Combinations of azetidine LPA1 receptor antagonists with pirfenidone and / or nintedanib for use in the treatment of fibrotic diseases

Abstract

The present invention provides R 1000 0.5% or more of a compound selected from the group consisting of pirfenidone, nintedanib, pirfenidone ... 1 , R 2 , R 3 The present invention relates to compounds of formula (I), wherein X, X, and Y are as defined herein, and their use as antagonists of the LPA1 receptor in the prevention and / or treatment of fibrotic diseases. The present invention further relates to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more therapeutically active ingredients that act as antifibrotic agents, such as pirfenidone or nintedanib. [Formula 1] TIFF2023504415000011.tif86165

Description

[Technical field]

[0001] The present invention relates in particular to compounds of formula (I) in combination with one or more therapeutically active ingredients acting as antifibrotic agents, such as pirfenidone.

[0002] [ka] and their use as antagonists of the LPA1 receptor in the prevention and / or treatment of fibrotic diseases (and / or diseases or disorders associated with fibrosis); such fibrotic diseases are in particular pulmonary fibrosis, especially idiopathic pulmonary fibrosis or pulmonary fibrosis secondary to systemic inflammatory diseases. The present invention further relates to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more therapeutically active ingredients acting as antifibrotic agents, such as pirfenidone or nintedanib, in particular pirfenidone. [Background technology]

[0003] Certain compounds of formula (I) are disclosed in WO2019234115 (PCT / EP2019 / 064690) and PCT / EP2020 / 066767 as antagonists of the LPA1 receptor, and may be useful in the prevention and / or treatment of fibrosis (and diseases or disorders associated with fibrosis) or other disorders mediated by LPA1 receptor signaling. In particular, it is disclosed that the compounds may have utility in the prevention and / or treatment of diseases such as: - fibrotic interstitial lung diseases, including idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma (systemic sclerosis; SSc), lupus (systemic lupus erythematosus; SLE), polymyositis or mixed connective tissue disease (MCDT); pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis, including radiation-induced pulmonary fibrosis; silicosis-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and pleural fibrosis; - Renal fibrosis, including chronic nephropathy such as CKD, chronic renal failure, tubulointerstitial nephritis and / or (primary) glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as lupus (SLE) and scleroderma (SSc), diabetes, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, renal transplantation and renal fibrosis associated with Alport syndrome; - gut fibrosis, including gut fibrosis secondary to scleroderma and radiation-induced gut fibrosis; - Liver cirrhosis, alcohol-induced liver fibrosis, non-alcoholic fatty liver disease, bile duct injury, (primary liver fibrosis, including primary biliary cirrhosis (also known as primary biliary cholangitis), infectious or virally induced liver fibrosis (e.g., chronic HCV infection) and autoimmune hepatitis; - Head and neck fibrosis, including radiation-induced head and neck fibrosis; - Corneal scarring, including sequelae of LASIK, corneal transplants and trabeculectomy; - Hypertrophic scars and keloids, including burn-induced or surgical hypertrophic scars and keloids; - as well as other fibrotic diseases, such as endometriosis, spinal fibrosis, myelofibrosis, cardiac fibrosis, perivascular fibrosis; as well as the formation of scar tissue, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis and nasal fibrosis.

[0004] Fibrosis is the process of abnormal and excessive extracellular matrix deposition, including the deposition and cross-linking of different collagen subtypes and distortion of tissue architecture, and is a major cause of organ failure in a variety of diseases.

[0005] Cellular damage and / or death as a result of injury usually initiates repair processes, leading to the re-establishment of native tissue structure and function. However, chronic and sometimes acute injuries can also lead to the development of fibrosis, leading to the loss of normal tissue structure and organ function. Fibrosis is recognized as a major cause of morbidity and mortality, especially in lung, liver, heart, kidney and skin diseases (Nanthakumar et al., Nat Rev 2002, 143:131-132). Drug Discov.2015;14(10):693-720). For the majority of fibrotic diseases, there is currently no effective treatment. Recently, two drugs (nintedanib, a tyrosine kinase inhibitor; and pirfenidone) have been approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF), and both compounds have been shown to slow the progression of the disease, although they do not provide a cure. Therefore, there is an urgent need for additional therapies to treat patients with IPF and other fibrotic diseases.

[0006] During the past few years, there has been progress in the molecular understanding of potential genetic risk factors (Kaur et al., 2014) and mechanisms (McDonough et al., JCI Insight. 2019;4(22).doi:10.1172 / jci.insight.131597; Reyfman et al., Am J Respir Crit Care Med. 2019;199(12):1517-1536) that drive the progression of IPF. Epithelial injury and subsequent infiltration of inflammatory cells triggers differentiation of resident fibroblasts into a proinflammatory and profibrotic myofibroblast phenotype that proliferates, is apoptosis-resistant, and secretes excess extracellular matrix (ECM) proteins. Tissue toughening further stimulates mechanosensing myofibroblasts to form a self-amplifying profibrotic state (Lv et al., Future Med Chem 2019;11:2595-2620). As a result, myofibroblasts are nowadays considered to be the main cellular effectors of the fibrotic response. Epithelial-mesenchymal transition (Hill et al., J Lung Health Dis. 2019;3(2):31-35) and infiltrating fibrocytes (Chong et al., Int J Biochem Cell Biol. 2019;116:105-95) have been proposed to expand the pool of fibroblasts capable of differentiating into a myofibroblast phenotype. Thus, targeting fibroblasts with a tendency to differentiate into myofibroblasts or inhibiting myofibroblast activity is a new strategy for the treatment of progressive fibrotic diseases.

[0007] In IPF, epithelial injury triggers a number of different signals that contribute to the differentiation of fibroblasts into a myofibroblast phenotype, which is characterized by increased expression of alpha smooth muscle actin (αSMA), the appearance of αSMA stress fibers, increased ECM protein secretory activity, and secretion of pro-inflammatory cytokines, which further exacerbate the fibrotic condition. These include TNFα, PDGFα, IL-1, IL-6, and lysophosphatidic acid (LPA). Among the known cytokines that trigger the transformation of fibroblasts into myofibroblasts, TGF-β and its downstream effectors are the most potent and prominent inducers of fibrosis, although other factors, including TGF-β, TGF-β-dependent cytokines, and TGF-β-dependent cytokines contribute (Alsafadi et al., Am J Physiol Lung Cell Mol Physiol. 2017;312(6):L896-L902; Peyser et al., Am J Respir Cell Mol Biol. 2019;61(1):74-85; Distler et al., Nat Rev Rheumatol. 2019;15:705-730).

[0008] Profibrotic conditions and their effects on lung fibroblast phenotype can be mimicked in vitro using exogenous stimuli such as TGFβ, PDGFα or LPA on primary human lung fibroblasts, and pharmacological interventions can be tested for their effects. According to secretory activity and gene expression analysis, the in vitro induced myofibroblast phenotype closely matches that of IPF-derived (myo)fibroblasts in vivo (Weigle et al., J Biol Methods. 2019;6(2):e115).

[0009] The LPA1 receptor antagonist BMS-986020 (CAS Reg. No.: 1257213-50-5; WO2010 / 141761, WO2012 / 7078805, hereafter also referred to as Compound D) was tested in a phase II clinical trial (NCT01766817) in patients with IPF. Patients treated with BMS-986020 bid experienced a significantly slower rate of decline in forced vital capacity (FVC) versus placebo. FVC is the total volume of air exhaled during a forced expiratory volume test, measured during spirometry; it may be considered the most important measure of pulmonary function. Dose-related elevations in liver enzymes were observed in both BMS-986020 treatment groups. The study was terminated early because three cases of cholecystitis occurred, which were determined after open label to be related to BMS-986020.

[0010] Nintedanib ((3Z)-2,3-dihydro-3-[[[4-[methyl-[(4-methyl-1-piperazinyl)-acetyl]-amino]-phenyl]-amino]-phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester ethanesulfonate; see, e.g., US 6,762,180, US 7,119,093, US 7,989,474, US 9,907,756, US 10,105,323, US 10,154,990) is a triple kinase inhibitor that targets the receptor tyrosine kinases, fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR), which are also associated with fibrosis and the pathogenesis of IPF. In two Phase 3 studies, nintedanib reduced the decline in lung function by about 50% over a one-year period. Nintedanib hard gelatin capsules, for example, contain nintedanib (150 mg or 100 mg) and the inactive ingredients medium-chain hard fat triglycerides and soy lecithin (E322). It was approved by the US FDA in 2014 and in Europe in 2015. In the United States, it is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and for slowing the rate of decline in lung function in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). The recommended dose is 150 mg (bid) twice daily, approximately 12 hours apart, taken with food. The recommended dose in patients with mild liver impairment (Child Pugh A) is 100 mg bid, approximately 12 hours apart, taken with food. Temporary dose reduction to 100 mg, interruption or cessation of treatment to address adverse reactions should be considered, and liver function tests are recommended for all patients and pregnancy tests for females of reproductive potential prior to initiation of treatment. Liver enzyme elevations and drug-induced liver injury: Nintedanib has caused ALT, AST and bilirubin elevations, including cases of drug-induced liver injury. Non-severe and severe cases of drug-induced liver injury have been reported during the post-marketing period, including severe liver injury with fatal outcomes. Further potential side effects of nintedanib have been reported, including gastrointestinal disorders such as diarrhea, nausea and vomiting; embryo-fetal toxicity; arterial thromboembolism; bleeding events; and gastrointestinal perforation. In the EU, nintedanib is approved for use in the treatment of idiopathic pulmonary fibrosis. It is indicated for the treatment of intravascular fibrosis (IPF) and, in combination with docetaxel, for the treatment of adult patients with locally advanced, metastatic, or locally recurrent non-small cell lung cancer (NSCLC) with adenocarcinoma tumor histology after initial chemotherapy; the recommended dose of nintedanib is 200 mg administered twice daily, approximately 12 hours apart, on days 2 through 21 of a standard 21-day docetaxel treatment cycle.

[0011] According to www.clinicaltrials.gov, nintedanib, in combination with pirfenidone, is being tested in clinical trials targeting IPF; as well as scleroderma-associated pulmonary fibrosis; progressive fibrotic interstitial lung disease (PF-ILD); and bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation; several trials are targeting cancers including, for example, thyroid cancer; non-small cell lung cancer; small cell lung cancer; esophagogastric cancer; recurrent malignant pleural mesothelioma; HER2-negative metastatic inflammatory breast cancer (MIBC); soft tissue sarcoma; advanced ovarian cancer; recurrent or persistent endometrial cancer; lung cancer; metastatic appendiceal cancer; endometrial cancer, malignant pleural mesothelioma; and refractory metastatic colorectal cancer.

[0012] Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is indicated for the treatment of IPF. Pirfenidone hard gelatin capsules contain pirfenidone (267 mg) and the inactive ingredients microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate. Pirfenidone film-coated tablets contain pirfenidone [267 mg (yellow) and 801 mg (brown)] and the inactive ingredients microcrystalline cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, and iron oxide.

[0013] The recommended dose of pirfenidone is 801 mg three times a day (tid), equivalent to 2403 mg / day; upon initiation of treatment or after treatment discontinuation, titration over 14 days is recommended, starting with a dose of 267 mg tid. Prior to treatment, liver function status testing (alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin) is recommended.

