound of any one of Embodiments 1-8 wherein R F is -H.
  • Embodiment 10 The compound of any one of Embodiments 1-9 wherein R G is -CHs.
  • Embodiment 11 The compound of any one of Embodiments 1-10 wherein CY is substituted or unsubstituted phenyl.
  • Embodiment 12 The compound of any one of Embodiments 1-11 wherein R H is -H, halogen, -CN, -N0 2 , -OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, and Cr C 4 alkoxy.
  • Embodiment 13 The compound of any one of Embodiments 1-12 wherein R H are independently selected from -H, halogen or substituted or unsubstituted C 1 -C 4 alkyl or substituted C 1 -C 4 alkoxy.
  • Embodiment 14 The compound of any one of Embodiments 1-13 wherein R H is independently -H, -Cl, -F, -CH 3 , -CF 3, -OCH 3 or -OCF 3 .
  • Embodiment 15 A compound of Formula II having the structure:
  • R B is optionally substituted C 1 -C 4 alkyl
  • L 1 is optionally substituted C1-C6 alkylene; C1-C6 fluoroalkylene; or optionally
  • substituted C1-C6 heteroalkylene or L 1 is , or disubstituted dimethylmethane.
  • Ring A has the structure:
  • R c is -CN, -F, -Cl, or CrC 4 fluoroalkyl
  • R E , R F and R G independently are -H or C1 -C4 alkyl or C3-C6 cycloalkyl or R E and R F independently are -H or C1 -C4 alkyl or C1 -C6 cycloalkyl and one R G is -C1 -C4 alkyl and is taken together with the R H pheny moiety of the Ring A R D substituent and the carbon atom to which R G and said phenyl moiety is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle;
  • R H is -H, halogen, -CN, -NO 3 ⁇ 4 -OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and C1 -C4 alkoxy;
  • R B is CH 3
  • R c is -F or -Cl
  • Embodiment 16 A compound of Formula III having the structure:
  • R B is optionally substituted C1 -C4 alkyl
  • L 1 is substituted C1-C6 alkylene; C1-C6 fluoroalkylene; or optionally substituted
  • Ring A has the structure of one of:
  • R F and R G independently are -H or C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl or R F independently is -H or C 1 -C 4 alkyl or C 1 -C 6 cycloalkyl and one R G is -C 1 -C 4 alkyl and is taken together with the R H pheny moiety of the Ring A R D substituent and the carbon atom to which R G and said phenyl moiety is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle;
  • R H is -H, halogen, -CN, -NO2, -OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and C 1 -C 4 alkoxy;
  • Embodiment 17 A composition comprising, essentially consisting of or consisting of one or more compounds of Formula l-lll and one or more excipients.
  • the composition comprises, consists essentially of, or consists of one compound of Formula l-lll and one or more excipients.
  • composition is a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of one compound of Formula l-lll and one or more pharmaceutically acceptable excipients.
  • Embodiment 18 A compound of Formula l-lll or a pharmaceutically acceptable salt or prodrug thereof wherein the binding affinity of the compound to lysophosphatidic acid receptor-1 (LPA1 R) is between about 10 mM and 1 pM or less
  • Embodiment 19 The compound of Embodiment 1-18 wherein the compound is a selective lysophosphatidic acid receptor-1 (LPA1 R) compound.
  • LPA1 R selective lysophosphatidic acid receptor-1
  • Embodiment 20 A compound of Formula l-lll or a pharmaceutically acceptable salt, or prodrug thereof wherein the compound is a selective lysophosphatidic acid receptor-1 (LPA1 R) compound.
  • LPA1 R selective lysophosphatidic acid receptor-1
  • Embodiment 21 The compound of Embodiment 1-20 wherein the compound is a selective lysophosphatidic acid receptor-1 (LPA1 R) compound wherein the binding affinity (i.e. , KD) of the LPA1 R compound is between about 1 pM and 1 pM or less.
  • the K D is 100 nM or less, more preferably 10 nM or less.
  • Embodiment 22 A compound of T able 1.
