USOO9346762B2

(12) United States Patent (10) Patent No.: US 9,346,762 B2 Nazare et al. (45) Date of Patent: May 24, 2016

(54) PYRAZOLE DERIVATIVES AND THEIR USE W 38: 28 3. A. 5.38: AS LPARSANTAGONSTS WO 2013171316 A1 11 2013 (71) Applicant: SANOFI, Paris (FR) OTHER PUBLICATIONS (72) Inventors: Marc Nazare, Frankfurt am Main (DE); Database Registry Chemical Abstracts Service, Columbus, Ohio, Detlef Kozian, Frankfurt am Main (DE); Accession No. RN 1280538-92-2, RN 1279877-48-3, RN 1279845 Andreas Evers, Frankfurt am Main 01-0, RN 1279842-08-8, RN 1279831-82-1, RN 1279830-96-4, and (DE); Werngard Czechtizky, Frankfurt RN 1279828-94-2, Entered STN: Apr. 14, 2011.* am Main (DE) Ito, Nobuyuki. Cancer Science 94(1), (2003) 3-8.* International Search Report for International Patent Application No. (73) Assignee: Sanofi, Paris (FR) PCT/EP2013/060171 dated Jun. 11, 2013 (mailed Jun. 27, 2013) p. 1-11. (*) Notice: Subject to any disclaimer, the term of this A. F. Littke et al., “Palladium-Catalyzed Coupling Reactions of Aryl Chlorides' Angew. Chem. Int. Ed. 2002, 41, 4176-4211. patent is extended or adjusted under 35 A. Padwa et al., “Reaction of Hydrazonyl Chlorides and U.S.C. 154(b) by 0 days. Carboalkoxymethylene Triphenylphosphoranes to Give 5-Alkoxy Substituted Pyrazoles' J. Heterocycl. Chem., 1987, 24, 1225-1227. (21) Appl. No.: 14/401,050 A. R. Mucietal, “Practical Palladium Catalysts for C N and C–O Bond Formation' Topics in current Chemistry 2002, 219, 131-209. (22) PCT Filed: May 16, 2013 A. Tunoori et al., “Polymer-Bound Triphenylphosphine as Traceless Reagent for Mitsunobu Reactions in Combinatorial Chemistry: Syn (86). PCT No.: PCT/EP2013/06O171 thesis of Aryl Ethers from Phenols and Alcohols' Tetrahedron Lett. 39 (1998) 8751-8754. S371 (c)(1), Amisten et al., “Gene expression profiling for the identification of (2) Date: Nov. 13, 2014 G-protein coupled receptors inhuman platelets' Thromb Res (2008), 122,47-57 (Oct. 24, 2007). (87) PCT Pub. No.: WO2013/171317 B. Yang et al. “Palladium-catalyzed amination of aryl halides and sulfonates' J. Organomet. Chem. 1999, 576, 125-146. PCT Pub. Date: Nov. 21, 2013 (Continued) (65) Prior Publication Data Primary Examiner — Samantha Shterengarts US 2015/O141477 A1 May 21, 2015 (74) Attorney, Agent, or Firm — McDonnell Boehnen (30) Foreign Application Priority Data Hulbert & Berghoff LLP (57) ABSTRACT May 18, 2012 (EP) ...... 12305552 The present invention relates to compounds of the formula (I), (51) Int. Cl. wherein the residues R' to R. V. GandM have the meanings CO7D 23L/2 (2006.01) indicated in the claims. The compounds of the formula (I) are CO7D 409/04 (2006.01) valuable pharmacologically active compounds for use in the CO7D 23L/56 (2006.01) treatment of diverse disorders, for example cardiovascular disorders like thromboembolic diseases or restenoses. The A6 IK3 L/45 (2006.01) compounds of the invention are effective antagonists of the (52) U.S. Cl. platelet LPA receptor LPAR5 (GPR92) and can in general be CPC ...... C07D 231/12 (2013.01); A61K31/415 applied in conditions in which an undesired activation of the (2013.01); C07D 231/56 (2013.01); C07D platelet LPA receptor LPAR5, the mast cell LPA receptor 409/04 (2013.01) LPAR5 or the microglia cell LPA receptor LPAR5 is present (58) Field of Classification Search or for the cure or prevention of which an inhibition of the CPC. C07D 231/12: C07D 231/56; C07D 409/04; platelet, mast cell or microglia cell LPA receptor LPAR5 is A61K 31/415 intended. The invention furthermore relates to processes for See application file for complete search history. the preparation of compounds of the formula (I), their use, in particular as active ingredients in medicaments, and pharma (56) References Cited ceutical compositions comprising them. U.S. PATENT DOCUMENTS

2008. O1946.17 A1 8, 2008 Tawaraishi (I)

FOREIGN PATENT DOCUMENTS

EP O382.276 A2 8, 1990 WO 2004022526 A1 3, 2004 WO 2009080227 A2 T 2009 WO 2009109613 A2 9, 2009 WO 2009109616 A2 9, 2009 WO 2009109618 A2 9, 2009 19 Claims, No Drawings US 9,346,762 B2 Page 2

