WO2014145873A2 - Heterocyclic compounds useful in the treatment of disease - Google Patents

Heterocyclic compounds useful in the treatment of disease Download PDF

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Publication number
WO2014145873A2
WO2014145873A2 PCT/US2014/030712 US2014030712W WO2014145873A2 WO 2014145873 A2 WO2014145873 A2 WO 2014145873A2 US 2014030712 W US2014030712 W US 2014030712W WO 2014145873 A2 WO2014145873 A2 WO 2014145873A2
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WIPO (PCT)
Prior art keywords
substituted
phenyl
unsubstituted
methyl
ethoxycarbonylamino
Prior art date
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PCT/US2014/030712
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English (en)
French (fr)
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WO2014145873A3 (en
Inventor
Graham Beaton
Fabio C. Tucci
Satheesh B. RAVULA
Chandravadan R. Shah
Hiep LIU
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EPIGEN BIOSCIENCES Inc
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EPIGEN BIOSCIENCES Inc
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Priority to BR112015023267-1A priority Critical patent/BR112015023267B1/pt
Priority to EA201591607A priority patent/EA033923B1/ru
Priority to EP14762555.2A priority patent/EP2988743B1/en
Priority to MX2015013303A priority patent/MX382748B/es
Priority to HK16109390.9A priority patent/HK1221167B/en
Priority to US14/776,954 priority patent/US10000459B2/en
Priority to CN201480015333.XA priority patent/CN105142635B/zh
Priority to AU2014232383A priority patent/AU2014232383B2/en
Priority to DK14762555.2T priority patent/DK2988743T3/da
Priority to JP2016503448A priority patent/JP6482086B2/ja
Priority to ES14762555T priority patent/ES2855173T3/es
Priority to CA2906931A priority patent/CA2906931C/en
Application filed by EPIGEN BIOSCIENCES Inc filed Critical EPIGEN BIOSCIENCES Inc
Priority to SG11201507459YA priority patent/SG11201507459YA/en
Priority to NZ712889A priority patent/NZ712889B2/en
Priority to KR1020157028061A priority patent/KR102090231B1/ko
Publication of WO2014145873A2 publication Critical patent/WO2014145873A2/en
Publication of WO2014145873A3 publication Critical patent/WO2014145873A3/en
Anticipated expiration legal-status Critical
Priority to US16/000,283 priority patent/US10570103B2/en
Priority to US16/010,755 priority patent/US10526298B2/en
Priority to AU2019202731A priority patent/AU2019202731B2/en
Priority to US16/784,486 priority patent/US11427552B2/en
Ceased legal-status Critical Current

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    • 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
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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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

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 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
  • LPAs lysophosphatidic acid receptors
  • LPA1 R lysophosphatidic acid receptor subtype 1
  • 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 disease
  • IBS irritable
  • the compounds of the invention include compounds of Formula I that have the structure:
  • R B is -H or -optionally substituted C C 4 alkyl, or has the structure of one of:
  • Rin A is a 5 or 6 membered heteroarene havin the structure of one of:
  • R c and R D are -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or C C 4 fluoroalkyl,
  • R E is -H, C 1 -C4 alkyl or C C 4 fluoroalkyl
  • R F is -H or C 1 -C4 alkyl
  • R G is independently selected R E , or one R G is C C 4 alkylne and is taken together with CY and the the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , if present, is as defined for R E ;
  • CY is optionally substituted C C 6 alkyl, optionally substituted C 3 -Ci 0 cycloalkyl, optionally substituted C 2 -Ci 0 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 independently selected R H ,
  • each R J is independently optionally substituted C C 6 alkyl, optionally substituted C C 6 heteroalkyl, optionally substituted C C 6 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C C 4 alkylene-(optionally substituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(optionally substituted heterocycloalkyl), -C C 4 alkylene-(optionally substituted aryl), or -C C 4 alkylene-(optionally substituted heteroaryl), and
  • R L is independently -H, optionally substituted C C 6 alkyl, optionally substituted C C 6 heteroalkyl, optionally substituted C C 6 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C C 4 alkylene-(optionally substituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-( optionally substituted heterocycloalkyl), -C C 4 alkylene-(optionally substituted aryl), or -C C 4 alkylene-(optionally substituted heteroaryl),
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle;
  • Ring B is a optionally substituted C 3 -Ci 0 cycloalkylene, optionally substituted C 2 - Cio heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, wherein if ring B is substituted then ring B is substituted with 1 ,2, or 3 independently selected R H , wherein R H is as previously defined; and [28] Ring C is absent or optionally substituted C 3 -Ci 0 cycloalkylene, optionally substituted C 2 -Ci 0 heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, where if ring C is substituted then ring C is substituted with 1 , 2, or 3 independently selected R H , wherein R H is as previously defined;
  • Ring B is optionally substituted arylene and Ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, or Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene and Ring C is substituted or unsubstituted arylene, L 2 is absent, L is C C 6 alkylene,
  • R c is -H or -CH 3 and R A is -C0 2 H or -C0 2 R B ,
  • Ring A has the structure of one of:
  • Ring A has the structure of one of:
  • invention embodiments also specifically include those compounds, compositions, compositions or methods that are or that consist of or that consist essentially of those specified components, elements or steps.
  • the terms “comprising”, “consist of” and “consist essentially of” have their normally accepted meanings under U.S. patent law unless otherwise specifically stated.
  • the term “comprised of” is used interchangeably with the term “comprising” and are stated as equivalent terms.
  • disclosed 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).
  • 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. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.
  • Bind 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 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., d -8 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(CH 3 ) 2 ), 1 -butyl (n-butyl), 2- methyl-1 -propyl (/so-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (sec-butyl, -CH(CH 3 )CH 2 CH 3 ), 2- methyl-2-propyl (/-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.