  • Embodiment 23 The compound of Embodiment 22 wherein the compound is (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H-pyrazol-1- yl)pyridin-2-yl)phenyl)cyclopropane-1 -carboxylic acid, (R)-1-(4'-(4-fluoro-5-(((1- phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 , T-biphenyl]-4-yl) cyclopropane- 1 - carboxylic acid, (R)-1-(3-fluoro-4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H- pyrazol-1-yl)
  • Embodiment 24 The compound of Embodiment 22 wherein the compound is (R)-1-(4-(5-(4-chloro-5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)pyridin-2-yl)phenyl)cyclopropane-1 -carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1- phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 , T-biphenyl]-4-yl) cyclopropane- 1 - carboxylic acid, (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)-3-fluoro-[1 ,T-biphenyl]-4-y
  • Embodiment 25 The compound of Embodiment 22 wherein the compound is (R)-1- ⁇ 4'-[5-(1-Phenyl-ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]-biphenyl-4- yl ⁇ -cyclopropanecarboxylic acid, or (R)-1- ⁇ 2-Fluoro-4'-[5-(1-phenyl- ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]-biphenyl-4-yl ⁇ - cyclopropanecarboxylic acid;
  • Embodiment 26 The compound of Embodiment 22 wherein the compound is (R)-1-(4'-(4-cyano-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 ,T-biphenyl]- 4-yl)cyclopropane-1 -carboxylic acid, (R)- 1-(4'-(5-(((1-(2- chlorophenyl)ethoxy)carbonyl)amino)-4-cyano-1 H-pyrazol-1-yl)-[1 ,T-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid, (R)- 2-(4'-(5-(((1-(2- chlorophenyl)ethoxy)carbonyl)amino)-4-cyano-1 H-pyrazol-1-yl)-[1 ,T-biphenyl]-4-yl)-yl
  • Embodiment 28 The compound of Embodiment 22 wherein the compound is (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1 , T-biphenyl]-4-yl)-4- fluoro-1 H-pyrazol-5-yl)carbamate, (R)-l-phenylethyl (1-(4'-(1-(1 H-tetrazol-5- yl)cyclopropyl)-[1 , T-biphenyl]-4-yl)-4-chloro-1 H-pyrazol-5-yl)carbamate, (R)-1-(2- chlorophenyl)ethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1 , T-biphenyl]-4-yl)-4-chloro-
  • Embodiment 29 The compound of Embodiment 22 wherein the compound is (R)-l-phenylethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-[1 , T-biphenyl]-4-yl)- 1 H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(4'-(1- (cyanocarbamoyl)cyclopropyl)-[1 , T-biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate, (R)-1-(2- chlorophenyl)ethyl (1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-2'-fluoro-[1 , T-biphenyl]-4-yl)- 4-fluoro-1 H-pyra
  • Embodiment 30 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Table 1 and one or more pharmaceutically acceptable excipients.
  • Embodiment 31 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 23 and one or more pharmaceutically acceptable excipients.
  • Embodiment 32 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 24 and one or more pharmaceutically acceptable excipients.
  • Embodiment 33 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 25 and one or more pharmaceutically acceptable excipients.
  • Embodiment 34 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 26 and one or more pharmaceutically acceptable excipients.
  • Embodiment 35 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 27 and one or more pharmaceutically acceptable excipients.
  • Embodiment 36 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 28 and one or more pharmaceutically acceptable excipients.
  • Embodiment 37 A pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Embodiment 29 and one or more pharmaceutically acceptable excipients.
  • Embodiment 38 A method comprising administering an effective amount of a Formula l-lll compound to a subject having a LPA-dependent or LPA-mediated disease or condition.
  • Embodiment 39 The method of Embodiment 38 wherein the LPA-dependent or LPA-mediated disease or condition is a disease with fibrosis of the organs.
  • Embodiment 40 The method of Embodiment 39 wherein the fibrosis is of the liver, kidney, lung, heart, eye and the like.
  • Embodiment 41 The method of Embodiment 38 wherein the LPA-dependent or LPA-mediated disease or condition is chronic pain
  • Embodiment 42 The method of Embodiment 38 wherein the LPA-dependent or LPA-mediated disease or condition is pruritus.
  • Embodiment 43 The method of Embodiment 38 wherein the LPA-mediated disease is a proliferative disease including cancer (solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like) and invasive metastasis of cancer cell, including ovarian, breast and triple negative breast cancer and the like,
  • cancer solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and the like
  • CLL chronic lymphocytic leukemia
  • Embodiment 44 The method of Embodiment 38 wherein the LPA-mediated disease is an inflammatory disease including psoriasis, nephropathy, pneumonia and the like,
  • Embodiment 45 The method of Embodiment 38 wherein the LPA-mediated disease is a gastrointestinal disease such as inflammatory bowel disease,
  • Embodiment 46 The method of Embodiment 38 wherein the LPA-mediated disease is an ocular disease including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, uveitis and the like,
  • AMD age-related macular degeneration
  • PVR proliferative vitreoretinopathy
  • cicatricial pemphigoid cicatricial pemphigoid
  • glaucoma filtration surgery scarring uveitis and the like
  • Embodiment 47 The method of Embodiment 38 wherein the LPA-mediated disease is a liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, nonalcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like,
  • a liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, nonalcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like
  • Embodiment 48 The method of Embodiment 38 wherein the LPA-mediated disease is a renal disease including chronic kidney disease, end stage renal disease, uremic pruritus, nephropathy including diabetic nephropathy and the like,
  • Embodiment 49 The method of Embodiment 38 wherein the LPA-mediated disease is a skin disease including scleroderma, skin scarring, atopic dermatitis, psoriasis and the like,
  • Embodiment 50 The method of any one of Embodiments 38-49 wherein the subject is a human.