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Chem. 1893, 276, 200-245. with Enamines—Regiospecific Synthesis of Highly Substituted Hartwig, J., Angew. Chem. Int. Ed. 1998, 37, 2046-2067. Dihydropyridines and Pyridines' Eur, J. Org. Chem., 2001, 2115 2122. * cited by examiner US 9,346,762 B2 1. 2 PYRAZOLE DERVATIVES AND THEIR USE grow to a Sufficient size to partly or completely block arterial AS LPARSANTAGONSTS blood vessels. Inveins thrombican also form in areas of stasis or slow blood flow. These venous thrombi can create emboli This application is a national stage application under 35 that travel through the circulatory system, as they easily U.S.C. S371 of International Application No. PCT/EP2013/ 5 detach portions of themselves. These traveling emboli can 060171, filed May 16, 2013, which claims priority of Euro block other vessels, such as pulmonary or coronary arteries, pean Application No. 12305552.7 filed on May 18, 2012, the which can result in the above-mentioned pathological out disclosure of which is explicitly incorporated by reference comes Such as pulmonary or coronary embolism. In Sum herein. mary, for venous thrombi, morbidity and mortality arise pri 10 marily after embolization or distant blockade of vessels, The present invention relates to pyrazole derivatives of the whereas arterial thrombi cause serious pathological condi formula I, tions by local blockade. Lysophosphatidic acid (LPA) is an important bioactive phospholipid with a wide range of cellular functions. Levels 15 of LPA are tightly regulated via its synthesis, controlled by R2 H. H R R5 two different pathways. The first consisting of phospholipase D (PLD) and phospholipase A2 (PLA) activity, the second consisting of PLA and lysophospholipase D (lysoPLD) -N-N2SRXX's- O activity. The most commonly used LPA in laboratory praxis is 18:1 LPA (1-acyl-2-hydroxy-sn-glycero-3-phosphate). How ever, many other forms of LPA exist in the organism, with wherein the residues R' to R. V. Gand M have the meanings varying length of the fatty acid chain, different Saturation indicated below. The compounds of the formula I are valuable grades and coupling of the fatty acid chain to the glycerol pharmacologically active compounds for use in the treatment backbone, i.e. coupling via an ester or ether bond (Choi et al., of diverse disorders. Compounds of the formula I exhibit a 25 Ann Rev Pharmacol Toxicol (2010), 50, 157-186). A key strong anti-aggregating effect on platelets and thus an anti enzyme for LPA synthesis is autotaxin (ATX), Enpp2 in mice. thrombotic effect and are suitable, for example, for the It has been shown that ATX has lysoPLD activity and that therapy and prophylaxis of cardiovascular disorders like Enpp2 mice die in utero at day 9.5. Enpp2" mice show thromboembolic diseases or restenoses. In addition, com reduced LPA plasma levels (van Meeteren et al., Mol Cell pounds of the formula I inhibit LPA-mediated activation of 30 Biol (2006), 26, 5015-5022). LPA exerts its extracellular mast cells and microglia cells. The compounds of the inven biological effects through binding to G protein-coupled tion are antagonists of the platelet LPA receptor LPAR5 receptors. So far, five different LPA receptors have been iden (GPR92) and can in general be applied in conditions in which tified, LPAR1 (EDG2), LPAR2 (EDG4), LPAR3 (EDG7), an undesired activation of the platelet LPA receptor LPAR5, LPAR4 (GPR23 and LPAR5 (GPR92). All described LPA the mast cell LPA receptor LPAR5 or the microglia cell LPA 35 receptors belong to the class A (Rhodopsin-like class) of G receptor LPAR5 is present or for the cure or prevention of protein-coupled receptors (GPCRs). which an inhibition of the platelet, mast cell or microglia cell LPAR5 has been identified in mouse and humandorsal root LPA receptor LPAR5 is intended. The invention furthermore ganglia and reduced perception of pain was seen in LPAR5 relates to processes for the preparation of compounds of the mice (Oh et al., J Biol Chem (2008), 283, 21054-21064; formula I, their use, in particular as active ingredients in 40 Kinlochet al., Expert Opin TherTargets (2005), 9, 685-698). medicaments, and pharmaceutical compositions comprising The coupling of LPARs to different G protein subunits in them. different cell types in concert with the differential expression In the industrialized world thrombotic complications are of the various LPA receptors on the same cell is the primary one of the major causes of death. Examples of conditions reason for the great variety of biological effects of LPA. The associated with pathological thrombus formation include 45 influence of LPA on the activation of human platelets has deep vein thrombosis, venous and arterial thromboembolism, been described in the early 1980s. 1-O-alkyl-sn-glycero-3- thrombophlebitis, coronary and cerebral arterial thrombosis, phosphate (an alkyl-LPA) has been identified to be a more cerebral embolism, renal embolism, pulmonary embolism, potent activator in platelets compared to oleoyl-LPA (Simon disseminated intravascular coagulation, transient ischemic et al., Biochem Biophys Res Commun (1982), 108, 1743 attacks, strokes, acute myocardial infarction, unstable angina, 50 1750). Further studies pointed out that the so-called alkyl chronic stable angina, peripheral vascular disease, preec LPA receptor is neither an EDG-type LPA receptor nor lampsiadeclampsia, and thrombotic cytopenic purpura. Also GPR23 (Tokumura et al., Biochem J. (2002), 365, 617-628; during or following invasive procedures, including insertion Noguchi et al., J Biol Chem (2003), 278, 25600-25606: of endovascular devices and protheses, carotid endarterec Khandoga et al., JThromb Haemost (2007), 5 Supplement 2: tomy, angioplasty, CABG (coronary artery bypass graft) Sur 55 P-M-246 (ISTH 2007)). When transiently expressed in the rat gery, vascular graft Surgery, and stent placements, thrombotic hepatoma cell line RH7777, LPAR5 can be activated more and restenotic complications could occur. strongly with alkyl-LPA than acyl-LPA (Williams et al., J Platelet aggregation plays a critical role in these intravas Biol Chem (2009), 284, 14558-14571). These data were in cular thrombotic events. Platelets can be activated by media line with the LPA-mediated activation observed for human tors released from circulating cells and damaged endothelial 60 blood platelets, in which the functional effect of alkyl-LPA, in cells lining the vessel or by exposed subendothelial matrix terms of inducing platelet aggregation is more pronounced molecules Such as collagen, lysophosphatidic acid or by than the effect of acyl-LPA. In addition, the LPA-receptors thrombin, which is formed in the coagulation cascade. Fol LPAR4 and LPAR5 are highly expressed by human platelets lowing activation, platelets, which normally circulate freely (Amisten et al., Thromb Res (2008), 122, 47-57). In contrast in the vasculature, and other cells, accumulate at the site of a 65 to LPAR5, which is coupled to G, LPAR4 couples to G, and vessel injury to form a thrombus and recruit more platelets to can therefore be excluded to participate in LPA-mediated the developing thrombus. During this process, thrombi can activation of human platelets. Consequently, LPAR5 was dis US 9,346,762 B2 3 4 cussed to be the central LPA-receptor responsible for LPA view of the relevance of LPAR5 for various disease states mediated activation in human platelets (Khandoga et al., there is a need for compounds which efficiently inhibit Platelets (2008), 19, 415-427). High expression of LPAR5 in LPAR5 and, for example, consequently inhibit mast cell acti human mast cell lines has been demonstrated, for example by Vation, for example in atherosclerotic plaques, or platelet Lundequist (Lundequist, J Allergy Clin Immunol (2008), activation in pathological settings, and allow novel therapeu 121, Suppl 1, Abstr 518), and further analyses. tic options for treating disorders. Thus, it is an object of the Mast cells are part of the immune system and generated as present invention to provide LPAR5 antagonists, which precursor cells in the bone marrow, differentiating to mature antagonize the effect of endogenous LPA on its LPAR5 recep mast cells in the homing tissue. Mast cells participate in a tor and which have further advantageous properties, for variety of pathophysiological processes that range from anti 10 microbial defense to anaphylaxis and inflammatory arthritis instance stability in plasma and liver and selectivity versus and have thus been discussed to be related to allergic other receptors whose agonism orantagonism is not intended. responses. When activated, mast cells degranulate and release This object is achieved in accordance with the invention by a plethora of mediators (cytokines such as TNFa. MCP-1, providing the pyrazole derivatives of the formula I, which Rantes) into the interstitium. This indicates a direct contribu 15 exhibit excellent LPAR5 antagonistic activity and are favor tion of mast cells to neuropathic pain by releasing algogenic able agents with high bioavailability, and can be used for mediators after degranulation. inhibiting platelet aggregation and treating thromboembolic Atherosclerosis is promoted by mast cells not only through diseases, for example. the release of proinflammatory cytokines, mast cell defi Further WO 2011/015501, WO 2009/109613, WO 2009/ ciency attenuates atherosclerosis in apolipoprotein E-defi 1096.16, WO 2009/109618 and EP 0382276 describe specific cient mice and infiltrates of activated mast cells can be 1-benzyl-indazole derivatives for the treatment of diseases observed at the site of coronary atheromatous erosion or based on the expression of MCP-1, CX3CR1 and p40. rupture in myocardial infarction (Sun et al., Nat Med (2007), GuoGang Tu et al. Journal of Enzyme Inhibition and Medici 13, 719-724; Smith et al., FASEB J (2008), 22, 1065.32: nal Chemistry, 2011, 26(2), 222-230 describe some com Kovanen et al., Circulation (1995), 92, 1084-1088). These 25 pounds derived from the 1,5-diarylpyrazole scaffold with data provide sound evidence for the central role of mast cells potency towards the inhibition of the CBI receptor. Self C. R. in the development and progression of atherosclerotic et al, Journal of Medicinal Chemistry, 1991, 34, 772-777 plaques. In the atherosclerotic plaque mast cells contribute to disclose potential disease-modifying antirheumatic drugs plaque growth and instability via release of stored and newly including specific 1-phenyl-pyrazole derivatives. synthesized mediators such as (a) inflammatory cytokines 30 A subject of the present invention are the compounds of the that lead to an increased invasion of monocytes and their formula I, in any of their stereoisomeric forms or a mixture of differentiation to macrophages, (b) angiogenic cytokines stereoisomeric forms in any ratio, and the pharmaceutically Such as VEGF that might induce angiogenesis in the plaque, acceptable salt thereof, with intraplaque hemorrhage leading to an increased risk of plaque rupture and (c) histamine, a vasoactive component 35 known to enhance vascular permeability with the potential risk of increased LDL influx available for foam cell forma tion. Although the absolute number of mast cells in athero sclerotic plaques is inferior to the number of other inflamma tory cells in the same region, LPA as a direct activating ligand 40 of mast cells is present at high concentrations in atheroscle rotic plaques (Rother et al., Circulation (2003), 108, 741 747). wherein Apart from the above discussed role of mast cells in ath R" is selected from the series consisting of hydrogen, (C- erosclerosis, the broad spectrum of mast cell functions 45 C)-alkyl, (C-C)-cycloalkyl, (C-C)-cycloalkyl-(C- explains why mast cells are involved in a variety of patholo Cl)-alkyl-, Ar and Ar—(C-C)-alkyl-, gies apart from allergic responses related to pathologies with R° and Rare independently of each other selected from the an inflammatory component. These diseases comprise hype series consisting of hydrogen, halogen, (C-C)-alkyl, (C- ralgesia, asthma, multiple Sclerosis and angiogenesis to name Cz)-cycloalkyl, (C-C,)-cycloalkyl-(C-C)-alkyl-, Ar. only a few (Zuo et al., Pain (2003), 105,467-479; Toews et al., 50 Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, (C-C)-cy Biochim Biophys Acta (2002), 1582, 240-250; Norby, cloalkyl-O , (C-C)-cycloalkyl-(C-C)-alkyl-O-, APMIS (2002), 110,355-371). Treatment of the human mast Ar—O— and Ar—(C-C)-alkyl-O , cell line LAD2 with a short hairpin RNA targeting LPAR5 R" and Rare independently of each other selected from the down-regulates LPAR5 expression and attenuates MIP-1B series consisting of hydrogen, fluorine and (C-C)-alkyl, following LPA activation (Lundequist, J Allergy Clin Immu 55 or the groups RandR together with the carbonatom carry nol (2008), 121, Suppl 1, Abstr 518). ing them forma (C-C,)-cycloalkane ring which is unsub Analyses of the LPA receptor profile in the murine micro stituted or substituted by one or more identical or different glia cell line BV-2, confirmed a high expression of LPAR5 in substituents selected from the series consisting of fluorine microglia cells, which are like mast cells a cell population of and (C-C)-alkyl; the inflammatory system. The finding that LPAR5 is highly 60 R'', R', RandR'' are independently of each other selected expressed not only in mast cells but as well in microglia cells from the series consisting of hydrogen and (C-C)-alkyl: underlines the central role of LPAR5 in the development and Ar is selected from the series consisting of phenyl, naphthyl progression of inflammatory disorders. Such as hyperalgesia, and an aromatic, 5-membered or 6-membered, monocyclic asthma, multiple Sclerosis, angiogenesis and others. heterocycle which comprises one or two identical or dif Further experiments confirmed that in human platelets and 65 ferent ring heteroatoms selected from the series consisting in human mast cells and microglia cells LPAR5 is the key of N, O and S, which are all unsubstituted or substituted by LPA-receptor responsible for LPA-mediated activation. In one or more identical or different substituents selected US 9,346,762 B2 5 6 from the series consisting of halogen, (C-C)-alkyl, (C- and all stereoisomeric forms and mixtures of stereoisomeric Cz)-cycloalkyl, (C-C2)-cycloalkyl-(C-C)-alkyl-, cyano forms in any ratio, and the pharmaceutically acceptable salts and (C-C)-alkyl-O-, thereof. V is selected from the series consisting of R' N(R') , In another embodiment the present invention relates to and in this case G and Mare not present, compounds of the formula I, wherein O R" is selected from the series consisting of (C-C)-alkyl, V is selected from the series consisting of N(R') , (C-C2)-cycloalkyl, Arand Ar—(C-C)-alkyl-, —N(R')–(C-C)-alkyl-, -O- and —O—(C-C)- R° and Rare independently of each other selected from the alkyl-, and in this case series consisting of hydrogen, (C-C)-alkyl, Ar. Ar—(C- 10 Cl)-alkyl-, (C-C)-alkyl-O-, (C-C)-cycloalkyl-O-, G is selected from the series consisting of a direct bond and Ar—O— and Ar—(C-C)-alkyl-O , phenylene which is unsubstituted or substituted by one or R" and Rare independently of each other selected from the more identical or different substituents selected from the series consisting of hydrogen and (C-C)-alkyl, series consisting of halogen, (C-C)-alkyl, cyano and (C- or the groups RandR together with the carbon atom carry C.)-alkyl-O-, provided that G is not a direct bond if V is 15 ing them forma (C-C)-cycloalkane ring which is unsub - N(R')—or —O , and stituted or substituted by one or more identical or different M is selected from the series consisting of R''-O-C(O)— substituents selected from the series consisting of fluorine and R' N(R') C(O) ; and (C-C)-alkyl; wherein all alkyl groups are unsubstituted or substituted by R'', R', RandR'' are independently of each other selected one or more fluorine Substituents, and all cycloalkyl groups from the series consisting of hydrogen and (C-C)-alkyl, are unsubstituted or substituted by one or more identical or Ar is selected from the series consisting of phenyl, naphthyl different substituents selected from the series consisting of and an aromatic, 5-membered or 6-membered, monocyclic fluorine and (C-C)-alkyl. heterocycle which comprises one or two identical or dif In one embodiment the present invention relates to com ferent ring heteroatoms selected from the series consisting pounds of the formula I, wherein 25 of N, O and S, which are all unsubstituted or substituted by R" is selected from the series consisting of hydrogen, (C- one or more identical or different substituents selected C)-alkyl, (C-C)-cycloalkyl, Arand Ar—(C-C)-alkyl-, from the series consisting of halogen, (C-C)-alkyl, (C- R° and Rare independently of each other selected from the Cz)-cycloalkyl and (C-C)-alkyl-O-: series consisting of hydrogen, (C-C)-alkyl, (C-C2)-cy V is selected from the series consisting of N(R') and cloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, Ar, Ar—(C- 30 —N(R')—(C-C)-alkyl-, and Cl)-alkyl-, (C-C)-alkyl-O-, (C-C7)-cycloalkyl-O , G is selected from the series consisting of a direct bond and phenylene which is unsubstituted or substituted by one or (C-C)-cycloalkyl-(C-C)-alkyl-O-, Ar—O— and more identical or different substituents selected from the Ar—(C-C)-alkyl-O , series consisting of halogen, (C-C)-alkyl and (C-C)- R" and Rare independently of each other selected from the 35 alkyl-O-, provided that G is not a direct bond if V is series consisting of hydrogen and (C-C)-alkyl, -N(R')—, and or the groups RandR together with the carbonatom carry M is selected from the series consisting of R'-O-C(O)— ing them forma (C-C)-cycloalkane ring which is unsub and R' N(R') C(O) ; stituted or substituted by one or more identical or different wherein all alkyl groups are unsubstituted or substituted by substituents selected from the series consisting of fluorine 40 one or more fluorine Substituents, and all cycloalkyl groups and (C-C)-alkyl; are unsubstituted or substituted by one or more identical or R'', R', RandR'' are independently ofeach other selected different substituents selected from the series consisting of from the series consisting of hydrogen and (C-C)-alkyl; fluorine and (C-C)-alkyl; Ar is selected from the series consisting of phenyl, naphthyl and all stereoisomeric forms and mixtures of stereoisomeric and an aromatic, 5-membered or 6-membered, monocyclic 45 form in any ratio, and the pharmaceutically acceptable salts heterocycle which comprises one or two identical or dif thereof. ferent ring heteroatoms selected from the series consisting In another embodiment the present invention relates to of N, O and S, which are all unsubstituted or substituted by compounds of the formula I, wherein one or more identical or different substituents selected R" is selected from the series consisting of (C-C)-alkyl, Ar from the series consisting of halogen, (C-C)-alkyl, (C- 50 and Ar—(C-C)-alkyl-, Cz)-cycloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, cyano R° and Rare independently of each other selected from the and (C-C)-alkyl-O-, series consisting of hydrogen, (C-C)-alkyl, Ar. Ar—(C- V is selected from the series consisting of N(R') , Cl)-alkyl-, and Ar—O—, —N(R')–(C-C)-alkyl- and —O—(C-C)-alkyl-, and R" and Rare independently of each other selected from the G is selected from the series consisting of a direct bond and 55 series consisting of hydrogen and (C-C)-alkyl, phenylene which is unsubstituted or substituted by one or or the groups RandR together with the carbon atom carry more identical or different substituents selected from the ing them forma (C-C)-cycloalkane ring which is unsub series consisting of halogen, (C-C)-alkyl, cyano and (C- stituted or substituted by one or more identical or different Cl)-alkyl-O provided that G is not a direct bond if V is substituents selected from the series consisting of fluorine - N(R')—, and 60 and (C-C)-alkyl; M is selected from the series consisting of R''—O C(O)— R'' and R'' are independently of each other selected from the and R' N(R') C(O) ; series consisting of hydrogen and (C-C)-alkyl; wherein all alkyl groups are unsubstituted or substituted by Ar is selected from the series consisting of phenyl, naphthyl one or more fluorine Substituents, and all cycloalkyl groups and an aromatic, 5-membered or 6-membered, monocyclic are unsubstituted or substituted by one or more identical or 65 heterocycle which comprises one or two identical or dif different substituents selected from the series consisting of ferent ring heteroatoms selected from the series consisting fluorine and (C-C)-alkyl; of N, O and S, which are all unsubstituted or substituted by US 9,346,762 B2 7 8 one or more identical or different substituents selected embodiment R' is Ar, wherein all Argroups are unsubstituted from the series consisting of halogen, (C-C)-alkyl, (C- or substituted as specified. In one embodiment an Ar—(C- Cz)-cycloalkyl and (C-C)-alkyl-O-, Cl)-alkyl-group representing R' is an Ar—(C-C)-alkyl V is selected from the series consisting of N(R') and group, in another embodiment an Ar—CH2— group. In one N(R')—(C-C)-alkyl-, and embodiment a group Ar representing R' is a phenyl group G is selected from the series consisting of a direct bond and which is unsubstituted or substituted as specified. In one phenylene which is unsubstituted or substituted by one or embodiment, a Substituted Argroup or phenyl group repre more identical or different substituents selected from the senting R' is substituted by one, two or three, in another series consisting of halogen, (C-C)-alkyl and (C-C)- embodiment by one or two, in another embodiment by one, alkyl-O-, provided that G is not a direct bond if V is 10 identical or different substituents, wherein in one embodi - N(R'), and ment the Substituents are selected from the series consisting M is R''-O-C(O)–: of halogen, (C-C)-alkyl, cyano and (C-C)-alkyl-O-, in wherein all alkyl groups are unsubstituted or substituted by another embodiment from the series consisting of halogen, one or more fluorine Substituents, and all cycloalkyl groups (C-C)-alkyl and cyano, in another embodiment from the are unsubstituted or substituted by one or more identical or 15 series consisting of halogen, (C-C)-alkyl and (C-C)- different substituents selected from the series consisting of alkyl-O-, in another embodiment from the series consisting fluorine and (C-C)-alkyl; of halogen and (C-C)-alkyl, and in another embodiment and all stereoisomeric forms and mixtures of stereoisomeric they are identical or different halogen substituents, for forms in any ratio, and the pharmaceutically acceptable salts example chlorine. thereof. In one embodiment compounds of the formula I are defined In another embodiment the present invention relates to as above and R and R are independently of each other compounds of the formula I, wherein selected from the series consisting of hydrogen, halogen, R" is selected from the series consisting of (C-C)-alkyl, Ar (C-C)-alkyl, Ar. Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, and Ar—(C-C)-alkyl-, Ar—O— and Ar—(C-C)-alkyl-O-, in another embodi R° and Rare independently of each other selected from the 25 ment from the series consisting of hydrogen, (C-C)-alkyl, series consisting of hydrogen, (C-C)-alkyl, Ar— and Ar, Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, Ar—O— and Ar—O—, Ar—(C-C)-alkyl-O-, in another embodiment from the R" and Rare independently of each other selected from the series consisting of hydrogen, (C-C)-alkyl, Ar., Ar—(C- series consisting of hydrogen and (C-C)-alkyl, Cl)-alkyl- and Ar—O—, in another embodiment from the or the groups RandR together with the carbon atom carry 30 series consisting of (C-C)-alkyl, Ar. Ar—(C-C)-alkyl ing them forma (C-C)-cycloalkane ring which is unsub and Ar—O , in another embodiment from the series con stituted or substituted by one or more fluorine substituents: sisting of hydrogen, (C-C)-alkyl, Ar and Ar—O—, in R'' and R'' are independently of each other selected from the another embodiment from the series consisting of (C-C)- series consisting of hydrogen and (C-C)-alkyl; alkyl, Ar and Ar—O—, in another embodiment from the Ar is selected from the series consisting of phenyl, naphthyl 35 series consisting of hydrogen, (C-C)-alkyl and Ar, in and an aromatic, 5-membered or 6-membered, monocyclic another embodiment from the series consisting of (C-C)- heterocycle which comprises one or two identical or dif alkyland Ar, wherein all groups Aroccurring in R and Rare ferent ring heteroatoms selected from the series consisting unsubstituted or substituted as specified. of N, O and S, which are all unsubstituted or substituted by In one embodiment, one of the groups RandR is group one or more identical or different substituents selected 40 Aror contains a group Ar, and the other of the groups R and from the series consisting of halogen, (C-C)-alkyl, (C- R is selected from the series consisting of hydrogen, (C- Cz)-cycloalkyl and (C-C)-alkyl-O-: Cl)-alkyl and Ar, in another embodiment from the series V is selected from the series consisting of N(R') and consisting of (C-C)-alkyl and Ar, in another embodiment - N(R')–(C-C)-alkyl-, and from the series consisting of hydrogen and (C-C)-alkyl. In G is selected from the series consisting of a direct bond and 45 one embodiment, a group Aroccurring in R or R is selected phenylene which is unsubstituted or substituted by one or from the series consisting of phenyl, naphthyl and an aro more identical or different substituents selected from the matic, 5-membered or 6-membered, monocyclic heterocycle series consisting of halogen, (C-C)-alkyl and (C-C)- which comprises one ring heteroatom selected from the series alkyl-O-, provided that G is not a direct bond if V is consisting of N, O and S. in another embodiment from the - N(R'), and 50 series consisting of phenyl and an aromatic, 5-membered or M is R'-O-C(O)–: 6-membered, monocyclic heterocycle which comprises one wherein all alkyl groups are unsubstituted or substituted by ring heteroatom selected from the series consisting of N, O one or more fluorine substituents; and S. in another embodiment from the series consisting of and all stereoisomeric forms and mixtures of stereoisomeric phenyl, naphthyl and thienyl, in another embodiment from forms in any ratio, and the pharmaceutically acceptable salts 55 the series consisting of phenyl and thienyl, in another thereof. embodiment from the series consisting of phenyl and naph In one embodiment compounds of the formula I are defined thyl, and in another embodiment it is a phenyl group, which as above and R' is selected from the series consisting of are all unsubstituted or substituted as specified. In one (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-cycloalkyl-(C- embodiment, the number of substituents in a substituted Cl)-alkyl-, Ar and Ar—(C-C)-alkyl-, in another embodi 60 group Aroccurring in R or R is one, two or three, in another ment from the series consisting of (C-C)-alkyl, Ar and embodiment it is one or two, in another embodiment it is one. Ar—(C-C)-alkyl-, in another embodiment from the series In one embodiment, the Substituents on a Substituted group Ar consisting of (C-C)-alkyl, Ar and Ar—(C-C)-alkyl-, in occurring in R or Rare selected from the series consisting of another embodiment from the series consisting of (C-C)- halogen, (C-C)-alkyl, (C-C)-cycloalkyl, cyano and (C- alkyl and Ar, in another embodiment from the series consist 65 Cl)-alkyl-O-, in another embodiment from the series con ing of (C-C)-alkyl and Ar, in another embodiment from the sisting of halogen, (C-C)-alkyl, (C-C)-cycloalkyl and series consisting of Ar and Ar—(C-C)-alkyl-, in another (C-C)-alkyl-O-, in another embodiment from the series US 9,346,762 B2 9 10 consisting of halogen and (C-C)-alkyl, wherein (C-C)- series consisting of N, O and S, in another embodiment one alkyl substituents are unsubstituted or substituted by one or ring heteroatom selected from the series consisting of N, O more fluorine Substituents. In one embodiment, a (C-C)- and S, and in another embodiment Ar is phenyl, which are all alkyl substituent present on a group Ar occurring in R or R unsubstituted or substituted by one or more identical or dif is a perfluoroalkyl group, for example a trifluoromethyl group ferent substituents selected from the series consisting of halo CF. in one embodiment, halogen Substituents present on a gen, (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-cycloalkyl group Ar occurring in R or R are fluorine and/or chlorine (C-C)-alkyl-, cyano and (C-C)-alkyl-O-, in another Substituents. embodiment from the series consisting of halogen, (C-C)- In one embodiment compounds of the formula I are defined alkyl, (C-C)-cycloalkyl, cyano and (C-C)-alkyl-O-, in as above and R and R are independently of each other 10 another embodiment from the series consisting of halogen, selected from the series consisting of hydrogen, fluorine and (C-C)-alkyl, (C-C)-cycloalkyl and (C-C)-alkyl-O-, in (C-C)-alkyl, in another embodiment from the series con another embodiment from the series consisting of halogen, sisting of hydrogen and (C-C)-alkyl, in another embodi (C-C)-alkyl and (C-C)-alkyl-O-, in another embodi ment from the series consisting of hydrogen and (C-C)- ment from the series consisting of halogen, (C-C)-alkyl and alkyl, in another embodiment from the series consisting of 15 (C-C)-cycloalkyl, in another embodiment from the series hydrogen, methyl, ethyl, n-propyl and isopropyl, in another consisting of halogen and (C-C)-alkyl, wherein alkyl Sub embodiment from the series consisting of hydrogen and stituents can be unsubstituted or substituted by one or more methyl, and in another embodiment at least one of the groups fluorine Substituents. In one embodiment, a Substituted group RandR is different from hydrogen, or the groups RandR Arcarries one, two or three identical or different substituents, together with the carbon atom carrying them forma (C-C)- in another embodiment one or two identical or different sub cycloalkane ring, in one embodiment a (C-C)-cycloalkane stituents, in another embodiment one Substituent, wherein all ring, in another embodiment a (C-C)-cycloalkane ring, groups Arare independent of each other. which cycloalkanerings are all unsubstituted or Substituted as If the divalent group V is the group —N(R') (C-C)- specified. alkyl- or the group —O—(C-C)-alkyl-, the group G is In another embodiment compounds RandR are indepen 25 bonded to the (C-C)-alkyl moiety thereof. In one embodi dently of each other selected from the series consisting of ment compounds of the formula I are defined as above and V hydrogen, fluorine and (C-C)-alkyl, in another embodiment is selected from the series consisting of N(R')— and from the series consisting of hydrogen and (C-C)-alkyl, in N(R')—(C-C)-alkyl-, and in this case G is selected from another embodiment from the series consisting of hydrogen the series consisting of a direct bond and phenylene, and in and (C-C)-alkyl, in another embodiment from the series 30 another embodiment is phenylene, wherein all phenylene consisting of hydrogen, methyl, ethyl, n-propyl and isopro groups are unsubstituted or substituted by one or more iden pyl, in another embodiment from the series consisting of tical or different substituents selected from the series consist hydrogen and methyl. ing of halogen, (C-C)-alkyl, cyano and (C-C)-alkyl-O-, In one embodiment one of the groups RandR is hydro provided that G is not a direct bond if V is N(R')—, and M gen and the other is as defined, in another embodiment the 35 is R'—O C(O) , in another embodiment HO C(O)—. groups Rand Rare both hydrogen, in another embodiment In another embodiment compounds of the formula I are at least one of the groups RandR is different from hydro defined as above and V is selected from the series consisting gen, in another embodiment the groups R and Rare both of R' N(R')—and in this case G and Mare not present. (C-C)-alkyl, in another embodiment the groups RandR In another embodiment, V is selected from the series con are both (C-C)-alkyl, and in another embodiment the 40 sisting of N(R') , N(R') (C-C)-alkyl-, -O- groups RandR are both selected from the series consisting and —O—(C-C)-alkyl-, in another embodiment from the of methyl, ethyl, n-propyl and isopropyl. In one embodiment, series consisting of N(R')— and N(R')—(C-C)- the groups Rand Rare identical. alkyl-, in another embodiment from the series consisting of In another embodiment RandR form together with the - N(R')—and N(R')–(C-C)-alkyl-, and in this case carbon atom carrying them a (C-C)-cycloalkane ring, in 45 G is selected from the series consisting of a direct bond and another embodiment a (C-C)-cycloalkane ring, in another phenylene, and in one embodiment is phenylene, wherein all embodiment a (C-C)-cycloalkane ring, which cycloalkane phenylene groups are unsubstituted or Substituted as speci rings are all unsubstituted or Substituted as specified. In gen fied, provided that G is not a direct bond if V is N(R')—or eral is the number of substituents in a substituted cycloalkane -O-, and M is R''-O-C(O)– or R'? N(R') C ring formed by R and R together with the carbon atom 50 (O) , in another embodiment R''-O-C(O) , in another carrying them in one embodiment of the invention one, two, embodiment HO C(O)—. three or four, in another embodiment one, two or three, in In one embodiment, G is a direct bond, in another embodi another embodiment one or two, and in another embodiment ment G is phenylene which is unsubstituted or substituted as a cycloalkane ring formed by R and R together with the specified. In one embodiment, a Substituted phenylene group carbon atom carrying them is unsubstituted. 55 representing G carries one or two identical or different sub In one embodiment compounds of the formula I are defined stituents, in another embodiment it carries one Substituent, as above and R', R', RandR'' are independently of each which is selected from the series consisting of halogen and other selected from the series consisting of hydrogen, methyl (C-C)-alkyl, and in another embodiment is halogen. In one and ethyl, in another embodiment from the series consisting embodiment a phenylene group representing G is unsubsti of hydrogen and methyl, and in another embodiment they are 60 tuted. In one embodiment, a phenylene group representing G hydrogen. is selected from the series consisting of 1,3-phenylene and In one embodiment compounds of the formula I are defined 1,4-phenylene, in another embodiment it is 1.4-phenylene. as above and Ar is selected from the series consisting of The group M-G-V C(O) C(R)(R)-O CH in phenyl and naphthyl, in another embodiment from the series the compounds of the formula I can be bonded to any of the consisting of phenyland an aromatic, 5-membered or 6-mem 65 ring carbon atoms of the 1H-pyrazole ring depicted in for bered, monocyclic heterocycle which comprises one or two mula I, i.e. in position 3, in position 4 or in position 5 of the identical or different ring heteroatoms selected from the 1H-pyrazole ring, as is symbolized by the free bond on the US 9,346,762 B2 11 12 CH moiety of the said group, which bond is not directed to a 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me specific ring carbon atom. In one embodiment of the inven thyl-1H-pyrazol-3-ylmethoxy-propionylamino-me tion, the group M-G-V C(O) C(R)(R)—O CH is thyl)-benzoic acid, bonded in position 3 of the pyrazole ring and the compound of 4-2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluorom the formula I thus is a compound of the formula Ia, in another 5 ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propiony embodiment the said group is bonded in position 4 of the lamino-benzoic acid, pyrazole ring and the compound of the formula I thus is a 4-2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me compound of the formula Ib, and in another embodiment the thyl-1H-pyrazol-3-ylmethoxy-3-methyl-butyrylamino said group is bonded in position 5 of the pyrazole ring and the benzoic acid, 10 4-2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl compound of the formula I thus is a compound of the formula phenyl)-1H-pyrazol-3-ylmethoxy)-propionylamino-ben Ic, in another embodiment the said group is bonded in posi Zoic acid, tion 3 or position 4, in another embodiment the said group is 4-2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-yl bonded in position3 or position5, and in another embodiment methoxy)-propionylamino-benzoic acid, the said group is bonded in position 4 or position 5. 15 4-2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl phenyl)-1H-pyrazol-3-ylmethoxy)-propionylamino-ben Zoic acid, Ia 4-2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)- H H R R5 propionylamino-benzoic acid, 2 N 3 V. M 4-2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propiony R-NAS-X-X-S- D3 lamino-benzoic acid, 2\a.JR O 4-2-1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol-4-yl 5 R2 methoxy)-propionylamino-benzoic acid, Ib 4-2-5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H-pyra 25 Zol-4-ylmethoxy-propionylamino-benzoic acid, H H R R5 4-2-3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4-yl x2 V.N, 1 M methoxy)-propionylamino-benzoic acid, N 4- 3 X- G 4-2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethoxy)- N- ff/ R O propionylamino-benzoic acid, and A RI 30 4-2-(1.5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propiony Ic lamino-benzoic acid, H H R R5 and all stereoisomeric forms and mixtures of stereoisomeric R3 V. M forms in any ratio, and the pharmaceutically acceptable salts R. MS N, 1 thereof. 35 If structural elements such as groups or Substituents, for N N O N1 NRI example alkyl, cycloalkyl or Ar groups, can occur several times in the compounds of the formula I, they are all inde pendent of each other and can in each case have any of the Likewise can the groups RandR in the compounds of the indicated meanings, and they can in each case be identical to formula I as well as in the compounds of the formulae Ia, Ib 40 or different from any other such element. and Ic be bonded to any ring carbon atom of the pyrazole ring The term alkyl is to be understood as meaning a residue of depicted in formula I which is not occupied by the group a saturated acyclic hydrocarbon which can be linear, i.e. M-G-V C(O) C(R)(R)-O-CH , i.e. in positions 3 straight-chain, or branched. If not otherwise defined, alkyl and 4, in positions 3 and 5 or in positions 4 and 5 of the has 1 to 6 carbon atoms or 1 to 4 carbon atoms. Examples of pyrazole ring. The groups R' to R. V. G and M in the com 45 (C-C)-alkyland (C-C)-alkyl are alkyl residues containing pounds of the formula Ia, Ib and Ic are defined as in the 1, 2, 3, 4, 5 or 6 carbon atoms or 1, 2, 3 or 4 carbon atoms, compounds of the formula I. respectively, including methyl, ethyl, propyl, butyl, pentyl In one embodiment of the invention, the compound of the and hexyl, the n-isomers of these residues, isopropyl, isobu formula I is selected from the series consisting of tyl, 1-methylbutyl, isopentyl, neopenty1, 2,2-dimethylbutyl, 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me 50 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-bu thyl-1H-pyrazol-3-ylmethoxy-2-methyl-propiony tyl and tert-pentyl. All these statements also apply if an alkyl lamino-methyl)-benzoic acid, group is Substituted or occurs as a Substituent on another 4-(2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluorom residue, for example in an alkyl-O-residue (alkyloxy residue, ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-pro alkoxy residue), an alkyl-O-C(O)— residue (alkyloxycar pionylamino-methyl)-benzoic acid, 55 bonyl residue) or an aryl-alkyl- residue. 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me Alkyl groups can in general, independently of any other thyl-1H-pyrazol-3-ylmethoxy-acetylamino-methyl)- Substituents which an alkyl groups carries, be unsubstituted benzoic acid, or substituted by one or more fluorine substituents, for 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me example by one, two, three, four or five fluorine substituents, thyl-1H-pyrazol-3-ylmethoxy-butyrylamino-methyl)- 60 or by one, two or three fluorine substituents. Such fluorine benzoic acid, Substituted alkyl group can also be perfluoroalkyl groups, i.e. 4-(2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl alkyl groups in which all hydrogen atoms are replaced by phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propiony fluorine atoms. Examples of fluorine-substituted alkyl groups lamino-methyl)-benzoic acid, are —CF, —CHF, —CHF and —CF, CF, of which 4-(2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl 65 —CF and —CF, CFs are examples of perfluoroalkyl phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propiony groups. In one embodiment, an alkyl group in any occurrence, lamino-methyl)-benzoic acid, independently of other occurrences, and independently of any US 9,346,762 B2 13 14 other Substituents which the alkyl groups carries, is not Sub ologically acceptable and pharmaceutically utilizable salts. stituted by fluorine, in another embodiment it is substituted by Such salts of compounds of the formula I containing acidic fluorine. groups, for example a carboxyl group COOH, are for example The term (C-C)-cycloalkyl is to be understood as mean alkali metal salts or alkaline earth metal salts such as sodium ing a residue of a saturated cyclic hydrocarbon cycle contain salts, potassium salts, magnesium salts and calcium salts, and ing from 3 to 7 ring carbon atoms in a monocyclic ring. also salts with pharmaceutically acceptable quaternary Examples of (C-C2)-cycloalkyl are cycloalkyl residues con ammonium ions such as tetramethylammonium or tetraethy taining 3, 4, 5, 6 or 7 ring carbon atoms like cyclopropyl. lammonium, and acid addition salts with ammonia and phar cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. All maceutically acceptable organic amines. Such as methy cycloalkyl groups can be unsubstituted or Substituted by one 10 lamine, dimethylamine, trimethylamine, ethylamine, or more, for example one, two, three or four, identical or triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. different substituents selected from the series consisting of Basic groups contained in the compounds of the formula I fluorine and (C-C)-alkyl. In one embodiment, a cycloalkyl form acid addition salts, for example with inorganic acids group is not substituted by fluorine and/or alkyl. Such as hydrochloric acid, hydrobromic acid, Sulfuric acid, The term (C-C)-cycloalkane, which refers to the group 15 nitric acid or phosphoric acid, or with organic carboxylic which can be formed by R and R together with the carbon acids and Sulfonic acids such as formic acid, acetic acid, atom carrying them, is to be understood as meaning a cyclo oxalic acid, citric acid, lactic acid, malic acid. Succinic acid, propane, cyclobutane, cyclopentane, cyclohexane or cyclo malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric heptane ring one ring carbon atom of which, which is the acid, methanesulfonic acid or p-toluenesulfonic acid. Com carbonatom depicted informula I which carries the groups R' pounds of the formula I which simultaneously contain a basic and R. is bonded to the adjacent oxygen atom and C(O) group and an acidic group, can also be present as Zwitterions group depicted in formula I. (betaines), which are likewise included in the present inven The term Ar is to be understood as meaning phenyl, naph tion. thyl or a residue of an aromatic, 5-membered or 6-membered, Salts of compounds of the formula I can be obtained by monocyclic hydrocarbon ring, wherein in the said hydrocar 25 customary methods known to those skilled in the art, for bon ring one or two ring carbon atoms are replaced by iden example by combining a compound of the formula I with an tical or different ring heteroatoms selected from the series inorganic or organic acid or base in a solvent or dispersant, or consisting of N, O and S. Such as furanyl, pyridinyl, oxazolyl, from other salts by cation exchange or anion exchange. The isoxazolyl, thiazolyl, isothiazolyl, imidazolyl pyrazinyl, present invention also includes all salts of the compounds of pyridazinyl, pyrimidinyl, pyrrolyl pyrazolyland thienyl resi 30 the formula I which, because of low physiologically tolerabil dues, which can all be unsubstituted or substituted by one or ity, are not directly Suitable for use in pharmaceuticals but are more identical or different substituents selected from the suitable, for example, as intermediates for carrying out fur series consisting of halogen, (C-C)-alkyl, (C-C2)-cy ther chemical modifications of the compounds of the formula cloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, cyano and (C- I or as starting materials for the preparation of pharmaceuti C.)-alkyl-O-. Naphthyl can be 1-naphthyl and 2-maphthyl. 35 cally acceptable salts. Halogen is fluorine, chlorine, bromine or iodine. In one The invention also includes Solvates, derivatives and modi embodiment, halogen is in any of its occurrences, indepen fications of the compounds of the formula I, for example dently of other occurrences, selected from the series consist prodrugs, protected forms and other pharmaceutically ing of fluorine, chlorine an bromine, in another embodiment acceptable derivatives. The invention relates in particular to from the series consisting of fluorine and chlorine. 40 prodrugs and protected forms of the compounds of the for Optically active carbonatoms present in the compounds of mula I, which can be converted into compounds of the for the formula I can independently of each other have R con mula I under physiological conditions. Suitable prodrugs for figuration or S configuration. The compounds of the formula the compounds of the formula I, i.e. chemically modified I can be present in the form of pure enantiomers or pure derivatives of the compounds of the formula I having prop diastereomers or in the form of mixtures of enantiomers and/ 45 erties which are improved in a desired manner, for example or diastereomers in any ratio, for example in the form of with respect to solubility, bioavailability or duration of action, racemates. The present invention relates to pure enantiomers are known to those skilled in the art. More detailed informa and mixtures of enantiomers as well as to pure diastereomers tion relating to prodrugs is found in standard literature like, and mixtures of diastereomers. The invention comprises mix for example, Design of Prodrugs, H. Bundgaard (ed.), tures of two or of more than two stereoisomers of the formula 50 Elsevier, 1985; Fleisher et al., Advanced Drug Delivery I, and it comprises all ratios of the Stereoisomers in the mix Reviews 19 (1996) 115-130; H. Bundgaard, Drugs of the tures. In case the compounds of the formula I can be present Future 16 (1991) 443; Hydrolysis in Drug and Prodrug as Eisomers or Z isomers (or cis isomers or trans isomers) the Metabolism, B. Testa, J. M. Mayer, Wiley-VCH, 2003. invention relates both to pure E isomers and pure Z isomers Suitable prodrugs for the compounds of the formula I are and to E/Zmixtures in all ratios. The invention also comprises 55 especially acyl prodrugs and carbamate prodrugs of acylat all tautomeric forms of the compounds of the formula I. able nitrogen-containing groups such as amino groups and Diastereomers, including E/Z isomers, can be separated ester prodrugs and amide prodrugs of carboxylic acid groups into the individual isomers, for example, by chromatography. which may be present in compounds of the formula I. In the Racemates can be separated into the two enantiomers by acyl prodrugs and carbamate prodrugs a hydrogenatoms on a customary methods, for example by chromatography on 60 nitrogenatom in Such groups is replaced with an acyl group or chiral phases or by resolution, for example by crystallization an ester group, for example a (C-C)-alkyl-O-C(O)— of diastereomeric salts obtained with optically active acids or group. Suitable acyl groups and ester groups for acyl pro bases. Stereochemically uniform compounds of the formula I drugs and carbamate prodrugs are, for example, the groups can also be obtained by employing stereochemically uniform R'-CO- and R’O CO-, wherein R' can be hydro starting materials or by using stereoselective reactions. 65 gen, (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-cycloalkyl Pharmaceutically acceptable salts of the compounds of (C-C)-alkyl-, Ar., (C-C)-aryl, (C-C)-aryl-(C-C)- formula I are understood to be nontoxic salts that are physi alkyl- or Ar (C-C)-alkyl-, for example, and wherein R' US 9,346,762 B2 15 16 has the meanings indicated for R' with the exception of 1) N. Kudo et al. Chem. Pharm. Bull. (1999) 47,857. hydrogen. The term (C-C)-aryl is understood as meaning a residue of a monocyclic, bicyclic or tricyclic aromatic hydro carbon containing from 6 to 14 ring carbon atoms, for example 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Examples are phenyl, naphthyl, for example 1-naphthyl and R 30 N-NHH 2 -- 2-naphthyl, or biphenylyl. Also with respect to all embodiments of the invention specified herein it applies that the comprised compounds of the formula I are a subject of the invention in all their stere 10 oisomeric forms and mixtures of stereoisomeric forms in any ratio, and in the form of their pharmaceutically acceptable salts, as well as in the form of their prodrugs. The present invention also relates to processes for the preparation of the compounds of the formula I, by which the 15 compounds are obtainable and which are another Subject of the invention. The compounds of the formula I can be prepared by utiliz 2) A. Padwa, J. Heterocycl. Chem. (1987) 24, 1225. ing procedures and techniques, which perse are well known and appreciated by one of ordinary skill in the art. Starting materials or building blocks for use in the general synthetic O procedures that can be applied in the preparation of the com C pounds of formula I are readily available to one of ordinary O-R + Ph3P= -e- skill in the art. In many cases they are commercially available - P 35 or have been described in the literature. Otherwise they can be 25 -N )—o R prepared from readily available precursor compounds analo HN O gously to procedures described in the literature, or by proce R33 dures or analogously to procedures described herein. O In general, compounds of the formula I can be prepared, for example in the course of a convergent synthesis, by linking 30 two or more fragments which can be derived retrosyntheti cally from the formula I. More specifically, suitably substi tuted Starting pyrazole derivatives are employed as building blocks in the preparation of the compounds of formula I. If not commercially available, such pyrazole derivatives can be pre 35 pared according to the well-known standard procedures for the formation of the pyrazole ring system. By choosing Suit able precursor molecules, these pyrazole syntheses allow the introduction of a variety of substituents into the various posi tions of the pyrazole system, which can be chemically modi 40 fied in order to finally arrive at the molecule of the formula I having the desired substituent pattern. As one of the compre C hensive reviews in which numerous details and literature references on the chemistry of pyrazole and on synthetic procedures for their preparation can be found J. Eiguero in 45 Comprehensive Heterocyclic Chemistry II, Eds. A. Katritzky, Ch. Rees, E. Scriven, Elsevier 1996, Vol. 3; K. Kirschke in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Ger many, 1994, Vol. E8b Hetarene; T. Nagai et al. Org. Prep. 50 Proced. Int. (1993), 25, 403; M. Elnagdi et al. Heterocycles (1985) 23, 3121; K. Makino et al. J. Heterocycl. Chem. (1998)35,489: K. Makino et al. J. Heterocycl. Chem. (1999) 36,321. If starting pyrazole derivatives are not commercially available and have to be synthesized this can be done, for 55 example, according to the well-known pyrazole syntheses mentioned above. Depending on the Substituents in the start ing materials, in certain pyrazole syntheses mixtures of posi tional isomers may be obtained, which, however, can also be O O O separated by modern separation techniques like, for example, 60 preparative HPLC. In the following, Some procedures of interest for the syn C O- R40 -- R41 lul R42 thesis of the compounds of the invention are listed and refer enced briefly. They illustrate some of the possible ways to HN1 N access Suitable pyrazole derivatives, and are standard proce 65 dures comprehensively discussed in the literature and well s known to one skilled in the art. US 9,346,762 B2 17 18 -continued 8) K. I. Bookermilburn, Synlett (1992) 327. R"So40

