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EP4622713A1 - Composés et compositions pour le traitement d'états associés à l'activité du récepteur de lpa - Google Patents

Composés et compositions pour le traitement d'états associés à l'activité du récepteur de lpa

Info

Publication number
EP4622713A1
EP4622713A1 EP23833268.8A EP23833268A EP4622713A1 EP 4622713 A1 EP4622713 A1 EP 4622713A1 EP 23833268 A EP23833268 A EP 23833268A EP 4622713 A1 EP4622713 A1 EP 4622713A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
cycloalkyl
heterocyclyl
alkynyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23833268.8A
Other languages
German (de)
English (en)
Inventor
Wei Huang
Hui Lei
Zhongmiao XU
Qiong Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lhotse Bio Inc
Original Assignee
Lhotse Bio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lhotse Bio Inc filed Critical Lhotse Bio Inc
Publication of EP4622713A1 publication Critical patent/EP4622713A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • Lysophospholipids are one class of these membrane-derived bioactive lipid mediators and include lysophosphatidic acid (LPA).
  • LPA lysophosphatidic acid
  • LPA is not a single molecular entity but a collection of endogenous structural variants with fatty acids of varied lengths and degrees of saturation. LPAs affect cellular functions that include cellular proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.
  • LPA has a role as a biological effector molecule and has a diverse range of physiological actions such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, and a variety of cellular effects, which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration.
  • the effects of LPA are predominantly receptor mediated.
  • Activation of the LPA receptors (LPA 1 , LPA 2 , LPA 3 , LPA 4 , LPA 5 , LPA 6 ) with LPA mediates a range of downstream signaling cascades.
  • Antagonizing LPA receptors may be useful for the treatment of a variety of disorders, including fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis and systemic sclerosis, and thus the diseases that result from fibrosis (e.g., pulmonary fibrosis, for example, Idiopathic Pulmonary Fibrosis (IPF), hepatic fibrosis, including Non-alcoholic Steatohepatitis (NASH), renal fibrosis, such as diabetic nephropathy, systemic sclerosis-scleroderma, etc.), COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis.
  • fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis and systemic sclerosis
  • diseases that result from fibrosis e.g., pulmonary fibrosis, for example
  • the present application describes LPA antagonists, as well as pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating LPA-associated diseases, disorders, and conditions.
  • A is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of A is independently optionally substituted with one to five Z 1 ;
  • L 1 is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -NR 10 -, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, or C 1-3 heteroalkylene; wherein the C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, or
  • compositions comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • LPA lysophosphatidic acid
  • the LPA-associated disease is an LPA1-associated disease, wherein modulating LPA1 receptor signaling can alter the pathology and/or symptoms and/or progression of the disease, disorder, or condition.
  • fibrosis refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • pharmaceutically acceptable indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith.
  • administering refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian.
  • the method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.
  • ⁇ ективное amount or “effective dosage” or “pharmaceutically effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, and can include curing the disease. “Curing” means that the symptoms of active disease are eliminated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • a chemical entity e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.
  • excipient or “pharmaceutically acceptable excipient” means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • modulate refers to a regulation or an adjustment (e.g., increase or decrease) and can include, for example agonism, partial agonism or antagonism.
  • Compounds [0072] Provided herein are compounds that are LPA antagonists. In some embodiments, provided is a compound of Formula I:
  • X 4 is O. In some embodiments, X 4 is O; and A is C 1-6 alkyl.
  • A is C 1-6 alkyl or C 3-10 cycloalkyl.
  • L 1 is a bond, -O-, -NR 10 -, C 1-3 alkylene, or C 1-3 heteroalkylene. In some embodiments, L 1 is a bond. In some embodiments, L 1 is -O-, -NR 10 -, C 1-3 alkylene, or C 1-3 heteroalkylene. In some embodiments, L 1 is -O- or -NR 10 -. In some embodiments, L 1 is a -O- or -NH-. In some embodiments, L 1 is C 1-3 alkylene or C 1-3 heteroalkylene.