[0014] Cases of drug-induced liver injury (DILI) have been observed with pirfenidone. Non-severe and severe cases of DILI, including severe liver injury with fatal outcomes, have been reported during the postmarketing period. In patients treated with 2403 mg / day pirfenidone, elevations of ALT or AST ≥3 times the upper limit of normal (ULN) occurred more frequently than in placebo patients in three phase 3 trials (3.7% vs. 0.8%, respectively). Elevations of ALT or AST ≥10 times the ULN occurred in 0.3% of patients in the pirfenidone 2403 mg / day group and 0.2% of patients in the placebo group. Elevations of ALT and AST ≥3 times the ULN could be reversed by dose modification or discontinuation of treatment.

[0015] As a result, temporary dose reduction, interruption or discontinuation of treatment is recommended to address adverse reactions such as DILI. In addition, photosensitivity reactions or rash; as well as gastrointestinal adverse reactions may require dose reduction or discontinuation in some cases. In clinical trials, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease, and abdominal pain were reported more frequently in patients treated with pirfenidone than in patients receiving placebo. Dose reduction or interruption due to gastrointestinal events was required in 18.5% of patients in the 2403 mg / day group compared with 5.8% of patients in the placebo group; treatment was discontinued due to gastrointestinal events in 2.2% of patients in the pirfenidone 2403 mg / day group compared with 1.0% of patients in the placebo group.

[0016] Patents exist relating to pirfenidone, its uses, and methods of mitigating some of the above disadvantages (e.g., US 7,566,729, US 7,635,707, US 7,696 See US 7,236, US 7,767,225, US 7,767,700, US 7,816,383, US 7,910,610, US 7,988,994, US 8,013,002, US 8,084,475, US 8,318,780, US 8,383,150, US 8,420,674, US 8,592,462, US 8,609,701, US 8,648,098, US 8,753,679, US 8,754,109, US 8,778,947. ). In addition, some patents have described that pirfenidone is useful in certain antifibrotic treatments (WO2012 / 162592).

[0017] According to www.clinicaltrials.gov, pirfenidone is being tested in clinical trials targeting rheumatoid arthritis-associated interstitial lung disease (RA-ILD), radiation-induced lung injury, chronic kidney disease (CKD), diabetic kidney disease, diabetic nephropathy, progressive interstitial lung disease associated with clinically amyopathic dermatomyositis, pulmonary fibrosis associated with anti-myeloperoxidase (MPO) antibodies or with anti-MPO-associated vasculitis, systemic sclerosis-associated interstitial lung disease (SSc-ILD), progressive fibrotic sarcoidosis, advanced liver fibrosis, skin fibrosis in systemic sclerosis, interstitial lung disease associated with systemic sclerosis, and fibrosis caused by radiation therapy for cancer. In Mexico, oral pirfenidone is approved for the treatment of pulmonary and liver fibrosis, and in gel form for the treatment of scars, fibrotic tissue, and skin ulcers.

[0018] Furthermore, the development of fibrosis, particularly pulmonary fibrosis, may be one of the sequelae of COVID-19, particularly moderate or severe COVID-19. As a result, it has been disclosed in recent years that clinical trials are testing nintedanib and pirfenidone in the context of COVID-19, particularly post-COVID-19 pulmonary fibrosis (see, e.g., NCT04607928, NCT04541680, NCT04338802, NCT04619680).

[0019] In preclinical models, the general antifibrotic effects of pirfenidone have been widely established in animal models of pulmonary, cardiac, renal and hepatic fibrosis, as well as in Dupuytren's contracture. It has been clearly shown that pirfenidone reduces the expression of fibrosis and fibrogenic mediators.

[0020] Both nintedanib and pirfenidone have been tested for their antifibrotic activity in vitro using various conditions of primary human lung (myo)fibroblasts (Atanelishvili et al., Clin Exp Rheumatol. 2019;37 Suppl. 119(4):115-124; Lehtonen et al., Respir Res. 2016;17:14; Hostettler et al., Respir Res. 2014;15:157). Both compounds attenuated, but generally did not completely inhibit, the differentiation of fibroblasts into myofibroblasts and / or the profibrotic activity of (myo)fibroblasts. These results show that such an in vitro system is suitable for evaluating compounds for antifibrotic activity, but also confirm that multiple signals and signaling pathways converge in inducing a profibrotic phenotype in these cells. Moreover, this suggests that neither pirfenidone nor nintedanib can reach a maximal effect even at high concentrations.

[0021] In particular for pirfenidone, which is administered to humans at a high dose of 801 mg orally three times per day (total of 2403 mg / day), the concentrations used to observe significant effects in vitro (>0.5 mM) are consistent with the high exposure required for the compound in humans. These findings could be used in addition to and in combination with currently available background therapies (i.e., pirfenidone and / or nintedanib, and optionally further background therapies). This highlights the need for additional therapies that augment the efficacy of such antifibrotic treatments by enhancing the efficacy of these treatments. Summary of the Invention

[0022] It has been found that LPA1 receptor antagonists, particularly compounds of formula (I) as defined below, which are useful in the prevention and treatment of fibrotic diseases and disorders (e.g., pulmonary fibrosis; renal fibrosis; gastrointestinal fibrosis; hepatic fibrosis; head and neck fibrosis; corneal scarring; hypertrophic scarring and keloids; and other fibrotic diseases mentioned herein (including endometriosis, spinal fibrosis, bone marrow fibrosis, myocardial fibrosis, perivascular fibrosis; scar tissue formation, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis, nasal fibrosis and fibroblast-mediated fibrosis), may have complementary or even synergistic effects when combined with pirfenidone in the treatment of such fibrotic diseases and disorders. Thus, such combinations may be particularly useful in the prevention and / or treatment of pulmonary fibrosis (especially IPF). Furthermore, the combination of LPA1 receptor antagonists, particularly those of the compound of formula (I), with pirfenidone may allow the dose of pirfenidone to be reduced, and may even be reduced to a dose below the established optimal effective dose of pirfenidone when administered alone.Therefore, certain safety disadvantages (e.g., effects on liver enzymes, photosensitivity, rash, or gastrointestinal side effects) associated with high doses of pirfenidone (2403 mg / day, which is generally administered as 801 mg tid) may be reduced.

[0023] Furthermore, LPA1 receptor antagonists, such as the compounds of formula (I) defined below, when combined with nintedanib, may have at least complementary effects in the treatment of such fibrotic diseases and disorders. In addition, the LPA1 receptor antagonists of the present invention may be combined with both pirfenidone and nintedanib in the triple combination prevention and / or treatment of such fibrotic diseases. [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 shows the effect of Compound A, pirfenidone and their combination on TGFβ-induced αSMA expression in human fibroblasts. [Diagram 2]FIG. 2 shows the effect of Compound B, pirfenidone and their combination on TGFβ-induced αSMA expression in human fibroblasts. [Diagram 3] FIG. 3 shows the effect of Compound C, pirfenidone and their combination on TGFβ-induced αSMA expression in human fibroblasts. [Figure 4] FIG. 4 shows the effect of Compound D, pirfenidone and their combination on TGFβ-induced αSMA expression in human fibroblasts. [Diagram 5] FIG. 5 shows the dose-response of pirfenidone on TGFβ-induced αSMA expression in NHLFs in the absence and presence of 10 nM, 100 nM and 1000 nM of Compound A. [Figure 6] FIG. 6 shows the effect of Compound A, nintedanib and their combination on TGFβ-induced αSMA expression in human fibroblasts. [Figure 7] FIG. 7 shows the effect of Compound B, nintedanib and their combination on TGFβ-induced αSMA expression in human fibroblasts. [Figure 8] FIG. 8 shows the effect of Compound C, nintedanib and their combination on TGFβ-induced αSMA expression in human fibroblasts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Detailed Description of the Invention 1) The first aspect is a compound of formula (I) or a pharma- ceutically acceptable salt thereof as an active ingredient:

[0026] [ka] (In the formula, - X is CH; Y is N; and R 2 is methyl, ethyl or isopropyl (especially methyl); or - X is N; Y is CH; and R 2is methyl, ethyl or isopropyl (especially methyl) or difluoromethyl; R 1 is fluoro, chloro, bromo or methyl (especially chloro or methyl); R 3 teeth, - -(CH2) 2-3 -C(CH3)2-COOH (especially -CH2-CH2-C(CH3)2-COOH); - -CO-(CH2) 1-2 -C(CH3)2-COOH (in particular -CO-CH2-C(CH3)2-COOH); or - -SO2-NH2; represents ); in combination with one or more therapeutically active ingredients acting as antifibrotic agents; and further comprising at least one pharma- ceutical acceptable excipient; the antifibrotic agents being in particular pirfenidone and / or nintedanib; or pharma- ceutical acceptable salts thereof.

[0027] The pharmaceutical composition according to embodiment 1) can be used as a medicament, for example in the form of a pharmaceutical composition for enteral (especially oral) or parenteral (including topical application or inhalation) administration. Such pharmaceutical compositions can be produced in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [Publisher: Lippincott Williams & Wilkins]) by combining the active ingredient combination of the present invention, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, pharma- ceutical acceptable solid or liquid carrier materials and, if necessary, with conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form. The pharmaceutical composition for oral administration can be in particular in the form of a capsule or tablet.

[0028] 2) A further embodiment is a compound of formula (I) - X is CH; Y is N; and R 2 is methyl, ethyl or isopropyl (especially methyl); or - X is N; Y is CH; and R 2 However, methyl or difluoromethyl (especially difluoromethyl); It relates to a pharmaceutical composition according to embodiment 1).

[0029] 3) A further embodiment is where X is CH; Y is N; and R 2 is methyl, ethyl or isopropyl (in particular methyl);

[0030] 4) A further embodiment is where X is N; Y is CH; and R 2 is difluoromethyl;

[0031] 5) A further aspect is R 1 is fluoro, chloro or bromo (particularly chloro); it relates to a pharmaceutical composition according to any one of embodiments 1) to 4) [particularly according to embodiment 3)].

[0032] 6) A further aspect is R 1 is methyl; the pharmaceutical composition according to any one of embodiments 1) to 4) [particularly according to embodiment 4)].

[0033] 7) A further aspect is R 3 but, - -CH2-CH2-C(CH3)2-COOH; -CO-CH2-C(CH3)2-COOH; or - -SO2-NH2; represents an integer of 1 to 6;

[0034] 8) A further aspect is R 3 Ga-(CH2) 2-3represents -C(CH3)2-COOH (in particular -CH2-CH2-C(CH3)2-COOH); relates to a pharmaceutical composition according to any one of embodiments 1) to 6) [in particular according to embodiment 4) or 6)].

[0035] 9) A further aspect is R 3 -CO-(CH2) 1-2 represents -C(CH3)2-COOH (in particular -CO-CH2-C(CH3)2-COOH); relates to a pharmaceutical composition according to any one of embodiments 1) to 6) [in particular according to embodiment 4) or 6)].

[0036] 10) A further aspect is R 3 represents -SO2-NH2; relates to a pharmaceutical composition according to any one of embodiments 1) to 6) [in particular according to embodiment 3) or 5)].

[0037] 11) A further embodiment is where the compound of formula (I) is: 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-5-oxopentanoic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; N-(2-ethoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl (III)-1-sulfamoylazetidine-3-carboxamide; or N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; It relates to a pharmaceutical composition according to embodiment 1).

[0038] 12) A further embodiment is where the compound of formula (I) is: 4-(3-((6-chloro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-chloro-4-ethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-chloro-4-isopropoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-bromo-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 5-(3-((6-chloro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid; 5-(3-((6-chloro-4-ethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid; 4-(3-((6-chloro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-((6-bromo-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-((6-chloro-4-ethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-ethoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-isopropoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-bromo-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; or 3-(2-isopropylphenyl)-N-(4-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; It relates to a pharmaceutical composition according to embodiment 1).