N

10 o==o Air

15

HepEtOH

O

He

25 R54

R54 30 Y \ O-R55 N N N O

35

R54 40

O-R7

45 N R45 N- a.

7) W. T. Ashton et al., J. Heterocycl. Chem. (1993)30, 307. 10) T. Hague et al., J. Med. Chem. (2002) 4669.

O NH2 HN EtOH 55 " so O NR49 R

O R48 60

O-R-9 (N \ N 65 US 9,346,762 B2 19 20 -continued 14) W. Sucrow et al., Angew. Chem., Int. Ed. (1975) 14,560.

O

-- Her O-R67 R68

10 O ( \ O-R67 N N

R66 O 15

C Base, Bn(Et3)NCI -e- f \ O-R70 CHCl N 25 R69 O

N s 16) G. M. Pilling et al., Tetrahedron Lett. (1988) 29, 1341. 30

R72 O

35 ) < O-R73 Hebase /

-as ~k

40 17) D. Sauer et al., J. Org. Chem. (1990) 55, 5535.

R60 R61 O ( \ 45 ls O N N r -- -2 O-R77 -- O R so R76 50

55

18) K. Washizuka et al., Tetrahedron Lett. (1999) 40,8849.

60 SiR-79

R78 1 - so -- 65 R80 US 9,346,762 B2 21 22 -continued 22) Leighton, J. Am. Chem. Soc. (1898) 20, 677. R82

O OH R81 O 5 O R89- N -NH2 O- -e- ( /\, R78 OH 10 HO R80

o OH 19) F. Foti et al., Tetrahedron Lett. (1999) 40, 2605. is N4 15 O

O OH O 23) H. Ochi et al., Chem. Pham. Bull. (1983)31, 1228.