  • Cycloalkyi as used here is a monocyclic, bicyclic or tricyclic ring system composed of only carbon atoms.
  • the term "cycloalkyi" 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 cycloalkyi 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., C 3 . 8 alkyl or C3-C8 alkyl means an cycloalkyi substituent, moiety or group containing 3, 4, 5, 6, 7 or 8 carbon atoms and C 3 . 6 alkyl or C3-C6 means an cycloalkyi substituent, moiety or group containing 3, 4, 5 or 6 carbon atoms.
  • Cycloalkyi 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.
  • cycloalkyi 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 cycloalkyi 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 cycloalkyi substituent, moiety or group that is not an aromatic ring carbon atom.
  • Cycloalkyi groups include groups having from 3 to 10 ring atoms. Cycloalkyi
  • 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. Cycloalkyi groups may be substituted or unsubstituted.
  • a cycloalkyi 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 ,
  • cycloalkyi When cycloalkyi is used as a Markush group (i.e., a substituent) the cycloalkyi is attached to a Markush formula with which it is associated through a carbon involved in a cyclic carbon ring system carbon of the cycloalkyi 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 C C 6 heteroalkylene or C C 4 heteroalkylene.
  • heteroalkylenes include, but are not limited to, -OCH 2 -, -OCH(CH 3 )-,
  • 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 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.
  • An alkenyl moiety, group or substituent with multiple double bonds may have the double bonds arranged
  • 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., C 2 . 8 alkenyl or C2-8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms and C 2 .
  • 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, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • 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., -C ⁇ C-), 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., -C ⁇ C-
  • 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., C 2 . 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
  • the term includes monocyclic or fused-ring polycyclic (i.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 C 6 -Ci 0 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., -CH 2 -C 6 l-l5 or -CH 2 CH(CH 3 )-C 6 H5.
  • 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., -C 6 H 4 -CH 3 or -C 6 H 4 -CH 2 CH(CH 3 ).
  • 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 aryl and the like as used herein 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.
  • substituent(s) are optionally substituted at a carbon that is one or more methylene moieties removed from the double bond.
  • substituted heteroaryl means 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.
  • 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(CH 3 ) 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(CH 3 ),
  • 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 also known as heterocycloalkyls
  • 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-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,
  • 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,
  • 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 -(CH 2 ) 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 -6 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
  • 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,
  • 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., C r C 9 heteroaryl).
  • Monocyclic heteroaryls include C1 -C5 heteroaryls.
  • Monocyclic heteroaryls include those having 5-membered or 6- membered ring systems.
  • Bicyclic heteroaryls include C 6 -C 9 heteroaryls.
  • a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
  • Heterocycloalkyl or “heteroalicyclic” as used herein means a cycloalkyi group, moiety or substituent wherein at least on carbon of the cycloalkyi 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,
  • heteroalicyclics further includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.
  • a heterocycloalkyl is a C 2 -Cio heterocycloalkyl and includes C 4 -Ci 0 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 C C 4 haloalkyl.
  • Example but non-limiting C C 4 haloalkyls are -CH 2 CI, CH 2 Br, -CH 2 I, -CHBrCI, -CHCI-CH 2 CI and -CHCI-CH 2 I.
  • 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-C 6 haloalkylenes or C C 4 haloalkylenes.
  • Fluoroalkyl as used herein means an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. Fluoroalkyl includes C C 6 and C C 4 fluoroalkyls. Example but non-limiting fluoroalkyls include -CH 3 F, -CH 2 F 2 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 C C 6 fluoroalkylenes or C C 4 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 , wherein R 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.
  • esters 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., Ci -2 o alkyl moieties, C 2 - 2 o alkenyl moieties, C 2 . 20 alkynyl moieties, aryl moieties, C 3 . 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
  • 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 Ci -8 alkyl or branched alkyl structure such as -C(CH 3 ) 2 -, -CH(CH 3 )-, -CH 2 -, -CH 2 -CH 2 -, -C[(C2-C4 alkyl) 2 ] 1 2 3 - or -[CH(C2-C4 alkyl)] 1 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 -0-CH 2 -CH 2 -CH 2 -0- or -0-CH 2 -CH 2 -0- moieties that form a spiro ring with the carbonyl carbon, and can be removed by chemical synthesis methods or by
  • 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 -
  • ethers comprise an organic moiety containing 1 -50 carbon atoms, 1 -20 carbon atoms or
  • 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 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 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 -OCH 2 CH 2 0-, 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.
  • R PR are independently -H, a protecting group or an organic moiety as described for ester, alkyl or optionally substituted alkyl.
  • a Markush group i.e., a substituent
  • C1 -C4 optionally substituted alkyl includes, e.g., 3 carbon alkyl, 4 carbon substituted alkyl and 4 carbon alkyl, including all positional isomers and the like are disclosed and can be expressly referred to or named.
  • the designated range includes the carbonyl carbon of the respective functional group.
  • 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).
  • 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,
  • 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 (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the like), renal disease, urinary tract-associated disease (e.g., benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease), spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms
  • IBS
  • 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.
  • a pharmaceutically acceptable formulation to be suitable for administration to a human 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.
  • 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
  • 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.
  • compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • the compounds described herein will exist as salts, including pharmaceutically acceptable salts.
  • the salt forms include inorganic addition salts such as F “ CI “ , Br “ , I " and sulfate salts and organic addition salts such as mesylate, besylate, tosylate, citrate, succinate, fumarate and malonate.
  • inorganic addition salts such as F “ CI “ , Br “ , I "
  • organic addition salts such as mesylate, besylate, tosylate, citrate, succinate, fumarate and malonate.
  • the compounds described herein exist as quaternary ammonium salts.
