(19) TZZ _ _T (11) EP 2 462 128 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 261/14 (2006.01) C07D 413/04 (2006.01) 21.09.2016 Bulletin 2016/38 A61K 31/42 (2006.01) A61K 31/4427 (2006.01) A61P 11/06 (2006.01) A61P 35/00 (2006.01) (21) Application number: 10807045.9 (86) International application number: (22) Date of filing: 03.08.2010 PCT/US2010/044284 (87) International publication number: WO 2011/017350 (10.02.2011 Gazette 2011/06) (54) COMPOUNDS AS LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS VERBINDUNGEN ALS LYSOPHOSPHATIDSÄURE-REZEPTORANTAGONISTEN COMPOSÉS EN TANT QU’ANTAGONISTES DU RÉCEPTEUR DE L’ACIDE LYSOPHOSPHATIDIQUE (84) Designated Contracting States: (74) Representative: Reitstötter Kinzebach AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Patentanwälte GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Sternwartstrasse 4 PL PT RO SE SI SK SM TR 81679 München (DE) (30) Priority: 04.08.2009 US 231282 P (56) References cited: WO-A1-2004/031118 WO-A2-2009/011850 (43) Date of publication of application: US-A1- 2003 114 505 US-A1- 2006 194 850 13.06.2012 Bulletin 2012/24 • YAMAMOTO, T. ET AL.: ’Synthesis and (73) Proprietor: Amira Pharmaceuticals, Inc. evaluation of isoxazole derivatives as Princeton, NJ 08543 (US) lysophosphatidic acid (LPA) antagonists’ BIOORGANIC & MEDICINAL CHEMISTRY (72) Inventors: LETTERS vol. 17, 2007, pages 3736 - 3740, • HUTCHINSON, John, Howard XP022114572 San Diego • OHTA, H. ET AL.: ’Ki16425, a Subtype-Selective CA 92103 (US) Antoganist for EDG-Family Lysophosphatidic • SEIDERS, Thomas, Jon AcidReceptors’ MOLECULAR PHARMACOLOGY San Diego vol. 64, no. 4, 2003, pages 994 - 1005, CA 92109 (US) XP008151135 • WANG, Bowei Westfield Remarks: NJ 07090 (US) Thefile contains technical information submitted after the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 462 128 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 462 128 B1 Description FIELD OF THE INVENTION 5 [0001] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose dis- eases, disorders or conditions associated with one or more of the lysophosphatidic acid (LPA) receptors. US 2003/0114505 discloses isoxazole and thiazole compounds having an excellent lysophosphatidic acid receptor antagonistic activity. The compounds are therefore useful as a therapeutic or preventive agent for cell proliferative 10 diseases, inflammatory diseases, kidney diseases, and cerebral or peripheral nerve disorders. US 2006/0194850 dis- closes inter alia isoxazole compounds which inhibit the physiological LPA activity and are therefore useful for the proph- ylaxis and treatment of diseases involving the LPA receptor. BACKGROUND OF THE INVENTION 15 [0002] Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids affect fundamental cel- lular functions that include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogensis. These functions influence many biological processes that include, but are not limited to, neurogensis, angiogenesis, wound healing, fibrosis, immunity, and carcinogenesis. 20 [0003] Lysophosphatidic acid (LPA) is a lysophospholipid that has been shown to act through sets of specific G protein- coupled receptors (GPCRs) in an autocrine and paracrine fashion. LPA binding to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a variety of biological responses. Antag- onists of the LPA receptors find use in the treatment of diseases, disorders or conditions in which LPA plays a role. 25 SUMMARY OF THE INVENTION [0004] In one aspect, presented herein are compounds of Formula (III) that inhibit the physiological activity of lyso- phosphatidic acid (LPA), and therefore, are useful as agents for the treatment or prevention of diseases in which inhibition of the physiological activity of LPA is useful, such as diseases in which an LPA receptor participates, is involved in the 30 etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease. In a related aspect, such compounds are useful as agents for the treatment or prevention of side effects, complications, or adverse events associated with the