r -- - O-R OH O R84 NH O R’-N-NH. . S O -e-

25 O r N R84 O-R8 HO

o OH N Br N 1 NR 83 so-N4 O 20) M. Martins et al., Synthesis (2003) 15, 2353. Although not always shown explicitly, in certain cases 35 positional isomers will occur also during the synthesis by the mentioned reactions. Such mixtures of positional isomers can O O be separated by modern separation techniques like, for C example, preparative HPLC. R-N-NH. -- O -e- Further, in order to obtain the desired substituents at the C \ 40 pyrazole ring system in the formula I, the functional groups C R87 introduced into the ring system during the pyrazole synthesis can be chemically modified. Especially the substituents present on the pyrazole ring system can be modified by a variety of reactions and thus the desired residues can be 45 obtained. For example, a pyrazole carrying a hydrogen atom in a certain position Such as the 4-position can also be obtained by Saponification and Subsequent decarboxylation of pyrazole carrying an ester group in the relevant position. Halogen atoms can be introduced, for example according to procedures like the following described in the literature. For 50 the fluorination of pyrazoles N-fluoro-2,4,6-trimethylpyri 21).J. Nef, Liebigs Ann. Chem. (1893)276, 231. dinium triflate can be used (T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomita, J. Am. Chem. Soc. (1990) 112, 8563; see also K. Manko et al., J. OH Fluorine Chem. (1988) 39, 435: R. Storer et al. Nucleosides 55 Nucleotides (1999) 18: 203). Other suitable fluorinating OH -> reagents may also be employed where appropriate. The chlo rination, bromination, or iodination of pyrazoles can be OH accomplished by the reaction with elemental halogens or by the use of N-halo-succinimides like NCS, NBS or NIS and HO 60 many other reagents well known to those skilled in the art. In addition suitable procedures are for example described by M. Rodriguez-Franco et al., Tetrahedron Lett. (2001) 42,863; J. OH Pawlas et al., J. Org. Chem. (2000) 65,9001:Y. Huang et al., R88 Y N YNa Org Lett (2000) 2, 2833; W. Holzer et al., J. Heterocycl. 65 Chem. (1995) 32, 1351; N. Kudo et al., Chem. Pharm. Bull. (1999) 47.857: G. Auzzi et al., Farmaco, Ed Sci. (1979) 34, 743; K. Morimoto et al., J. Heterocycl. Chem. (1997)34,537; US 9,346,762 B2 23 24 D. Jeon et al., Synth. Commun. (1998) 28, 2159. Depending During the course of the synthesis in order to modify the on the reaction conditions, reagent, Stoichiometry and Substi groups attached to the pyrazole ring system by application of tution pattern the halogen is introduced in the 3-position parallel synthesis methodology, besides a variety of reac and/or 4-position and/or 5-position. By selective halogen/ tions, palladium, nickel or copper catalysis can be extremely metal exchange or metalation by selective hydrogen/metal useful. Such reactions are described for example in F. Dieder exchange and Subsequent reaction with a wide range of elec ich, P. Stang, Metal-catalyzed Cross-coupling Reactions, trophiles various substituents can be introduced at the hetero cyclic nucleus (M. R. Grimmett, Heterocycles (1994) 37, Wiley-VCH, 1998; M. Beller, C. BoIm, Transition Metals for 2087; V. D. Gardner et al., J. Heterocycl. Chem. (1984), 21, Organic Synthesis, Wiley-VCH, 1998: J. Tsuji, Palladium 121: D. Butler et al., J. Org. Chem. (1971) 36,2542). Among 10 Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. others, the corresponding pyrazolones can be useful precur Chem. 1998, 110, 2154: B. Yang, S. Buchwald, J. Organomet. sors for the introduction of halogen atoms. For example, a Chem. 1999, 576, 125; P. Lam, C. Clark, S. Saubern, J. 1H-pyrazol-3-ol can be converted to a 5-chloro-1H-pyrazole Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett. by using phosphorous oxychloride, for example. The 15 1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, 5-bromo-1H-pyrazole can be obtained from 1H-pyrazol-3-ol Tetrahedron Lett. 1998, 39, 2933; J. Wolfe, H. Tomori, J. by similar standard procedures using phosphorous oxybro mide, phosphorous tribromide or phosphorous pentabro Sadight, J. Yin, S. Buchwald, J. Org. Chem. 2000, 65, 1158; V. mide. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction, Halogens, hydroxy groups (via the triflate or nonaflate) or Wiley, 1994; S. Buchwald et al., J. Am. Chem. Soc. 2001, primary amines (via the diazonium salt), or after interconver 123,7727; S. Kang et al., Synlett 2002, 3, 427; S. Buchwald sion to the corresponding Stannanes and boronic acids, et al., Org. Lett. 2002, 4, 581. present in the pyrazole structure can be converted into a The previously-mentioned reactions for the conversion of functional groups are furthermore, in general, extensively variety of other functional groups like for example —CN, 25 —CF, —CFs, ethers, acids, amides, amines, alkyl or aryl described in textbooks of organic chemistry like M. Smith, J. groups mediated by means of transition metals, such as pal March, March's Advanced Organic Chemistry, Wiley-VCH, ladium or nickel catalysts or copper salts and reagents for 2001 and in treatises like Houben-Weyl, Methoden der Orga example referred to below (F. Diederich, P. Stang, Metal nischen Chemie (Methods of Organic Chemistry), Georg catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; M. 30 Thieme Verlag, Stuttgart, Germany; or Organic Reactions, Beller, C. Bolm, Transition Metals for Organic Synthesis, John Wiley & Sons, New York; R. C. Larock, Comprehensive Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Cata Organic Transformations, Wiley-VCH, 2" ed., 1999; B. lysts, Wiley, 1996; J. Hartwig, Angew. Chem. 1998, 110, Trost, I. Fleming (eds.), Comprehensive Organic Synthesis, 2154: B. Yang, S. Buchwald, J. Organomet. Chem. 1999, 576, 35 Pergamon, 1991; A. Katritzky, C. Rees, E. Scriven, Compre 125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I, hensive Heterocyclic Chemistry II, Elsevier Science, 1996, in 1999, 2323; D. Nichols, S. Frescas, D. Marona-Lewicka, X. which details on the reactions and primary Source literature Huang, B. Roth, G. Gudelsky, J. Nash, J. Med. Chem, 1994, can be found. Due to the fact that in the present case the functional groups are attached to a pyrazole ring it may in 37,4347: P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, 40 D. Chan, A. Combs, Tetrahedron Lett., 1998, 39, 2941; D. certain cases become necessary to specifically adapt reaction Chan, K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. conditions or to choose specific reagents from a variety of 1998, 39, 2933: V. Farina, V. Krishnamurthy, W. Scott, The reagents that can in principle be employed in a conversion Stille Reaction, Wiley, 1994: F. Qing et al. J. Chem. Soc. reaction, or otherwise to take specific measures for achieving Perkin Trans. 11997, 3053: S. Buchwald et al. J. Am. Chem. 45 a desired conversion, for example to use protection group Soc. 2001, 123,7727; S. Kang et al. Synlett 2002, 3, 427; S. techniques. However, finding Suitable reaction variants and Buchwaldetal. Organic Lett. 2002, 4,581; T. Fuchikamietal. reaction conditions in Such cases does not cause any problems Tetrahedron Lett. 1991, 32, 91; Q. Chen et al. Tetrahedron for one skilled in the art. The structural elements attached to Lett. 1991, 32,7689; M. R. Netherton, G. C. Fu, Topics in 50 the pyrazole ring in the compounds of the formula I can also Organometallic Chemistry 2005, 14, 85-108; A. F. Littke, G. be introduced into the starting pyrazole derivative using the F. Fu, Angew. Chem. Int. Ed. 2002, 41, 4176-4211; A. R. methods outlined herein by consecutive reaction steps using Muci, S. L. Buchwald, Topics in Current Chemistry 2002, parallel synthesis methodologies using procedures which per 219, 131-209). se are well known to one skilled in the art. Ester groups present in the pyrazole nucleus can be hydro 55 lyzed to the corresponding carboxylic acids, which after acti A subject of the present invention also is a process for Vation can then be reacted with amines or alcohols under preparing a compound of the formula I, which is outlined in standard conditions. Furthermore these ester or acid groups the following scheme, can be reduced to the corresponding alcohols by many stan 60 dard procedures. Ether groups present at the pyrazole, for R2 example benzyloxy groups or other easily cleavable ether R3 Xsiss R101 Reductieduction groups, can be cleaved to give hydroxy groups which then can R- -e- be reacted with a variety of agents, for example etherification \21 agents or activating agents allowing replacement of the 65 O hydroxy group by other groups. Sulfur-containing groups can II be reacted analogously. US 9,346,762 B2 25 26 -continued LG is a leaving group Such as halogen like chlorine or bro R2 mine, a Sulfonyloxy group like methanesulfonyloxy or R3 4-methylbenzenesulfonyloxy, an azide group, or a diazo R Xis nium group, for example; and NeX R' is (C-C)-alkyl-O or HO , for example. H. H. Compounds of the formula III can be obtained, for II example, by reduction of a corresponding carboxylic acid or carboxylic ester of the formula II using well-known proce dures and reagents like for example BH, NaBH or LiAlH. 10 If structural features present in the pyrazole derivatives of the formula I, which are contained in the compounds of the formula V or the formula VI, have not already been intro Xsis O duced during a preceding step, for example during a synthesis LG W-G-M. of the pyrazole nucleus, the respective groups can, for H. H. 15 example, be introduced into the pyrazole system by standard IV R4' R5 alkylation procedures well-known to one skilled in the art. VI The starting pyrazole derivative III that is to be employed in O Such a reaction carries a hydroxymethylen group. Alkylation of the aforementioned group can, for example, be performed HO under standard conditions, preferably in the presence of a W-G-M. base like KCO, CsCO, NaH or KOtBu, using an alkylat R4 R5 ing compound of the formula VI wherein LG is a leaving V y group, such as for example halogen like chlorine, bromine or O iodine, or a Sulfonyloxy group like tosyloxy, mesyloxy or H 25 trifluorimethylsulfonyloxy. Alternatively, the hydroxymethyl H O enegroup of a pyrazole derivative of the formula III can be W-G-M. activated by transformation into a leaving group LG by con R2 R.4. R.5 version into a halomethylene group or Sulfonyloxymethylene group like tosyloxymethylene, mesyloxymethylene or trif 30 luorimethylsulfonyloxymethylene to give a pyrazole deriva YN tives of the formula IV. These pyrazole derivatives of the RI' formula IV can then be etherified, for example, under stan dard conditions, preferably in the presence of a base like I KCO, CsCO, NaH or KOtBu, using a hydroxy derivative 35 of the formula V. These standard procedures are for example and which comprises described in treatises like M. Smith, J. March, March's A) reducing a corresponding carboxylic acid or carboxylic Advanced Organic Chemistry, Wiley-VCH, 2001; Houben acid ester of a pyrazole derivative of the formula II to a Weyl, Methoden der Organischen Chemie (Methods of pyrazole derivative of the formula III carrying a hydroxym Organic Chemistry), Georg Thieme Verlag, Stuttgart, Ger ethylene group, 40 many; Organic Reactions, John Wiley & Sons, New York; R. B1) activating the hydroxymethylene group in the obtained C. Larock, Comprehensive Organic Transformations, Wiley pyrazole derivative of the formula III by transformation VCH, 2" ed., 1999: B. Trost, I. Fleming (eds.), Comprehen into a leaving group LG to give a pyrazole derivative of the sive Organic Synthesis, Pergamon, 1991. formula IV, and subsequently etherifying the latter com The group LG may, for example, also be a hydroxy group pound with a hydroxy compound of the formula V to obtain 45 which, in order to achieve the alkylation reaction, can be a pyrazole derivative of the formula I", which can already be activated under the well-known conditions of the Mitsunobu the final compound of the formula I, procedure (0. Mitsunobu, Synthesis 1981, 1) or by further O modified procedures (A. Tunoori, D. Dutta, G. Gunda, Tetra B2) reacting the obtained pyrazole derivative of the formula hedron Lett. 39 (1998) 8751; J. Pelletier, S. Kincaid, Tetra III with an alkylating compound of the formula VI, wherein 50 hedron Lett. 41 (2000)797; D. L. Hughes, R. A. Reamer, J.J. LG is a leaving group, to obtain a pyrazole derivative of the Bergan, E. J. J. Grabowski, J. Am. Chem. Soc. 110 (1998) formula I", which can already be the final compound of the 6487; D. J. Camp, I. D. Jenkins, J. Org. Chem. 54 (1989) formula I, 3045; D. Crich, H. Dyker, R. J. Harris, J. Org. Chem. 54 C) optionally modifying the obtained compound of the for (1989)257). mula I' by conversion and/or introduction any groups to 55 The compounds of the formulae II, III, IV, V, VI and I' give the final compound of the formula I, and/or converting obtained according to the reactions described herein can the compound into a pharmaceutically acceptable salt already contain the desired final groups, i.e. R. R. R. R. thereof, R, V", G' and M can be the groups R', R. R. R. R. V. G. D) isolating the final compound of the formula I or the phar and Mas defined informula I, or optionally in the compounds maceutically acceptable salt thereof. 60 of the formulae II, Ill. IV, V, VI and I' the residues R. R. R. wherein R. R. V. G' and M' are subsequently converted into the in the compounds of the formulae II, III, IV, V, VI and I the residues R. R. R. R. R. V. G and M to give the desired residues R. R. R. R. R. V', G' and M'are defined as in compound of the formula I. Thus, the residues R. R. R. the compound of the formula I, and additionally functional R", R, V", G' and M' contained in the compounds of the groups can be present in protected form or in the form of 65 formulae II, III, IV, V, VI and I' can have the denotations of the precursor groups which are Subsequently converted into the residues in the compounds of the formula I, or in addition they final groups present in the compound of the formula I; can also be present in the form of groups that can Subse US 9,346,762 B2 27 28 quently be transformed into the final groups of the formula I phate (HATU), bromo-tris-pyrrolidino-phosphonium and, for example, functional groups can be present in the form hexafluorophosphate (Pybrop) and many others. of precursor groups or of derivatives or in protected form. In The activation of the carboxylic acid function may also the course f the preparation of the compounds of the formula favorably be carried out, for example, by conversion of the I it can generally be advantageous or necessary to introduce carboxylic acid group into the pentafluorophenyl ester using functional groups which reduce or prevent undesired reac dicyclohexylcarbodiimide and pentafluorophenol or by using tions or side reactions in the respective synthesis steps, in the reagents like pentafluorophenyl trifluoroacetate, tert-butyl form of precursor groups which are later converted into the pentafluorophenyl carbonate, bis(pentafluorophenyl)carbon desired functional groups, or to temporarily block functional ate, -pentafluorophenyl 4-methylbenzenesulfonate, pen groups by a protective group strategy Suited to the synthesis 10 tafluorophenyl-tetramethyluronium hexafluorophosphate, problem. Such strategies are well known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups octafluoroacetophenone. The activation of the carboxylic in Organic Synthesis, Wiley, 1991; or P. Kocienski, Protecting function by conversion to other phenyl esters like for example Groups. Thieme, 1994). Examples of precursor groups are 4-nitro-phenyl esters or 2-nitro-phenyl esters can be also cyano groups and nitro groups. The cyano group can, in a later 15 effective. The activation and the subsequent reaction with a step, be transformed into carboxylic acid derivatives or by group of the formula H. V-G-M are usually carried out in reduction into aminomethyl groups. Nitro groups may be the presence of an inert solvent or diluent, for example dichlo transformed by reduction like catalytic hydrogenation into romethane, chloroform, tetrahydrofuran (THF), diethyl ether, amino groups. Protective groups can also have the meaning of n-heptane, n-hexane, n-pentane, cyclohexane, diisopropyl a solid phase, and cleavage from the Solid phase stands for the ether, methyl tert-butyl ether, acetonitrile, N,N-dimethylfor removal of the protective group. The use of such techniques is mamide (DMF), N,N-dimethylacetamide (DMA), N-meth known to those skilled in the art (Burgess K (Ed.) Solid Phase ylpyrrolidin-2-one (NMP), dimethyl sulfoxide, dioxane, Organic Synthesis, New York, Wiley, 2000). For example, a toluene, benzene, ethyl acetate or a mixture of these solvents, phenolic hydroxy group can be attached to a trityl-polysty if appropriate with addition of a base Such as, for example, rene resin, which serves as a protecting group, and the mol 25 potassium tert-butoxide or tributylamine or triethylamine or ecule is cleaved from this resin by treatment with trifluoro diisopropylethylamine or N-ethylmorpholine. acetic acid (TFA) or other acids at a later stage of the The residues R. R. R. R. R. present in a pyrazole of synthesis. the formulae II, III, IV, V, VI and I", or a residue in which The residue —V'-G-M in the compounds of the formulae functional groups within the residue are present in protected V, VI and I", which can be identical or different, can be, for 30 form or in the form of a precursor group, can for example be example, hydroxy or (C-C)-alkoxy, i.e., the groups introduced into the pyrazole system by conventional litera —C(O). V-G-M present in the compounds of the formulae ture procedures for the alkylation, arylation, amination, V, VI and I' can be, for example, the free carboxylic acids or etherification or thioetherification of pyrazoles well-known esters thereof like alkyl esters. The groups can also be any to those skilled in the art. The appropriately substituted pyra other activated derivative of a carboxylic acid which allows 35 Zole useful for these reactions carries a leaving group like for amide or ester formation with a compound of the formula example halogen, triflate, nonaflate, tosylate, azide, or a dia H. V-G-M. The activated derivative can be, for example, Zonium salt. Preferably the reaction is carried out in the an acid chloride, an activated ester like a Substituted phenyl presence of a base like KCO, CsCO, NaH or KOtBu. The ester or thioester, an azolide like an imidazolide, an azide or a desired transformation can also be accomplished with halo mixed anhydride, for example a mixed anhydride with a 40 gens, hydroxy groups (via the triflate or nonaflate) or primary carbonic acid ester or with a sulfonic acid. These derivatives amines (via the diazonium salt) or after interconversion to the can all be prepared from the carboxylic acid by standard corresponding Stannane, or boronic acid present in the procedures and can be reacted with an amine or alcohol of the pyrazole structure—can be converted into a variety of other formula H. V-G-M understandard conditions. A carboxy functional groups like for example —CN. —CF, —CFs, lic acid group—COOH representing—C(O). V-G-M in a 45 ethers, acids, amides, amines, alkyl or aryl groups mediated compound of the formulae V and VI can be obtained, for by means of transition metals, such as palladium or nickel example by standard hydrolysis procedures, from an ester catalysts or copper salts and reagents for example referred to group introduced into the pyrazole system during a pyrazole below (F. Diederich, P. Stang, Metal-catalyzed Cross-cou synthesis. pling Reactions, Wiley-VCH, 1998; M. Beller, C. BoIm. Compounds of the formula I in which a group —C(O)— 50 Transition Metals for Organic Synthesis, Wiley-VCH, 1998: V"-G-M is an amide group can be prepared from amines and J. Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. compounds is a carboxylic acid group or an ester or thioester Hartwig, Angew. Chem. 1998, 110, 2154: B. Yang, S. Buch thereof by common amidation reactions. Especially for the wald, J. Organomet. Chem. 1999, 576, 125: T. Sakamoto, K. preparation of amides the compounds containing a carboxylic Ohsawa, J. Chem. Soc. Perkin Trans I, 1999, 2323; D. acid group can be condensed under standard conditions with 55 Nichols, S. Frescas, D. Marona-Lewicka, X. Huang, B. Roth, compounds of the formula H. V-G-M' which are amines by G. Gudelsky, J. Nash, J. Med. Chem., 1994, 37,4347: P. Lam, means of common coupling reagents used in peptide synthe C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. sis. Such coupling reagents are, for example, carbodiimides Combs, Tetrahedron Lett., 1998, 39, 2941; D. Chan, K. like dicyclohexylcarbodiimide (DCC) or diisopropylcarbodi Monaco, R. Wang, M. Winters, Tetrahedron Lett. 1998, 39, imide, carbonyldiazoles like carbonyldiimidazole (CU) and 60 2933: V. Farina, V. Krishnamurthy, W. Scott, The Stille Reac similar reagents, propylphosphonic anhydride, O-((cyano tion, Wiley, 1994: F. Qing et al. J. Chem. Soc. Perkin Trans. (ethoxycarbonyl)-methylene)amino)-N.N.N',N'-tetramethy 11997, 3053: S. Buchwald etal.J. Am. Chem. Soc. 2001, 123, luronium tetrafluoroborate (TOTU), diethylphosphoryl cya 7727; S. Kang et al. Synlett 2002, 3, 427; S. Buchwald et al. nide (DEPC), bis-(2-oxo-3-oxazolidinyl)-phosphoryl Organic Lett. 2002, 4, 581; T. Fuchikami et al. Tetrahedron chloride (BOP-Cl), O-(benzotriazol-1-yl)-1,1,3,3-tetram 65 Lett. 1991, 32,91: Q. Chen et al. Tetrahedron Lett. 1991, 32, ethyluronium hexafluorophosphate (HBTU), O-(7-azaben 7689; M. R. Netherton, G. C. Fu, Topics in Organometallic Zotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophos Chemistry 2005, 14, 85-108; A. F. Littke, G. F. Fu, Angew. US 9,346,762 B2 29 30 Chem. Int. Ed. 2002, 41, 4176-4211; A. R. Muci, S. L. Buch of the LPA receptor LPAR5 and/or the reduction or inhibition wald, Topics in Current Chemistry 2002, 219, 131-209. of platelet aggregation or thrombus formation and/or the The compounds of the formula I are effective LPAR5 reduction or inhibition of activation of mast cells and/or the antagonists which antagonize the effect of endogenous LPA reduction or inhibition of activation of microglial cells. on its LPAR5 receptor. In particular are the compounds of the 5 As inhibition of the LPA receptor LPAR5 influences plate formula I effective platelet, mast cell and microglial cell LPA let activation and platelet aggregation, the compounds of the receptor LPAR5 antagonists. The compounds of the invention formula I and/or their pharmaceutically acceptable salts and/ antagonize the platelet aggregating effect of the activation of or their prodrugs are generally Suitable for reducing blood the platelet LPA receptor LPAR5, the LPA-mediated activa thrombus formation, or for the treatment, including therapy tion of human mast cells and the LPA-mediated activation of 10 microglia cells. In addition, the compounds of the formula I of and prophylaxis, of conditions and diseases in which the the invention also have further advantageous properties, for activity of the platelet aggregation plays a role or has an instance stability in plasma and liver and selectivity versus undesired extent, or which can favorably be influenced by other receptors whose agonism orantagonism is not intended. reducing thrombus formation, or for the prevention, allevia This good selectivity, for example, makes it possible to 15 tion or cure of which a decreased activity of the platelet reduce potential side effects existing with regard to molecules aggregation system is desired by the physician. A specific having inadequate selectivity. subject of the present invention thus is the reduction or inhi A subject of the present invention also are the compounds bition of unwanted thrombus formation, in particular in an of the formula I and/or the pharmaceutically acceptable salts individual, by administering an effective amount of a com thereof and/or prodrugs thereof for use as a medicament or as pound of the formula I and/or a pharmaceutically acceptable a pharmaceutical, and pharmaceutical compositions which salt and/or a prodrug thereof, as well as pharmaceutical com comprise an effective amount of at least one compound of the positions therefore. formula I and/or a pharmaceutical acceptable salt thereof As inhibition of the LPA receptor LPAR5 influences mast and/or a prodrug thereof and a pharmaceutically acceptable cell activation the compounds of the formula I and/or their carrier, i.e. one or more pharmaceutically acceptable carrier 25 pharmaceutically acceptable salts and/or their prodrugs are Substances or excipients and/or auxiliary Substances or addi generally Suitable for reducing mast cell activation, or for the tives, and can be employed in human, Veterinary or phytopro treatment, including therapy and prophylaxis, of conditions tective use. and diseases in which the activity of mast cells plays a role or The activity of the compounds of the formula I can be has an undesired extent, or which can favorably be influenced determined, for example, in the assays described below or in 30 by reducing mast cell activation, or for the prevention, alle other in vitro or ex vivo assays known to those skilled in the viation or cure of which a decreased activity of the mast cell art. The ability of the compounds to inhibit LPA-induced system is desired by the physician. A specific subject of the aggregation of platelets may be measured by methods similar present invention thus is the reduction or inhibition of to those described in the literature (for example, Holub and unwanted activation of mast cells, in particular in an indi Waston in Platelets: A Practical Approach, pp. 236-239, 35 vidual, by administering an effective amount of a compound Oxford University Press 1996) and by the methods described of the formula I and/or a pharmaceutically acceptable salt below. The results of these assays clearly demonstrate that the and/or a prodrug thereof, as well as pharmaceutical compo compounds of the invention are functional antagonists of the sitions therefore. platelet LPA receptor LPAR5 and are therefore useful for As inhibition of the LPA receptor LPAR5 influences inhibiting platelet aggregation and thrombus formation. The 40 microglial cell activation the compounds of the formula I ability of the compounds to inhibit LPA-induced activation of and/or their pharmaceutically acceptable salts and/or their mast cells or microglial cells may also be measured by using prodrugs are generally Suitable for reducing microglial cell the FLIPR system. activation, or for the treatment, including therapy and pro As LPA receptor LPAR5 antagonists, the compounds of the phylaxis, of conditions in which the activity of microglial formula I and/or their pharmaceutically acceptable salts and/ 45 cells plays a role or has an undesired extent, or which can or their prodrugs are generally suitable for the treatment, favorably be influenced by reducing microglial cell activa including therapy and prophylaxis, of conditions in which the tion, or for the prevention, alleviation or cure of which a activity of LPAR5 receptor plays a role or has an undesired decreased activity of the microglial cell system is desired by extent, or which can favorably be influenced by inhibiting the physician. A specific Subject of the present invention thus LPAR5 receptors or decreasing the activity, or for the preven 50 are the reduction or inhibition of unwanted activation of tion, alleviation or cure of which an inhibition of LPA recep microglial cell, in particular in an individual, by administer tor LPAR5 or a decrease in the activity is desired by the ing an effective amount of a compound of the formula I and/or physician. a pharmaceutically acceptable salt and/or a prodrug thereof, Thus, a Subject of the invention also are the compounds of as well as pharmaceutical compositions therefore. the formula I and/or the pharmaceutically acceptable salts 55 The present invention also relates to the compounds of the thereof and/or the prodrugs thereof for the use in the treat formula I and/or their pharmaceutically acceptable salts and/ ment, including therapy and prophylaxis, of a disease or or their prodrugs for the use in the treatment, including disease state responsive to the inhibition of the LPA receptor therapy and prophylaxis, of thromboembolic diseases. Such LPAR5 and/or the reduction or inhibition of platelet aggre as deep vein thrombosis, venous and arterial thromboembo gation or thrombus formation and/or the reduction or inhibi 60 lism, thrombophlebitis, coronary and cerebral arterial throm tion of activation of mast cells and/or the reduction or inhi bosis, cerebral embolism, renal embolism, pulmonary embo bition of activation of microglial cells. lism, disseminated intravascular coagulation, cardiovascular A subject of the invention also is the use of a compound of disorders, such as transient ischemic attacks, strokes, acute the formula I and/or the pharmaceutically acceptable salts myocardial infarction, unstable angina, chronic stable thereof and/or the prodrugs thereof for the manufacture of a 65 angina, peripheral vascular disease, preeclampsiadeclampsia, medicament for the treatment, including therapy and prophy and thrombotic cytopenic purpura and development and pro laxis, of a disease or disease state responsive to the inhibition gression of inflammatory disorders, such as hyperalgesia, US 9,346,762 B2 31 32 asthma, multiple Sclerosis, inflammatory pain, angiogenesis, thereof for the manufacture of a medicament for the treat atherothrombosis or allergic responses, or restenoses. ment, including therapy and prophylaxis of said disease The present invention also relates to the use of the com States. pounds of the formula I and/or their pharmaceutically accept The compounds of the formula I and their pharmaceuti able salts and/or their prodrugs for the manufacture of phar cally acceptable salts and their prodrugs can be administered maceutical compositions or medicaments for inhibition of the to animals, preferably to mammals, and in particular to LPA receptor LPAR5 or for influencing platelet activation, humans as pharmaceuticals for therapy or prophylaxis. They platelet aggregation and platelet degranulation and promote can be administered alone, or in mixtures with one another or platelet disaggregation, inflammatory response and/or for the in the form of pharmaceutical compositions, which permit treatment, including therapy and prophylaxis of the diseases 10 enteral or parenteral administration. mentioned above or below, for example for the production of The pharmaceutical compositions according to the inven medicaments for the treatment, including therapy and pro tion can be administered orally, for example in the form of phylaxis, of cardiovascular disorders, thromboembolic dis pills, tablets, lacquered tablets, coated tablets, granules, hard eases or restenosis, for the treatment of deep vein thrombosis, and Soft gelatine capsules, Solutions, syrups, emulsions, Sus venous and arterial thromboembolism, thrombophlebitis, 15 pensions or aerosol mixtures. Administration can also be coronary and cerebral arterial thrombosis, cerebral embo carried out rectally, for example in the form of suppositories, lism, renal embolism, pulmonary embolism, disseminated or parenterally, for example intravenously, intramuscularly or intravascular coagulation, transientischemic attacks, strokes, Subcutaneously, in the form of injection Solutions or infusion acute myocardial infarction, unstable angina, chronic stable Solutions, microcapsules, implants or rods, or percutaneously angina, peripheral vascular disease, preeclampsiadeclampsia, or topically, for example in the form of ointments, solutions or and thrombotic cytopenic purpura and development and pro tinctures, or in other ways, for example in the form of aerosols gression of inflammatory disorders, such as hyperalgesia, or nasal sprays. asthma, multiple Sclerosis, angiogenesis, allergic responses The pharmaceutical compositions according to the inven and others. tion are prepared in a manner known perse and familiar to one The invention also relates to the compounds of the formula 25 skilled in the art, pharmaceutically acceptable inert inorganic I and/or their pharmaceutically acceptable salts and/or their and/or organic carrier Substances and/or auxiliary Substances prodrugs for the use in the treatment, including therapy and being used in addition to one or more compounds of the prophylaxis, of the diseases mentioned above or below, for formula I and/or their pharmaceutically acceptable salts and/ example for use in the treatment of cardiovascular disorders, or their prodrugs. For the production of pills, tablets, coated thromboembolic diseases, atherothrombosis or restenoses, 30 tablets and hard gelatine capsules it is possible to use, for and to methods of treatment aiming at Such purposes includ example, lactose, cornstarch or derivatives thereof, talc, ing methods for said therapies and prophylaxis. Stearic acid or its salts, etc. Carrier substances for softgelatine Due to the central role of the platelet LPA receptor LPAR5 capsules and Suppositories are, for example, fats, waxes, in LPA-mediated activation of platelets, the invention also semisolid and liquid polyols, natural or hardened oils, etc. relates to compounds of the formula I and/or the pharmaceu 35 Suitable carrier substances for the production of solutions, for tically acceptable salts thereof for the use in the treatment, example injection solutions, or of emulsions or syrups are, for including therapy and prophylaxis, of disease states such as example, water, Saline, alcohols, glycerol, polyols. Sucrose, abnormal thrombus formation, acute myocardial infarction, invert Sugar, glucose, vegetable oils, etc. Suitable carrier Sub unstable angina, thromboembolism, acute vessel closure stances for microcapsules, implants or rods are, for example, associated with thrombolytic therapy or percutaneous trans 40 copolymers of glycolic acid and lactic acid. The pharmaceu luminal coronary angioplasty (PTCA), transient ischemic tical compositions normally contain about 0.5% to about 90% attacks, stroke, intermittent claudication or bypass grafting of by weight of the compounds of the formula I and/or their the coronary or peripheral arteries, vessel luminal narrowing, pharmaceutically acceptable salts and/or their prodrugs. The restenosis post coronary or venous angioplasty, maintenance amount of the active ingredient of the formula I and/or its of vascular access patency in long-term hemodialysis 45 pharmaceutically acceptable salts and/or its prodrugs in the patients, pathologic thrombus formation occurring in the pharmaceutical compositions normally is from about 0.5 mg veins of the lower extremities following abdominal, knee or to about 1000 mg, preferably from about 1 mg to about 500 hip Surgery, a risk of pulmonary thromboembolism, or dis ng. seminated systemic intravascular coagulatopathy occurring In addition to the active ingredients of the formula I and/or in vascular systems during septic shock, certain viral infec 50 their pharmaceutically acceptable salts and/or prodrugs and tions or cancer. The invention also relates to the use of a to carrier Substances or excipients, the pharmaceutical com compound of the formula I and/or the pharmaceutically positions can contain auxiliary Substances or additives Such acceptable salts thereof for the manufacture of a medicament as, for example, fillers, disintegrants, binders, lubricants, wet for the treatment, including therapy and prophylaxis of said ting agents, stabilizers, emulsifiers, preservatives, Sweeten disease states. 