  • L 1 is -O-. In some embodiments, L 1 is -NR 10 -. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is C 1-3 alkylene. In some embodiments, L 1 is -CH 2 -. In some embodiments, L 1 is C 1-3 heteroalkylene. In some embodiments, L 1 is -O-CH 2 -. In some embodiments, L 1 is -NHCH 2 -. [0084] In some embodiments, L 2 is a bond, C 1-3 alkylene, or C 1-3 heteroalkylene. In some embodiments, L 2 is C 1-3 alkylene. In some embodiments, L 2 is -CH 2 -.
  • R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-10 cycloalkyl optionally substituted by one to five Z 1 . In some embodiments, R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-6 cycloalkyl optionally substituted by one to five Z 1 . In some embodiments, R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-10 cycloalkyl optionally substituted by one to five halo. In some embodiments, R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-6 cycloalkyl optionally substituted by one to five halo.
  • R 1 and R 2 are taken together with the atom to which they are attached to form a heterocyclyl optionally substituted by one to five Z 1 . In some embodiments, R 1 and R 2 are taken together with the atom to which they are attached to form a heterocyclyl. [0088] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl, or R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-10 cycloalkyl or heterocyclyl; wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted by one to five Z 1 .
  • R 1 and R 2 are each independently C 1-9 alkyl, or R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-10 cycloalkyl or heterocyclyl; wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted by one to five halo.
  • R 1 and R 2 are each independently C 1-9 alkyl; wherein each alkyl is independently optionally substituted by one to five halo.
  • R 1 and R 2 are taken together with the atom to which they are attached to form a C 3-10 cycloalkyl or heterocyclyl; wherein the cycloalkyl or heterocyclyl is optionally substituted by one to five halo.
  • each R 13 is independently hydrogen or C 1-9 alkyl. In some embodiments, each R 13 is independently hydrogen or methyl. In some embodiments, each R 13 is hydrogen. In some embodiments, one R 13 is hydrogen and one R 13 is C 1-9 alkyl. In some embodiments, one R 13 is hydrogen and one R 13 is methyl.
  • a compound of Formula ID: or a pharmaceutically acceptable salt or solvate thereof wherein A, R 4 , R 8 , R 9 , X 1 , X 2 , X 3 , X 4 , X 6 , n, L 1 , and L 2 are each independently as defined herein; p is 0, 1, or 2; q is 0, 1, or 2; X 5 is absent, O, NR 17 , or C(R 18 ) 2 ; R 17 is hydrogen, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R 20 , -S(O) 2 R 20 , -S(O)NR 20 R 21 , or -S(O) 2 NR 20
  • a compound of Formula IE or a pharmaceutically acceptable salt or solvate thereof, wherein A, R 4 , X 1 , X 2 , X 3 , X 5 , X 6 , p, and q are each independently as defined herein; [0105]
  • X 1 is CR 3 .
  • X 1 is CR 3 ; and R 3 is hydrogen, halo, or C 1-5 alkyl optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano.
  • X 1 is CR 3 ; and R 3 is hydrogen, halo, or C 1-5 alkyl optionally substituted with one to five halo. In some embodiments, X 1 is CR 3 ; and R 3 is hydrogen, fluoro, chloro, methyl, or difluoromethyl.
  • X 2 is N. In some embodiments, X 2 is CR 5 . In some embodiments, X 2 is N or CR 5 ; and R 5 is hydrogen or C 1-5 alkyl. In some embodiments, X 2 is N or CR 5 ; and R 5 is hydrogen or methyl. In some embodiments, X 2 is CR 5 ; and R 5 is hydrogen or C 1-5 alkyl.
  • X 6 is CR 6 ; and R 6 is hydrogen or C 1-5 alkoxy. In some embodiments, X 6 is CR 6 ; and R 6 is hydrogen or methoxy. [0110] In some embodiments, the moiety . [0111] In some embodiments, the moiety [0112] In some embodiments, the moiety [0113] In some embodiments, X 1 is CR 3 ; and R 3 is hydrogen, halo, or C 1-5 alkyl optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano. In some embodiments, R 3 is hydrogen, halo, or C 1-5 alkyl optionally substituted with one to five halo.
  • R 5 is hydrogen, -C(O)-C 1-5 alkyl, or C 1-5 alkyl. In some embodiments, R 5 is hydrogen or C 1-5 alkyl. In some embodiments, R 5 is hydrogen or methyl.
  • R 6 is hydrogen or C 1-5 alkoxy. In some embodiments, R 6 is hydrogen or methoxy.