  • cycloalkylene, or C C 6 fluoroalkylene or Z is -C(R L ) 2 -; and n is 0, 1 , or 2;
  • R B is substituted or unsubstituted C C 4 alkyl, or has the structure of one f:
  • Ring A is a 5 or 6 membered heteroarene having the structure of one of:
  • R c and R D are -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl,
  • R E is -H, -C C 4 alkyl or -C C 4 fluoroalkyl
  • R F is -H or C C 4 alkyl
  • R G is independently selected R E or one R G is C C 4 alkyl and is taken together with CY and the the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle and the other
  • R G if present, is as defined for R E ;
  • each R J is independently substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), and -C C 4 alkylene-(substituted or unsubstituted heteroaryl), and
  • each R L is independently -H, C C 6 alkyl, C C 6 heteroalkyl, C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl), or
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L is independently -H, C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle;
  • Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, substituted or unsubstituted C 2 -Ci 0 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, where if ring B is substituted then ring B is substituted with 1 ,2, or 3 independently selected R H , wherein R H is as previously defined; and
  • Ring B is substituted or unsubstituted arylene and Ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, or Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene and Ring C is substituted or unsubstituted arylene, L 2 is absent, L is C C 6 alkylene,
  • R c is -H or -CH 3 and R A is -C0 2 H or -C0 2 R B ,
  • Ring A has the structure of one of:
  • Ring B is C 2 -Ci 0 heterocycloalkylene
  • Ring C is substituted or unsubstituted arylene
  • L 2 is absent
  • L is C C 6 alkylene
  • R c is -CH 3
  • R A is -C0 2 H or -C0 2 R B
  • Ring A has the structure of one of:
  • L is absent or substituted or unsubstituted C C 6 alkylene, C C 6 fluoroalkylene, or substituted or unsubstituted C C 6 heteroalkylene.
  • L is -CH 2 -
  • dimethylmethane i.e., -C(CH 3 ) 2 -
  • Ring A is a 5 or 6 membered heteroarene having one of the structures of:
  • Formula I compounds have R c defined as -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or C C 4 fluoroalkyl.
  • Formula I compounds have R c defined as -H, -F, -CN, -CH 3 , or -CF 3 .
  • Formula I compounds have R D defined as
  • R F is -H or C C 4 alkyl and X, CY and R G are as previously defined.
  • Formula I compounds have R E defined as -H or Ci-C 4 alkyl, C C 6 cycloalkyl or C C 4 fluoroalkyl.
  • Formula I compounds have R E defined as -H, - CH 3 , cyclopropyl or -CF 3 .
  • Formula I compounds have R F defined as H, C C 4 alkyl or C 3 -C 6 cycloalkyl.
  • Formula I compounds have R F defined as -H.
  • one R G is -CrC 4 alkyl and is taken together with CY and the the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the other R G , if present is -H.
  • R G is independently -H or C C 4 alkyl.
  • Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, substituted or unsubstituted C 2 -Ci 0 heterocycloalkylene, a substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring B is substituted then ring B is substituted with 1 , 2, or 3 independently selected R H .
  • Ring C is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, substituted or unsubstituted C 2 -Ci 0
  • heterocycloalkylene a substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring C is substituted then ring C is substituted with 1 , 2, or 3 independently selected R H .
  • Ring A has the structure of one of:
  • Ring B defined as 1 ,4- substituted aryl or heteroaryl
  • R A is -C0 2 H
  • R E is -CH 3
  • R c , R F , R G , and CY are as previously defined.
  • n 0, 1 , or 2.
  • R B is optionally substituted C C 4 alkyl or has the structure of one of: [173]
  • W is optionally substituted C C 3 alkylene or W is -C(R L ) 2 -
  • Z is optionally substituted C C 6 alkylene or C C 6 fluoroalkylene or Z is -C(R L ) 2 -
  • n is 0, 1 , or 2;
  • Ring A is a 5 or 6 membered heteroarene having the structure of one of:
  • R c is -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or C C 4 fluoroalkyl;
  • R E is -H or C C 4 alkyl, C C 6 cycloalkyl or C C 4 fluoroalkyl;
  • R F is -H, C C 4 alkyl or C C 6 cycloalkyl
  • R G is independently selected R E , or one of R G is C C 4 alkyl and is taken together with CY and the the carbon atom to which R G and CY are attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the other R G , if present, is as defined for R E ;
  • Ring B is optionally substituted C 3 -Ci 0 cycloalkylene, optionally substituted C 2 - Cio heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, where if ring B is substituted then ring B is substituted with 1 , 2, or 3 independntly selected R H ;
  • Ring C is absent or optionally substituted C 3 -Ci 0 cycloalkylene, optionally substituted C 2 -Cio heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, wherein if ring C is substituted then ring C is substituted with 1 , 2, or 3 independently selected R H ;
  • CY is optionally substituted C C 6 alkyl, optionally substituted C 3 -Ci 0 cycloalkyl, optionally substituted C 2 -Ci 0 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 independently selected R H , or
  • R J is optionally substituted C C 6 alkyl, optionally substituted C C 6 heteroalkyl, optionally substituted C C 6 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C C 4 alkylene-(optionally substituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(optionally substituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or -C C 4 alkylene-(optionally substituted heteroaryl), and
  • each R L is independently -H, optionally substituted C C 6 alkyl, optionally substituted C C 6 heteroalkyl, optionally substituted C C 6 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C C 4 alkylene-(optionally substituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(optionally substituted heterocycloalkyl), -C C 4 alkylene-(optionally substituted aryl), or -C C 4 alkylene-(optionally substituted heteroaryl), or
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define an optionally substituted heterocycle,
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle;