[0039] 13) A further embodiment is where the compound of formula (I) is: 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; or N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl (l)-1-sulfamoylazetidine-3-carboxamide; It relates to a pharmaceutical composition according to embodiment 1).

[0040] 14) A further embodiment relates to a pharmaceutical composition according to embodiment 1), wherein the compound of formula (I) is N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide.

[0041] 15) A further embodiment relates to a pharmaceutical composition according to embodiment 1), wherein the compound of formula (I) is 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid.

[0042] 16) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 15), wherein the one or more therapeutically active ingredients acting as antifibrotic agents are pirfenidone or a pharma- ceutically acceptable salt thereof.

[0043] 17) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 15), wherein the composition comprises a compound of formula (I) and, in addition, two therapeutically active ingredients acting as antifibrotic agents, the antifibrotic agents being pirfenidone or a pharma- ceutical acceptable salt thereof in combination with nintedanib or a pharma-ceutical acceptable salt thereof.

[0044] 18) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) having pirfenidone or a pharmaceutical acceptable salt thereof in a pharmaceutical unit dosage suitable for oral administration of pirfenidone, the pharmaceutical composition comprising pirfenidone or a pharmaceutical acceptable salt thereof in a pharmaceutical unit dosage suitable for oral administration of about 2403 mg or less total pirfenidone per day (e.g., about 801 mg or less total tid).

[0045] 19) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 18), comprising pirfenidone or a pharma- ceutically acceptable salt thereof at a dose that is or is lower than the tolerated efficacious dose of pirfenidone when given as monotherapy (e.g., as set forth in an approval letter for pirfenidone for a particular disease or disorder when given as monotherapy).

[0046] 20) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 18), comprising pirfenidone or a pharma- ceutically acceptable salt thereof at a dose lower than the tolerated effective dose of pirfenidone when given as monotherapy (e.g., as set out in the approved literature for pirfenidone for a particular disease or disorder when given as monotherapy); such dose may be a total of 1602 mg / day or less (e.g., 534 mg three times a day); in particular a total of 801 mg / day (e.g., 267 mg three times a day).

[0047] 21) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 20), wherein the one or more therapeutically active ingredients acting as antifibrotic agents are nintedanib or a pharma- ceutically acceptable salt thereof (such as, in particular, the ethanesulfonate salt).

[0048] 22) A further embodiment comprises nintedanib or a pharma- ceutically acceptable salt thereof, when present (e.g., the ethanesulfonate salt), in a pharmaceutical unit dose suitable for oral administration of nintedanib; nintedanib or a pharma- ceutically acceptable salt thereof, in a total amount of about 200 mg or less (e.g., 100 mg or less) per day. bid or less), about 300 mg or less per day (e.g., 150 mg bid or less), or in a pharmaceutical unit dose suitable for oral administration of about 400 mg or less (e.g., 200 mg or less) of nintedanib per day;

[0049] 23) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 22), comprising nintedanib or a pharma- ceutically acceptable salt thereof at a dose that is or is lower than the tolerated effective dose of nintedanib when given as monotherapy (e.g., as set forth in the approval letter for nintedanib for a particular disease or disorder when given as monotherapy).

[0050] 24) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 23), comprising nintedanib or a pharma- ceutically acceptable salt thereof at a dose lower than the tolerated effective dose of nintedanib when given as monotherapy (e.g., as set out in the approval letter for nintedanib for a particular disease or disorder when given as monotherapy); such dose may be a total of 200 mg or less (e.g., 100 mg bid) nintedanib per day.

[0051] Such combination pharmaceutical compositions according to aspects 1) to 24) are particularly useful for the prevention or treatment of a fibrotic disease as defined herein, in particular pulmonary fibrosis (in particular IPF), and in a method for the prevention or treatment of a fibrotic disease as defined herein, in particular pulmonary fibrosis (in particular IPF), comprising administering a pharma- ceutical effective dose of such combination pharmaceutical composition to a subject (in particular a human) in need thereof.

[0052] 25) Another aspect of the invention relates to a pharmaceutical composition according to embodiments 1) to 24) for use in the prevention of pulmonary fibrosis (in particular IPF), said prevention of pulmonary fibrosis (in particular IPF) comprising delaying the onset of pulmonary fibrosis (in particular IPF) in patients suffering / diagnosed as suffering from pneumonia or interstitial lung disease (ILD; alternatively referred to as diffuse parenchymal lung disease (DPLD)); in particular such pneumonia or ILD is interstitial pneumonia, in particular common interstitial pneumonia.

[0053] 26) In another aspect, the invention relates to a pharmaceutical composition according to any one of embodiments 1) to 24) for use in the prevention or treatment of pulmonary fibrosis; - said preventing pulmonary fibrosis includes delaying the onset of pulmonary fibrosis; - the treatment of pulmonary fibrosis involves slowing the rate of decline in lung function; In particular, said prevention or treatment of pulmonary fibrosis is carried out in subjects having (diagnosed as having) a systemic inflammatory disease such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic erythematosus), polymyositis or mixed connective tissue disease (MCTD); in subjects having (diagnosed as having) sarcoidosis; in subjects who have experienced radiation / treated with radiotherapy; or in subjects who have experienced exposure to silica dust (silicosis) or asbestos; in particular in subjects who have (diagnosed as having) an interstitial lung disease.

[0054] 27) In a specific embodiment of the present invention, the combination pharmaceutical composition according to any one of embodiments 1) to 26) comprises - in the prevention or treatment of abnormal accumulation of cells and / or fibronectin and / or collagen in the lung and / or increased recruitment of fibroblasts; and / or - to prevent or treat the progression of / to slow the rate of structural changes in the lungs; Intended to be used; In particular, said subject to be treated has been diagnosed with pulmonary fibrosis and / or pneumonia or interstitial lung disease as defined herein.

[0055] 28) A second aspect of the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of aspects 1) to 15) for use in the prophylaxis or treatment of a fibrotic disease as defined herein, in particular pulmonary fibrosis (in particular IPF); said compound of formula (I) is / is intended to be administered in combination with one or more (in particular one or two) therapeutically active ingredients acting as antifibrotic agents; in a sub-embodiment, said combination is preferably - in combination with pirfenidone or a pharma- ceutical acceptable salt thereof (especially pirfenidone in free form); - in combination with nintedanib or a pharma- ceutical acceptable salt thereof (especially the ethanesulfonate salt, etc.); or - a combination of both pirfenidone or a pharma- ceutical acceptable salt thereof (especially pirfenidone in free form) and nintedanib or a pharma- ceutical acceptable salt thereof (especially the ethanesulfonate salt, etc.); and; Or, the combination drug is - a combination with a pirfenidone analogue or a pharma- ceutically acceptable salt thereof; or - a combination of both a pirfenidone analogue or a pharma- ceutically acceptable salt thereof and nintedanib or a pharma- ceutically acceptable salt thereof (especially the ethanesulfonate salt, etc.); It is.

[0056] The compounds of formula (I) as defined in aspects 1) to 15) are useful for the prevention and / or treatment of fibrotic diseases as defined herein, in particular pulmonary fibrosis (especially IPF) (and diseases or disorders associated with such fibrotic diseases), particularly when combined with one or more therapeutically active ingredients acting as antifibrotic agents such as pirfenidone and / or nintedanib, and may additionally be useful for the prevention and / or treatment of other disorders mediated by LPA1 receptor signaling.

[0057] 29) A further embodiment relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of embodiments 1) to 15) for use according to embodiment 28); such use comprises - pulmonary fibrosis; in particular idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to a systemic inflammatory disease such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus), polymyositis or mixed connective tissue disease (MCTD); pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis, including radiation-induced fibrosis; silicosis-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and pleural fibrosis; and, in addition to the above, pulmonary fibrosis associated with COVID-19 (in particular moderate or severe COVID-19); - renal fibrosis, in particular selected from chronic nephropathy such as CKD, chronic renal failure, tubulointerstitial nephritis and / or (primary) glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as lupus (SLE) or scleroderma (SSc), diabetes, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, kidney transplantation and renal fibrosis associated with Alport syndrome; or - liver fibrosis, in particular selected from liver cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis, bile duct injury, primary biliary cirrhosis (also known as primary biliary cholangitis), infectious or virally induced liver fibrosis (e.g. chronic HCV infection) and autoimmune hepatitis; The present invention is intended for the prevention and / or treatment of

[0058] 30) A further embodiment is any of embodiments 1) to 15) for use according to embodiment 28). or a pharma- ceutically acceptable salt thereof; such use is intended for the prophylaxis and / or treatment of pulmonary fibrosis, in particular the pulmonary fibrosis being - idiopathic pulmonary fibrosis; - pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus), polymyositis or mixed connective tissue disease (MCTD); - Pulmonary fibrosis, a secondary disease of sarcoidosis; - Iatrogenic pulmonary fibrosis, including radiation-induced fibrosis; -Silicosis-induced pulmonary fibrosis; - Asbestos-induced pulmonary fibrosis; or - pleural fibrosis; or, in addition to the above, - pulmonary fibrosis associated with COVID-19 (especially moderate or severe COVID-19); It is.

[0059] 31) A further embodiment relates to a compound of formula (I) as defined in any one of embodiments 1) to 15) or a pharma- ceutically acceptable salt thereof for use according to embodiment 28); such use comprises - idiopathic pulmonary fibrosis; - pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus), polymyositis or mixed connective tissue disease (MCTD); - Pulmonary fibrosis, a secondary disease of sarcoidosis; - Radiation-induced fibrosis; - silicosis-induced pulmonary fibrosis; or - asbestos-induced pulmonary fibrosis; or, in addition to the above, - pulmonary fibrosis associated with COVID-19 (especially moderate or severe COVID-19); The present invention is intended for the prevention and / or treatment of

[0060] 32) A further embodiment relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of embodiments 1) to 15), for combination use according to any one of embodiments 28) to 31); the features as defined in any one of embodiments 16) to 27) apply mutatis mutandis to such a compound for combination use.

[0061] 33) In particular, such a compound of formula (I) for combined use according to any one of embodiments 28) to 32) relates to such uses, in which the compound of formula (I) is (is intended to be) administered / is administered together with one therapeutically active ingredient acting as an antifibrotic agent, said ingredient being pirfenidone or a pharma- ceutically acceptable salt thereof (in particular pirfenidone in free form).

[0062] 34) Such a compound of formula (I) for combined use according to embodiment 33) particularly relates to such a use, wherein the compound of formula (I) is (is intended to be) administered / administered together with pirfenidone; and wherein pirfenidone or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical unit dosage form suitable for oral administration of about 2403 mg or less in total per day (e.g., about 801 mg or less in total tid).

[0063] 35) Such a compound of formula (I) for combined use according to embodiment 33) further includes a compound of formula (I) that is (is intended to be) administered / administered together with pirfenidone; and pirfenidone or a pharma- ceutically acceptable salt thereof is (is intended to be) administered together with ... The tolerable effective dose of pirfenidone is administered at or below the tolerable effective dose (as set forth in the approval letter for pirfenidone for the disorder);

[0064] 36) Such compounds of formula (I) for combined use according to embodiment 33) further relate to uses in which the compound of formula (I) will be (is intended to be) administered / is administered together with pirfenidone; pirfenidone or a pharma- ceutically acceptable salt thereof is administered at a dose lower than the tolerated effective dose of pirfenidone when given as monotherapy (e.g. as set out in the approval letter for pirfenidone for a particular disease or disorder when given as monotherapy); such dose may be a total of 1602 mg / day or less (e.g. 534 mg three times a day); in particular a total of 801 mg / day (e.g. 267 mg three times a day).