  • Embodiment 51 The method of any one of Embodiments 38-50 wherein the compound is selected from Table 1.
  • Embodiment 52 The method of any one of Embodiments 78-90 wherein the compound is (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H- pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid, (R)-1-(4-(5-(4-chloro-5- (((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)pyridin-2- yl)phenyl)cyclopropane-1 -carboxylic acid, (R)-1-(4'-(4-fluoro-5-(((1- phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 ,T-biphenyl]-4
  • Embodiment 53 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 23.
  • Embodiment 54 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 24.
  • Embodiment 55 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 25.
  • Embodiment 56 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 26.
  • Embodiment 57 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 27.
  • Embodiment 58 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 28.
  • Embodiment 59 The method of any one of Embodiments 38-50 wherein the compound is selected from Embodiment 29.
  • Embodiment 60 A composition comprising, consisting essentially of or consisting of one or more compounds of Formula (l-lll) and one or more agents currently used to treat a LPA -dependent or LPA -mediated disease or a disease or condition described herein.
  • Embodiment 61 A pharmaceutically acceptable formulation comprising, consisting essentially of or consisting of one or more compounds of Formula (l-lll), one or more agents currently used to treat a LPA -dependent or LPA -mediated disease and one or more pharmaceutically acceptable excipients.
  • Embodiment 62 A method comprising administering in combination with or co administrating a compound of Formula (l-lll) to a subject with a LPA-dependent or LPA- mediated disease or condition and a currently used agent to treat a LPA -dependent or LPA -mediated disease
  • the one or more additional therapeutically active agents other than compounds of Formula (l-lll) are selected from: corticosteroids, immunosuppressants, analgesics, anti-cancer agents, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, platelet activating factor receptor antagonists, monoacylglycerol kinase inhibitors, phospholipase Ai inhibitors, phospholipase A 2 inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, decon-gestants, mast cell stabilizers, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and b-2 agonists.
  • corticosteroids corticosteroids
  • immunosuppressants analgesics
  • anti-cancer agents anti-inflammatories
  • the currently used agent(s) are selected from those described in the Merck Index known to affect lysophosphatidic acid receptor signaling.
  • the Formula (l-lll) compound is selected from Table 1.
  • therapies which combine a compound of Formula (l-lll), with currently used agents that act on differing signalling pathways to the LPA synthesis or signalling pathway so as to provide complementary clinical outcomes, are encompassed herein for treating LPA-dependent or LPA-mediated diseases or conditions.
  • additional therapeutic agents include, but are not limited to, any of the following: gossypol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5- aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, geldanamycin, 17-N-Allylamino-17 -Demethoxygeldanamycin (17 -AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD 184352, TaxolTM (paclitaxel), and analogs ofTaxolTM, such as TaxotereTM, U0126, PD98059, PD184352,
  • Embodiment 63 The method of Embodiments 60-62 wherein the subject is a human.
  • Embodiment 64 The method of Embodiments 60-62 wherein the Formula l-lll compound(s) are selected from Table 1.
  • Embodiment 65 The method of Embodiments 60-62 wherein the Formula l-lll compound(s) are selected from the group consisting of (R)-1-(4-(5-(5-(((1-(2- chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H-pyrazol-1-yl)pyridin-2- yl)phenyl)cyclopropane-1 -carboxylic acid, (R)-1-(4-(5-(4-chloro-5-(((1-(2- chlorophenyl)ethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane- 1-carboxylic acid, (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)-[1 ,
  • Embodiment 66 The method of Embodiments 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 23.
  • Embodiment 67 The method of Embodiments 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 24.
  • Embodiment 68 The method of Embodiments 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 25.
  • Embodiment 69 The method of Embodiment 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 26.
  • Embodiment 70 The method of Embodiment 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 27.
  • Embodiment 71 The method of Embodiment 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 28.
  • Embodiment 72 The method of Embodiment 60-63 wherein the Formula l-lll compound(s) are selected from Embodiment 29.