  • R 7 is hydrogen, halo, or C 1-5 alkyl, wherein the C 1-5 alkyl is optionally substituted with one to five halo.
  • R 4 is C 1-5 alkoxy or -O-C 3-10 cycloalkyl.
  • A is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • L 1 is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -NR 10 -, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, or C 1-3 heteroalkylene;
  • L 2 is a bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, or C 1-3 heteroalkylene;
  • X 1 is N or CR 3 ;
  • X 2 is N or CR 5 ;
  • X 3 is N or CR 7 ;
  • X 6 is N or CR 6 ;
  • X 4 is O or CHR 11 ; provided that when A is C 1-6 alkyl, then X 4 is O; one of Y 2 , Y 3 , and Y 6 is N, and the other
  • the compounds of Formula I provided herein encompass stereochemical forms of the compounds, for example, optical isomers, such as enantiomers, diastereomers, as well as mixtures thereof, e.g., mixtures of enantiomers and/or diastereomers, including racemic mixtures, as well as equal or non-equal mixtures of individual enantiomers and/or diastereomers. All stereochemical forms are contemplated in this disclosure. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including but not limited to those delineated in Table 2. In some embodiments, provided is compound selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof:
  • the compounds of Formula I include pharmaceutically acceptable salts thereof.
  • the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I.
  • Non- limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetic acid salts.
  • the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure.
  • the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art.
  • the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • this disclosure provides methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which inhibition of one or more LPA receptors (i.e., an LPA- associated disease) is beneficial for the treatment of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition.
  • the methods provided herein can include or further include treating one or more conditions associated, co-morbid or sequela with any one or more of the conditions provided herein.
  • a method for treating a LPA-associated disease comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as disclosed herein.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • kits for treating or preventing fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as disclosed herein.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • the methods can include treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis or systemic sclerosis.
  • pulmonary fibrosis e.g., Idiopathic Pulmonary Fibrosis (IPF)
  • the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is used to treat or prevent fibrosis in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein can be used to treat fibrosis of an organ or tissue in a subject.
  • a method for preventing a fibrosis condition in a subject comprising administering to the subject at risk of developing one or more fibrosis conditions a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein.
  • the subject may have been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of an organ or tissue.
  • the subject has been exposed to one or more environmental conditions that are known to increase the risk of lung, liver or kidney fibrosis.
  • the subject has a genetic predisposition of developing fibrosis of an organ or tissue.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is administered to a subject to prevent or minimize scarring following injury.
  • the injury can include surgery.
  • Exemplary diseases, disorders, or conditions that involve fibrosis include, but are not limited to: lung diseases associated with fibrosis, for example, idiopathic pulmonary fibrosis, iatrogenic drug induced, occupational/environmental induced fibrosis (Farmer lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease (scleroderma and others), alveolar proteinosis, langerhans cell granulonmatosis, lymphangioleiomyomatosis, inherited diseases (e.g., Hermansky-Pudlak Syndrome, Tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease), pulmonary fibrosis secondary to systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis, chronic obstructive pulmonary disease (COPD), sc
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is used to treat usual interstitial pneumonia in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is used to treat diffuse parenchymal interstitial lung diseases in subject such as iatrogenic drug induced, occupational/environmental induced fibrosis (Farmer lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease (scleroderma and others), alveolar proteinosis, langerhans cell granulonmatosis, lymphangioleiomyomatosis, inherited diseases (e.g., Hermansky-Pudlak Syndrome, Tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease).
  • diffuse parenchymal interstitial lung diseases such as iatrogenic drug induced, occupational/environmental induced fibrosis (Farmer lung), granulomatous diseases (sarcoidosis, hyper
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is useful to treat cutaneous fibrosis in a subject such as cutaneous scleroderma, Dupuytren disease, and keloids.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is useful to treat hepatic fibrosis with or without cirrhosis in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is useful to treat renal fibrosis in a subject (e.g., tubulointerstitium fibrosis and glomerular sclerosis).