[0065] 37) The compound of formula (I) for combined use according to any one of embodiments 28) to 32) further relates to a use in which the compound of formula (I) is (is intended to be) / administered together with one therapeutically active ingredient acting as an antifibrotic agent, said ingredient being nintedanib or a pharma- ceutically acceptable salt thereof (such as the ethanesulfonate salt, in particular);

[0066] 38) Such compounds of formula (I) for combined use according to embodiment 37) relate in particular to such uses, wherein nintedanib or a pharma- ceutically acceptable salt thereof is administered in a pharmaceutical unit dose suitable for oral administration of nintedanib; having nintedanib or a pharma- ceutically acceptable salt thereof in a pharmaceutical unit dosage form suitable for oral administration of a total amount of about 200 mg or less (e.g. 100 mg bid or less) per day, about 300 mg or less (e.g. 150 mg bid or less) per day, or about 400 mg or less (e.g. 200 mg bid or less) of nintedanib per day.

[0067] 39) Such compounds of formula (I) for combined use according to embodiment 37) further comprise administering nintedanib or a pharma- ceutically acceptable salt thereof at a dose that is or is lower than the tolerated effective dose of nintedanib when given as monotherapy (e.g., as set out in the approval letter for nintedanib for a particular disease or disorder when given as monotherapy); for such uses.

[0068] 40) Such compounds of formula (I) for combined use according to embodiment 37) further comprise administering nintedanib or a pharma- ceutically acceptable salt thereof at a dose lower than the tolerated effective dose of nintedanib when given as monotherapy (e.g., as set out in the approval letter for nintedanib for a particular disease or disorder when given as monotherapy); such dose may be a total of 200 mg or less (e.g., 100 mg bid) nintedanib per day; for such uses.

[0069] 41) Another particular aspect of the invention relates to such compounds of formula (I) for combined use according to embodiments 28) to 40); said compounds of formula (I) are intended to be used in the prevention of pulmonary fibrosis (particularly IPF); said prevention of pulmonary fibrosis (particularly IPF) comprises delaying the onset of pulmonary fibrosis (particularly IPF) in subjects suffering / diagnosed as suffering from pneumonia or interstitial lung disease (ILD; or acute interstitial pneumonia (DPLD)); in particular such pneumonia or ILD is interstitial pneumonia, in particular common interstitial pneumonia.

[0070] 42) Another particular aspect of the invention relates to such compounds of formula (I) for combined use according to embodiments 28) to 41); said compounds of formula (I) are intended for use in the prevention or treatment of pulmonary fibrosis; - said preventing pulmonary fibrosis includes delaying the onset of pulmonary fibrosis; - the treatment of pulmonary fibrosis involves slowing the rate of decline in lung function; In particular, the prevention or treatment of pulmonary fibrosis is carried out in subjects having (diagnosed as having) a systemic inflammatory disease such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic erythematosus), polymyositis or mixed connective tissue disease (MCTD); in subjects having (diagnosed as having) sarcoidosis; in subjects who have experienced radiation / treated with radiotherapy; or in subjects who have experienced exposure to silica dust (silicosis) or asbestos; in particular in subjects who have (diagnosed as having) an interstitial lung disease.

[0071] In the context of the present invention, slowing the rate of decline in pulmonary function may specifically be expressed as slowing the rate of decline in forced vital capacity (FVC) (e.g., relative to standard care treatment or relative to placebo).

[0072] 43) Another particular aspect of the invention relates to such compounds of formula (I) for combined use according to embodiments 28) to 41); said compounds of formula (I) - to prevent or treat abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment in the lung; and / or - to prevent or treat the progression of / to slow the rate of structural changes in the lungs; Used; In particular, the subject to be treated has been diagnosed with pulmonary fibrosis and / or pneumonia or interstitial lung disease as defined herein.

[0073] Thus, according to the present invention, a compound of formula (I) as defined in any one of embodiments 1) to 15) or a pharma- ceutically acceptable salt thereof is intended for use in combination (or combination therapy) with said further pharma- ceutical active ingredient, as defined herein, having antifibrotic activity.

[0074] The definitions set forth herein are intended to be uniformly applied to any one of embodiments 1) to 43) and apply mutatis mutandis throughout the specification and claims unless a broader or narrower definition is expressly given by another definition. It is to be understood that any definition or preferred definition of a term may independently (and together) define and replace the respective term in any or all other terms defined herein.

[0075] The term "therapeutically active ingredient acting as an antifibrotic agent" or "antifibrotic agent" refers to any antifibrotic agent that has shown potential for therapeutic use (in tests in in vitro and / or in vivo models, particularly in clinical trials) and / or is adapted for such therapeutic use; such therapeutic use is for at least one fibrotic disease. Examples are, in particular, pirfenidone or a pharmaceutically acceptable salt thereof; and nintedanib or a pharmaceutically acceptable salt thereof. In addition, further examples of antifibrotic agents are pirfenidone analogues (i.e., compounds that have structural similarity to pirfenidone and essentially act by a similar / same mechanism of action as pirfenidone). Specific pirfenidone analogs include deuterated pirfenidone analogs such as 1-phenyl-5-(trideuteromethyl)pyridin-2(1H)-one (SD-560); the compound 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (AK-3280, CAS Reg. No. 1799412-33-1, WO2014 / 055548, WO2019 / 152863; and 7-(4-fluorophenyl)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one, 3-ethyl-7-(1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydro Further compounds disclosed in WO2014 / 055548, such as 1-methyl-4H-imidazo[4,5-c]pyridin-4-one or 7-(1-isopropyl-1H-pyrazol-4-yl)-3-methyl-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one; and compounds disclosed in WO2015 / 153683 / US10,233,195 [in particular the compounds disclosed therein, 712-714 and 716-738, especially 1-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (compound 724)]. Pirfenidone analogs may additionally be used in combination with nintedanib.

[0076] Thus, in a sub-embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of embodiments 1) to 15) for use in the prophylaxis or treatment of a fibrotic disease as defined herein, in particular pulmonary fibrosis (in particular IPF); said compound of formula (I) will be (is intended to be) administered / is administered in particular in combination with 1-phenyl-5-(trideuteromethyl)pyridin-2(1H)-one; or a pirfenidone analogue such as 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one or a pharma- ceutically acceptable salt thereof (in particular the tosylate); optionally further in combination with nintedanib or a pharma- ceutically acceptable salt thereof (in particular the esylate).

[0077] The term "pirfenidone or a pharma- ceutically acceptable salt thereof" refers specifically to pirfenidone in the free form.

[0078] The term "nintedanib or a pharma- ceutically acceptable salt thereof" refers in particular to nintedanib in free form or in the form of a pharma- ceutically acceptable salt, the preferred pharma- ceutically acceptable salt form being nintedanib ethanesulfonate (nintedanib esylate).

[0079] The term "fibrotic disease" or, alternatively, "fibrosis" means a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen in an organ and / or increased fibroblast recruitment; including fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0080] The term fibrosis specifically refers to - all forms of fibrotic interstitial lung disease, in particular idiopathic pulmonary fibrosis (also called idiopathic fibrosing alveolitis); pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus), polymyositis or mixed connective tissue disease (MCTD); pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis, including radiation-induced fibrosis; silicosis-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and all forms of pulmonary fibrosis, including pleural fibrosis; - Renal fibrosis, including chronic nephropathy such as CKD, chronic renal failure, tubulointerstitial nephritis and / or (primary) glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as lupus (SLE) or scleroderma (SSc), diabetes, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, renal transplantation and renal fibrosis associated with Alport syndrome; - gastrointestinal fibrosis, including gastrointestinal fibrosis secondary to scleroderma and radiation-induced gastrointestinal fibrosis; - All forms of liver fibrosis, including cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis, bile duct injury, primary biliary cirrhosis (also known as primary biliary cholangitis), infectious or virally induced liver fibrosis (e.g. chronic HCV infection) and autoimmune hepatitis ; - Head and neck fibrosis, including radiation-induced head and neck fibrosis; - Corneal scarring, including sequelae of LASIK, corneal transplants and trabeculectomy; - Hypertrophic scars and keloids, including burn-induced or surgical hypertrophic scars and keloids; - as well as other fibrotic diseases, such as endometriosis, spinal fibrosis, bone marrow fibrosis, myocardial fibrosis, perivascular fibrosis; as well as scar tissue formation, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis, nasal fibrosis and fibroblast-mediated fibrosis; may be defined as including

[0081] In addition to the above, the term fibrosis further encompasses all forms of fibrosis (in particular pulmonary, renal or hepatic fibrosis, especially pulmonary fibrosis) associated with SARS-CoV-2 infection and / or COVID-19 (especially moderate or severe COVID-19). The term "associated with" is understood to mean that the fibrosis (in particular pulmonary, renal or hepatic fibrosis, especially pulmonary fibrosis) occurs simultaneously with or subsequent to a diagnosed SARS-CoV-2 infection and / or COVID-19, and the actual cause of the fibrosis may be unknown / undiagnosed. Such fibrosis (in particular pulmonary fibrosis, renal fibrosis or hepatic fibrosis, especially pulmonary fibrosis) associated with such SARS-CoV-2 infection and / or COVID-19 (in particular moderate or severe COVID-19) may be a sequela of said SARS-CoV-2 infection and / or COVID-19; and / or may be induced by (caused by) said SARS-CoV-2 infection and / or COVID-19.

[0082] Similarly, the term pulmonary fibrosis encompasses the above forms of fibrotic interstitial lung disease as well as pulmonary fibrosis associated with SARS-CoV-2 infection and / or COVID-19 (especially moderate or severe COVID-19).

[0083] The term "fibrosis prevention / prophylaxis" includes the prevention of fibrosis in subjects exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis, particularly the risk of pulmonary, hepatic or renal fibrosis; or in subjects with a genetic predisposition to developing organ or tissue fibrosis; as well as the prevention or minimization of scarring following injury, including surgery.

[0084] The term "prevention of pulmonary fibrosis", in particular IPF, further encompasses delaying the onset of pulmonary fibrosis, in particular IPF, in patients who have experienced / have been diagnosed with pneumonia or interstitial lung disease (ILD; alternatively referred to as acute interstitial pneumonia (DPLD)); in particular, such pneumonia or ILD is interstitial pneumonia, in particular common interstitial pneumonia.

[0085] The term "treatment of pulmonary fibrosis", which in particular is IPF, further encompasses slowing the rate of decline in lung function in patients suffering from / diagnosed as suffering from pneumonia or interstitial lung disease (ILD; alternatively referred to as acute interstitial pneumonia (DPLD)); in particular, such pneumonia or ILD is interstitial pneumonia, in particular common interstitial pneumonia.

[0086] The term "prevention of pulmonary fibrosis" further encompasses delaying the onset of pulmonary fibrosis, and the term "treatment of pulmonary fibrosis" further encompasses slowing the rate of decline in lung function; said prevention or treatment being in subjects / patients with (diagnosed as having) a systemic inflammatory disease such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus), polymyositis or mixed connective tissue disease (MCTD); in subjects / patients with (diagnosed as having) sarcoidosis; in subjects / patients who have experienced radiation / have been treated with radiation therapy. or in subjects / patients who have experienced exposure to silica dust (silicosis) or asbestos; said subjects / patients in particular have / have been diagnosed as having interstitial lung disease.

[0087] The term "systemic inflammatory disease" refers in particular to systemic inflammatory and / or autoimmune diseases such as rheumatoid arthritis, scleroderma (systemic sclerosis), lupus (systemic lupus erythematosus), polymyositis, and mixed connective tissue disease (MCTD).