55 ers, colorants, flavorings, aromatizers, thickeners, diluents, Due to the central role of the LPA receptor LPAR5 in buffer Substances, solvents, solubilizers, agents for achieving LPA-mediated activation of mast cells and/or microglia cells, a depot effect, salts for altering the osmotic pressure, coating the invention also relates to compounds of the formula I agents or antioxidants. They can also contain two or more and/or the pharmaceutically acceptable salts thereof for the compounds of the formula I, and/or their pharmaceutically use in the treatment, including therapy and prophylaxis, of 60 acceptable salts and/or their prodrugs. In case a pharmaceu disease states such as inflammatory pain, asthma, angiogen tical composition contains two or more compounds of the esis, demyelating diseases of (a) the central nervous system formula I, the selection of the individual compounds can aim Such as, multiple Sclerosis, transverse myelitis, optic neuritis, at a specific overall pharmacological profile of the pharma Devic's disease and (b) the peripheral nervous system such as ceutical composition. For example, a highly potent com Guillain-Barre syndrome or chronic inflammatory demyeli 65 pound with a shorter duration of action may be combined with nating polyneuropathy, as well as to the use of a compound of a long-acting compound of lower potency. The flexibility the formula I and/or the pharmaceutically acceptable salts permitted with respect to the choice of substituents in the US 9,346,762 B2 33 34 compounds of the formula I allows a great deal of control over illustrative of the present invention and not limiting it in either the biological and physico-chemical properties of the com scope or spirit. Those with skill in the art will readily under pounds and thus allows the selection of Such desired com stand that known variations of the conditions and processes pounds. Furthermore, in addition to at least one compound of described in the examples can be used to synthesize the com the formula I and/or a pharmaceutically acceptable salt and/or 5 pounds of the present invention. its prodrug, the pharmaceutical compositions can also con Furthermore, the following subject-matters (1) to (12) are tain one or more other pharmaceutically, therapeutically and/ disclosed herein, which comprise additional compounds or prophylactically active ingredients. beside the compounds as covered by the claim set. The addi When using the compounds of the formula I the dose can tional compounds can be prepared by the same methods as vary within wide limits and, as is customary and is known to 10 the physician, is to be suited to the individual conditions in disclosed herein for the preparation of the inventive com each individual case. It depends, for example, on the specific pounds. compound employed, on the nature and severity of the disease (1) A compound of the formula I, to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or 15 whether prophylaxis is carried out. An appropriate dosage can be established using clinical approaches well known in the medical art. In general, the daily dose for achieving the desired results in an adult weighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from 0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg, (in each case in mg per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large wherein amounts, into several, for example 2, 3 or 4, part administra R" is selected from the series consisting of hydrogen, (C- tions. As usual, depending on individual behavior it may be 25 C)-alkyl, (C-C)-cycloalkyl, (C-C)-cycloalkyl-(C- necessary to deviate upwards or downwards from the daily Cl)-alkyl-, Ar and Ar—(C-C)-alkyl-, dose indicated. R° and Rare independently of each other selected from the The compounds of the present invention are also useful as series consisting of hydrogen, halogen, (C-C)-alkyl, (C- standard or reference compounds, for example as a quality Cz)-cycloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, Ar. standard or control, in tests or assays involving the inhibition 30 of the LPA receptor LPAR5. Such compounds may be pro Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, (C-C,)-cy vided in a commercial kit, for example, for use in pharma cloalkyl-O , (C-C)-cycloalkyl-(C-C)-alkyl-O-, ceutical research involving the LPA receptor LPAR5. For Ar—O— and Ar—(C-C)-alkyl-O , example, a compound of the present invention can be used as or the groups Rand R, in case they are bonded to adjacent a reference in an assay to compare its known activity to a 35 ring carbonatoms, together with the carbonatoms carrying compound with an unknown activity. This would ensure the them form a benzene ring which is unsubstituted or sub experimenter that the assay was being performed properly stituted by one or more identical or different substituents and provide a basis for comparison, especially if the test selected from the series consisting of halogen, (C-C)- compound was a derivative of the reference compound. When alkyl, cyano and (C-C)-alkyl-O-; developing new assays or protocols, compounds according to 40 R" and Rare independently of each other selected from the the present invention can be used to test their effectiveness. series consisting of hydrogen, fluorine and (C-C)-alkyl, A compound of the formula I can also advantageously be or the groups RandR together with the carbonatom carry used as an antiaggregant outside an individual. For example, ing them forma (C-C,)-cycloalkane ring which is unsub an effective amount of a compound of the invention can be stituted or substituted by one or more identical or different contacted with a freshly drawn blood sample to prevent 45 substituents selected from the series consisting of fluorine aggregation of the blood sample. Further, a compound of the and (C-C)-alkyl; formula I or its salts can be used for diagnostic purposes, for R'', R', RandR'' are independently of each other selected example in vitro diagnoses, and as an auxiliary in biochemi from the series consisting of hydrogen and (C-C)-alkyl: cal investigations. For example, a compound of the formula I Ar is selected from the series consisting of phenyl, naphthyl can be used in an assay to identify the presence of the LPA 50 receptor LPAR5 or to isolate the LPA receptor LPAR5 con and an aromatic, 5-membered or 6-membered, monocyclic taining tissue in a Substantially purified form. A compound of heterocycle which comprises one or two identical or dif the invention can be labeled with, for example, a radioisotope, ferent ring heteroatoms selected from the series consisting and the labeled compound bound to the LPA receptor LPAR5 of N, O and S, which are all unsubstituted or substituted by one or more identical or different substituents selected is then detected using a routine method useful for detecting 55 the particular label. Thus, a compound of the formula I or a from the series consisting of halogen, (C-C)-alkyl, (C- salt thereof can be used as a probe to detect the location or Cz)-cycloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, cyano amount of LPAR5 activity in vivo, in vitro or ex vivo. and (C-C)-alkyl-O-: Furthermore, the compounds of the formula I can be used V is selected from the series consisting of R'-O- and as synthesis intermediates for the preparation of other com 60 R'° N(R')—, and in this case G and Mare not present, pounds, in particular of other pharmaceutical active ingredi O ents, which are obtainable from the compounds of the for V is selected from the series consisting of N(R') , mula I, for example by introduction of substituents or —N(R')–(C-C)-alkyl-, -O- and —O-(C-C)- modification of functional groups. alkyl-, and in this case The general synthetic sequences for preparing the com 65 G is selected from the series consisting of a direct bond and pounds useful in the present invention are outlined in detail in phenylene which is unsubstituted or substituted by one or the examples given below which are intended to be merely more identical or different substituents selected from the US 9,346,762 B2 35 36 series consisting of halogen, (C-C)-alkyl, cyano and (C- in any of its stereoisomeric forms or a mixture of stereoiso C.)-alkyl-O-, provided that G is not a direct bond if V is meric forms in any ratio, or a pharmaceutically acceptable N(R')—or —O , and salt thereof. M is selected from the series consisting of R''-O-C(O)— (3) A compound of the formula I according to one or more of and R' N(R') C(O) ; subject-matters (1) and (2) wherein wherein all alkyl groups are unsubstituted or substituted by R" is selected from the series consisting of (C-C)-alkyl, one or more fluorine Substituents, and all cycloalkyl groups (C-C2)-cycloalkyl, Arand Ar—(C-C)-alkyl-, are unsubstituted or substituted by one or more identical or R° and Rare independently of each other selected from the different substituents selected from the series consisting of series consisting of hydrogen, (C-C)-alkyl, Ar. Ar—(C- 10 Cl)-alkyl-, (C-C)-alkyl-O-, (C-C)-cycloalkyl-O-, fluorine and (C-C)-alkyl; Ar—O— and Ar—(C-C)-alkyl-O , in any of its stereoisomeric forms or a mixture of stereoiso or the groups Rand R, in case they are bonded to adjacent meric forms in any ratio, or a pharmaceutically acceptable ring carbonatoms, together with the carbonatoms carrying salt thereof. them form a benzene ring which is unsubstituted or sub (2) A compound of the formula I according to Subject-matter 15 stituted by one or more identical or different substituents (1), wherein selected from the series consisting of halogen, (C-C)- R" is selected from the series consisting of hydrogen, (C- alkyl, cyano and (C-C)-alkyl-O-; C)-alkyl, (C-C2)-cycloalkyl, Arand Ar—(C-C)-alkyl-, R" and Rare independently of each other selected from the R° and Rare independently of each other selected from the series consisting of hydrogen and (C-C)-alkyl, series consisting of hydrogen, (C-C)-alkyl, (C-C)-cy or the groups RandR together with the carbonatom carry cloalkyl, (C-C2)-cycloalkyl-(C-C)-alkyl-, Ar. Ar—(C- ing them forma (C-C,)-cycloalkane ring which is unsub Cl)-alkyl-, (C-C)-alkyl-O-, (C-C)-cycloalkyl-O , stituted or substituted by one or more identical or different (C-C)-cycloalkyl-(C-C)-alkyl-O-, Ar—O— and substituents selected from the series consisting of fluorine Ar—(C-C)-alkyl-O , and (C-C)-alkyl; or the groups R and R, in case they are bonded to adjacent 25 R'', R', RandR'' are independently of each other selected ring carbonatoms, together with the carbonatoms carrying from the series consisting of hydrogen and (C-C)-alkyl, them form a benzene ring which is unsubstituted or sub Ar is selected from the series consisting of phenyl, naphthyl stituted by one or more identical or different substituents and an aromatic, 5-membered or 6-membered, monocyclic selected from the series consisting of halogen, (C-C)- heterocycle which comprises one or two identical or dif alkyl, cyano and (C-C)-alkyl-O-, 30 ferent ring heteroatoms selected from the series consisting of N, O and S, which are all unsubstituted or substituted by R" and Rare independently of each other selected from the one or more identical or different Substituents selected series consisting of hydrogen and (C-C)-alkyl, from the series consisting of halogen, (C-C)-alkyl, (C- or the groups RandR together with the carbonatom carry Cz)-cycloalkyl and (C-C)-alkyl-O-, ing them forma (C-C)-cycloalkane ring which is unsub 35 V is R'—O , and in this case G and Mare not present, stituted or substituted by one or more identical or different O substituents selected from the series consisting of fluorine V is selected from the series consisting of N(R') and and (C-C)-alkyl; —N(R')–(C-C)-alkyl-, and in this case R'', R', RandR'' are independently ofeach other selected G is selected from the series consisting of a direct bond and from the series consisting of hydrogen and (C-C)-alkyl; 40 phenylene which is unsubstituted or substituted by one or Ar is selected from the series consisting of phenyl, naphthyl more identical or different substituents selected from the and an aromatic, 5-membered or 6-membered, monocyclic series consisting of halogen, (C-C)-alkyl and (C-C)- heterocycle which comprises one or two identical or dif alkyl-O-, provided that G is not a direct bond if V is ferent ring heteroatoms selected from the series consisting -N(R')—, and of N, O and S, which are all unsubstituted or substituted by 45 M is selected from the series consisting of R'—O C(O)— one or more identical or different substituents selected and R' N(R') C(O) ; from the series consisting of halogen, (C-C)-alkyl, (C- wherein all alkyl groups are unsubstituted or substituted by Cz)-cycloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, cyano one or more fluorine Substituents, and all cycloalkyl groups and (C-C)-alkyl-O-: are unsubstituted or substituted by one or more identical or V is R'-O-, and in this case G and Mare not present, 50 different substituents selected from the series consisting of O fluorine and (C-C)-alkyl; V is selected from the series consisting of N(R') , in any of its stereoisomeric forms or a mixture of stereoiso —N(R')–(C-C)-alkyl-and-O-(C1-C4)-alkyl-, and meric forms in any ratio, or a pharmaceutically acceptable in this case salt thereof. G is selected from the series consisting of a direct bond and 55 (4) A compound of the formula I according to one or more of phenylene which is unsubstituted or substituted by one or subject-matters 1 to 3, wherein more identical or different substituents selected from the R" is selected from the series consisting of (C-C)-alkyl, Ar series consisting of halogen, (C-C)-alkyl, cyano and (C- and Ar—(C-C)-alkyl-, Cl)-alkyl-O provided that G is not a direct bond if V is R° and Rare independently of each other selected from the - N(R')—, and 60 series consisting of hydrogen, (C-C)-alkyl, Ar. Ar—(C- M is selected from the series consisting of R''—O C(O)— C)-alkyl-, and Ar—O—, and R' N(R') C(O) ; or the groups R and R, in case they are bonded to adjacent wherein all alkyl groups are unsubstituted or substituted by ring carbonatoms, together with the carbonatoms carrying one or more fluorine Substituents, and all cycloalkyl groups them form a benzene ring which is unsubstituted or sub are unsubstituted or substituted by one or more identical or 65 stituted by one or more identical or different substituents different substituents selected from the series consisting of selected from the series consisting of halogen, (C-C)- fluorine and (C-C)-alkyl; alkyl and (C-C)-alkyl-O-, US 9,346,762 B2 37 38 R" and Rare independently of each other selected from the V is selected from the series consisting of N(R') and series consisting of hydrogen and (C-C)-alkyl, —N(R')—(C-C)-alkyl-, and in this case or the groups RandR together with the carbon atom carry G is selected from the series consisting of a direct bond and ing them forma (C-C)-cycloalkane ring which is unsub phenylene which is unsubstituted or substituted by one or stituted or substituted by one or more identical or different more identical or different substituents selected from the substituents selected from the series consisting of fluorine series consisting of halogen, (C-C)-alkyl and (C-C)- and (C-C)-alkyl; alkyl-O-, provided that G is not a direct bond if V is R'' and R'' are independently of each other selected from the - N(R'), and series consisting of hydrogen and (C-C)-alkyl; M is R'-O-C(O)–: Ar is selected from the series consisting of phenyl, naphthyl 10 wherein all alkyl groups are unsubstituted or substituted by and an aromatic, 5-membered or 6-membered, monocyclic one or more fluorine substituents; heterocycle which comprises one or two identical or dif in any of its stereoisomeric forms or a mixture of stereoiso ferent ring heteroatoms selected from the series consisting meric forms in any ratio, or a pharmaceutically acceptable of N, O and S, which are all unsubstituted or substituted by 15 salt thereof. one or more identical or different substituents selected (6) A compound of the formula I according to one or more of from the series consisting of halogen, (C-C)-alkyl, (C- subject-matters (1) to (5), which is selected from the series Cz)-cycloalkyl and (C-C)-alkyl-O-: consisting of V is R'-O-, and in this case G and Mare not present, 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl O 1H-pyrazol-3-ylmethoxy-2-methyl-propionic acid, V is selected from the series consisting of N(R') and 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl - N(R')–(C-C)-alkyl-, and in this case 1H-pyrazol-3-ylmethoxy-acetic acid, G is selected from the series consisting of a direct bond and 1-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl phenylene which is unsubstituted or substituted by one or 1H-pyrazol-3-ylmethoxy-cyclopentanecarboxylic acid, more identical or different substituents selected from the 25 2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl series consisting of halogen, (C-C)-alkyl and (C-C)- phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propionic alkyl-O-, provided that G is not a direct bond if V is acid, - N(R'), and 2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phe M is R'-O-C(O)–: nyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propionic acid, wherein all alkyl groups are unsubstituted or substituted by 30 2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phe one or more fluorine Substituents, and all cycloalkyl groups nyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propionic acid, are unsubstituted or substituted by one or more identical or 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl different substituents selected from the series consisting of 1H-pyrazol-3-ylmethoxy-butyric acid, fluorine and (C-C)-alkyl; 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl in any of its stereoisomeric forms or a mixture of stereoiso 35 1H-pyrazol-3-ylmethoxy-propionic acid, meric forms in any ratio, or a pharmaceutically acceptable 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me salt thereof. thyl-1H-pyrazol-3-ylmethoxy-2-methyl-propiony (5) A compound of the formula I according to one or more of lamino-methyl)-benzoic acid, Subject-matters (1) to (4), wherein 4-(2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluorom R" is selected from the series consisting of (C-C)-alkyl, Ar 40 ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-pro and Ar—(C-C)-alkyl-, pionylamino-methyl)-benzoic acid, R° and Rare independently of each other selected from the 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me series consisting of hydrogen, (C-C)-alkyl, Ar— and thyl-1H-pyrazol-3-ylmethoxy-acetylamino-methyl)- Ar—O—, benzoic acid, or the groups Rand R, in case they are bonded to adjacent 45 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me ring carbonatoms, together with the carbonatoms carrying thyl-1H-pyrazol-3-ylmethoxy-butyrylamino-methyl)- them form a benzene ring which is unsubstituted or sub benzoic acid, stituted by one or more identical or different substituents 4-(2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl selected from the series consisting of halogen and (C-C)- phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propiony alkyl-, 50 lamino-methyl)-benzoic acid, R" and Rare independently of each other selected from the 4-(2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl series consisting of hydrogen and (C-C)-alkyl, phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-propiony or the groups RandR together with the carbonatom carry lamino-methyl)-benzoic acid, ing them forma (C-C2)-cycloalkane ring which is unsub 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me stituted or substituted by one or more fluorine substituents: 55 thyl-1H-pyrazol-3-ylmethoxy-propionylamino-me R'' and R'' are independently of each other selected from the thyl)-benzoic acid, series consisting of hydrogen and (C-C)-alkyl; 4-2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluorom Ar is selected from the series consisting of phenyl, naphthyl ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propiony and an aromatic, 5-membered or 6-membered, monocyclic lamino-benzoic acid, heterocycle which comprises one or two identical or dif 60 4-2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-me ferent ring heteroatoms selected from the series consisting thyl-1H-pyrazol-3-ylmethoxy-3-methyl-butyrylamino of N, O and S, which are all unsubstituted or substituted by benzoic acid, one or more identical or different substituents selected 4-2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl from the series consisting of halogen, (C-C)-alkyl, (C- phenyl)-1H-pyrazol-3-ylmethoxy)-propionylamino-ben Cz)-cycloalkyl and (C-C)-alkyl-O-, 65 Zoic acid, V is R'—O , and in this case G and Mare not present, 4-2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-yl O methoxy)-propionylamino-benzoic acid, US 9,346,762 B2 39 40 4-2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl pain, asthma, angiogenesis, demyelating diseases of the phenyl)-1H-pyrazol-3-ylmethoxy)-propionylamino-ben central nervous system or the peripheral nervous system, Zoic acid, multiple Sclerosis, transverse myelitis, optic neuritis, 4-2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)- Devic's disease, Guillain-Barre syndrome or chronic propionylamino-benzoic acid, 5 inflammatory demyelinating polyneuropathy. 4-2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propiony (12) A pharmaceutical composition comprising a compound lamino-benzoic acid, 4-2-1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol-4-yl of the formula I or a pharmaceutically acceptable salt methoxy)-propionylamino-benzoic acid, thereof according to one or more of Subject-matters (1) to 4-2-5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H-pyra- 10 (6), and a pharmaceutically acceptable carrier. Zol-4-ylmethoxy-propionylamino-benzoic acid, EXAMPLES 4-2-(2-Methyl-2H-indazol-3-ylmethoxy)-propiony lamino-benzoic acid, When in the final step of the synthesis of a compound an 4-2-3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4-yl acid Such as trifluoroacetic acid or acetic acid was used, for methoxy)-propionylamino-benzoic acid, 15 example when trifluoroacetic acid was employed to an acid 4-2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethoxy)- labile protecting group, for example atEu group, or when a propionylamino-benzoic acid, and compound was purified by chromatography using an eluent 4-2-(1.5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propiony which contained such an acid, in Some cases, depending on lamino-benzoic acid, the work-up procedure, for example the details of a freeze in any of its stereoisomeric forms or a mixture of stereoiso- 20 drying process, the compound was obtained partially or com meric forms in any ratio, or a pharmaceutically acceptable pletely in the form of a salt of the acid used, for example in the salt thereof. form of the acetic acid salt, formic acid salt or trifluoroacetic (7) A compound of the formula I or a pharmaceutically acid salt or hydrochloric acid salt. Likewise starting materials acceptable salt thereof according to one or more of subject or intermediates bearing a basic center like for example a matters (1) to (6) for use as medicament. 25 basic nitrogen were either obtained and used as free base or in (8) A compound of the formula I or a pharmaceutically salt form like, for example, a trifluoroacetic acid salt, a hydro acceptable salt thereof according to one or more of subject bromic acid salt, a Sulfuric acid salt, or a hydrochloric acid matters (1) to (6) for use in the treatment of a disease salt. Room temperature means a temperature of about 20°C. responsive to the inhibition of the LPA receptor LPAR5 or to 25° C. the reduction or inhibition of platelet aggregation orthrom- 30 Abbreviations bus formation or the reduction or inhibition of activation of Acetonitrile MeCN mast cells or the reduction or inhibition of activation of tert-Butyl tRu microglial cells. N,N-Dimethylformamide DMF (9) A compound of the formula I or a pharmaceutically N-Ethylmorpholine NEM acceptable salt thereof according to one or more of subject- 35 Tetrahydrofuran THF matters (1) to (6) for use in the treatment of thromboem Trifluoroacetic acid TFA bolic diseases, deep vein thrombosis, Venous or arterial thromboembolism, thrombophlebitis, coronary or cerebral Example 1 arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, disseminated intravascular coagula- 40 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- tion, cardiovascular disorders, transient ischemic attacks, methyl-1H-pyrazol-3-ylmethoxy-2-methyl-propi strokes, acute myocardial infarction, unstable angina, onic acid chronic stable angina, peripheral vascular disease, preec lampsia/eclampsia, thrombotic cytopenic purpura, inflam O matory disorders, hyperalgesia, asthma, multiple Sclerosis, 45 inflammatory pain, angiogenesis, atherothrombosis, aller ( \, /SA-, gic responses, or restenoses. N OH (10) A compound of the formula I or a pharmaceutically C acceptable salt thereof according to one or more of subject C matters (1) to (6) for use in the treatment of abnormal 50 thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, C stroke, intermittent claudication, bypass grafting of the 55 coronary or peripheral arteries, vessel luminal narrowing, (i) 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- restenosis post coronary venous angioplasty, maintenance methyl-1H-pyrazol-3-yl)-methanol of vascular access patency in long-term hemodialysis patients, pathologic thrombus formation occurring in the To a solution of 5 g of 5-(4-Chloro-phenyl)-1-(2,4- veins of the lower extremities following abdominal, knee 60 dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid or hip Surgery, a risk of pulmonary thromboembolism, or in 130 ml of THF, were added dropwise 40 ml of a 1M disseminated systemic intravascular coagulatopathy solution of borane in THF at room temperature. Then the occurring in vascular systems during septic shock, viral reaction mixture was heated to reflux for 10 h. The reaction infections or cancer. mixture was cooled to room temperature and 20 ml of metha (11) A compound of the formula I or a pharmaceutically 65 nol were carefully added. The solvents were removed under acceptable salt thereof according to one or more of subject reduced pressure and the residue was dissolved in ethyl matters (1) to (6) for use in the treatment of inflammatory acetate. The organic layer was washed with 1 M hydrochloric US 9,346,762 B2 41 42 acid, Saturated Sodium chloride solution and Saturated Example 3 Sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO, filtered and concentrated 1-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- under reduced pressure. The product was obtained as a white methyl-1H-pyrazol-3-ylmethoxy-cyclopentanecar solid and used without further purification. boxylic acid Yield: 4.6 g. (ii) 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-1H-pyrazol-3-ylmethoxy-2-methyl-propi OH onic acid ethyl ester 10 To a solution of 1.6 g of 5-(4-Chloro-phenyl)-1-(2,4- dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl)-methanol in 15 ml of DMF were added 870 mg of sodium hydride (60% in O mineral oil) at room temperature. After 15 min 1.6 g of tet rabutylammonium iodide and 3.4 g of 2-Bromo-2-methyl 15 propionic acid ethyl ester were added and the reaction mix ture was stirred for 16 hat room temperature. After dilution ( \, with Saturated aqueous Sodium hydrogen carbonate Solution the reaction mixture was filtered through a chem ElutR) car C tridge by eluting with ethyl acetate The solvents were C removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gra dient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under C reduced pressure. Yield: 1.3 g. 25 (iii) 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-1H-pyrazol-3-ylmethoxy-2-methyl-propi The title compound was prepared analogously as described onic acid in example 1. MS (ES-): m/e=477, chloro pattern. To a solution of 735 mg of 2-5-(4-Chloro-phenyl)-1-(2,4- 30 dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy-2- methyl-propionic acid ethyl ester in 10 ml THF was added a Example 4 solution of 51 mg of LiOH in 1 ml water at room temperature. After 16h the mixture was brought to pH2 by addition of 1 M 2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo hydrochloric acid. The reaction mixture was concentrated 35 romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-me under reduced pressure and the aqueous layer was extracted thyl-propionic acid with dichloromethane. The combined organic phases were dried over MgSO and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/ OH MeCN gradient with 0.1%TFA). The fractions containing the 40 product were evaporated and lyophilized to yield a white O solid. Yield: 677 mg. MS (ES-): m/e=451, chloro pattern. O Example 2 45 F W \ 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- F N1 methyl-1H-pyrazol-3-ylmethoxy-acetic acid Cl F OH 50