  • Ring B is substituted or unsubstituted arylene and Ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, or Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene and Ring C is substituted or unsubstituted arylene and L is C C 6 alkylene,
  • Ring A has the structure of one of:
  • Ring B is C 2 -Ci 0 heterocycloalkylene
  • Ring C is substituted or unsubstituted arylene
  • L is C C 6 alkylene
  • R c is -CH 3
  • R A is -C0 2 H or -C0 2 R B ,
  • Rin A has the structure of one of:
  • R B is substituted or unsubstituted C C 4 alkyl or has the structure of one of
  • L is absent or is substituted or unsubstituted C C 6 alkylene, C C 6
  • Ring A -6 membered heteroarenes having one the structure of one of:
  • R c is -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or C C 4 fluoroalkyl;
  • R E is -H or C C 4 alkyl, C C 6 cycloalkyl or C C 4 fluoroalkyl;
  • R F -H C C 4 alkyl or C C 6 cycloalkyl
  • R G is independently selected R E , or one R G is -C C 4 alkyl and is taken together with CY and the the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle and the other R G , if present, is as defined for R E ;
  • Ring C is absent or substituted or unsubstituted C 3 -Ci 0 cycloalkylene, substituted or unsubstituted C 2 -Ci 0 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein if ring C is substituted then ring C is substituted with 1 , 2, or 3 independently selected R H ;
  • CY is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C 3 - Cio cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is
  • CY is substituted with 1 , 2, or 3 R H ;
  • each R J is independently substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted d-C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or C C 4 alkylene-(substituted or unsubstituted heteroaryl);
  • each R L is independently -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl), or -C C 4 alkylene-(substituted or unsubstituted
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle, or
  • Ring C is substituted or unsubstituted arylene or substituted or unsubstituted C 3 -Ci 0 cycloalkylene
  • R c is -H or -CH 3 and R A is -C0 2 H or -C0 2 R B ,
  • Ring A has the structure of one of:
  • Ring C is substituted or unsubstituted arylene
  • L is C C 6 alkylene
  • R c is -CH 3
  • R A is -C0 2 H or -C0 2 R B
  • Ring A has the structure of one of:
  • Ring A has the structure of one of:
  • Rin A is a 5 or 6 membered heteroarene havin one of the structures of:
  • R c is -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or C1 -C4 fluoroalkyl;
  • R E is -H or C C 4 alkyl, C 3 -C 6 cycloalkyl or C C 4 fluoroalkyl;
  • R F is -H, C C 4 alkyl or C 3 -C 6 cycloalkyl
  • R G is independently selected R E , or one R G is -C C 4 alkyl and is taken together with CY and the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , if present, is as defined for R E ;
  • CY is Ci-C 6 alkyl, a substituted or unsubstituted C 3 -Ci 0 cycloalkyl, a substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 R H ;
  • R J is independently substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or C C 4 alkylene-(substituted or unsubstituted heteroaryl); and
  • each R L is independently -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle, [249] or when W or Z is -C(R L ) 2 -, each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle,
  • each R L is independently is -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L is independently -H, d-C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle;
  • a 1 CH-
  • R c is -H or -CH 3 and R A is -C0 2 H or C0 2 R B ,
  • Ring A has the structure of one of:
  • R B is optionally substituted C C 4 alkyl or has the structure of one of
  • Ring A is a 5 membered heteroarene having the structure of one of:
  • R c is -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or Ci-C 4 fluoroalkyl;
  • R E is -H or C C 4 alkyl, C 3 -C 6 cycloalkyl or C C 4 fluoroalkyl;
  • R F is -H, C C 4 alkyl or -C 3 -C 6 cycloalkyl
  • R G is independently selected R E , or one R G is -C C 4 alkyl and is taken together with CY and the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , if present, is as defined for R E ;
  • CY is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C 3 - Cio cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 independently selected R H ;
  • each R J is independently substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyi, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyi), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or C C 4 alkylene-(substituted or unsubstituted heteroaryl);
  • each R L is independently -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyi, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyi), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle.
  • Ring A has the structure of one of:
  • R B is optionally substituted C C 4 alkyl or has the structure of one of:
  • L is UV-Z- wherein -UV-is defined by -OW-, -WO-, -N(R J )W-, -WN(R J )-,
  • W is substituted or unsubstituted C C 3 alkylene or W is -C(R L ) 2 -
  • Z is substituted or unsubstituted C C 6 alkylene or substituted or unsubstituted C C 6 fluoroalkylene or Z is -C(R L ) 2 -
  • n is 0, 1 , or 2;
  • Ring A is a 5 membered heteroarene having one of the structures of:
  • R G is independently selected R E , or one R G is -CrC 4 alkyl and is taken together with CY and the carbon atom to which R G and CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , if present, is as defined for R E ;
  • R F is -H, -C1 -C4 alkyl or -C 3 -C 6 cycloalkyl;
  • R J is substituted or unsubstituted d-C 6 alkyl, substituted or
  • heterocycloalkyl substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -d-d alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -d-d alkylene-(substituted or unsubstituted heterocycloalkyl), -d-d alkylene-(substituted or unsubstituted aryl), or C1 -C4 alkylene-(substituted or unsubstituted heteroaryl);
  • each R L is independently -H, substituted or unsubstituted d-C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -d-d alkylene-(substituted or unsubstituted cycloalkyl), -d-C 4 alkylene- (substituted or unsubstituted heterocycloalkyl), -d-C 4 alkylene(substituted or unsubstituted aryl), or -d-C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are d-C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L is independently -H or d-d alkyl, or the R L groups independently are d-C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle.