[0088] The term "prevention or treatment of pulmonary fibrosis", which in particular is IPF, further encompasses prevention or treatment of abnormal accumulation of cells and / or fibronectin and / or collagen in the lungs and / or increased fibroblast recruitment, and / or prevention or treatment of progression of / slowing down the rate of structural changes in the lungs; in particular, said subject / patient to be treated has been diagnosed with pulmonary fibrosis and / or pneumonia or interstitial lung disease.

[0089] Lung architectural changes are associated with well-known histopathological appearances such as septal thickening, honeycombing, nodular patterns, lung attenuation patterns, and ground-glass opacity (GGO), and can be routinely detected and quantified using high-resolution computed tomography (HRCT) of the thorax.

[0090] The compounds of formula (I) as defined in any one of aspects 1) to 15), when combined with pirfenidone and / or nintedanib, may further be useful for the prevention and / or treatment of diseases or disorders mediated by LPA1 receptor signaling, including in particular skin diseases, pain, malignant and benign proliferative diseases, respiratory diseases, nervous system disorders, cardiovascular and inflammatory diseases, obesity and insulin resistance.

[0091] The term "dermatological disease" means a skin disease, including systemic sclerosis, atopic dermatitis, bullous diseases, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, proliferative or inflammatory diseases of the skin such as urticaria; in particular systemic sclerosis.

[0092] The term "pain" refers to acute pain, chronic pain and neuropathic pain. Specific examples are fibromyalgia, in particular fibromyalgia resulting from the formation of fibrous scar tissue within contracting muscles, and cancer pain.

[0093] The term "malignant and benign proliferative disorders" refers in particular to cancer and the control of tumor cell proliferation, carcinoma invasion and / or metastasis.

[0094] The term "cancer" means all types of cancer, including carcinoma; adenocarcinoma; leukemia; sarcoma; lymphoma; myeloma; metastatic cancer; brain tumor; neuroblastoma; pancreatic cancer; gastrointestinal cancer; lung cancer; breast cancer; prostate cancer; uterine cancer; skin cancer; bladder cancer; head and neck cancer; neuroendocrine tumors; ovarian cancer; cervical cancer; oral tumors; nasopharyngeal tumors; breast cancer; and virally induced tumors. In particular, the term includes brain tumors, including pleural mesothelioma, peritoneal mesothelioma and bone metastases, as well as brain metastases, malignant glioma, glioblastoma multiforme, medulloblastoma, meningioma; neuroblastoma; pancreatic cancer, including pancreatic adenocarcinoma / pancreatic ductal adenocarcinoma; gastrointestinal cancers, including colon cancer, colorectal adenoma, colorectal adenocarcinoma, metastatic colorectal cancer, familial adenomatous polyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; Kaposi's sarcoma; leukemias, including acute myeloid leukemia, adult T-cell leukemia; lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma, and primary intraocular B-cell lymphoma; lung cancer, including non-small cell lung cancer; breast cancer, including triple-negative breast cancer; "means rhabdomyosarcoma; prostate cancer, including castration-resistant prostate cancer; esophageal squamous cell carcinoma; (oral) squamous cell carcinoma; uterine cancer; thyroid cancer, including papillary thyroid cancer; metastatic cancer; lung metastases; skin cancer, including melanoma and metastatic melanoma; urinary bladder cancer, including urothelial carcinoma; multiple myeloma; osteosarcoma; head and neck cancer; and renal cancer, including renal cell carcinoma, renal clear cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; as well as neuroendocrine tumors; ovarian cancer; cervical cancer; oral tumors; nasopharyngeal tumors; breast cancer; choriocarcinoma; Ewing's sarcoma; and virally induced tumors.

[0095] The term "respiratory disease" refers to diseases affecting the organs involved in breathing, such as the nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal), and nerves. Respiratory disease refers to interstitial pneumonia, asthma (any pulmonary disorder characterized by altered pulmonary gas flow associated with narrowing of the airways regardless of cause (intrinsic, extrinsic, or both; allergic or non-allergic), and includes adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, allergic rhinitis, including seasonal allergic rhinitis, perennial allergic rhinitis; chronic obstructive pulmonary disease (COPD), including chronic bronchitis or emphysema; airway inflammation, sarcoidosis, cystic fibrosis, hypoxia and acute lung injury and acute respiratory distress syndrome (ARDS), including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced or aspiration-induced ARDS.

[0096] The term "nervous system disorder" means a disease that alters the structure or function of the brain, spinal cord or peripheral nervous system and includes, but is not limited to, Alzheimer's disease, cerebral edema, multiple sclerosis, neuropathy, Parkinson's disease, nervous system disorders due to blunt or surgical trauma (including post-operative cognitive dysfunction and spinal cord or brain stem injury and head injury), cerebral edema, migraine headaches, and the neurological aspects of disorders such as degenerative disc disease and sciatica.

[0097] The term "cardiovascular disease" as used herein means diseases affecting the heart or blood vessels or both, including, but not limited to, arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; cerebral ischemia, stroke, angina; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms, including aortic aneurysms; retinal ischemia; reperfusion injury after ischemia of the brain, heart or other organs or tissues; restenosis; peripheral occlusive arteriopathy of the limbs, organs or tissues; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, blood pressure abnormalities; shock; vascular stenosis (including that associated with migraines); vascular abnormalities, thrombosis, and dysfunction limited to a single organ or tissue.

[0098] The term "inflammatory disease" includes psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, inflammatory myopathy, vaginitis, interstitial cystitis, scleroderma, eczema, allo- or xenograft (organ, bone marrow, stem cells and other cells and tissues) rejection, graft versus host disease, mixed connective tissue disease, lupus erythematosus, type I diabetes mellitus, dermatomyositis, phlebitis, Sjogren's syndrome, granulomatosis with polyangiitis (GPA, Wegener's granulomatosis), thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, chronic relapsing hepatitis, allergic conjunctivitis, atopic dermatitis, sinusitis and neutrophil-mediated inflammation.

[0099] Further disorders in which the LPA1 receptor is involved are in particular prostate and bladder disorders such as benign prostatic hyperplasia, eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes and and / or diseases associated with T cell recruitment, cardiomyopathy, myocardial remodeling, vascular remodeling, vascular permeability disorders, kidney disease, renal papillary necrosis, kidney failure, tumor growth, metabolic diseases, pruritus, eye diseases, macular degeneration, endocrine diseases, hyperthyroidism, osteoporosis, diabetes-related diseases (nephropathy, retinopathy).

[0100] The term "subject" means a mammal, particularly a human.

[0101] The combination treatment (or combination therapy) may be performed simultaneously (in a fixed or non-fixed dose), separately or over a period of time (particularly simultaneously).

[0102] "Concurrently" in relation to a dosage form means in this application that the dosage form concerned is an approximately simultaneous administration of two or more active ingredients and / or treatments; by simultaneous administration, it is understood that the subject is exposed to the two or more active ingredients and / or treatments at the same time. When administered simultaneously, the two or more active ingredients may be administered in a fixed dose combination, or in a non-fixed dose combination, where such a non-fixed combination may be equivalent to a fixed dose combination (e.g., by using two or more different pharmaceutical compositions to be administered at approximately the same time by the same route of administration), or in a non-fixed dose combination using two or more different routes or regimens of administration; in each case, the administration results in the subject being exposed essentially simultaneously to the two or more active ingredients and / or treatments being combined. An example of the simultaneous administration of a non-fixed dose combination using two different pharmaceutical compositions to be administered at approximately the same time by the same administration route is a non-fixed dose combination in which the compound of formula (I) as defined in any one of the embodiments 1) to 15) is administered bid and each antifibrotic agent is administered bid. Another example of the simultaneous administration of a non-fixed dose combination using two different administration routes is a non-fixed dose combination in which the compound of formula (I) as defined in any one of the embodiments 1) to 15) is administered once a day or bid and each antifibrotic agent is administered tid. Another example of the simultaneous administration of a non-fixed dose combination using two different administration routes is a non-fixed dose combination in which the compound of formula (I) as defined in any one of the embodiments 1) to 15) is administered once a day and each antifibrotic agent is administered bid. When used in combination with pirfenidone and / or nintedanib; or in combination with a pirfenidone analogue and / or nintedanib; a compound of formula (I) as defined in any one of embodiments 1) to 15) is in particular used "concurrently", especially in a non-fixed dose combination.

[0103] "Fixed dose combination", when referring to a dosage form, means in the present application that the relevant dosage form is the administration of one single pharmaceutical composition having two or more active ingredients, in particular the pharmaceutical composition according to any one of embodiments 1) to 24).

[0104] "Separately" in the present application, when referring to a dosage form, means that the dosage form concerned is the administration of two or more active ingredients and / or treatments at different times; separate administration leads to a treatment phase in which the subject is exposed to two or more active ingredients and / or treatments simultaneously (e.g., for at least 1 h, in particular for at least 6 h, especially for at least 12 h); however, it is understood that separate administration may also lead to a treatment phase in which the subject is exposed to only one of said two or more active ingredients and / or treatments for a certain period of time (e.g., for at least 12 h, in particular for at least one day). Separate administration particularly refers to the situation in which at least one active ingredient and / or treatment is given with a periodicity substantially different from daily administration (such as once or twice or three times a day) (e.g., one active ingredient and / or treatment is given, for example, once or twice or three times a day and another, for example, every other day, once a week or at longer intervals).

[0105] Administration "over a period of time" in this application means the sequential administration of two or more active ingredients and / or treatments at different times. This term is particularly applicable to the administration of one active ingredient and This refers to a dosing regimen in which the administration of one or more other active ingredients and / or treatments is completed before the administration of the other active ingredient and / or treatment is commenced, where one of the active ingredients and / or treatments can be administered for several months before the administration of the other active ingredient and / or treatment.

[0106] Any of the embodiments relating to a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of embodiments 1) to 15) for combined use in the treatment of a fibrotic disease as defined herein, wherein said compound of formula (I) is (intended to be) administered / is administered in combination with one or more anti-fibrotic agents, such as pirfenidone and / or nintedanib or a pharma- ceutically acceptable salt thereof, further comprises - the antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutically acceptable salt thereof, for use in the treatment of a fibrotic disease; the antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutically acceptable salt thereof, wherein the antifibrotic agent, in particular pirfenidone and / or nintedanib, is (intended to be) administered in combination with the compound of formula (I); - use of the compound of formula (I) or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament / pharmaceutical composition comprising the compound of formula (I) or a pharma- ceutical acceptable salt thereof and the antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutical acceptable salt thereof, wherein the medicament / pharmaceutical composition is intended for use in the treatment of the fibrotic disease; - the use of the compound of formula (I) or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament / pharmaceutical composition having the compound of formula (I) or a pharma- ceutical acceptable salt thereof as an active ingredient, the medicament / pharmaceutical composition being intended for use in the treatment of the fibrotic disease; the use of the medicament / pharmaceutical composition being (intended to be) used in combination with the antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutical acceptable salt thereof; - the use of said antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutical acceptable salt thereof, for the manufacture of a medicament / pharmaceutical composition having said antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutical acceptable salt thereof, as active ingredients, said medicament / pharmaceutical composition intended for use in the treatment of said fibrotic disease; said medicament / pharmaceutical composition (intended for use) in combination with said compound of formula (I) or a pharma- ceutical acceptable salt thereof; - the use of a pharmaceutical composition comprising said compound of formula (I) or a pharma- ceutically acceptable salt thereof and said antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutically acceptable salt thereof, for the treatment of said fibrotic disease; - a medicament for use in the prevention or treatment of said fibrotic disease, said medicament comprising said compound of formula (I) or a pharma- ceutical acceptable salt thereof; said medicament being (intended to be) administered in combination with said antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutical acceptable salt thereof; - a method for preventing or treating said fibrotic disease, comprising administering to a subject (preferably a human) in need thereof an effective amount of said compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein said compound of formula (I) is administered in combination with an effective amount of said antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutically acceptable salt thereof; it being understood that said combined administration may be a fixed dose combination or a non-fixed dose combination; - a method for preventing or treating said fibrotic disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising said compound of formula (I) or a pharma- ceutical acceptable salt thereof and said antifibrotic agent, in particular pirfenidone and / or nintedanib or a pharma- ceutical acceptable salt thereof; and - an effective amount of said antifibrotic agent, in particular pirfenidone and / or nintedanib or its A method of preventing or treating said fibrotic disease comprising administering to a subject (preferably a human) in need thereof a pharma- ceutical acceptable salt, wherein said antifibrotic agent, in particular pirfenidone and / or nintedanib, is administered in combination with an effective amount of said compound of formula (I) or a pharma- ceutical acceptable salt thereof; it being understood that said combination administration may be a fixed dose combination or a non-fixed dose combination; This also relates to:

[0107] When the plural forms are used with respect to compounds, salts, pharmaceutical compositions, diseases, and the like, these are intended to refer to a singular compound, salt, or the like.