  • Embodiment 73 The composition of Embodiment 60 where the currently used agent is a mast cell stabilizing agent
  • Embodiment 74 The composition of Embodiment 60 where the currently used agent is a platelet activating factor receptor antagonist,
  • Embodiment 75 The composition of Embodiment 73 where the mast cell stabilizing agent is cromoglicate, nedocromil, azelastine, bepotastine, epinastine, ketotifen, olopatadine and rupatadine.
  • the mast cell stabilizing agent is cromoglicate, nedocromil, azelastine, bepotastine, epinastine, ketotifen, olopatadine and rupatadine.
  • Embodiment 76 The composition of Embodiment 74 where the platelet activating factor receptor antagonist is rupatadine, SM- 12502, CV-3988 and WEB 2170.
  • Embodiment 1A A compound wherein the compound has the structure of Formula I Formula I, or a pharmaceutically acceptable salt or prodrug thereof,
  • R B is substituted or unsubstituted C1-C4 alkyl
  • U is substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted Cr
  • Ring A has the structure of one of
  • R c is -CN, -F, -Cl, -Br, -I, -OC1-C4 alkyl, C 3 -C 6 cycloalkyl, or C1-C4 fluoroalkyl;
  • R E , R F and R G independently are -H or C1-C4 alkyl or C 3 -C 6 cycloalkyl or R E and R F independently are -H or C1-C4 alkyl or C1-C 6 cycloalkyl and one R G is -C1-C4 alkyl and is taken together with the R H pheny moiety of the Ring A R D substituent and the carbon atom to which R G and said phenyl moiety is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle;
  • R H is independently -H, halogen, -CN, -N0 2 , -OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 alkoxy,
  • U is substituted or unsubstituted C1-C6 alkylene, C1-C6 fluoroalkylene, or substituted or unsubstituted C1-C6 heteroalkylene.
  • Formula I compounds have R c defined as -CN, -F, -Cl, or C 1 -C 4 fluoroalkyl.
  • Formula I compounds have R c defined as -F, or -Cl.
  • Formula I compounds have R F defined as H, C 1 -C 4 alkyl or C3-C6 cycloalkyl.
  • Formula I compounds have R F defined as -H.
  • R G is independently -H or C 1 -C 4 alkyl.
  • Formula I compounds have R G defined as -CH 3 .
  • CY is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 independently selected R H .
  • R F , R G , and CY are as previously defined.
  • R F , R G , and CY are as previously defined.
  • R B is -F or -Cl
  • R B , R F , R G , and CY are as previously defined.
  • R A is -CONHCN
  • R c is -F or -Cl
  • R F , R G , and CY are as previously defined.
  • Embodiment 2A The compound of Embodiment 1A, wherein: [247] R A is -CO2H, tetrazolyl
  • U is -CH 2 -, , or disubstituted dimethylmethane
  • Ring A has the structure of
  • R c is -F, -Cl, -CN, or -CF 3 ;
  • R F is -H
  • R G is -CH 3 in an R configuration
  • Embodiment 3A The compound of Embodiment 2A, wherein:
  • R A is -C0 2 H
  • R c is -F; and [262] in the CY ring
  • R H can be located at any available
  • Embodiment 4A The compound of Embodiment 2A, wherein:
  • R A is -CO2H
  • R c is -Cl
  • R H can be located at any available
  • Embodiment 5A The compound of Embodiment 2A, wherein
  • Embodiment 6A The compound of Embodiment 5A, wherein:
  • R A is -CO2H
  • Embodiment 7A The compound of Embodiment 6A, wherein:
  • Embodiment 8A The compound of Embodiment 7A, wherein
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 3, (R)-1-(4'-(4- fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 , 1'-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 9A The compound of Embodiment 7A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 4, (R)-1-(4'-(4- chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 , 1'-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 10A The compound of Embodiment 7A, wherein:
  • R c is -CN; and [289] in the ring
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 5, (R)- 1-(4'-(4- cyano-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 11 A The compound of Embodiment 7A, wherein:
  • R c is -CN
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 6, (R)- 1-(4'-(5-(((1- (2-chlorophenyl)ethoxy)carbonyl)amino)-4-cyano-1 H-pyrazol-1-yl)-[1 , 1'-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 12A The compound of Embodiment 6A, wherein:
  • Embodiment 13A The compound of Embodiment 12A, wherein:
  • R c is -F
  • R H can be located at any available
  • Exemplary molecules with this structure are Compound 7, (R)-1-(3-fluoro-4'- (4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-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)-1 H-pyrazol-1-yl)-[1 , Y-biphenyl]-4-yl) cyclopropane- 1 - carboxylic acid.