  • Ring A has the structure of one of:
  • B is optionally substituted C C 4 alkyl or has the structure of one of:
  • Ring A has the structure of one of :
  • R c is -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyl, or C C 4 fluoroalkyl;
  • R E , R F and R G independently are -H or C C 4 alkyl
  • Z is -C(R L ) 2 -;
  • R J is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyi, C C 6 fiuoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyi, substituted or unsubstituted heterocycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyi), -C 1 -C 4 alkylene-(substituted or unsubstituted heterocycloalkyi), -C C 4 alkylene- (substituted or unsubstituted aryl), or C 1 -C 4 alkylene-(substituted or unsubstituted heteroaryl) ;
  • R L is -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyi, substituted or unsubstituted C C 6 fiuoroalkyi, substituted or
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L in Z is independently -H or d-C 6 alkyl, or the R L groups
  • Formula VI I compounds have R F defined as -H, C C 4 alkyl or C C 6 cycloalkyi and each R H R J and R L are as previously defined;
  • R A is -C0 2 H.
  • R B is optionally substituted C C 4 alkyl or has the structure of one of:
  • Ring A has the structure of one of:
  • R F and R E independently are -H or C C 4 alkyl or C 3 -C 6 cycloalkyl
  • R G is -H or C C 4 alkyl or is C C 4 alkyl that is taken together with the 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 carbocycle;
  • W is -C(R L ) 2 -;
  • Z is -C(R L ) 2 -;
  • R J is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyi, is substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -d-C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -d-C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -d-C 4 alkylene-(substituted or unsubstituted aryl), or C1 -C4 alkylene- (substituted or unsubstituted heteroaryl);
  • R L independently are -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyi, substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • each R L is in W or Z independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle.
  • Formula VIII compounds have R F defined as -H, C C 4 alkyl or C 3 -C 6 cycloalkyl.
  • R A is -C0 2 H and R J is -H.
  • R B is optionally substituted C C 4 alkyl or has the structure of one of:
  • R E , R F and R G independently are -H, C C 4 alkyl or C C 6 cycloalkyl or R E and R F independent are -H, C C 4 alkyl or C C 6 cycloalkyl and R G is C C 4 alkyl that is taken together with the 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 carbocycle;
  • R J is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or C C 4 alkylene- (substituted or unsubstituted heteroaryl);
  • W is -C(R L ) 2 -;
  • Z is -C(R L ) 2 -;
  • R L independently are -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L in W or Z independently are C C 6 alkyl which are taken together with the carbon atom to which they are attached to define a carbocycle.
  • R A is -C0 2 H.
  • R B is o tionally substituted C C 4 alkyl or has the structure of one of:
  • L is absent or optionally substituted C C 6 alkylene; C C 6 fluoroalk lene; or
  • C C 6 heteroalkylen or L when present is -CH 2 -, or disubstituted dimethylmethane.
  • 366 Rin A has the structure of one of::
  • R c is -H, -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyi, or C C 4 fluoroalkyl;
  • R E , R F and R G independently are -H or C C 4 alkyl or C 3 -C 6 cycloalkyi or R E and R F independently are -H, C C 4 alkyl or C C 6 cycloalkyi and one R G is C C 4 alkyl and is taken together with CY and the carbon atom to which R G and CY are attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , if present, is as defined for R E ;
  • R L independently are -H, substituted or unsubstituted C C 6 alkyi, substituted or unsubstituted C C 6 heteroalkyi, substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L is independently -H or C C 6 alkyi, or the R L groups independently are C C 6 alkyi which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle;
  • CY is substituted or unsubstituted C C 6 alkyi, substituted or unsubstituted C 3 - Cio cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 R H ,
  • Ring A has the structure of one of:
  • Ring A has the structure of one of:
  • R B is optionally substituted C C 4 alkyl or has the structure of one of:
  • L is absent or optionally substituted C C 6 alkylene; C C 6 fluoroalk lene; or
  • Ci -C 6 heteroalkylene or L when present is -CH 2 -, , or disubstituted dimethylmethane.
  • 387 Rin A has the structure of one of:
  • R c is -H , -CN, -F, -CI, -Br, -I , -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyi, or C C 4 fluoroalkyl;
  • R J is substituted or unsubstituted C C 6 alkyi, substituted or unsubstituted C C 6 heteroalkyi, substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or C C 4 alkylene- (substituted or unsubstituted heteroaryl);
  • R L independently are -H, substituted or unsubstituted C C 6 alkyi, substituted or unsubstituted C C 6 heteroalkyi, substituted or unsubstituted C C 6 fluoroalkyi, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L is independently -H or C C 6 alkyi, or the R L groups independently are C C 6 alkyi which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • CY is Ci-C 6 alkyi, a substituted or unsubstituted C 3 -Ci 0 cycloalkyl, a substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, wherein if CY is substituted then CY is substituted with 1 , 2, or 3 R H ,
  • Ring A has the structure of one of: [399] In particularly preferred Formula XI compounds R A is -C0 2 H, and R D is
  • R B is o tionally substituted C C 4 alkyl or has the structure of one of:
  • L is absent or optionally substituted C C 6 alkylene; C C 6 fluoroalk lene; or optionally substituted C C 6 heteroalkylene, or L , when present is -CH 2 - or disubstituted dimethylmethane.
  • Ring A has the structure of one of:
  • R c is - H, -CN, -F, -CI, -Br,- 1, -OC C 4 alkyl, C C 4 alkyl, C 3 -C 6 cycloalkyi, or C C 4 fluoroalkyl;
  • R J is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene-(substituted or unsubstituted aryl), or C C 4 alkylene- (substituted or unsubstituted heteroaryl);
  • R L independently are -H, substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C C 6 heteroalkyl, substituted or unsubstituted C C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -C C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), -C C 4 alkylene(substituted or unsubstituted aryl), or -C C 4 alkylene-(substituted or unsubstituted heteroaryl),
  • each R L is independently -H or C C 6 alkyl, or the R L groups independently are C C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle,
  • Ring A has the structure of one
  • R A is -C0 2 H.
  • composition comprising, essentially consisting of or consisting of one or more compounds of Formula l-XII and one or more excipients.
  • composition comprises, consists essentially of, consists of one compound of Formula l-XII and one or more excipients.