use of a different therapeutic agent or therapeutic action (e.g., radiation, surgery, etc) used in treating a disease or condition. [0005] In one aspect, the compounds of Formula (III) are useful for the treatment of fibrosis of organs (liver, kidney, 35 lung, heart and the like), liver diseases (acute hepatatis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hyperten sion, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like), cell proliferative disease (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, and the like), inflammatory disease (psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract disease 40 (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the like), renal disease, urinary tract-associated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract, and the like), inflammatory disease of lower urinary tract, dysuria, frequent urination, and the like), pancreas disease, abnormal angiogenesis-associated disease (arterial obstruction and 45 the like), scleroderma, brain-associated disease (cerebral infarction, cerebral hemorrhage, and the like), neuropathic pain, peripheral neuropathy, and the like, ocular disease (age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, and the like). In one aspect, the compounds of Formula (III) are used in the treatment of fibrotic diseases or conditions. [0006] In one aspect, described herein are compounds of Formula (III) pharmaceutically acceptable salts, pharma- 50 ceutically acceptable solvates, and prodrugs thereof. Compounds of Formula (III) are antagonists of at least one of the LPA receptors selected from LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6. In one embodiment, compounds of Formula (III) are antagonists of LPA1. In one embodiment, compounds of Formula (III) are antagonists of LPA1 and/or LPA3. In some embodiments, compounds of Formula (III) are antagonists of LPA 1 and/or LPA 2.In some embodiments,compounds of Formula (III) are selective antagonists for one of the LPA receptors relative to the other LPA receptors. In some 55 embodiments, such a selective antagonist is selective for the LPA 1 receptor. [0007] Compounds of Formula (III) are used in the treatment of diseases, disorders, or conditions in which activation of at least one LPA receptor by LPA contributes to the symptomology or progression of the disease, disorder or condition. These diseases, disorders, or conditions may arise from one or more of a genetic, iatrogenic, immunological, infectious, 2 EP 2 462 128 B1 metabolic, oncological, toxic, surgical, and/or traumatic etiology. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of LPA receptors. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of LPA 1. [0008] In one aspect, provided herein is a compound of Formula (III), pharmaceutically acceptable salt, or pharma- 5 ceutically acceptable solvate thereof: 10 15 wherein 20 1 A A A is CH, CR or N; R is F, Cl, Br, I, -CH3, or -CF3; A4 is CH or N; 1 L is absent, C1-C4alkylene, C3-C6cycloalkylene or C3-C6cycloalkyleneC1-C4alkylene; 2 2 2 L is absent, C1-C4alkylene, C1-C4heteroalkylene, -O-, -S-, -SO-, -SO2-, -NR -, or -C(=O)-; R is H or -CH3; CY is substituted or unsubstituted C 3-C6cycloalkyl or a substituted or unsubstituted phenyl, wherein if CY is substi- 25 C C tuted then CY is substituted with R; R is F, Cl, Br, I, -OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, or C1-C4alkoxy. 1 [0009] In some embodiments, L is absent, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-,CH2CH2CH2-, cyclopropyl-1,1- diyl, cyclobutyl-1,1-diyl, cyclopentyl-1,1-diyl, cyclohexyl-1,1-diyl, or -C(CH2CH2)CH2-. 30 2 [0010] In some embodiments, L is absent, -CH 2-, -CH2O- -OCH 2-, -CH2S-, -SCH2-, -O-, or -S-. In some embodiments, L2 is absent. [0011] In some embodiments, A1 is CH. [0012] In some embodiments, A4 is CH. [0013] In some embodiments, CY is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a substituted or unsubstituted 35 pentenyl, a substituted or unsubstituted cyclohexenyl, or a substituted or unsubstituted phenyl; wherein if CY is substituted