  • diseases, disorders, or conditions as provided herein include atherosclerosis, thrombosis, heart disease, vasculitis, formation of scar tissue, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis and cystitis, fibrosis of the nasal passages, sinusitis, inflammation mediated by neutrophils, and fibrosis mediated by fibroblasts.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is useful to treat one or more symptoms of COVID-19.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • COPD chronic obstructive pulmonary disease
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is useful to treat neuroinflammation.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is administered to a subject with fibrosis of an organ or tissue or with a predisposition of developing fibrosis of an organ or tissue with one or more other agents that are used to treat fibrosis.
  • the one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as provided herein, is used to treat a dermatological disorder in a subject.
  • Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, or urticaria.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a compound disclosed herein can be used in the treatment or prevention of inflammatory/immune disorders in a subject.
  • inflammatory/immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto’s and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunc
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein, is used in the treatment of pain in a subject.
  • the pain is acute pain or chronic pain.
  • the pain is neuropathic pain.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is used in the treatment of fibromyalgia.
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein.
  • the methods provided herein further include administration of a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.
  • cancer refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • the types of cancer include, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias) at any stage of the disease with or without metastases.
  • solid tumors such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias) at any stage of the disease with or without metastases.
  • cancers include, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gall
  • a method of treating an allergic disorder in a subject comprising administration of a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) as provided herein.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a compound disclosed herein is useful for the treatment of respiratory diseases, disorders, or conditions in a subject.
  • a compound disclosed herein can treat asthma (e.g., chronic asthma) in a subject.
  • asthma e.g., chronic asthma
  • the term “respiratory disease,” as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphragm and intercostals), and nerves.
  • Non-limiting examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non- allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.
  • asthma refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic).
  • the term asthma may be used with one or more adjectives to indicate cause.
  • a therapeutically effective amount of a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • chronic obstructive pulmonary disease examples include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, and cystic fibrosis.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment or prevention of a nervous system disorder in a subject.
  • Non-limiting examples of CNS disorders include multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury.
  • methods of treating or preventing cardiovascular disease in a subject include multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury.
  • cardiovascular disease refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.
  • arrhythmia atrial or ventricular or both
  • atherosclerosis and its sequelae angina
  • cardiac rhythm disturbances myocardial ischemia
  • myocardial infarction myocardial infarction
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • methods for reducing the constriction of blood vessels in a subject comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof).
  • methods for lowering or preventing an increase in blood pressure of a subject comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) are provided herein.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • LPA receptor inhibitors can be assayed in vitro, in vivo, or in a cell line.
  • Chinese hamster ovary cells overexpressing human LPA1 can be plated overnight (15,000 cells/well) in microplates in DMEM/F12 medium.
  • test compounds solubilized in DMSO are transferred to a multiwell non- binding surface plate and diluted with assay buffer (e.g., IX HBSS with calcium/magnesium, 20 mM HEPES, and 0.1% fatty acid free BSA) to a final concentration of 0.5% DMSO. Diluted compounds are added to the cells at final concentrations ranging from 0.08 nM to 5 mM and are then incubated for 20 min at room temperature at which time LPA is added at final concentrations of 10 nM to stimulate the cells.
  • assay buffer e.g., IX HBSS with calcium/magnesium, 20 mM HEPES, and 0.1% fatty acid free BSA
  • the compound IC 50 value is defined as the concentration of test compound which inhibited 50% of the calcium flux induced by LPA alone. IC 50 values can be determined by fitting data to a 4-parameter logistic equation.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a compound disclosed herein is dosed orally p.o.2 hours to CD-l female mice prior to an LPA challenge. The mice are then dosed via tail vein (IV) with 0.15 mL of LPA in 0.l%BSA/PBS (2 pg/pL).
  • mice Exactly 2 minutes following the LPA challenge, the mice are euthanized by decapitation and the trunk blood is collected. These samples are collectively centrifuged and individual 75 pL samples are frozen at -20°C until performance of a histamine assay.
  • the plasma histamine analysis can be run by standard EIA (Enzyme Immunoassay) methods. Plasma samples are thawed and diluted 1 :30 in 0.1% BSA in PBS. An EIA protocol for histamine analysis as previously described can be used in this assay.
  • LPA has a role as a biological effector molecule, and has a diverse range of physiological actions that include effects on blood pressure, platelet activation, and smooth muscle contraction, and a variety of cellular effects, which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration. These effects are predominantly receptor mediated.