  • Embodiment 14A The compound of Embodiment 12A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • Exemplary molecules with this structure are Compound 9, (R)-1-(4'-(4- chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-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)-1 H-pyrazol-1-yl)-2-fluoro-[1 , T-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 15A The compound of Embodiment 6A, wherein:
  • Embodiment 16A The compound of Embodiment 15A, wherein:
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 1 1 , (R)-1-(2-chloro- 4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 , T-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 17A The compound of Embodiment 15A, wherein: [312] R c is -Cl; and
  • R H can be located at any available
  • Embodiment 18A The compound of Embodiment 6A, wherein:
  • Embodiment 19A The compound of Embodiment 18A, wherein:
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 13, (R)-1-(4'-(4- fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-2-methyl-[1 ,1'-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • Embodiment 20A The compound of Embodiment 18A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 14, (R)-1-(4'-(4- chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-2-methyl-[1 ,1'-biphenyl]-4- yl)cyclopropane-1 -carboxylic acid.
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 15, (R)-1-(2- chlorophenyl)ethyl (1-(4'-(1-carbamoylcyclopropyl)-[1 , 1'-biphenyl]-4-yl)-4-fluoro-1 H- pyrazol-5-yl)carbamate.
  • Embodiment 22A The compound of Embodiment 5A, wherein:
  • Embodiment 23A The compound of Embodiment 22A, wherein:
  • Embodiment 24A The compound of Embodiment 23A, wherein:
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 16, (R)-1-(2- chlorophenyl)ethyl (4-fluoro-1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)- [1 ,1'-biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate.
  • Embodiment 25A The compound of Embodiment 23A, wherein:
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 17, (R)-1- phenylethyl (4-fluoro-1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1 , Y- biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate.
  • Embodiment 26A The compound of Embodiment 23A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 18, (R)-1-(2- chlorophenyl)ethyl (4-chloro-1-(2'-fluoro-4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)- [1 , 1'-biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate.
  • Embodiment 27A The compound of Embodiment 22A, wherein:
  • Embodiment 28A The compound of Embodiment 27A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • Embodiment 29A The compound of Embodiment 27A, wherein:
  • R c is -F
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 20, (R)-1-(2- chlorophenyl)ethyl (4-fluoro-1-(4'-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1 , T- biphenyl]-4-yl)-1 H-pyrazol-5-yl)carbamate.
  • Embodiment 30A The compound of Embodiment 5A, wherein:
  • R A is tetrazolyl
  • Embodiment 31A The compound of Embodiment 30A, wherein:
  • R c is -F
  • R H can be located at any available
  • Embodiment 32A The compound of Embodiment 30A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • Embodiment 33A The compound of Embodiment 30A, wherein:
  • R c is -Cl
  • R H can be located at any aval ab e
  • An exemplary molecule with this structure is Compound 23, (R)-1-(2- chlorophenyl)ethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1 , 1'-biphenyl]-4-yl)-4-chloro- 1 H-pyrazol-5-yl)carbamate.
  • Embodiment 35A The compound of Embodiment 34A, wherein:
  • R c is -Cl
  • R H can be located at any aval ab e
  • An exemplary molecule with this structure is Compound 24(R)-1- phenylethyl (4-chloro-1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-[1 , 1'-biphenyl]-4-yl)-1 H- pyrazol-5-yl)carbamate.
  • Embodiment 36A The compound of Embodiment 33A, wherein:
  • R c is -Cl
  • R H can be located at any available
  • Embodiment 37A The compound of Embodiment 5A, wherein:
  • R A is CONHCN
  • Embodiment 38A The compound of Embodiment 37A, wherein:
  • R c is -F
  • R H can be located at any available
  • Embodiment 39A The compound of Embodiment 2A, wherein:
  • R A is -CO2H; [397] U is dimethylmethane
  • R c is -CN.
  • Embodiment 40A The compound of Embodiment 39A, wherein:
  • R H can be located at any available
  • Embodiment 41A The compound of Embodiment 39A, wherein:
  • R H in the CY ring [407]
  • R H can be located at any available
  • An exemplary molecule with this structure is Compound 28, (R)- 2-(4'-(4- cyano-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2- methylpropanoic acid.
  • Embodiment 42A The compound of Embodiment 1A, wherein R G is in an R or S configuration.
  • Embodiment 43A The compound of Embodiment 2A wherein the compound is selected from Table 1.