  • composition is a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of one compound of Formula l-XII and one or more pharmaceutically acceptable excipients.
  • LPA1 R selective lysophosphatidic acid receptor-1
  • [425] 29 The compound of embodiment 20, 21 or 22 wherein the compound is a selective lysophosphatidic acid receptor-1 (LPA1 R) compound wherein the binding affinity (i.e., K D ) of the LPA1 R compound is between about 1 ⁇ and 1 pM or less.
  • the K D is 100 nM or less, more preferably 10 nM or less.
  • the compound of embodiment 30 wherein the compound is (R)-2-[[4-[1 ,5- dimethyl-4-((R)-1 -phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-3-phenyl- propanoic acid, (R)-2-[[4-[1 ,5-dimethyl-4-((R)-1 -phenylethoxycarbonylamino)pyrazol-3- yl]benzoyl]amino]-3-(4-fluorophenyl)propanoic acid, (R)- 3-(4-bromophenyl)-2-[[4-[1 ,5- dimethyl-4-((R)-1 -phenylethoxycarbonyl-amino)pyrazol-3-yl]benzoyl]amino]propanoic acid, ((R)- 3-(4-chlorophenyl)-2-[[4-[
  • a compound of embodiment 30 wherein the compound is 2-Benzyl-3- ⁇ 5-[3- cyano-4-(1 -phenylethoxycarbonylamino)-5-isoxazolyl]-2-pyridylamino ⁇ propionic acid, 2- Benzyl-3-(5- ⁇ 4-[1 -(o-chlorophenyl)ethoxycarbonylamino]-3-cyano-5-isoxazolyl ⁇ -2- pyridylamino)-propionic acid, 3- ⁇ 5-[3-Cyano-4-(1 -phenylethoxycarbonylamino)-5- isoxazolyl]-2-pyridyl-amino ⁇ -2-(cyclopropylmethyl)propionic acid, 3-(5- ⁇ 4-[1 -(o- Chlorophenyl)ethoxycarbonyl-amino]-3-cyano-5-isoxazolyl ⁇ -2-pyridylamin
  • a compound of embodiment 30 wherein the compound is 2-Benzyl-3- ⁇ 5-[3- methyl-4-(1 -phenylethoxycarbonylamino)-5-isoxazolyl]-2-pyridylamino ⁇ propionic acid, 2- Benzyl-3-(5- ⁇ 4-[1 -(o-chlorophenyl)ethoxycarbonylamino]-3-methyl-5-isoxazolyl ⁇ -2- pyridylamino)-propionic acid, 2-(Cyclopropylmethyl)-3- ⁇ 5-[3-methyl-4-(1 - phenylethoxycarbonylamino)-5-isoxazolyl]-2-pyridylamino ⁇ propionic acid, 3-(5- ⁇ 4-[1 -(o- Chlorophenyl)ethoxycarbonylamino]-3-methyl-5-isoxazolyl ⁇ -2-pyridylamino)-2- (cycloprop
  • a compound of embodiment 30 wherein the compound is 2-[[4-[1 ,5-dimethyl-4-(1 - phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-3-(4-methoxyphenyl)propanoic acid, 2-[[4-[1 ,5-dimethyl-4-(1 -phenylethoxycarbonylamino)pyrazol-3-yl]benzoyl]amino]-3- (4-fluorophenyl)propanoic acid, 3-(2,6-difluorophenyl)-2-[[4-[1 ,5-dimethyl-4-(1 - phenylethoxy-carbonylamino)pyrazol-3-yl]benzoyl]amino]propanoic acid, 3-(3- cyanophenyl)-2-[[4-[1 ,5-dimethyl-4-(1 -phenylethoxycarbonyla
  • a compound of embodiment 30 wherein the compound is 3-phenyl-2-[[4-[5- (1 -phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]amino]propanoic acid, 3- cyclopropyl-2-[[4-[5-(1 -phenylethoxycarbonylamino)pyrimidin-4- yl]benzoyl]amino]propanoic acid, 4-phenyl-2-[[4-[5-(1 - phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]amino]butanoic acid, 3-phenoxy-2- [[4-[5-(1 -phenylethoxycarbonylamino)pyrimidin-4-yl]benzoyl]amino]-propanoic acid, 3- Phenyl-2-[( ⁇ p-[5-(1 -phenylethoxycarbonylamino)-4-yl]benz
  • a compound of embodiment 30 wherein the compound is 3-phenyl-2-[[4-[4- (1 -phenylethoxycarbonylamino)pyrimidin-5-yl]benzoyl]amino]propanoic acid, 3- cyclopropyl-2-[[4-[4-(1 -phenylethoxycarbonylamino)pyrimidin-5- yl]benzoyl]amino]propanoic acid, 4-phenyl-2-[[4-[4-(1 - phenylethoxycarbonylamino)pyrimidin-5-yl]benzoyl]amino]butanoic acid or 3-phenoxy-2- [[4-[4-(1 -phenylethoxycarbonylamino)pyrimidin-5-yl]benzoyl]amino]-propanoic acid,
  • a compound of embodiment 30 wherein the compound is 3-phenyl-2-[[4-[3- (1 -phenylethoxycarbonylamino)pyrazin-2-yl]benzoyl]amino]propanoic acid, 3- cyclopropyl-2-[[4-[3-(1 -phenylethoxycarbonylamino)pyrazin-2- yl]benzoyl]amino]propanoic acid, 4-phenyl-2-[[4-[3-(1 - phenylethoxycarbonylamino)pyrazin-2-yl]benzoyl]amino]butanoic acid or 3-phenoxy-2- [[4-[3-(1 -phenylethoxycarbonylamino)pyrazin-2-yl]benzoyl]amino]propanoic acid.