  • Activation of the LPA receptors (LPA 1 , LPA 2 , LPA 3 , LPA 4 , LPA 5 , LPA 6 ) with LPA mediates a range of downstream signaling cascades.
  • Non-limiting examples include, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C (PLC) activation/Ca2+ mobilization, arachidonic acid release, Akt/PKB activation, and the activation of small GTPases, Rho, ROCK, Rae, and Ras.
  • MAPK mitogen-activated protein kinase
  • AC adenylyl cyclase
  • PLC phospholipase C activation/Ca2+ mobilization
  • arachidonic acid release Akt/PKB activation
  • small GTPases Rho, ROCK, Rae, and Ras.
  • Additional pathways that are affected by LPA receptor activation include, for example, cyclic adenosine monophosphate (cAMP), cell division cycle 42/GTP-binding protein (Cdc42), proto-oncogene serine/threonine-protein kinase Raf (c-RAF), proto- oncogene tyrosine- protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PBK), protein kinase A (
  • LPA1 (previously called VZG-l/EDG-2/mrecl.3) couples with three types of G proteins, G i/o , G q , and G 12/13 .
  • LPA induces a range of cellular responses through LPA 1 including, for example, cell proliferation, serum-response element (SRE) activation, mitogen- activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca 2+ mobilization, Akt activation, and Rho activation.
  • SRE serum-response element
  • MAPK mitogen- activated protein kinase
  • AC adenylyl cyclase
  • PLC phospholipase C
  • Ca 2+ mobilization Akt activation
  • Rho activation Rho activation
  • LPA 1 is expressed in human tissues such as the brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.
  • LPA 2 (EDG-4) also couples with three types of G proteins, G i/o , G q , and G 12/13 , to mediate LPA- induced cellular signaling. Expression of LPA 2 is observed in the testis, kidney, lung, thymus, spleen, and stomach of adult mice and in the human testis, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes.
  • LPA 4 (p2y 9 /GPR23) is of divergent sequence compared to LPA 1 , LPA 2 , and LPA 3 with closer similarity to the platelet-activating factor (PAF) receptor.
  • LPA 4 mediates LPA induced Ca 2+ mobilization and cAMP accumulation, and functional coupling to the G protein Gs for AC activation, as well as coupling to other G proteins.
  • the LPA 4 gene is expressed in the ovary, pancreas, thymus, kidney and skeletal muscle.
  • LPA 5 (GPR92) is a member of the purinocluster of GPCRs and is structurally most closely related to LPA 4 .
  • this disclosure provides methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which inhibition of one or more LPA receptors (i.e., an LPA- associated disease) is beneficial for the treatment of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition.
  • the methods provided herein can include or further include treating one or more conditions associated, co-morbid or sequela with any one or more of the conditions provided herein.
  • an LPA-associated disease includes, but is not limited to treating fibrosis of an organ (e.g., liver, kidney, lung, heart, and skin), liver disease (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like), cell proliferative disease (e.g., cancer, including solid tumors, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi’s sarcoma, leukemia, and chronic lymphocytic leukemia (CLL), and invasive metastasis of cancer cells), inflammatory disease (e.g., psoriasis, nephropathy, and pneumonia), gastrointestinal tract disease (e.g., irritable bowel syndrome (TBS), inflammatory bowel
  • organ e.g.
  • kits for treating or preventing fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as disclosed herein, and one or more additional therapeutic agents.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • the methods can include treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis or systemic sclerosis.
  • pulmonary fibrosis e.g., Idiopathic Pulmonary Fibrosis (IPF)
  • the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein, and one or more additional therapeutic agents.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein, and one or more additional therapeutic agents.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein, and one or more additional therapeutic agents is used to treat or prevent fibrosis in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein, and one or more additional therapeutic agents can be used to treat fibrosis of an organ or tissue in a subject.
  • a method for preventing a fibrosis condition in a subject comprising administering to the subject at risk of developing one or more fibrosis conditions a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein, and one or more additional therapeutic agents.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein e.g., a pharmaceutical composition as provided herein, and one or more additional therapeutic agents.
  • the subject may have been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of an organ or tissue.
  • the subject has been exposed to one or more environmental conditions that are known to increase the risk of lung, liver or kidney fibrosis.