  • Embodiment 44A The compound of Embodiment 43A wherein the compound is (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H-pyrazol-1- yl)pyridin-2-yl)phenyl)cyclopropane-1 -carboxylic acid, (R)-1-(4-(5-(4-chloro-5-(((1-(2- chlorophenyl)ethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane- 1-carboxylic acid, (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)-[1 ,1'-biphenyl]-4-yl)cycl
  • Embodiment 45A A compound of any one of Embodiments 1A-44A for preparation of mendicant for treating a LPA-dependent disease or condition.
  • HPLC traces for examples synthesized were recorded using a HPLC consisting of Agilent HPLC pumps, degasser and UV detector, equipped with an Agilent 1100 series auto-sampler.
  • a MS detector (APCI) PE Sciex API 150 EX was incorporated for purposes of recording mass spectral data.
  • HPLC/mass traces were obtained using one of three chromatographic methods:
  • Method 4 Column Zorbax C18, size 4.6mm X 50 mm, 5m particle size; Solvent A: acetonitrile; Solvent B: 0.1% HCOOH in water; Flow Rate - 1.5 mL/min; Gradient 10- 95% A in 2.5 minutes.
  • Example 1 (R)-1 -(4-(5-(5-(((1 -(2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H- pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane-1 -carboxylic acid [Compound 1].
  • Step 1 Ethyl 2-(6-chloro-3-pyridyl)-2H-pyrazole-3-carboxylate
  • 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 hexanes/ethyl acetate gradient. Two regioisomers were separated - the desired isomer A [ethyl 2-(6-chloro-3-pyridyl)-2H- pyrazole-3-carboxylate] eluted off the column first and the undesired regioisomer B [ethyl 1-(6-chloro-3-pyridyl)-1 H-pyrazole-3-carboxylate] was isolated as the more polar compound.
  • the desired product was obtained as a yellow oil, which solidified upon standing.
  • Step 3 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-(6-chloro-3-pyridyl)- 2H-pyrazole
  • Step 4 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-(6-chloro-3-pyridyl)-4- fluoro-2H-pyrazole
  • Step 5 (R)-1-(4-(5-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H- pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid
  • the resulting mixture was heated to 85°C and stirred for 16 hours at that temperature.
  • 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 MgSC and filtered.
  • concentration in vacuo the crude product was directly dissolved in THF (1 ml_) and treated with a 1 M LiOH aqueous solution (1 ml_).
  • the resulting mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was treated with 1 M HCI aqueous in order to bring pH to 1.
  • the product was extracted with ethyl acetate.
  • the organic layer was washed with water and brine, dried over anhydrous MgSCU and filtered.
  • Step 1 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-4-chloro-2-(6-chloro-3- pyridyl)-2H-pyrazole
  • Step 2 (R)-1-(4-(5-(4-chloro-5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-1 H- pyrazol-1-yl)pyridin-2-yl)phenyl)cyclopropane-1-carboxylic acid
  • 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 MgSC>4 and filtered. After concentration in vacuo , the crude product was directly dissolved in THF (1 ml_) and treated with a 1 M LiOH aqueous solution (1 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with 1 M HCI aqueous in order to bring pH to 1. The product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSC and filtered.
  • Step 1 Ethyl-2-acetyl-3-(dimethylamino)acrylate
  • Step 6 3-[(R)-1-Phenylethoxycarbonylamino]-2-(p-bromophenyl)-2H-pyrazole
  • Step 7 3-[(R)-1-Phenylethoxycarbonylamino]-2-(p-bromophenyl)-4-fluoro-2H- pyrazole
  • Step 8 (R)-1-(4'-(4-fluoro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid
  • the resulting mixture was heated to 85°C and stirred for 16 hours at that temperature.
  • 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 MgSCL and filtered.
  • concentration in vacuo the crude product was directly dissolved in THF (1 mL) and treated with a 1 M LiOH aqueous solution (1 mL).
  • the resulting mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was treated with 1 M HCI aqueous in order to bring pH to 1.
  • the product was extracted with ethyl acetate.
  • the organic layer was washed with water and brine, dried over anhydrous MgSCL and filtered.