  • a compound of embodiment 30 wherein the compound is 1 - ⁇ p-[3-Methyl-4- (1 -phenylethoxycarbonylamino)-5-isoxazolyl]phenyl ⁇ -4-piperidinecarboxylic acid, (1 - ⁇ p- [3-Methyl-4-(1 -phenylethoxycarbonylamino)-5-isoxazolyl]phenyl ⁇ -4-piperidyl)acetic acid, 1 -(1 - ⁇ p-[3-Methyl-4-(1 -phenylethoxycarbonylamino)-5-isoxazolyl]phenyl ⁇ -4- piperidyl)cyclo-propanecarboxylic acid, [1 -(1 - ⁇ p-[3-Methyl-4-(1 - phenylethoxycarbonylamino)-5-isoxazolyl]-phenyl ⁇ -4-piperidyl)cyclopropanecarboxylic acid, [1
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of Table 1 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 31 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 32 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 33 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 34 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 35 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 36 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 37 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 38 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 39 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 40 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 41 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 42 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 43 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 44 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 45 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 46 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 47 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 48 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 49 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 50 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 51 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 52 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of, or consisting of a compound of embodiment 53 and one or more pharmaceutically acceptable excipients.
  • [472] 78 A method comprising administering an effective amount of a Formula l-XII compound to a subject having a LPA-dependent or LPA-mediated disease or condition.
  • 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
  • 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
  • LPA-mediated disease is a liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, nonalcoholic liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, nonalcoholic liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, nonalcoholic liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative failure, nonalcoholic liver disease including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, cholestatic pruritus, portal hypertension, regenerative
  • NASH steatohepatitis
  • liver hypofunction hepatic blood flow disorder
  • LPA-mediated disease is a renal disease including chronic kidney disease, end stage renal disease, uremic pruritus, nephropathy including diabetic nephropathy and the like,
  • a composition comprising, consisting essentially of or consisting of one or more compounds of Formula (l-XII) and one or more agents currently used to treat a LPA -dependent or LPA -mediated disease or a disease or condition described herein.
  • a pharmaceutically acceptable formulation comprising, consisting essentially of or consisting of one or more compounds of Formula (l-XII), one or more agents currently used to treat a LPA -dependent or LPA -mediated disease and one or more pharmaceutically acceptable excipients.
  • [512] 1 18. A method comprising administering in combination with or co-administrating a compound of Formula (l-XII) 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-XII) 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 ⁇ -2 agonists.
  • lysophospholipase D (lysoPLD) inhibitors autotaxin inhibitors, decon-gestants, mast cell stabilizers, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and ⁇ -2 agonists.
  • the currently used agent(s) are selected from those described in the Merck Index known to affect lysophosphatidic acid receptor signaling.
  • the Formula (l-XII) compound is selected from Table 1 .
  • therapies which combine a compound of Formula (l-XII), 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 provided.
  • 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 1 1 -7082, PKC412, or PD 184352, TaxolTM (paclitaxel), and analogs ofTaxolTM, such as TaxotereTM, U0126, PD98059, PD
  • aldesleukin aldesleukin; altretamine; ambomycin; ametantrone acetate; amino glutethimide;
  • cactinomycin calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; deazaguanine; deazaguanine mesylate; diaziquone;
  • doxorubicin doxorubicin hydrochloride
  • droloxifene droloxifene citrate
  • dromostanolone propionate duazomycin; edatrexate
  • eflornithine hydrochloride elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; camrabine; fenretinide; floxuridine;
  • fludarabine phosphate fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
  • gemcitabine gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;
  • ifosfamide; iimofosine; interleukin II including recombinant interleukin II, or rlL2
  • interleukin II including recombinant interleukin II, or rlL2
  • interferon alfa-2a interferon alfa-2b
  • interferon alfa-n1 interferon alfa-n3
  • interferon beta-l a interferon gamma-l b
  • methotrexate methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide;
  • hydrochloride spiromustine; spiroplatin; streptonigrin; streptozotocin; sulofenur;
  • talisomycin tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfm;
  • hydroxyprogesterone caproate megestrol acetate, medroxyprogesterone acetate, estrogens, diethlystilbestrol, ethinyl estradiol, tamoxifen), testosterone propionate, fluoxymesterone, flutamide, leuprolide, cisplatin, carboblatin, mitoxantrone),
  • Eleutherobins such as Desmethyleleutherobin, Desacetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin
  • Caribaeoside Caribaeolin, Halichondrin B, Diazonamide A, Taccalonolide A, Diozostatin, (-)-Phenylahistin, Myoseverin B, Resverastatin phosphate sodium, Aprepitant, cannabis, marinol, dronabinol, erythropoetin-a, Filgrastim, rituximab, natalizumab, cyclophosphamide, penicillamine, cyclosporine, nitrosoureas, cisplatin, carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogues, protein synthesis inhibitors, dactinomycin, anthr
  • meclofenamate meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, valdecoxib, parecoxib, etoricoxib, lumiracoxib, betamethasone, prednisone,
  • TROLOXTM citicoline and minicycline
  • (2R)-2-propyloctanoic acid propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol and acebutolol, memantine, traxoprodil, tirofiban lamifiban, argatroban, enalapril, cyclandelate, losartan, valsartan, candesartan, irbesartan, telmisartan, olmesartan mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate,
  • pheniramine chlorphenamine (chlorpheniramine), dexchlorpheniramine,
  • compound(s) are selected from the group consisting of 1 -(4- ⁇ 4-[1 -(2-Chloro-phenyl)- ethoxycarbonylamino]-3-methyl-isoxazol-5-yl ⁇ -benzoylamino)-cyclo-propanecarboxylic acid, 2-(4- ⁇ 4-[1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl ⁇ - benzoylamino)-indan-2-carboxylic acid, 2-(S)- (4- ⁇ 4-[(R,S)-1 -(2-Chloro-phenyl)- ethoxycarbonylamino]-3-methyl-isoxazol-5-yl ⁇ -benzoylamino) phenyl acetic acid, 2-(R)- (4- ⁇ 4-[(R,S)-1 -(2-Chloro-phenyl)-ethoxycarbonylamino
  • compound(s) are selected from embodiment 35.