  • the subject has a genetic predisposition of developing fibrosis of an organ or tissue.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein, and one or more additional therapeutic agents is administered to a subject to prevent or minimize scarring following injury.
  • the injury can include surgery.
  • Exemplary diseases, disorders, or conditions that involve fibrosis include, but are not limited to: lung diseases associated with fibrosis, for example, idiopathic pulmonary fibrosis, iatrogenic drug induced, occupational/environmental induced fibrosis (Farmer lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease (scleroderma and others), alveolar proteinosis, langerhans cell granulonmatosis, lymphangioleiomyomatosis, inherited diseases (e.g., Hermansky-Pudlak Syndrome, Tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease), pulmonary fibrosis secondary to systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis, chronic obstructive pulmonary disease (COPD), sc
  • a method of improving lung function in a subject comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein, and one or more additional therapeutic agents, to the subject in need thereof.
  • the subject has been diagnosed as having lung fibrosis.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is used to treat idiopathic pulmonary fibrosis in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein is used to treat usual interstitial pneumonia in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein and one or more additional therapeutic agents is useful to treat post- transplant fibrosis associated with chronic rejection in a subject such as Bronchiolitis obliterans following a lung transplant.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein and one or more additional therapeutic agents is useful to treat cutaneous fibrosis in a subject such as cutaneous scleroderma, Dupuytren disease, and keloids.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein and one or more additional therapeutic agents is useful to treat hepatic fibrosis with or without cirrhosis in a subject.
  • toxic/drug induced (hemochromatosis) alcoholic liver disease
  • viral hepatitis hepatitis B virus, hepatitis C virus, HCV
  • NAFLD nonalcoholic liver disease
  • metabolic and auto-immune disease e.g., hemochromatosis
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein and one or more additional therapeutic agents is useful to treat renal fibrosis in a subject (e.g., tubulointerstitium fibrosis and glomerular sclerosis).
  • diseases, disorders, or conditions as provided herein include atherosclerosis, thrombosis, heart disease, vasculitis, formation of scar tissue, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis and cystitis, fibrosis of the nasal passages, sinusitis, inflammation mediated by neutrophils, and fibrosis mediated by fibroblasts.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein and one or more additional therapeutic agents is useful to treat neuroinflammation.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutical composition as provided herein, and one or more additional therapeutic agents is useful to treat multiple sclerosis.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • one or more additional therapeutic agents can be used in the treatment or prevention of inflammatory/immune disorders in a subject.
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • parenteral administration to the subject one or more times per day (e.g., 1 to 4 times one time per day, two times per day, three times per day, four times per day or a single daily dose).
  • a compound disclosed herein e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof
  • parenteral administration is administered by parenteral administration to the subject weekly.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated.
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany), or Millipore Sigma (Burlington MA USA).
  • the compounds of Formula I are prepared by first coupling compound I-1, followed by deprotection to afford the free acid of Formula I, wherein B is a suitable functional group such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic ester (cyclic or acyclic), zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, fluorosulfonyl esters, tin, sodium, hydrogen, and the like.
  • B is a suitable functional group such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic ester (cyclic or acyclic), zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, fluorosulfonyl esters, tin, sodium, hydrogen, and the like.
  • Such reactions are commonly utilized for aromatic functionalization, and are typically conducted in the presence of suitable catalyst such as, but not limited to, a palladium catalyst including [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc) 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 or tris(dibenzylideneacetone)dipalladium(0), and the like, or a copper catalyst such as CuCl or CuI, and if required suitable mediator, co-catalyst and/or base known to one skilled in the art using suitable solvents/solvent mixtures.
  • a palladium catalyst including [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc) 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 or tris(dibenzylid
  • compounds of Formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.
  • proper control of reaction conditions and selection of substituents for the reagents can at least partially dictate or preserve the formation of the various stereoisomers.
  • Compounds I-1 and I-2 may be commercially obtained or synthesized de novo.
  • Compound I- 1 may be prepared by coupling compound I-3 with compound I-4 under standard nucleophilic aromatic substitution conditions.
  • each intermediate e.g., compound I-1, I-2, I-3, and I-4
  • the ring A may be appended before or after the steps shown above in Scheme I.
  • the ring A moiety may be coupled to an X 4 precursor under substitution reaction conditions.