[0108] Any reference to a compound will, where appropriate, be understood to also refer to the salts of such compounds (particularly the pharma- ceutically acceptable salts).

[0109] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. For reference, see, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

[0110] When not used in relation to temperature, the term "about" placed before a numerical value "X" in this application represents between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In the specific case of temperatures, the term "about" placed before a temperature "Y" in this application represents between Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C, in particular between Y-3°C and Y+3°C. Room temperature means a temperature of about 25°C. When the term n equivalents (n is a number) is used in this application, it is intended that within the scope of this application n means about n, preferably n means exactly n.

[0111] Whenever the words "between" or "to" are used to describe a numerical range, it is understood that the endpoints of the stated range are expressly included in that range. This means, for example, that when a temperature range is described as being between 40° C. and 80° C. (or 40° C. to 80° C.), the endpoints 40° C. and 80° C. are meant to be included in the range; or, when a variable is defined as an integer between 1 and 4 (or 1 to 4), it means that the variable is the integer 1, 2, 3, or 4.

[0112] The term "essentially" is understood in the context of the present invention to mean that each amount / purity / time etc. is at least 90 percent, particularly at least 95 percent, and especially at least 99 percent of the respective total. For example, when used in the term "essentially simultaneous exposure", it is understood to mean that in cases where chronic / steady-state exposure to pharmacoactive ingredients is intended, each exposure results in simultaneous exposure of pharmacoactive amounts of all co-active ingredients for at least 90 percent of the time, particularly at least 95 percent, and especially at least 99 percent of the relevant days.

[0113] Certain aspects of the present invention are described in the following examples, which are presented to more fully illustrate the present invention and are not intended to limit its scope in any way. . EXAMPLES

[0114] Experimental section All temperatures are given in °C. Commercially available starting materials were used as received without further purification. All reactions were carried out under a nitrogen or argon atmosphere unless otherwise noted. Compounds were purified by flash chromatography on silica gel (Biotage) using preparative TLC (Merck TLC plates, Silica gel 60 F 254 ) or by preparative HPLC. The compounds described in this invention were 1 H-NMR (400 MHz or 500 MHz Bruker; chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, quint=quintet, hex=sexlet, hept=septet, m=multiplet, br=broad; coupling constants are given in Hz) and / or LC-MS (retention times t R are given in min.; molecular weights obtained from mass spectrometry are given in g / mol.) using the conditions described below.

[0115] LC-MS under acidic conditions LCMS-1: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Waters Acquity UPLC CSH C18 1.7μm 2.1x50mm thermostated at 60℃ in Acquity UPLC Column Manager. Eluent: A: H2O+0.05% formic acid; B: AcCN+0.045% FA. Method: Gradient: 2% B 98% B over 2.0min. Flow rate: 1.0mL / min. Detection: UV214nm and ELSD.

[0116] LCMS-2: Aligent 1100 series with mass spectrometric detection (MS: Finnigan single quadrupole). Column: Zorbax RRHD SB-Aq (1.8 μm, 3.0×50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B to 5% B over 5 min (flow rate: 4.5 mL / min).

[0117] Preparative HPLC under acidic conditions Prep-HPLC-1: Column: Waters XBridge C18 (10 μm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% formic acid [eluent B]. Gradient: 95% B to 5% B over 5 min (flow rate: 75 mL / min). Detection: UV / Vis+MS.

[0118] Prep-HPLC-2: Column: Waters Zorbax SB-Aq (5 μm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% formic acid [eluent B]. Gradient: 95% B to 5% B over 5 min (flow rate: 75 mL / min). Detection: UV / Vis+MS.

[0119] Preparative HPLC under basic conditions Prep-HPLC-3: Column: Waters XBridge C18 (10 μm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH4OH [eluent B]. Gradient: 90% B to 5% B over 6.5 min (flow rate: 75 mL / min). Detection: UV / Vis+MS.

[0120] Abbreviations (as used herein): AcOH Acetic acid aq. aqueous solution bid (bis in die): twice a day Boc tert-butoxycarbonyl BSA Bovine Serum Albumin Butyl in tert.-Bu (= tertiary butyl) etc. DCM Dichloromethane DIPEA Diisopropyl-ethylamine, Huenig's base, Ethyl-diisopropylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide Et (OEt: ethoxy, etc.) ethyl EtOAc Ethyl acetate EtOH Ethanol Example: h time HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography i Pr Isopropyl LC-MS Liquid Chromatography-Mass Spectrometry LPA Lysophosphatidic acid LPAR1 Lysophosphatidic receptor 1 Me (OMe: methoxy, etc.) methyl MeCN Acetonitrile MeOH Methanol PBS Phosphate Buffered Saline Pd(OH)2 / C Palladium hydroxide on carbon prep. for preparative preparation qd (quaque die): once a day Ref Ex Reference Example rt room temperature sat. saturation TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran tid (ter in die); 3 times a day TLC Thin Layer Chromatography T3P Propylphosphonic anhydride t R retention time

[0121] Preparation of intermediates Intermediate 1.A: 6-chloro-4-methoxypyridin-3-amine 2-Chloro-4-methoxy-5-nitropyridine (440 mg, 2.33 mmol), ammonium chloride (624 mg, 11.7 mmol) and iron powder (526 mg, 11.7 mmol). A mixture of I-1.A (1.2 mmol) in EtOH (12 mL) and water (1.2 mL) is heated at 80° C. for 2 days. The reaction mixture is cooled, filtered through a Whatmann glass filter and evaporated. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The phases are separated. The aqueous phase is extracted with EtOAc and the combined organic extracts are dried over MgSO4, filtered and evaporated to give the title compound I-1.A as a brownish solid (253 mg, 72%). 1 H NMR (400MHz, DMSO D6) δ:7.61(s, 1H), 6.89(s, 1H), 5.02(s, 2H), 3.86(s, 3H).

[0122] Intermediate 1.B: 6-chloro-4-isopropoxypyridin-3-amine To a solution of 2-chloro-4-isopropoxy-5-nitropyridine (1 g, 4.62 mmol) in EtOAc (40 mL) is added platinum 1% and vanadium 2% on activated carbon (50-70% wet powder) (75 mg) and platinum 3% on activated carbon (25 mg). The reaction mixture is hydrogenated at rt for 5 days, then filtered through a pad of Celite, dried over MgSO4, filtered and evaporated to give the title compound I-1.B as a yellow oil (0.87 g, quantitative yield). 1 H NMR (400MHz, DMSO D6) δ:7.61(s, 1H), 6.89(s, 1H), 4.92(s, 2H), 4.74(hept, J=6.0Hz, 1H), 1.29(d, J=6.0Hz, 6H).

[0123] Intermediate 1.C: 4-Methoxy-6-methylpyridin-3-amine To a solution of 2-chloro-4-methoxy-6-methyl-3-nitropyridine (190 mg, 0.92 mmol) in MeOH (10 mL) is added 10% palladium on carbon-50% water (30 mg). The reaction mixture is hydrogenated at rt for 1 h, degassed with argon, then filtered through a pad of Celite, dried over MgSO4, filtered and evaporated. The crude is crystallized in MeCN to give the title compound I-1.C as an off-white solid (121 mg, 95% yield). 1 H NMR (400MHz, DMSO D6) δ:7.76(s, 1H), 7.30(s, 1H), 5.82(s, 2H), 4.03(s, 3H).

[0124] Intermediate 1.D: 2-Methoxy-6-methylpyridin-3-amine Step 1. Methanol (256 μL, 6.39 mmol) is added dropwise to a stirred suspension of NaH (60% dispersion in oil, 256 mg, 6.39 mmol) in anhydrous THF (10 mL) at 0° C., and the resulting solution is stirred for 0.5 h. To this solution is added dropwise a solution of 2-fluoro-6-methyl-3-nitropyridine (1.0 g, 6.09 mmol) in anhydrous THF (5 mL). After the addition is complete, the solution is stirred at 0° C. for 0.5 h and then allowed to warm to ambient temperature. The reaction is stirred at ambient temperature for 18 h, quenched with water (30 mL), and the aqueous layer is extracted with EtOAc (3×50 mL). The combined organic extracts are washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. 2-Methoxy-6-methyl-3-nitropyridine is obtained after purification by prep-HPLC (Prep-HPLC-3) as a yellow oil (539 mg, 53% yield). 1 H NMR (400MHz, DMSO D6) δ:8.34(d, J=8.1Hz, 1H), 7.09(d, J=8.1Hz, 1H), 4.01(s, 3H), 2.51(s, 3H).

[0125] Step 2. To a degassed solution of 2-methoxy-6-methyl-3-nitropyridine (539 mg, 3.21 mmol) in methanol (10 mL) is added Pd(OH)2 / C (255 mg) followed by ammonium formate. The reaction mixture is stirred at 50° C. for 20 h, then filtered through a Whatmann-Filter and evaporated. The residue is dissolved in EtOAc (30 mL) and the organic solution is washed with sat.NaHCO3sol. (15 mL) followed by brine (15 mL). The organic phase is dried over MgSO4, filtered and evaporated to give 2-methoxy-6-methylpyridin-3-amine I-1.D as a yellow oil (199 mg, 45% yield). LCMS-2:t R =0.38min, [M+1] + 139.13; 1 H NMR (400MHz, DMSO D6) δ:6.78(d, J=7.5Hz, 1H), 6.54(d, J=7.5Hz, 1H), 4.65(s, 2H), 3.82(s, 3H), 2.23(s, 3H).

[0126] Intermediate 1.E: 2-isopropoxy-6-methylpyridin-3-amine 2-Isopropoxy-6-methylpyridin-3-amine I-1.E is synthesized starting from commercially available 2-fluoro-6-methyl-3-nitropyridine and isopropanol using the method described for I-1.D. 1 H NMR (400MHz, DMSO D6) δ:6.77(d, J=7.5Hz, 1H), 6.49(d, J=7.5Hz, 1H), 5.22(m, 1H), 4.53(s, 2H), 2.21(s, 3H), 1.27(d, J=6.2Hz, 6H).