C

55

C (i) Lithium 3-ethoxycarbonyl-2-methyl-3-oxo-1-(4- C trifluoromethyl-phenyl)-propan-1-olate

60 To a solution of 118 ml of lithium bis(trimethylsilyl)amide (Lithium Hexamethyldisilazide: 0.9 M in methylcyclohex ane) was added dropwise over 15 min, 20g of 1-(4-Trifluo C romethyl-phenyl)-propan-1-one in 51 ml methylcyclohexane at while maintaining the reaction mixture at 15-25°C. After The title compound was prepared analogously as described 65 stirring for 2 h, 15 ml of diethyl oxalate were added dropwise in example 1. over 30 min and the reaction mixture was stirred for 16 h. MS (ES-): m/e=423, chloro pattern. Then, the precipitated product was collected by filtration and US 9,346,762 B2 43 44 washed with n-heptane. The isolated crude product was used methoxy-2-methyl-propionic acid ethyl ester in 6 ml THF in the next reaction step after drying in vacuo. Yield: 19 g. was added a solution of 232 mg of LiOH in 1 ml water at room temperature. After 16 h the mixture was brought to pH 2 by (ii) 1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo addition of 1 M hydrochloric acid. The reaction mixture was romethyl-phenyl)-1H-pyrazole-3-carboxylic acid concentrated under reduced pressure and the aqueous layer A solution of 10 g of Lithium 3-ethoxycarbonyl-2-methyl was extracted with dichloromethane. The combined organic 3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate, 6.9 g of phases were dried over MgSO and the solvents were (2,4-Dichloro-phenyl)-hydrazine hydrochloride and 74 ml of removed under reduced pressure. The residue was purified by sulfuric acid (50%) in 184 ml of ethanol was heated to reflux preparative HPLC (C18 reverse phase column, elution with a for 7 h. After cooling to room temperature the organic Sol 10 water/MeCN gradient with 0.1% TFA). The fractions con vents were removed under reduced pressure and the residue taining the product were evaporated and lyophilized to yield was diluted with 100 ml of water and extracted with ethyl a yellow solid. Yield: 634 mg. acetate. The combined organic layers were dried over MgSO MS (ES-): m/e=485, chloro pattern. and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml THF and a solution of 1.4g 15 Example 5 of LiOH in 20 ml water was added at room temperature. The reaction mixture was heated to 60° C. for 7 h. Then, after cooling to room temperature the mixture was acidified to pH 2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluorom 1 by addition of half-concentrated hydrochloric acid. The ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl precipitating product was collected by filtration and washed propionic acid with water. The residue was codistilled twice with dichlo romethane and twice with toluene. The isolated crude product was used in the next reaction step. Yield: 13 g. O OH (iii) (1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo romethyl-phenyl)-1H-pyrazol-3-yl)-methanol 25 C O To a solution of 4.5 g of 1-(2,4-Dichloro-phenyl)-4-me N thyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxy N1 N lic acid in 30 ml of THF, were added dropwise 43 ml of a 1M solution of borane in THF at room temperature. Then the 30 reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of metha nol were carefully added. The solvents were removed under F reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric 35 F F acid, Saturated Sodium chloride solution and Saturated Sodium hydrogen carbonate solution. The organic layers were combined and dried over MgSO, filtered and concentrated The title compound was prepared analogously as described under reduced pressure. The product was obtained as a white in example 5. solid and was used without further purification. 40 MS (ES-): m/e=451, chloro pattern. Yield: 4.3.g. (iv) 2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trif Example 6 luoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2- methyl-propionic acid ethyl ester 2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluorom 45 ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl To a solution of 2 g of 1-(2,4-Dichloro-phenyl)-4-methyl propionic acid 5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl)-methanol in 15 ml of DMF were added 997 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min 1.8g of tet rabutylammonium iodide and 2.9 g of 2-Bromo-2-methyl 50 propionic acid ethyl ester were added and the reaction mix ture was stirred for 16 hat room temperature. After dilution with Saturated aqueous Sodium hydrogen carbonate Solution C O the reaction mixture was filtered through a chem ElutR) car tridge by eluting with ethyl acetate. The solvents were 55 removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gra dient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g. 60 (v) 2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trif luoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2- methyl-propionic acid 65 The title compound was prepared analogously as described To a solution of 1 g of 2-1-(2,4-Dichloro-phenyl)-4-me in example 5. thyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl MS (ES-): m/e=451, chloro pattern. US 9,346,762 B2 45 46 Example 7 (i) 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- methyl-1H-pyrazol-3-yl)-methanol 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- methyl-1H-pyrazol-3-ylmethoxy-butyric acid To a solution of 5 g of 5-(4-Chloro-phenyl)-1-(2,4- dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid in 130 ml of THF, were added dropwise 40 ml of a 1M solution of borane in THF at room temperature. Then, the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of metha 10 nol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric C acid saturated Sodium chloride Solution and Saturated sodium hydrogen carbonate Solution. The combined organic layers 15 were dried over MgSO filtered and concentrated under reduced pressure. The product was obtained as a white solid and was used without further purification. Yield: 4.6 g. C (ii) 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- The title compound was prepared analogously as described 4-methyl-1H-pyrazol-3-ylmethoxy-2-methyl-propi in example 5. onic acid ethyl ester MS (ES-): m/e=452, chloro pattern. To a solution of 1.6 g of 5-(4-Chloro-phenyl)-1-(2,4- dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl)-methanol in 15 Example 8 25 ml of DMF were added 870 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min, 1.6 g of 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- tetrabutylammonium iodide and 3.4 g of 2-Bromo-2-methyl methyl-1H-pyrazol-3-ylmethoxy-propionic acid propionic acid ethyl ester were added and the reaction mix ture was stirred for 16 hat room temperature. After dilution 30 with Saturated aqueous sodium hydrogen carbonate Solution the reaction mixture was filtered through a chem Elut(R) car ) { tridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gra 35 dient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g. (iii) 2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- 40 4-methyl-1H-pyrazol-3-ylmethoxy-2-methyl-propi onic acid To a solution of 1.3 g of 2-5-(4-Chloro-phenyl)-1-(2,4- The title compound was prepared analogously as described dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy-2- in example 5. 45 methyl-propionic acid ethyl ester in 10 ml THF was added a solution of 130 mg of LiOH in 3 ml water at room tempera MS (ES-): m/e=439, chloro pattern. ture. After 5h the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concen Example 9 trated under reduced pressure and the aqueous layer was 50 extracted with dichloromethane. The combined organic 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- phases were dried over MgSO and the solvents were 4-methyl-1H-pyrazol-3-ylmethoxy-2-methyl-pro removed under reduced pressure. The isolated crude product pionylamino-methyl)-benzoic acid was used in the next reaction step. Yield: 1.5 g.