  • the necessary starting materials generally may be determined by inspection.
  • Starting materials are typically obtained from commercial sources or synthesized using published methods.
  • inspection of the structure of the compound to be synthesized will provide the identity of each substituent group.
  • the identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.
  • compounds described herein are typically stable and isolatable at room temperature and pressure.
  • the process further comprises a deprotection step after the contacting step.
  • the conditions comprises a base.
  • the conditions comprises an acid.
  • the conditions comprises temperatures of about 50 °C to about 120 °C.
  • a process for preparing compound I-1, or a pharmaceutically acceptable salt or solvate thereof comprising contacting a compound of Formula I-3: with a compound of Formula I-4: wherein each of R 1 , R 2 , R 4 , R 8 , R 9 , X 1 , X 2 , X 3 , X 4 , X 6 , Y 2 , Y 3 , Y 6 , A, n, L 1 and L 2 are independently as defined herein, LG and LG’ are a suitable leaving group, where LG and LG’ are not the same, and PG is a suitable carboxyl protecting group; under conditions sufficient to provide the compound of Formula I-3, or a pharmaceutical
  • Example A1 4-( ⁇ 4-[(cyclopentyloxy)methyl]-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2- yl ⁇ amino)oxane-4-carboxylic acid (Compound 101) [0254]
  • Step A (2-chloro-6-methylpyridin-4-yl)methanol [0255]
  • DIBALH 7.6 mL, 107.7 mmol, 1.5 M solution in toluene
  • Step B 4-(bromomethyl)-2-chloro-6-methylpyridine
  • Step D N-(4-((cyclopentyloxy)methyl)-6-methylpyridin-2-yl)-1,1-diphenylmethanimine
  • diphenylmethanimine 389 mg, 2.14 mmol
  • 2-chloro-4- ((cyclopentyloxy)methyl)-6-methylpyridine 440 mg, 1.95 mmol
  • t-BuONa 281 mg, 2.92 mmol
  • BINAP (12.1 mg, 19.5 ⁇ mol
  • Pd 2 (dba) 3 89.3 mg, 97.5 ⁇ mol
  • Step F 5-bromo-4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine
  • NBS 190 mg, 1.07 mmol
  • the reaction mixture was concentrated.
  • the residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2).
  • the combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Step G 4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2- amine
  • 5-bromo-4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine 100 mg, 351 ⁇ mol
  • 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 97.5 mg, 351 ⁇ mol
  • THF 0.5 mL
  • H 2 O 0.1 mL
  • XPhos Pd G3 29.7 mg, 35.1 ⁇ mol
  • Cs 2 CO 3 (229 mg, 701 ⁇ mol).
  • Step H 4-((4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6- methylpyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 101) [0269] To a solution of 4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6- methylpyridin-2-amine (110 mg, 309 ⁇ mol) in THF (5 mL) was added NaOH (37.0 mg, 926 ⁇ mol), dihydro-2H-pyran-4(3H)-one (61.8 mg, 617 ⁇ mol) and followed by CHCl 3 (111 mg, 926 ⁇ mol) at 0 °C.
  • Step A 5-bromo-4-(bromomethyl)-2-chloropyridine
  • Example A3 4-((4-((cyclopentyloxy)methyl)-5-(3-cyclopropoxy-2-fluoro-5-methoxyphenyl)pyridin-2- yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 103) [0279]
  • Step A 2-(2-chloroethoxy)-1-fluoro-4-methoxybenzene [0280] To a solution of 2-fluoro-5-methoxyphenol (5.0 g, 35.18 mmol) in EtOH (40 mL) and H 2 O (4 mL) was added NaOH (1.41 g, 35.18 mmol). The mixture was stirred at 25 °C for 30 min.
  • Step B 1-fluoro-4-methoxy-2-(vinyloxy)benzene
  • 2-(2-chloroethoxy)-1-fluoro-4-methoxybenzene 4.8 g, 23.46 mmol
  • THF 40 mL
  • t-BuOK 5.26 g, 46.91 mmol
  • the mixture was stirred at 25 °C for 16 h.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Step D 2-(3-cyclopropoxy-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [0286] To a solution of 2-cyclopropoxy-1-fluoro-4-methoxybenzene (1.28 g, 7.03 mmol) and bis(pinacolato)diboron (1.96 g, 7.73 mmol) in THF (20 mL) was added [Ir(COD)OMe] 2 (47 mg, 0.70 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy) (38 mg, 0.14 mmol).