[0127] Intermediate 1.F: 2-ethoxy-6-methylpyridin-3-amine 2-Ethoxy-6-methylpyridin-3-amine I-1.F is synthesized starting from commercially available 2-fluoro-6-methyl-3-nitropyridine and ethanol using the method described for I-1.D. 1 H NMR (400MHz, DMSO D6) δ:6.78(d, J=7.5Hz, 1H), 6.52(d, J=7.5Hz, 1H), 4.59(s, 2H), 4.28(q, J=7.0Hz, 2H), 2.22(s, 3H), 1.31(t, J=7.0Hz, 3H).

[0128] Intermediate 1.G: 2-(difluoromethoxy)-6-methylpyridin-3-amine Step 1. A suspension of 6-methyl-3-nitropyridin-2-ol (10 g, 61.6 mmol) and Na2SO4 (21.89 g, 15.4 mmol) in MeCN (250 mL) is heated to 60° C. and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (8.8 mL, 80 mmol) is added dropwise over 10 min. The reaction mixture is stirred for an additional hour, then quenched with NaOH 3M (250 mL) and the acetonitrile is removed under vacuum. The remaining aqueous components are extracted with EtOAc (3×200 mL). The combined organic extracts are washed with water (50 mL) then brine (100 mL), dried over MgSO4, filtered and concentrated under vacuum. The yellow oil was purified by column chromatography (Biotage, heptane:EtOAc 1:0 to 1:1) to give 2-(difluoromethoxy)-6-methyl-3-nitropyridine as a yellow oil (10.9 g, 85% yield) which crystallized on standing. 1 H NMR (400MHz, DMSO D6) δ:8.51(d, J=8.2Hz, 1H), 7.82(t, J=71.3Hz, 1H), 7.39(d, J=8.2Hz, 1H), 2.55(s, 3H).

[0129] Step 2. To 2-(difluoromethoxy)-6-methyl-3-nitropyridine (4.65 g, 22.8 mmol) in degassed methanol (100 mL) is added 10% palladium on carbon-50% water (350 mg) and the reaction is hydrogenated at atmospheric pressure for 18 h. The mixture is filtered through a pad of Celite. The pad is rinsed with THF (3x10 mL) and the organic solution is concentrated under vacuum to give 2-(difluoromethoxy)-6-methylpyridin-3-amine I-1.G as a pale yellow oil that crystallizes on standing (4.1 g, 92% yield). LCMS-2:t R = 0.75 min, no mass analysis; 1 H NMR (400MHz, CDCl3) δ:7.52(t, J=73.5Hz, 1H), 6.96(d, J=7.8Hz, 1H), 6.77(d, J=7.8Hz, 1H), 2.36(s, 3H).

[0130] Intermediate 2: 1-Benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylic acid Step 1. To a solution of commercially available 1-bromo-2-fluorobenzene (5 g, 28.6 mmol) in THF (60 mL) was added 1-benzhydrylazetidine-3-carbonitrile (1 0.6 g, 42.9 mmol) and KHMDS 95% (10.3 mL, 42.9 mmol) are added. The reaction mixture is left stirring at rt overnight. The reaction mixture is then concentrated under vacuum to an oil, diluted with EtOAc (100 mL) and washed with water (2x50 mL). The organic phase is dried over MgSO4 and concentrated under vacuum. The crude is purified by prep. HPLC (Prep-HPLC-2 conditions) to give 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carbonitrile as a beige solid (7.64 g, 66% yield). 1 H NMR (400MHz, DMSO D6) δ:7.70(d, J=7.9Hz, 1H), 7.47-7.42(m, 6H), 7.36-7.31(m, 5H), 7.25-7.21(m, 2H), 4.56(s, 1H), 3.98(d, J=8.0Hz, 2H), 3.49-3.42(m, 2H).

[0131] Step 2. To a solution of 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carbonitrile (7.2 g, 17.9 mmol) in ethanol (80 mL) is added NaOH 25% (40 mL). The reaction mixture is stirred at 80° C. for 3-4 days (reaction monitored by LCMS), then cooled to 0° C. and acidified with aq. 2M HCl. The mixture is extracted with EtOAc (2×200 mL), dried over MgSO4, filtered and evaporated. The crude is purified by column chromatography (eluent: DCM / MeOH 9:1) to give 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylic acid I-2 as a yellow foam (6.37 g, 84% yield). LCMS-2:t R =0.83min, [M+1] + 423.99; 1H NMR (400MHz, DMSO D6) δ:7.54(d, J=7.8Hz, 1H), 7.43-7.41(m, 4H), 7.37(d, J=4.2Hz, 2H), 7.29(t, J=7.3Hz , 4H), 7.21-7.17(m, 3H), 4.47(s, 1H), 3.88(d, J=7.8Hz, 2H), 3.36(d, J=7.7Hz, 2H).

[0132] Intermediate 3: 1-Benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride 1-Benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylic acid I-2 (538 mg, 1.38 mmol) is dissolved in DCM (10 mL). Three drops of DMF are added followed by thionyl chloride (0.5 mL, 6.9 mmol) and the reaction is stirred at 50° C. for 1 h (monitored by LCMS). The reaction mixture is then evaporated to give crude 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride I-3 as a wax (620 mg) which is used as is.

[0133] Intermediate 4: 1-(tert-butoxycarbonyl)-3-(2-isopropylphenyl)azetidine-3-carboxylic acid Step 1. To a solution of I-2 (5.0 g, 11.8 mmol) in MeOH (30 mL) is added concentrated sulfuric acid (10 mL). The reaction mixture is stirred at 75 °C for 24 h and then evaporated. The residue is dissolved in EtOAc (100 mL) and washed with sat.NaHCO3. The phases are separated and the organic phase is washed with brine (50 mL), dried over MgSO4, filtered and evaporated. The crude compound is purified by chromatography (CombiFlash Hept / EtOAc 9:1) to give methyl 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylate as a yellow oil (4.12 g, 80% yield). 1H NMR (400MHz, CDCl3) δ:7.54(dd, J1=1.1Hz, J2=8.0Hz, 1H), 7.49-7.41(m, 4H), 7.38-7.32(m, 1H), 7.32-7.26(m, 5H), 7.24-7.19(m, 2 H), 7.17(td, J1=1.9Hz, J2=7.9Hz, 1H), 4.43(s, 1H), 4.08(d, J=8.3Hz, 2H), 3.74(s, 3H), 3.51(d, J=8.2Hz, 2H).

[0134] Step 2. To a solution of methyl 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylate (4.12 g, 9.44 mmol) in dioxane (50 mL) is added isopropenylboronic acid pinacol ester (2.5 g, 14.2 mmol), followed by K2CO3 (6.5 g) and water (25 mL). Pd(PPh3)4 (327 mg, 0.28 mmol) is then added and the reaction mixture is stirred at 80° C. for 15 h. Water is added at rt and the reaction mixture is extracted with EtOAc. The organic extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography (Combiflash, Hept / EtOAc 9:1) to give methyl 1-benzhydryl-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxylate as a yellow oil (3.64 g, 97% yield). 1 H NMR (400MHz, DMSO D6) δ:7.40-7.38(m, 4H), 7.30-7.23(m, 7H), 7.21-7.17(m, 2H), 7.12-7.10(m, 1H), 5.06(s, 1H), 4. 59(s, 1H), 4.42(s, 1H), 3.82(d, J=7.7Hz, 2H), 3.66(s, 3H), 3.21(d, J=7.7Hz, 2H), 1.92(s, 3H).

[0135] Step 3. To a solution of methyl 1-benzhydryl-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxylate (3.64 g, 9.16 mmol) in MeOH / THF 1:1 (20 mL) is added aq. 2M LiOH (10 mL). The reaction mixture is stirred at 50° C. for 2 days, then cooled to 5° C. and acidified to pH 4 with 2M HCl. The reaction mixture is extracted with EtOAc. The organic extract is dried over MgSO4, filtered and evaporated to give 1-benzhydryl-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxylic acid as a beige solid (3.35 g, 95% yield). 1 H NMR (400MHz, DMSO D6) δ:7.39(d, J=7.3Hz, 4H), 7.28(t, J=7.4Hz, 4H), 7.23-7.17(m, 5H), 7.11-7.09(m, 1H), 5.06( s, 1H), 4.71(s, 1H), 4.39(s, 1H), 3.82(d, J=7.6Hz, 2H), 3.14(d, J=7.5Hz, 2H), 1.95(s, 3H).

[0136] Step 4. A mixture of 1-benzhydryl-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxylic acid (3.35 g, 8.74 mmol), 25% HCl solution (18 mL) and Pd(OH)2 / C 20% (1.6 g) in MeOH (100 mL) is degassed and then hydrogenated at 1 bar for 18 h (reaction monitored by LCMS). The reaction mixture is then degassed with argon and filtered through a pad of Celite, which is rinsed with MeOH. The volatiles are evaporated and the residue is crystallized in MeCN to give the hydrochloride salt of 3-(2-isopropylphenyl)azetidine-3-carboxylic acid as a white solid (1.17 g, 61% yield). 1 H NMR (400MHz, DMSO D6) δ:13.55(s br, 1H), 9.40(s br, 1H), 9.15(s br, 1H), 7.39(d, J=6.9Hz, 1H), 7.34(t, J=7.2Hz, 1H), 7.24(t, J=7.0Hz, 1H), 7.1 8(d, J=7.6Hz, 1H), 4.57-4.54(m, 2H), 4.39-4.35(m, 2H), 1.13(d, J=6.7Hz, 6H).

[0137] Step 5. To a suspension of 3-(2-isopropylphenyl)azetidine-3-carboxylic acid hydrochloride (1.17 g, 4.57 mmol) in DCM (25 mL) is added DIPEA (5.9 mL, 34.4 mmol) followed by Boc2O (1.1 g, 5.02 mmol). The mixture is stirred at rt for 24 h. 1N HCl is added at 5° C. to adjust the pH to 1 and the reaction mixture is extracted with DCM (4 times). The combined organic extracts are dried over MgSO4, filtered and evaporated. The residue is purified by chromatography (CombiFlash Hept / EtOAc 1.5:1) to give 1-(tert-butoxycarbonyl)-3- (2-Isopropylphenyl)azetidine-3-carboxylic acid I-4 is obtained as a white solid (0.85 g, 58% yield). 1 H NMR (400MHz, CDCl3) δ:7.36-7.31(m, 2H), 7.26-7.21(m, 1H), 7.18(d, J=7.0Hz, 1H), 4.64(d, J=8.5Hz, 2H), 4.37(d, J=8.5Hz, 2H), 2.61-2.51(m, 1H), 1.46(s, 9H), 1.19(d, J=6.7Hz, 6H).

[0138] Reference Example 1: N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide Step 1. To a solution of 1-(tert-butoxycarbonyl)-3-(2-isopropylphenyl)azetidine-3-carboxylic acid I-4 (110 mg, 0.34 mmol) and DMF (0.3 mL) in pyridine (3 mL) is added dropwise over 35 min (monitored by LCMS for complete conversion to the acyl chloride and quenched with MeOH). Then, a solution of 6-fluoro-4-methoxypyridin-3-amine (50.5 mg, 0.34 mmol) in pyridine (1 mL) is added to the reaction mixture. After several hours, the mixture is quenched with water and then NaHCO3. The aqueous solution is then extracted twice with EtOAc. The combined organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by prep. HPLC (Prep-HPLC-3 conditions) to give tert-butyl 3-((6-fluoro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate (77 mg, 50% yield) as a pale yellow oil. LCMS-1:t R =1.28min, [M+1] + 444.20.