  • Step 1 3-[(R)-1-Phenylethoxycarbonylamino]-2-(p-bromophenyl)-4-chloro-2H- pyrazole
  • N-Chlorosuccinimide (97 mg, 0.73 mmol) was added to a stirring solution containing 3-[(R)-1-phenylethoxycarbonylamino]-2-(p-bromophenyl)-2H-pyrazole
  • Step 2 Methyl 1-(4'- ⁇ 5-[(R)-1-phenylethoxycarbonylamino]-4-chloro-1 H-pyrazol- 1-yl ⁇ -4-biphenylyl)cyclopropanecarboxylate
  • Step 3 (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)-[1 ,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid
  • Step 1 3-[(R)-1-Phenylethoxycarbonylamino]-2-(p-bromophenyl)-2H-pyrazole-4- carbonitrile
  • Step 2 Methyl 1-[p-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]cyclopropanecarboxylate
  • Step 4 (R)- 1-(4'-(4-cyano-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)-[1 ,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid
  • Step 1 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-(p-bromophenyl)-2H- pyrazole-4-carbonitrile
  • Step 2 Methyl 1-(4'- ⁇ 5-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-4-cyano- 1 H-pyrazol-1-yl ⁇ -4-biphenylyl)cyclopropanecarboxylate
  • Step 3 (R)- 1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4-cyano-1 H- pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid
  • Example 11 (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 [Compound 11].
  • Example 12 (R)-1-(2-chloro-4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 12].
  • Example 13 (R)-1 -(4'-(4-fluoro-5-(((1 -phenylethoxy)carbonyl)amino)-1 H-pyrazol-1 - yl)-2-methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 13].
  • Example 14 (R)-1-(4'-(4-chloro-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1- yl)-2-methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid [Compound 14].
  • Step 2 1-[p-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]cyclopropanecarboxamide
  • Step 5 2-(4-Bromo-phenyl)-4-fluoro-2H-pyrazole-3-carboxylic acid ethyl ester
  • Step 7 (R)-[2-(4-Bromo-phenyl)-4-fluoro-2H-pyrazol-3-yl]-carbamic acid 1-(2- chloro-phenyl)-ethyl ester
  • Step 8 (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-carbamoylcyclopropyl)-[1 ,T- biphenyl]-4-yl)-4-fluoro-1 H-pyrazol-5-yl)carbamate
  • Step 1 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-(p-bromophenyl)-2H- pyrazole
  • Oxalyl chloride (65.6 ml_, 752 mmol) was added dropwise via addition funnel in approximately 30 minutes.
  • the acyl azide was obtained as a beige solid. This material was dissolved in toluene (1880 mL) with mechanical stirring. The reaction was heated to 100°C for 1 hour and N2 evolution was observed. Conversion to the isocyanate intermediate was monitored by LCMS after MeOH quenching. (1 R)-1-(o-Chlorophenyl)-1-ethanol (64.77 g, 413.6 mmol) was added dropwise and the resulting mixture was stirred overnight at 65°C. The reaction was cooled concentrated in vacuo to dryness. The crude is a thick amber oil. This oil was dissolved in iP ⁇ O (500 mL) and stirred for 1 hour at rt.
  • Step 2 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-(p-bromophenyl)-4- fluoro-2H-pyrazole
  • Step 4 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-N- (methylsulfonyl)cyclopropane-l-carboxamide
  • Step 5 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-2- ⁇ 2'-fluoro-4'- [1-(methylsulfonylamino)carbonylcyclopropyl]-4-biphenylyl ⁇ -2H-pyrazole
  • Step 1 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-(p-bromophenyl)-4- chloro-2H-pyrazole
  • N-Chlorosuccinimide (155 mg, 1.16 mmol) was added to a stirring solution containing 3-[(R)-1-(o-chlorophenyl)ethoxycarbonylamino]-2-(p-bromophenyl)-2H- pyrazole [Example 16, Step 1] (486 mg, 1.16 mmol) in acetonitrile (6 ml_) at room temperature. The resulting mixture was heated to 80°C for 4 hours, after which time the reaction was deemed complete by LCMS.