  • Step B 1-fluoro-4-methoxy-2-(methoxymethoxy)-3-methylbenzene
  • Step C 6-fluoro-3-methoxy-2-methylphenol
  • 1-fluoro-4-methoxy-2-(methoxymethoxy)-3-methyl-benzene (10.0 g, 50.0 mmol) in THF (2 mL) was added 6 M aq. HCl (8.32 mL). The mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with water (60 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give 6-fluoro-3-methoxy-2-methyl- phenol (5.0 g, 64% yield).
  • reaction mixture was quenched by water (20 mL), extracted with ethyl acetate (20 mL x3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 8% EtOAc/PE gradient @ 40mL/min) to give 2-ethoxy-1-fluoro-4-methoxy-3-methylbenzene (0.35 g, 59% yield).
  • Step E 2-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [0297] To a solution of 2-ethoxy-1-fluoro-4-methoxy-3-methyl-benzene (0.35 g, 1.90 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (434 mg, 1.71 mmol) in THF (5 mL) was added [Ir(COD)OMe]2 (6.30 mg, 9.50 ⁇ mol) and 4-tert-butyl-2-(4-tert-butyl- 2-pyridyl)pyridine (dtbpy) (5.10 mg, 19.00 ⁇ mol).
  • Step F 5-chloro-4-(cyclopropylethynyl)pyridin-2-amine
  • 4-bromo-5-chloro-pyridin-2-amine (3.0 g, 14.5 mmol) and ethynylcyclopropane (3.00 mL, 36.2 mmol) in MeCN (120 mL) was added Pd(PPh 3 ) 2 Cl 2 (1.02 g, 1.45 mmol), CuI (275 mg, 1.45 mmol) and DIEA (12.6 mL, 72.3 mmol).
  • Pd(PPh 3 ) 2 Cl 2 (1.02 g, 1.45 mmol
  • CuI 275 mg, 1.45 mmol
  • DIEA (12.6 mL, 72.3 mmol
  • Step G 4-((5-chloro-4-(cyclopropylethynyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4- carboxylic acid
  • 5-chloro-4-(2-cyclopropylethynyl)pyridin-2-amine 2.5 g, 13.0 mmol
  • NaOH 2.60 g, 64.9 mmol
  • tetrahydropyran-4-one 2.60 g, 26.0 mmol, 2.38 mL).
  • Step H 4-((5-chloro-4-(2-cyclopropylethyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4- carboxylic acid
  • Step I 4-((4-(2-cyclopropylethyl)-5-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)pyridin- 2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid [0305] To a solution of 4-((5-chloro-4-(2-cyclopropylethyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4- carboxylic acid (200 mg, 616 ⁇ mol) and 2-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (229 mg, 739 ⁇ mol) in THF (3 mL) and H 2 O (1.5 mL) was added XPhos Pd G3 (52.1 mg, 61.6 ⁇ mol) and Cs 2 CO 3 (401 mg, 1.23 mmol).

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Abstract

La présente invention concerne des antagonistes de LPA, ainsi que des compositions pharmaceutiques comprenant les composés de l'invention. L'invention concerne également des méthodes de traitement de maladies, de troubles et d'états associés au LPA.
EP23833268.8A 2022-11-24 2023-11-22 Composés et compositions pour le traitement d'états associés à l'activité du récepteur de lpa Pending EP4622713A1 (fr)

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AR128613A1 (es) 2022-02-25 2024-05-29 Lhotse Bio Inc Compuestos y composiciones para el tratamiento de afecciones asociadas con la actividad del receptor de lpa
WO2025043079A1 (fr) * 2023-08-23 2025-02-27 Lhotse Bio, Inc. Composés, compositions et procédés

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WO2019041340A1 (fr) * 2017-09-04 2019-03-07 Eli Lilly And Company Composés inhibiteurs du récepteur 1 de l'acide lysophosphatidique (lpar1)
AR128613A1 (es) * 2022-02-25 2024-05-29 Lhotse Bio Inc Compuestos y composiciones para el tratamiento de afecciones asociadas con la actividad del receptor de lpa

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