  • compound(s) are selected from embodiment 38.
  • compound(s) are selected from embodiment 40.
  • compound(s) are selected from embodiment 41 .
  • compound(s) are selected from embodiment 42.
  • compound(s) are selected from embodiment 48.
  • compound(s) are selected from embodiment 49.
  • compound(s) are selected from embodiment 50.
  • compound(s) are selected from embodiment 51 .
  • compound(s) are selected from embodiment 53.
  • composition of embodiment 1 16 where the currently used agent is a mast cell stabilizing agent is a mast cell stabilizing agent
  • composition of embodiment 1 16 where the currently used agent is a platelet activating factor receptor antagonist
  • R B is -H or -CrC 4 alkyl, or has the structure of one of:
  • R E is -H, -C1 -C4 alkyl or -C C 4 fluoroalkyl
  • R F is -H or C C 4 alkyl
  • R G is independently selected R E , or one R G is -CrC 4 alkyl and is taken together with the carbon atom to which R G is attached and the carbon or heteroatom to which CY is attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , if present, is as defined for R E ;
  • CY is substituted or unsubstituted C C 6 alkyl, substituted or unsubstituted C 3 - C10 cycloalkyi, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyi, 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 ;
  • Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, substituted or unsubstituted C 2 -Ci 0 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, where if ring B is substituted then ring B is substituted with 1 , 2, or 3 independently selected R H , wherein R H is as previously defined;
  • Ring C is absent or substituted or unsubstituted C 3 -Ci 0 cycloalkylene, substituted or unsubstituted C 2 -Ci 0 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, where if ring C is substituted then ring C is substituted with 1 , 2, or 3 independently selected R H , wherein R H is as previously defined,
  • Ring B is substituted or unsubstituted arylene and Ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, or Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene and Ring C is substituted or unsubstituted arylene, L 2 is absent, L is C C 6 alkylene,
  • R c is -H or -CH 3 and R A is -C0 2 H or C0 2 R B ,
  • Ring A has the structure of one of::
  • Rin A is selected from one of:
  • R c is -H, -CH 3 or -CF 3
  • Ring B is substituted or unsubstituted arylene and Ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C 3 -Ci 0 cycloalkylene, or Ring B is substituted or unsubstituted C 3 -Ci 0 cycloalkylene and Ring C is substituted or unsubstituted arylene, L 2 is absent and L is C C 6 alkylene.
  • cycloalkylene i.e., cyclopropyl-di-yl
  • R c is -H, -CN, -CH 3 , or -CF 3
  • CY is unsubstituted or substituted phenyl, wherein substituted phenyl is phenyl that is substituted with one or two of independently selected R J .
  • R F is -H
  • CY is substituted phenyl
  • substituted phenyl is phenyl that is substituted with one or two of independently selected R J , wherein R J are halogens.
  • unsubstituted C C 4 alkyl or halogen substituent or substituents of the aryl or heteroaryl of -CH(CH 2 -aryl) or -CH(CH 2 -heteroaryl) are selected from the group consisting of -CH 3 , -CF 3 , -F, -CI or -Br.
  • Ring A has the structure of one of:
  • Ring C is a substituted or unsubstituted arylene or heteroarylene
  • L is CrC 6 alkylene
  • R A is -C0 2 H or C0 2 R B
  • R F is -H
  • R G is -CH 3
  • CY is substituted phenyl
  • R c is - is -CN, -F, -CI, -Br, -I, -OC C 4 alkyl, -C 2 -C 4 alkyl, -C 3 -C 6 cycloalkyl, or -C 2 -C 4 fluoroalkyl.
  • R F and R G independently are -H or - CH 3 ;
  • R A is -C0 2 H or -C0 2 R B .
  • Ring A is a 5 membered heteroarene having one of the structures of:
  • R H is -C0 2 H or -C0 2 R B ; W is -C(R L ) 2 - or ; R E and R F independently are
  • R G is -H or -CH 3
  • R H independently are -H, halogen, -CH 3 or -CF 3 ;
  • Z is -C(R L ) 2 , wherein one R L is -H and the other R L is -H or C C 4 alkyl.
  • W is -C(R L ) 2 - or ;
  • R E and R F independently are -H or C C 4 alkyl;
  • R G is -H or -CH 3 ;
  • R H independently are -H, halogen, -CH 3 or -CF 3 ;
  • Z is -C(R L ) 2 , wherein one R L is -H and the other R L is -H or C 1 -C4 alkyl.
  • 50A The compound of embodiment 2A wherein the compound has the structure
  • R D is the
  • R H is -C0 2 H or -C0 2 R B ; wherein W is -C(R L ) 2 - or ; R E and R F independently are -H or C C 4 alkyl; R G is -H or -CH 3 ; R H independently are -H, halogen, -CH 3 or -CF 3 ; and Z is -C(R L ) 2 , wherein one R L is -H and the other R L is -H or C C 4 alkyl.
  • 53A A compound of any one of embodiments 1 A-52A for preparation of mendicant for treating a LPA-dependent disease or condition.
  • the compounds of Table 1 are exemplary of the invention but not limiting, wherein compounds 57-458 are prepared according to the appropriately modified procedures of the examples for preparation of compounds 1 -458.

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CN201480015333.XA CN105142635B (zh) 2013-03-15 2014-03-17 有用于治疗疾病的杂环化合物
BR112015023267-1A BR112015023267B1 (pt) 2013-03-15 2014-03-17 Composto, e medicamento para tratar um indivíduo com doença ou condição lisofosfatídica dependente de ácido
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