55 (iv) 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy-2-me thyl-propionylamino-methyl)-benzoic acid To a solution of 710 mg of 2-5-(4-Chloro-phenyl)-1-(2,4- 60 dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy-2- methyl-propionic acid in 5 ml of DMF, 360 mg of N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 345 mg of pentafluorophenol and 392 mg of NEM were added and the reaction mixture was stirred for 3 hat C OH 65 room temperature. Then, 353 mg of 4-Aminomethyl-benzoic acid and 540 mg of NEM in 5 ml of DMF were added. After 16 h the reaction mixture was diluted with water and filtered US 9,346,762 B2 47 48 through a chem Elut(R) cartridge by eluting with ethyl acetate. (iii) (1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo The solvents were removed under reduced pressure and the romethyl-phenyl)-1H-pyrazol-3-yl)-methanol residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% To a solution of 4.5 g of 1-(2,4-Dichloro-phenyl)-4-me TFA). The fractions containing the product were evaporated 5 thyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxy and lyophilized to yield a white solid. Yield: 288 mg. lic acid in 30 ml of THF, were added dropwise 43 ml of a 1M MS (ES-): m?e=586, chloro pattern. solution of borane in THF at room temperature. Then the reaction mixture was heated to reflux for 10 h. The reaction Example 10 mixture was cooled to room temperature and 20 ml of metha 10 nol were carefully added. The solvents were removed under 4-(2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trif reduced pressure and the residue was dissolved in ethyl luoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2- acetate. The organic layer was washed with 1 M hydrochloric methyl-propionylamino-methyl)-benzoic acid acid, Saturated sodium chloride Solution and Saturated Sodium hydrogen carbonate solution. The combined organic 15 layers were dried over MgSO, filtered and concentrated under reduced pressure. The product was obtained as a white solid and used without further purification. Yield: 4.3 g. (iv) 2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trif luoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2- methyl-propionic acid ethyl ester To a solution of 2 g of 1-(2,4-Dichloro-phenyl)-4-methyl 5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl)-methanol in 25 12 ml of DMF were added 997 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min, 1.8 g of tetrabutylammonium iodide and 2.9 g of 2-Bromo-2- methyl-propionic acid ethyl ester were added and the reaction HO mixture was stirred for 16 hat room temperature. After dilu 30 tion with Saturated aqueous Sodium hydrogen carbonate solu tion the reaction mixture was filtered through a chem ElutR) (i) Lithium 3-ethoxycarbonyl-2-methyl-3-oxo-1-(4- cartridge by eluting with ethyl acetate. The solvents were trifluoromethyl-phenyl)-propan-1-olate removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gra To a solution of 118 ml of lithium bis(trimethylsilyl)amide 35 dient of n-heptane/ethyl acetate. The fractions containing the (Lithium Hexamethyldisilazide: 0.9 M in methylcyclohex product were combined and the solvent evaporated under ane) was added dropwise over 15 min 20 g of 1-(4-Trifluo reduced pressure. Yield: 735 mg. romethyl-phenyl)-propan-1-one in 51 ml methylcyclohexane (v) 2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trif at while maintaining the reaction mixture at 15-25°C. After a luoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2- stirring for 2 h, 15 ml of diethyl oxalate were added dropwise methyl-propionic acid over 30 min and the reaction mixture was stirred for 16 h. Then, the precipitated product was collected by filtration and To a solution of 735 mg of 2-1-(2,4-Dichloro-phenyl)-4- washed with n-heptane. The isolated crude product was used methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl in the next reaction step after drying in vacuo. Yield: 19 g. 45 methoxy-2-methyl-propionic acid ethyl ester in 5 ml THF was added a solution of 51 mg of LiOH in 1 ml water at room (ii) 1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo temperature. After 5 h the mixture was brought to pH 2 by romethyl-phenyl)-1H-pyrazole-3-carboxylic acid addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer A solution of 10 g of Lithium 3-ethoxycarbonyl-2-methyl- 50 was extracted with dichloromethane. The combined organic 3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate, 6.9 g of phases were dried over MgSO and the solvents were (2,4-Dichloro-phenyl)-hydrazine hydrochloride and 74 ml of removed under reduced pressure. The isolated crude product sulfuric acid (50%) in 184 ml of ethanol was heated to reflux was used in the next reaction step. Yield: 677 mg. for 7 h. After cooling to room temperature the organic Sol vents were removed under reduced pressure and the residue 55 (vi) 4-(2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4- was diluted with 100 ml of water and extracted with ethyl trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2- acetate. The combined organic layers were dried over MgSO methyl-propionylamino-methyl)-benzoic acid and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml THF and a solution of 1.4g To a solution of 600 mg of 2-1-(2,4-Dichloro-phenyl)-4- of LiOH in 20 ml water was added at room temperature. The 60 methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl reaction mixture was heated to 60° C. for 7 h. Then, after methoxy-2-methyl-propionic acid in 9 ml of DMF, 283 mg cooling to room temperature the mixture was acidified to pH of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydro 1 by addition of half-concentrated hydrochloric acid. chloride (EDC), 271 mg of pentafluorophenol and 300 mg of The precipitating product was collected by filtration and NEM was added and the reaction mixture was stirred for 3 h washed with water. The residue was codistilled twice with 65 at room temperature. Then, 278 mg of 4-Aminomethyl-ben dichloromethane and twice with toluene. The isolated crude Zoic acid and 424 mg of NEM in 10 ml of DMF were added. product was used in the next reaction step. Yield: 13 g. After 16 h the reaction mixture was diluted with water and US 9,346,762 B2 49 50 filtered through a chem Elut(R) cartridge by eluting with ethyl Example 13 acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient 4-(2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluo with 0.1% TFA). The fractions containing the product were 5 romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-me evaporated and lyophilized to yield a white solid. Yield: 204 thyl-propionylamino-methyl)-benzoic acid ng. MS (ES-): m/e=618, chloro pattern. Example 11 10 O 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- H 4-methyl-1H-pyrazol-3-ylmethoxy-acetylamino- O N OH methyl)-benzoic acid C 15 O N N1 N O o O / \N \- 2O N1 N F C H C Fr Y. 25

C HO O 30 The title compound was prepared analogously as described in example 11. The title compound was prepared analogously as described MS (ES-): m?e=584, chloro pattern. in example 11. MS (ES-): m?e=556, chloro pattern. Example 12 35 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- Example 14 4-methyl-1H-pyrazol-3-ylmethoxy-butyrylamino methyl)-benzoic acid 40 4-(2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluo romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-me

OH thyl-propionylamino-methyl)-benzoic acid

45 O O H O N OH NH 50

O O

W N 55 N C C

60

The title compound was prepared analogously as described The title compound was prepared analogously as described 65 in example 11. in example 11. MS (ES-): m?e=586, chloro pattern. MS (ES-): m?e=584, chloro pattern. US 9,346,762 B2 51 52 Example 15 (i) 4-(2-Bromo-propionylamino)-benzoic acid methyl ester 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- To a solution of 1.1 g of 4-Amino-benzoic acid methyl ester 4-methyl-1H-pyrazol-3-ylmethoxy-propiony in 17 ml of toluene were added 2.2 ml of pyridine and 1.5g of lamino-methyl)-benzoic acid 2-Bromo-propionyl bromide at room temperature. After 16h the reaction mixture was diluted with water and filtered through a chem Elut(R) cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the OH crude product was purified by chromatography on silica gel 10 eluting with a gradient of n-heptane/ethyl acetate. The frac tions containing the product were combined and the Solvent evaporated under reduced pressure. Yield: 2 g. (ii) 4-2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4- 15 trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy propionylamino-benzoic acid To a solution of 100 mg of 1-(2,4-Dichloro-phenyl)-4- methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl)- methanol in 3 ml of DMF were added 54 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min, 100 mg of tetrabutylammonium iodide and 117 mg of C 4-(2-Bromo-propionylamino)-benzoic acid methyl ester C were added and the reaction mixture was heated to 80°C. for 25 8 h. After cooling to room temperature and dilution with 1 M aqueous hydrochloric acid the reaction mixture was filtered through a chem Elut(R) cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the C residue was purified by preparative HPLC (C18 reverse phase 30 column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated The title compound was prepared analogously as described and lyophilized to yield a white solid. Yield: 24 mg. in example 11. MS (ES-): m?e=590, chloro pattern. MS (ES-): m?e=570, chloro pattern. 35 Example 17 Example 16 4-2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-1H-pyrazol-3-ylmethoxy-3-methyl-bu 4-2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo tyrylamino-benzoic acid romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propio 40 nylamino-benzoic acid

HO

OH 45

NH 50 N

55

C C C

60

C C 65 The title compound was prepared analogously as described in example 16. MS (ES-): m?e=584, chloro pattern. US 9,346,762 B2 53 54 Example 18 Example 20 4-2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluo 4-2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluo romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propio- 5 romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propio nylamino-benzoic acid nylamino-benzoic acid

OH OH 10

O

NH NH 15

O

2O

C

25

C 30

The title compound was prepared analogously as described The title compound was prepared analogously as described in example 16. in example 16. 35 MS (ES-): m?e=556, chloro pattern. MS (ES-): m?e=556, chloro pattern. Example 21 Example 19 40 4-2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl methoxy)-propionylamino-benzoic acid 4-2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4- ylmethoxy)-propionylamino-benzoic acid

45 OH

OH NH 50 N O O N N O M N H 55 N

The title compound was prepared analogously as described as The title compound was prepared analogously as described in example 16. in example 16. MS (ES-): m/e=590. MS (ES-): m/e=392. US 9,346,762 B2 55 56 Example 22 Example 25 4-2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-pro pionylamino-benzoic acid 4-2-(2-Methyl-2H-indazol-3-ylmethoxy)-propiony lamino-benzoic acid

OH

OH

O O N 10 O M | 2N N O / N H 15 The title compound was prepared analogously as described in example 16. MS (ES-): m/e=352. The title compound was prepared analogously as described in example 16. 2O Example 26 MS (ES-): m/e=440. Example 23 4-2-3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyra Zol-4-ylmethoxy-propionylamino-benzoic acid 4-2-1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol 4-ylmethoxy-propionylamino-benzoic acid 25

OH

N OH 30 O O Y O / O O N N N O M N H 35

O \ 40 The title compound was prepared analogously as described The title compound was prepared analogously as described in example 16. in example 16. MS (ES-): m/e=484. 45 MS (ES-): m?e=522. Example 24 4-2-5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H- Example 27 pyrazol-4-ylmethoxy)-propionylamino-benzoic acid F 50 4-2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl methoxy)-propionylamino-benzoic acid