  • Step 1 1-(4-bromophenyl)-N-(methylsulfonyl)cyclopropane-1-carboxamide
  • Step 2 N-(methylsulfonyl)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclopropane-1 -carboxamide
  • Step 1 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-[4'-(1- cyanocyclopropyl)-4-biphenylyl]-4-fluoro-2H-pyrazole
  • Step 2 (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1 ,T- biphenyl]-4-yl)-4-fluoro-1 H-pyrazol-5-yl)carbamate
  • Step 1 3-[(R)-1-Phenylethoxycarbonylamino]-4-chloro-2-[4'-(1- cyanocyclopropyl)-4-biphenylyl]-2H-pyrazole
  • Step 2 (R)-l-phenylethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1 , Y-biphenyl]- 4-yl)-4-chloro-1 H-pyrazol-5-yl)carbamate
  • Step 1 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-4-chloro-2-[4'-(1- cyanocyclopropyl)-4-biphenylyl]-2H-pyrazole
  • Step 2 (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(1 H-tetrazol-5-yl)cyclopropyl)-[1 , T- biphenyl]-4-yl)-4-chloro-1 H-pyrazol-5-yl)carbamate
  • Step 1 1-(4-bromophenyl)-N-cyanocyclopropane-1-carboxamide
  • Step 2 N-cyano-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclopropane-1 -carboxamide
  • Step 1 (R)-1-(4'-(5-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-4-fluoro-1 H- pyrazol-1-yl)-2-fluoro-[1 ,1'-biphenyl]-4-yl)cyclopropane-1 -carboxylic acid
  • Step 2 (R)-1-(2-chlorophenyl)ethyl (1-(4'-(1-(cyanocarbamoyl)cyclopropyl)-2'- fluoro-[1 , 1 '-biphenyl]-4-yl)-4-fluoro-1 H-pyrazol-5-yl)carbamate
  • Step 1 Methyl 2-methyl-2-[p-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]propionate
  • Step 2 Methyl 2-(4'- ⁇ 5-[(R)-1-phenylethoxycarbonylamino]-4-cyano-1 H-pyrazol- 1-yl ⁇ -4-biphenylyl)-2-methylpropionate
  • Step 3 (R)-2-(4'-(4-cyano-5-(((1-phenylethoxy)carbonyl)amino)-1 H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2-methylpropanoic acid
  • Core pyrazole (8) may be prepared according to the approach depicted in Scheme 2:
  • Binding affinity of compounds of Formula l-lll were determined based on their ability to displace tritiated lysophosphatidic acid ([ 3 H]-LPA) from CHO cells expressing LPA1 R in a protocol similar to that described in reference 17.
  • CHO cells expressing human LPA1 R [Cerep] were treated with [ 3 H]-LPA (2nM).
  • Test compounds were added in increasing concentration to each well and incubated at room temperature for 90 minutes. At this time the plates were washed and the wells counted for radioactivity. Results were compared to a control in which cells were treated with [ 3 H]-LPA in the presence of 10mM unlabeled LPA.
  • the specific ligand binding to the receptors was defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabeled ligand.
  • the results were expressed as a percent of control specific binding ((measured specific binding/control specific binding) x 100) and as a percent inhibition of control specific binding (100- ((measured specific binding/control specific binding) x 100)) obtained in the presence of the test compounds.
  • IC50 value concentration causing a half-maximal inhibition of control specific binding
  • This analysis was performed using a software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® ( ⁇ 1997 by SPSS Inc.).
  • Ki inhibition constant
  • the agonist assay was conducted on a FLIPR TETRA instrument where the test compound(s), vehicle controls, and reference agonist were added to the assay plate after a fluorescence baseline was established.
  • the agonist assay was a total of 180 seconds and was used to assess each compound’s ability to activate each GPCR assayed.
  • the assay plate was removed from the FLI PR TETRA and incubated at 25°C for seven (7) minutes. After the incubation period, the assay plate was placed back in the FLIPR TETRA and the antagonist assay was initiated.
  • Antagonist Assay Using ECso potency values determined during the agonist assay, all pre-incubated sample compound wells were challenged with ECso concentration of reference agonist after establishment of a fluorescence baseline. The antagonist assay was conducted using the same assay plate that was used for the agonist assay. The antagonist assay was conducted on a FLI PR TETRA instrument where 9 vehicle controls and ECso concentration of reference agonist were added to appropriate wells. The antagonist assay was a total of 180 seconds and was used to assess each compound’s ability to inhibit each GPCR assayed.

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Abstract

L'invention concerne des composés hétérocycliques qui sont des ligands du récepteur de l'acide lysophosphatidique utiles dans le traitement de maladies et d'états dépendant du récepteur de l'acide lysophosphatidique.
PCT/US2019/037749 2013-03-15 2019-06-18 Composés hétérocycliques utiles dans le traitement d'une maladie WO2019246109A1 (fr)

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Cited By (2)

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WO2023160672A1 (fr) * 2022-02-25 2023-08-31 Lhotse Bio , Inc. Composés et compositions pour le traitement d'états associés à l'activité du récepteur de lpa
US11884627B2 (en) 2022-02-25 2024-01-30 Lhotse Bio, Inc. Compounds and compositions for treating conditions associated with LPA receptor activity

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EP3807254A4 (fr) 2022-03-23
KR20210010635A (ko) 2021-01-27
JP7467361B2 (ja) 2024-04-15
CA3046894A1 (fr) 2019-12-18
CA3104465A1 (fr) 2019-12-26
EP3807254A1 (fr) 2021-04-21

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