OH OH ( ! 55 N O O Y O O Y

N H 1. M 60 N O / s S le The title compound was prepared analogously as described 65 The title compound was prepared analogously as described in example 16. in example 16. MS (ES-): m/e=488. MS (ES-): m/e=446. US 9,346,762 B2 57 58 Example 28 cium citrate solution (10 mM in HO) and 20 ul of fibrinogen solution (20 mg/ml HO) were added. The aggregation assay 4-2-(1.5-Diphenyl-1H-pyrazol-3-ylmethoxy)-pro was performed in the assay cuvette at 37° C. and with 1.200 pionylamino-benzoic acid rpm stirring. To determine the ECso, eight assay cuvettes were loaded as described above with different concentrations of LPA. Aggregation was measured over 6 minutes at 37°C. with 1200 rpm (revolutions per minute) stirring. Results of the assay are expressed as % activation, and are calculated using maximum aggregation (T,) or area under curve 10 OH (AUC) of the absorbance over 6 minutes. The inhibitory effect (ICs) of the test compounds was determined as the reduction of the maximal aggregation. Test compound was added prior starting the experiment with an incubation time of the test compound of 5 minutes at 37° C. with 1200 rpm 15 stirring. The ICso data of the above described platelet aggre N gation assay using human washed platelets for exemplary compounds of the present invention are shown in Table 1. The title compound was prepared analogously as described in example 16. TABLE 1 MS (ES-): m/e=440. Example ICso (LIM) Pharmacological Testing 7 4.7 The ability of the compounds of the formula Ito inhibit or 8 4.1 bind the LPA receptor LPAR5 can be assessed by determining 9 2.9 the effect on cellular function. This ability of such compounds 25 12 4.3 was evaluated in a platelet aggregation assay Such as the Born 15 6.5 method using single cuvettes and for mast cells and microglia 17 15.9 cells with the Fluorometric Imaging Plate Reader (FLIPR) assay by Molecular Devices Inc. B) Use of the Fluorometric Imaging Plate Reader (FLIPR) A) Aggregation Assay for Washed Human Blood Platelets 30 Assay for the Determination of Intracellular Ca" Release in (Thrombocytes) Human Mast Cell Line HMC-1 and the Murine Microglia cell Whole blood was collected from healthy volunteers using line BV-2 3x20 ml syringes containing each /10 volume of buffered The ability of the compounds of the formula Ito inhibit or citrate. The anticoagulated whole blood was transferred into bind the LPA receptor LPAR5 can be assessed by determining 50ml polypropylene conical tubes (30 ml pertube). The tubes 35 the intracellular Ca" release inhuman oranimal cells. For the were centrifuged for 10 minutes at 150xg at room tempera analysis of activating potential of LPA and the inhibitory ture without using the centrifuge brake. This procedure effects of compounds of the formula I two cell lines were used results in a lower phase of cellular components and a Super with high LPAR5 expression, the human mast cell line natant (upper phase) of platelet rich plasma (PRP). The PRP HMC-1 and the murine microglia cell line BV-2 (FIGS. 1 and phase was collected from each tube and pooled for each 40 2). For the FLIPR assay using human mast cells in a 96-well donor. To avoid carry over of cellular components following format, HMC-1 suspension cells from flask culture were har first centrifugation, approximately 5 ml of PRP was left in the vested, resuspended and counted. 14x10 HMC-1 cells were tube. The platelet concentration was determined usinga ABX transferred into a new 50 ml tube, centrifuged for 3 minutes at Micros 60 counter. The PRP phase was transferred to a new 540xg. The resulting cell pellet at the bottom of the tube was 50 ml tube. After 10 minutes standing at room temperature, 1 45 resuspended with 15 ml loading buffer (loading buffer con ul PGI, (1 mM in Tris-HC1/pH 8.8) and 180 ul ACD/A were tained HBSS buffer (pH 7.4), 0.1% BSA (bovine serum albu added per ml PRP. The PRP was then transferred to new 10 ml min), 2 uM FLUO-4 dye; HBSS buffer (pH 7.4) contained tube and centrifuged for 10 minutes at 500xg. After centrifu 1xEHBSS, 20 mM HEPES, 0.01% Pluronic F-127, 2.5 mM gation a cellular pellet is visible at the bottom of the tube. The Probenicid). Supernatant was carefully discarded and the cellular pellet, 50 Cells in loading buffer were incubated for 45-60 minutes at consisting of human blood platelets was then dissolved in 10 37°C. After incubation cells were centrifuged for 3 minutes at ml bufferT (buffer T composition: 145 mMNaCl, 5 mMKC1, 540xg and resuspended with 21 ml of HBSS buffer (pH 7.4). 0.1 mMMgCl2x6HO, 15 mMHEPES, 5.5 mMglucose, pH Each well of a poly-D-lysine coated 96-well-plate was filled 7.4). Platelet concentration in this solution was determined with 150 ulcell solution, an equivalent of 100 000 cells/well. and buffer T was added to obtain a final concentration of 55 The 96-well-plate was centifuged for 2 minutes at 100xg 3.5x10 platelets per ml. (without brake) prior a recovery time of 30 minutes at 37°C. After 10 minutes at room temperature, 1 ul PGI per ml After this procedure cells were stimulated with LPA (in platelet solution was added and distributed into new 10 ml HBSS pH 7.4 and 0.1% BSA) to determine the ECs of LPA tubes. After a centrifugation step, 10 minutes at 500xg, Super in HMC-1 cells. For the determination of the inhibitory effect natant was discarded and the platelets were resuspended in 60 of compounds of the formula I, test compounds were added to buffer T to a final concentration of 3.5x10 platelets per ml the cells in the 96-well-plate 10 minutes prior the addition of buffer T. Before use, platelet-containing buffer equilibrated LPA. Results of the assay are expressed as % activation, and for 30 minutes at room temperature. The human platelet are calculated using maximum peak of activation (A). The aggregation assay was performed in single use cuvettes using ICso data of the above described FLIPR assay using human the Platelet Aggregation Profiler(R) (PAP-4 or -8E, BIO/DATA 65 mast cell line HMC-1 for exemplary compounds of the Corporation). For a single experiment, 320 ul of platelet present invention are shown in Table 2. Adherent BV-2 cells Solution were transferred into an assay cuvette, 20 Jul of cal were seeded onto poly-D-lysine coated 96-well-plates US 9,346,762 B2 59 60 (100000 cells/well) the day before performing the FLIPR RandR are independently of each other selected from the assay. The density of the cells in the 96-well-plate at the day series consisting of hydrogen, fluorine and (C-C)- of the FLIPR assay should be 90%. After aspiration of the alkyl: culture media, BV-2 cells were incubated for 30 minutes at or the groups R and R together with the carbon atom 37° C. with loading buffer and recovered in 150 ul HBSS carrying them forma (C-C,)-cycloalkane ring which is buffer for 30 minutes at 37° C. After this procedure cells were unsubstituted or substituted by one or more identical or stimulated with LPA (in HBSS pH 7.4 and 0.1% BSA) to different substituents selected from the series consisting determine the ECso of LPA in BV-2 cells. For the determina of fluorine and (C-C)-alkyl: tion of the inhibitory effect of compounds of the formula I, R'', R', R' and R'' are independently of each other test compounds were added to the cells in the 96-well-plate 10 10 minutes prior the addition of LPA. The ICso data of the above Selected from the series consisting of hydrogen and (C- described FLIPR assay using the murine microglia cell line Cl)-alkyl: BV-2 for exemplary compounds of the present invention are Ar is selected from the series consisting of phenyl, naph shown in Table 3. thyl and an aromatic, 5-membered or 6-membered, 15 monocyclic heterocycle which comprises one or two TABLE 2 identical or different ring heteroatoms selected from the series consisting of N, O and S, which are all unsubsti Example ICso (IM) tuted or substituted by one or more identical or different 1 8.3 Substituents selected from the series consisting of halo 3 8.8 gen, (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-cy 4 6.6 cloalkyl-(C-C)-alkyl-, cyano and (C-C)-alkyl-O-: 7 11.4 8 6.3 V is selected from the series consisting of R' N(R') , 9 1.3 and in this case G and Mare not present, or 10 O.O3 V is selected from the series consisting of N(R') , 11 8.6 25 —N(R')–(C-C)-alkyl-, -O-and-O-(C1-C4)- 12 6.3 13 1.3 alkyl-, and in this case G is selected from the series 14 3.4 consisting of a direct bond and phenylene which is 15 8.8 unsubstituted or substituted by one or more identical or 16 4.1 17 4.2 different substituents selected from the series consisting 30 18 3.8 of halogen, (C-C)-alkyl, cyano and (C-C)-alkyl 2O 5.2 O— provided that G is not a direct bond if V is 22 16 - N(R')—or -O-, and M is selected from the series consisting of R'' —O C (O) and R' N(R') C(O) ; 35 wherein all alkyl groups are unsubstituted or substituted by TABLE 3 one or more fluorine Substituents, and all cycloalkyl Example ICso (IM) groups are unsubstituted or Substituted by one or more identical or different substituents selected from the 9 1.8 10 O.2 series consisting of fluorine and (C-C)-alkyl; 40 provided that that the compound is not: 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- The invention claimed is: methyl- 1 H-pyrazol-3-ylmethoxyl)-2-methyl-propio 1. A compound of the formula I, nylamino-methyl)-benzoic acid; 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- 45 methyl-1H-pyrazol-3-ylmethoxyl-acetylamino-me I thyl)-benzoic acid; H H R R5 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- R2 V. M methyl-1H-pyrazol-3-ylmethoxy-butyrylamino-me ^ N1 thyl)-benzoic acid; N° 50 4-(2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- \N- i?-Rs/ O methyl-1H-pyrazol-3-ylmethoxy-propionylamino A methyl)-benzoic acid; and R1 provided that when R' is 2,4-dichlorophenyl, R and Rare methyl, R is 4-methylphenyl, 4-trifluoromethoxyphenyl or in any of its stereoisomeric forms or a mixture of stereoiso 55 2,4-dichlorophenyl, V is —NH-CH G is phenyl and M meric forms in any ratio, or a pharmaceutically acceptable is COOH, R is not methyl; and salt thereof, provided that when R' is 2,4-dichlorophenyl, RandR are wherein methyl, R is 4-trifluoromethylphenyl or 4-trifluo R" is selected from the series consisting of hydrogen, (C- romethoxyphenyl, V is NH R is not methyl; and C)-alkyl, (C-C)-cycloalkyl, (C-C)-cycloalkyl-(C- 60 provided that when R' is 4-trifluoromethoxyphenyl, Rand Cl)-alkyl-, Ar and Ar—(C-C)-alkyl-, Rare methyl, R is 2,4-dichlorophenyl, V is NH RandR are independently of each otherselected from the CH. Gisphenyland Mis-COOH, R is not methyl. series consisting of hydrogen, halogen, (C-C)-alkyl, 2. A compound of the formula I according to claim 1, (C-C)-cycloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, wherein Ar, Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, (C-C)- 65 R" is selected from the series consisting of hydrogen, (C- cycloalkyl-O-, (C-C)-cycloalkyl-(C-C)-alkyl C)-alkyl, (C-C)-cycloalkyl, Ar and Ar—(C-C)- O—, Ar—O—and Ar—(C-C)-alkyl-O-, alkyl-, US 9,346,762 B2 61 62 RandR are independently of each otherselected from the Substituents selected from the series consisting of halo series consisting of hydrogen, (C-C)-alkyl, (C-C2)- gen, (C-C)-alkyl, (C-C) -cycloalkyl and (C-C)- cycloalkyl, (C-C)-cycloalkyl-(C-C)-alkyl-, Ar, Ar— alkyl-O : (C-C)-alkyl-, (C-C)-alkyl-O-, (C-C)-cycloalkyl V is selected from the series consisting of N(R')—and O—, (C-C)-cycloalkyl-(C-C)-alkyl-O-, Ar—O— 5 N(R')—(C-C)-alkyl and Ar—(C-C)-alkyl-O-, G is selected from the series consisting of a direct bond and RandRare independently of each other selected from the phenylene which is unsubstituted or substituted by one series consisting of hydrogen and (C-C)-alkyl; or more identical or different substituents selected from or the groups R and R together with the carbon atom the series consisting of halogen, (C-C)-alkyl and (C- carrying them forma (C-C)-cycloalkanering which is 10 C)-alkyl-O provided that G is not a direct bond if V unsubstituted or substituted by one or more identical or different substituents selected from the series consisting is N(R') ; and of fluorine and (C-C)-alkyl, M is selected from the series consisting of R'-O-C R'', R', R'' and R'' are independently of each other (O) and R' N(R') C(O) ; Selected from the series consisting of hydrogen and (C- 15 wherein all alkyl groups are unsubstituted or substituted by Cl)-alkyl: one or more fluorine Substituents, and all cycloalkyl Ar is selected from the series consisting of phenyl, naph groups are unsubstituted or Substituted by one or more thyl and an aromatic, 5-membered or 6-membered, identical or different substituents selected from the monocyclic heterocycle which comprises one or two series consisting of fluorine and (C-C)-alkyl; identical or different ring heteroatoms selected from the in any of its stereoisomeric forms or a mixture of Stereoi series consisting of N, O and S, which are all unsubsti Someric forms in any ratio, or a pharmaceutically tuted or substituted by one or more identical or different acceptable salt thereof. Substituents selected from the series consisting of halo 4. A compound of the formula I according to claim 1, gen, (C-C)-alkyl, (C-C) -cycloalkyl, (C-C)-cy wherein cloalkyl-(C-C)-alkyl-, cyano and (C-C)-alkyl-O-, 25 R" is selected from the series consisting of (C1-C4)-alkyl, V is selected from the series consisting of N(R') , Ar and Ar—(C-C)-alkyl-, - N(R') (C-C)-alkyl-and-O (C-C)-alkyl; RandR are independently of each other selected from the G is selected from the series consisting of a direct bond and series consisting of hydrogen, (C-C)-alkyl, Ar, Ar— phenylene which is unsubstituted or substituted by one (C-C)-alkyl-, and Ar—O—; or more identical or different substituents selected from 30 RandR are independently of each other selected from the the series consisting of halogen, (C-C)-alkyl, cyano series consisting of hydrogen and (C-C)-alkyl; and (C-C)-alkyl-O provided that G is not a direct or the groups R and R together with the carbon atom bond if V is N(R') ; and carrying them forma (C-C,)-cycloalkane ring which is M is selected from the series consisting of R'—O C unsubstituted or substituted by one or more identical or (O) and R' N(R') C(O) ; 35 different substituents selected from the series consisting wherein all alkyl groups are unsubstituted or substituted by of fluorine and (C-C)-alkyl, one or more fluorine Substituents, and all cycloalkyl R'' and R'' are independently of each other selected from groups are unsubstituted or Substituted by one or more the series consisting of hydrogen and (C-C)-alkyl; identical or different substituents selected from the Ar is selected from the series consisting of phenyl, naph series consisting of fluorine and (C-C)-alkyl; 40 thyl and an aromatic, 5-membered or 6-membered, in any of its stereoisomeric forms or a mixture of stereoi monocyclic heterocycle which comprises one or two Someric forms in any ratio, or a pharmaceutically identical or different ring heteroatoms selected from the acceptable salt thereof. series consisting of N, O and S, which are all unsubsti 3. A compound of the formula I according to claim 1, tuted or substituted by one or more identical or different wherein 45 Substituents selected from the series consisting of halo R" is selected from the series consisting of (C-C)-alkyl, gen, (C-C)-alkyl, (C-C) -cycloalkyl and (C-C)- (C-C)-cycloalkyl, Ar and Ar—(C-C)-alkyl-, alkyl-O : RandR are independently of each otherselected from the V is selected from the series consisting of N(R')—and series consisting of hydrogen, (C-C)-alkyl, Ar. N(R')—(C-C)-alkyl-, and Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, (C-C)-cy 50 G is selected from the series consisting of a direct bond and cloalkyl-O-, Ar—O— and Ar—(C-C)-alkyl-O-; phenylene which is unsubstituted or substituted by one RandRare independently of each other selected from the or more identical or different substituents selected from series consisting of hydrogen and (C-C)-alkyl; the series consisting of halogen, (C-C)-alkyl and (C- or the groups R and R together with the carbon atom Cl)-alkyl-O-, provided that G is not a direct bond if V carrying them forma (C-C)-cycloalkanering which is 55 is N(R'), and M is R'-O-C(O)–: unsubstituted or substituted by one or more identical or wherein all alkyl groups are unsubstituted or substituted by different substituents selected from the series consisting one or more fluorine Substituents, and all cycloalkyl of fluorine and (C-C)-alkyl, groups are unsubstituted or Substituted by one or more R'', R', R'' and R'' are independently of each other identical or different substituents selected from the Selected from the series consisting of hydrogen and (C- 60 series consisting of fluorine and (C-C)-alkyl; Cl)-alkyl: in any of its stereoisomeric forms or a mixture of Stereoi Ar is selected from the series consisting of phenyl, naph Someric forms in any ratio, or a pharmaceutically thyl and an aromatic, 5-membered or 6-membered, acceptable salt thereof. monocyclic heterocycle which comprises one or two 5. A compound of the formula I according to claim 1, identical or different ring heteroatoms selected from the 65 wherein series consisting of N, O and S, which are all unsubsti R" is selected from the series consisting of (C-C)-alkyl, tuted or substituted by one or more identical or different Ar and Ar—(C-C)-alkyl-, US 9,346,762 B2 63 64 RandR are independently of each otherselected from the 4-2-3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4- series consisting of hydrogen, (C-C)-alkyl, Ar—and ylmethoxy-propionylamino-benzoic acid, Ar—O—; 4-2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl RandR are independently of each otherselected from the methoxy)-propionylamino-benzoic acid, and series consisting of hydrogen and (C-C)-alkyl: 4-2-(1.5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propiony or the groups R and R together with the carbon atom lamino-benzoic acid, carrying them forma (C-C)-cycloalkane ring which is in any of its stereoisomeric forms or a mixture of Stereoi unsubstituted or substituted by one or more fluorine Someric forms in any ratio, or a pharmaceutically Substituents; acceptable salt thereof. 10 7. A compound of the formula I according to claim 1, R'' and R'' are independently of each other selected from wherein the series consisting of hydrogen and (C-C)-alkyl: R" is selected from the series consisting of (C-C)-alkyl, Ar is selected from the series consisting of phenyl, naph Ar and Ar—(C-C)-alkyl-, thyl and an aromatic, 5-membered or 6-membered, wherein the Ar is selected from the series consisting of monocyclic heterocycle which comprises one or two 15 phenyl, naphthyl and an aromatic, 5-membered or identical or different ring heteroatoms selected from the 6-membered, monocyclic heterocycle which com series consisting of N, O and S, which are all unsubsti prises one or two identical or different ring heteroat tuted or substituted by one or more identical or different oms selected from the series consisting of N, O and S. Substituents selected from the series consisting of halo which are all unsubstituted or substituted by one or gen, (C-C)-alkyl, (C-C)-cycloalkyl and (C-C)- more identical or different substituents selected from alkyl-O : the series consisting of halogen, (C-C)-alkyl, (C- V is selected from the series consisting of N(R')—and Cz)-cycloalkyl and (C-C)-alkyl-O-, N(R')—(C-C)-alkyl-, and R° and Rare independently of each other selected from the G is selected from the series consisting of a direct bond and series consisting of hydrogen, (C-C)-alkyl, Ar—and phenylene which is unsubstituted or substituted by one 25 Ar—O—, or more identical or different substituents selected from wherein the Ar is selected from the series consisting of the series consisting of halogen, (C-C)-alkyl and (C- phenyl, naphthyl and an aromatic, 5-membered or Cl)-alkyl-O-, provided that G is not a direct bond if V 6-membered, monocyclic heterocycle which com is N(R'), and M is R'-O-C(O)–: prises one or two identical or different ring heteroat wherein all alkyl groups are unsubstituted or substituted by 30 oms selected from the series consisting of N, O and S. one or more fluorine substituents; which are all unsubstituted or substituted by one or in any of its stereoisomeric forms or a mixture of stereoi more (C-C)-alkyl, Someric forms in any ratio, or a pharmaceutically wherein the alkyl group is substituted by one or more acceptable salt thereof. fluorine substituents; 6. A compound of the formula I according to claim 1, 35 RandR are independently of each other selected from the selected from the series consisting of series consisting of hydrogen and (C-C)-alkyl; and V 4-(2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluo is selected from the series consisting of N(R)- and romethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl - N(R)-(C-C)-alkyl-; in any of its stereoisomeric propionylamino-methyl)-benzoic acid, forms or a mixture of stereoisomeric forms in any ratio, 4-(2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluorom 40 or a pharmaceutically acceptable salt thereof. ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-pro 8. A compound of the formula I according to claim 7. pionylamino-methyl)-benzoic acid, wherein 4-(2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluorom R" is selected from the series consisting of Ar and Ar— ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-2-methyl-pro (C-C)-alkyl-, pionylamino-methyl)-benzoic acid, 45 wherein the Ar is selected from the series consisting of 4-2-1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluorom phenyl or naphthyl, each of which is unsubstituted or ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propiony substituted by one or more identical or different sub lamino-benzoic acid, stituents selected from the series consisting of halo 4-2-5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- gen, (C-C)-alkyl, (C-C,)-cycloalkyl and (C-C)- methyl-1H-pyrazol-3-ylmethoxy-3-methyl-butyry 50 alkyl-O : laminol-benzoic acid, RandR are independently of each other selected from the 4-2-1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluorom series consisting of hydrogen, (C-C)-alkyl and Ar—, ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propiony wherein the Ar is selected from the series consisting of lamino-benzoic acid, phenyl and naphthyl, each of which is unsubstituted 4-2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-yl 55 or Substituted by one or more (C-C)-alkyl, methoxy)-propionylamino-benzoic acid, wherein the alkyl group is substituted by one or more 4-2-1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluorom fluorine Substituents; in any of its stereoisomeric ethyl-phenyl)-1H-pyrazol-3-ylmethoxy-propiony forms or a mixture of Stereoisomeric forms in any lamino-benzoic acid, ratio, or a pharmaceutically acceptable salt thereof. 4-2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)- 60 9. A compound of the formula I according to claim 8. propionylamino-benzoic acid, wherein 4-2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propiony R" is phenyl, unsubstituted or substituted by one or more lamino-benzoic acid, identical or different substituents selected from the 4-2-1-Benzyl-3-(3-methoxy-phenyl)-1 H-pyrazol-4-yl series consisting of halogen, (C-C)-alkyl, (C-C)- methoxy-propionylamino-benzoic acid, 65 cycloalkyl and (C-C)-alkyl-O-, 4-2-5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H R° and Rare independently of each other selected from the pyrazol-4-ylmethoxy)-propionylamino-benzoic acid, series consisting of hydrogen, (C-C)-alkyland phenyl, US 9,346,762 B2 65 66 unsubstituted or substituted by one or more (C-C)- V is selected from the series consisting of R' N(R') , alkyl, wherein the alkyl group is substituted by one or and in this case G and Mare not present, or more fluorine substituents; V is selected from the series consisting of N(R') — in any of its stereoisomeric forms or a mixture of stereoi N(R')–(C-C)-alkyl-, - O - and —O (C-C)- Someric forms in any ratio, or a pharmaceutically alkyl-, in this case G is selected from the series consist acceptable salt thereof. ing of a direct bond and phenylene which is 10. A compound of the formula I according to claim 9. unsubstituted or substituted by one or more identical or wherein different substituents selected from the series consisting R" is phenyl substituted by one or more halogen; of halogen, (C-C)-alkyl, cyano and (C-C)-alkyl R is hydrogen or (C-C)-alkyl; and 10 O— provided that G is not a direct bond if V is R is phenyl substituted by one or more CF; N(R')—or —O and in any of its stereoisomeric forms or a mixture of stereoi M is selected from the series consisting of R' —O C Someric forms in any ratio, or a pharmaceutically (O) and R' N(R') C(O) ; acceptable salt thereof. 15 wherein all alkyl groups are unsubstituted or substituted by 11. A compound of the formula I according to claim 10, one or more fluorine Substituents, and all cycloalkyl wherein groups are unsubstituted or Substituted by one or more R is (C-C)-alkyl; and identical or different substituents selected from the R is hydrogen. series consisting of fluorine and (C-C)-alkyl; 12. A compound of the formula I according to claim 10, in any of its stereoisomeric forms or a mixture of Stereoi wherein Someric forms in any ratio, or a pharmaceutically R" and Rare each (C-C)-alkyl. acceptable salt thereof. 13. A method for the inhibition of the LPA receptor LPAR5 14. A method according to claim 13 wherein the method is or the reduction or inhibition of platelet aggregation orthrom for the treatment of thromboembolic diseases, deep vein bus formation or the reduction or inhibition of activation of 25 thrombosis, venous or arterial thromboembolism, throm mast cells or the reduction or inhibition of activation of micro bophlebitis, coronary or cerebral arterial thrombosis, cerebral glial cells in a mammal in need thereof, the method compris embolism, renal embolism, pulmonary embolism, dissemi ing administering the mammal an compound of formula I, nated intravascular coagulation, cardiovascular disorders, transient ischemic attacks, strokes, acute myocardial infarc 30 I tion, unstable angina, chronic stable angina, peripheral vas R2 H R R5 cular disease, preeclampsia/eclampsia, thrombotic cytopenic purpura, inflammatory disorders, hyperalgesia, asthma, mul M X- N1 tiple Sclerosis, inflammatory pain, angiogenesis, athero N X 35 thrombosis, allergic responses, or restenosis. R11 'SMYR3 O 15. A method according to claim 13 wherein the method is for the treatment of abnormal thrombus formation, acute wherein myocardial infarction, unstable angina, thromboembolism, R" is selected from the series consisting of hydrogen, (C- acute vessel closure associated with thrombolytic therapy or C)-alkyl, (C-C)-cycloalkyl, (C3-C7)-cycloalkyl-(C- 40 percutaneous transluminal coronary angioplasty (PTCA), Cl)-alkyl-, Ar and Ar—(C-C)-alkyl-, transient ischemic attacks, stroke, intermittent claudication, RandR are independently of each other selected from the bypass grafting of the coronary or peripheral arteries, vessel series consisting of hydrogen, halogen, (C-C)-alkyl, luminal narrowing, restenosis post coronary venous angio (C-C)-cycloalkyl, (C-C)-cycloalkyl-(C-C)-al plasty, maintenance of vascular access patency in long-term kyl-, Ar, Ar—(C-C)-alkyl-, (C-C)-alkyl-O-, (C- 45 hemodialysis patients, pathologic thrombus formation occur Cz)-cycloalkyl-O-, (C-C)-cycloalkyl-(C-C)-alkyl ring in the veins of the lower extremities following abdomi O—, Ar—O—and Ar—(C-C)-alkyl-O-: nal, knee or hip Surgery, a risk of pulmonary thromboembo RandR are independently of each otherselected from the lism, or disseminated systemic intravascular coagulatopathy series consisting of hydrogen, fluorine and (C-C)- occurring invascular systems during septic shock, viral infec alkyl: 50 tions or cancer. or the groups R and R together with the carbon atom 16. A method according to claim 13 wherein the method is carrying them forma (C-C)-cycloalkane ring which is for the treatment of inflammatory pain, asthma, angiogenesis, unsubstituted or substituted by one or more identical or demyelating diseases of the central nervous system or the different substituents selected from the series consisting peripheral nervous system, multiple Sclerosis, transverse of fluorine and (C-C)-alkyl, 55 myelitis, optic neuritis, Devic's disease, Guillain-Barre Syn R'', R', R'' and R'' are independently of each other drome or chronic inflammatory demyelinating polyneuropa Selected from the series consisting of hydrogen and (C- thy. Cl)-alkyl, 17. A pharmaceutical composition comprising a com Ar is selected from the series consisting of phenyl, naph pound of the formula I or a pharmaceutically acceptable salt thyl and an aromatic, 5-membered or 6-membered, 60 thereof according to claim 1, and a pharmaceutically accept monocyclic heterocycle which comprises one or two able carrier. identical or different ring heteroatoms selected from the 18. A method for the inhibition of the LPA receptor LPAR5 series consisting of N, O and S, which are all unsubsti or the reduction or inhibition of platelet aggregation orthrom tuted or substituted by one or more identical or different bus formation or the reduction or inhibition of activation of Substituents selected from the series consisting of halo 65 mast cells or the reduction or inhibition of activation of micro gen, (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-cy glial cells in a mammal in need thereof, the method compris cloalkyl-(C-C)-alkyl-, cyano and (C-C)-alkyl-O-, ing administering the mammal an compound according to US 9,346,762 B2 67 68 claim tin any of its stereoisomeric forms or a mixture of thrombolytic therapy or percutaneous transluminal coronary Stereoisomeric forms in any ratio, or a pharmaceutically angioplasty (PTCA), transientischemic attacks, stroke, inter acceptable salt thereof. mittent claudication, bypass grafting of the coronary or 19. A method according to claim 18, wherein the method is peripheral arteries, vessel luminal narrowing, restenosis post for the treatment of thromboembolic diseases, deep vein coronary venous angioplasty, maintenance of vascular access thrombosis, venous or arterial thromboembolism, throm patency in long-term hemodialysis patients, pathologic bophlebitis, coronary or cerebral arterial thrombosis, cerebral thrombus formation occurring in the veins of the lower embolism, renal embolism, pulmonary embolism, dissemi extremities following abdominal, knee or hip Surgery, a risk nated intravascular coagulation, cardiovascular disorders, of pulmonary thromboembolism, or disseminated systemic transient ischemic attacks, strokes, acute myocardial infarc 10 intravascular coagulatopathy occurring in vascular systems tion, unstable angina, chronic stable angina, peripheral vas during septic shock, viral infections, cancer, inflammatory cular disease, preeclampsiadeclampsia, thrombotic cytopenic pain, asthma, angiogenesis, demyelating diseases of the cen purpura, inflammatory disorders, hyperalgesia, asthma, mul tral nervous system or the peripheral nervous system, mul tiple Sclerosis, inflammatory pain, angiogenesis, athero tiple Sclerosis, transverse myelitis, optic neuritis, Devic's thrombosis, allergic responses, restenosis, abnormal throm 15 disease, Guillain-Barre syndrome or chronic inflammatory bus formation, acute myocardial infarction, unstable angina, demyelinating polyneuropathy. thromboembolism, acute vessel closure associated with k k k k k