[0139] Step 2. To tert-butyl 3-((6-fluoro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate (76 mg, 0.17 mmol) in dioxane (2 mL), 4N HCl (0.5 mL) is added. The reaction mixture is stirred at rt overnight. The volatiles are evaporated to give the hydrochloride salt of the title compound Ex1 as a white solid (70 mg, quantitative yield). LCMS-1:t R =0.58min, [M+1] + 344.28. 1H NMR (400MHz, DMSO D6) δ:8.58(s, 1H), 8.21(s, 1H), 7.49-7.40(m, 3H), 7.34(t, J=7.3Hz, 1H), 6.90(s, 1H), 4.66(d, J =10.4Hz, 2H), 4.40(d, J=10.4Hz, 2H), 3.74(s, 3H), 2.50-2.40(m, 1H), 1.12(d, J=6.5Hz, 6H).

[0140] Table 1: Reference Examples 2-6 Ref Ex2-6 are prepared analogously to the method described for Ref. Ex1 using commercially available or synthesized pyridin-3-amines and intermediate I-4.

[0141] [Table 1]

[0142] Reference Example 7: 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide Step 1. To a solution of 2-methoxy-6-methylpyridin-3-amine I-1.D (191 mg, 1.38 mmol) in THF (10 mL) is added a suspension of NaH (60% dispersion in oil, 120 mg, 2.76 mmol). After stirring the mixture for 30 min, a suspension of benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride I-3 (608 mg, 1.38 mmol) in THF (10 mL) is added dropwise and stirring is continued for 2 h (reaction monitored by LCMS). The reaction mixture is then diluted with DCM (50 mL) and washed with water (20 mL). The organic phase is dried over MgSO4, filtered and evaporated. The crude compound is crystallized in MeCN to give 1-benzhydryl-3-(2-bromophenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide as an off-white solid (278 mg, 37% yield). 1H NMR (400MHz, DMSO D6) δ:11.10(s, 1H), 8.42(d, J=7.9Hz, 1H), 7.62-7.57(m, 5H), 7.40-7.34(m, 5H), 7.28-7.18(m, 4H), 6.88 (d, J=7.9Hz, 1H), 4.73(s, 1H), 4.17(s, 3H), 4.01(d, J=7.0Hz, 2H), 3.52(d, J=7.3Hz, 2H), 2.42(s, 3H).

[0143] Step 2. 1-Benzhydryl-N-(2-methoxy-6-methylpyridin-3-yl)-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxamide is prepared from 1-benzhydryl-3-(2-bromophenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide according to the method described for I-4-Step 2 (216 mg, 84% yield). 1 H NMR (400MHz, DMSO D6) δ:11.24(s, 1H), 8.44(d, J=7.9Hz, 1H), 7.57(d, J=7.5Hz, 4H), 7.36(t, J=7.5Hz, 4H), 7.26-7.15(m, 5H), 7.00(d, J=7.3Hz, 1H), 6.88(d, J =7.9Hz, 1H), 4.98(s, 1H), 4.74(s, 1H), 4.68(s, 1H), 4.16(s, 3H), 3.87(d, J=7.4Hz, 2H), 3.33(d, J=7.4Hz, 2H), 2.42(s, 3H), 1.94(s, 3H).

[0144] Step 3. A mixture of 1-benzhydryl-N-(2-methoxy-6-methylpyridin-3-yl)-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxamide (216 mg, 0.43 mmol), 25% HCl solution (4.5 mL) and Pd(OH)2 / C20 wt.% (300 mg) in MeOH (25 mL) is degassed and then hydrogenated at 1 bar for 18 h (reaction monitored by LCMS). The reaction mixture is then degassed with argon, filtered through a pad of Celite and rinsed with MeOH (10 mL). The volatiles are evaporated and the residue is dissolved in EtOAc (60 mL). The organic solution is washed with a 5N aqueous solution of NaOH (30 mL), dried over MgSO4, filtered and evaporated. The crude material is purified by prep-TLC (eluent: DCM / MeOH: 9 / 1) to give 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide Ref Ex7 as a white solid (32 mg, 22% yield). LCMS-1:t R =0.68min, [M+1] + 340.43; 1 H NMR (400MHz, CD3OD) δ:8.34(d, J=7.9Hz, 1H), 7.46-7.35(m, 4H), 6.78(d, J=7.9Hz, 1H), 4.31(d, J=8.5Hz, 2H ), 4.17(d, J=8.5Hz, 2H), 3.72(s, 3H), 2.49(m, 1H), 2.36(s, 3H), 1.13(d, J=6.7Hz, 6H).

[0145] Reference Example 8: N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide is prepared from 2-isopropoxy-6-methylpyridin-3-amine I-1.E (1.8 g) and benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride I-3 (4.36 g) according to the method described for Ref Ex7 (1.29 g, white solid). LCMS-1:t R =0.80min, [M+1] + 368.34; 1 H NMR (400MHz, CD3OD) δ:8.45(d, J=7.9Hz, 1H), 7.49-7.47(m, 2H), 7.43-7.40(m, 2H), 6.74(d, J=8.0Hz, 1H), 5.51(s, 1H), 5.18-5.11(m, 1H), 4. 38(d, J=8.2Hz, 2H), 4.21(d, J=8.0Hz, 2H), 2.37-2.44(m, 1H), 2.33(s, 3H), 1.13(d, J=6.7Hz, 7H), 1.02(d, J=6.2Hz, 6H).

[0146] Reference Example 9: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine I-1.G (229 mg) and benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride I-3 (608 mg) according to the method described for Ref Ex7 (110 mg, yellow oil). LCMS-1:t R =0.71min, [M+1] + 376.22; 1H NMR (500MHz, DMSO D6) δ:9.90(s, 1H), 8.24(d, J=8.0Hz, 1H), 7.63(t, J=72.6Hz, 1H), 7.33(dd, J1=1.3Hz, J2=7.8Hz, 1H), 7.28(td, J1=1.2Hz, J2=7.3Hz, 1H), 7.19(m, J1 =1.4Hz, J2=7.7Hz, 1H), 7.14(dd, J1=1.1Hz, J2=7.7Hz, 1H), 7.11(d, J=8.4Hz, 1H), 4.07(m, 2H), 4.01(m, 2H), 2.38(s, 3H), 1.09(d, J=6.7Hz, 6H).

[0147] Reference Example 10: N-(6-chloro-2-methoxypyridin-3-yl)-3-(2 -Isopropylphenyl)azetidine-3-carboxamide Step 1. To a solution of I-4 (40 mg, 0.125 mmol), commercially available 6-chloro-2-methoxypyridin-3-amine (25 mg, 0.15 mmol) and pyridine (70 μL, 0.07 mmol) in EtOAc (1 mL) is added T3P 50% sol. in EtOAc (300 μL, 0.5 mmol). The reaction mixture is stirred at 65° C. overnight. Then water (5 mL) is added and the reaction mixture is extracted with EtOAc (3×10 mL). The combined organic extracts are dried over MgSO4, filtered and evaporated. The residue is purified by prep. HPLC (Prep-HPLC-1 conditions) to give tert-butyl 3-((6-chloro-2-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate as a yellow oil (54 mg, 62% yield). LCMS-2:t R =1.22min, [M+1] + 460.37. 1H NMR (400MHz, CDCl3) δ:8.58(d, J=8.2Hz, 1H), 7.48-7.41(m, 2H), 7.39-7.32(m, 3H), 6.92(d, J=8.2Hz, 1H), 4.80-4 .54(m, 2H), 4.52-4.28(m, 2H), 3.75(s, 3H), 2.43(m, 1H), 1.48(s, 9H), 1.14(d, J=6.6Hz, 6H).

[0148] Step 2. tert-Butyl 3-((6-chloro-2-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate is subjected to standard Boc deprotection conditions: To a solution of the Boc protected precursor (1.41 mmol) in DCM (20 mL) is added TFA (1.1 mL, 14.1 mmol) at 10° C. The reaction mixture is stirred at rt for 2 h (monitored by LCMS) and then evaporated. The residue is purified by prep. HPLC (Prep-HPLC-3 conditions) to give Ref Ex10 as a colorless oil (30 mg, 75% yield). LCMS-1:t R =0.72min, [M+1] + 360.30. 1 H NMR (400MHz, CDCl3) δ:8.62(d, J=8.2Hz, 1H), 8.38(s, 1H), 7.41-7.36(m, 2H), 7.34-7.29(m, 1H), 7.17(d, J=7.7Hz, 1H), 6.92(d, J=8.2Hz, 1H), 4.27(s br, 4H), 3.85(s, 3H), 2.51-2.41(m, 1H), 1.14(d, J=6.7Hz, 6H).

[0149] Reference Example 11: N-(2-ethoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide N-(2-ethoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide is prepared analogously to Reference Example 8 from 2-ethoxy-6-methylpyridin-3-amine I-1.F.

[0150] Working Example Table 2: Reference Example and Examples 2-1 to 2-11: Reductive amination A solution of the appropriate Ref Ex1-11 (0.139 mmol) and the appropriate aldehyde (0.417 mmol) in dry MeOH (2 mL) is stirred under inert atmosphere for 2 h. Cyanoborohydride (43 mg, 0.695 mmol) is then added. The reaction mixture is stirred at 50° C. for 2 h (reaction monitored by LCMS) and then quenched with water (2 mL). The mixture is diluted with MeCN (2 mL) and purified by prep. HPLC (Prep-HPLC-2 conditions) to give the desired product.

[0151] Reference Examples and Examples 2-1 to 2-11 are synthesized from the appropriate Ref Exs 1 to 11 by reductive amination. Functional groups such as acids may be protected with appropriate ester protecting groups. For example, esters are saponified with 2N LiOH after the reductive amination step.

[0152] [Table 2]

[0153] Table 3: Example 3-1: Alkylation Step 1. A mixture of the appropriate amine precursor Ref Ex1-11, e.g. Ref Ex3 hydrochloride (50 mg, 0.11 mmol), the appropriate methyl(bromoalkyl)carboxylate (0.17 mmol) and Cs2CO3 (150 mg, 0.46 mmol) in MeCN (1 mL) is stirred for 18 h at 50° C. The reaction mixture is evaporated and the residue is purified by prep-HPLC (Prep-HPLC-3 conditions) to give the desired ester.

[0154] Step 2. Dissolve the above ester (0.06 mmol) in MeOH (2 mL) and add 2M Treat with LiOH (1 mL, 2.0 mmol). Stir the reaction at rt overnight (reaction progress monitored by LCMS). Cool the reaction mixture to 0° C. and slowly acidify to pH 4 with a solution of 2N HCl. The aqueous solution is then extracted twice with EtOAc. The organic extract The extracts are combined, dried over MgSO4, filtered and evaporated to give the hydrochloride salt of the desired product.

[0155] [Table 3]

[0156] Table 4: Reference Example and Examples 4-1 to 4-7: Amide coupling To a solution of the appropriate Ref Ex1-11, e.g. N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide Ref Ex2 (30 mg, 0.08 mmol) and the appropriate acid (0.12 mmol) in DMF (2 mL) is added EDC (21 mg, 0.11 mmol), HOBt (17 mg, 0.11 mmol) and DIPEA (43 μL, 0.25 mmol). The mixture is stirred at rt for 18 h, then diluted with sat. aq. NaHCO3 and extracted twice with EtOAc. The organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (Prep-HPLC-3 conditions) to give the desired product.

[0157] Reference Examples and Examples 4-1 to 4-7 are synthesized from the appropriate Ref Ex1 to 11 by amide coupling with acyl chlorides or carboxylic acids in the presence of EDC / HOBt, HATU or T3P and an organic base (e.g., DIPEA or pyridine). Functional groups such as carboxylic acids may be protected with appropriate ester protecting groups. For example, esters are saponified with 2N LiOH after a reductive amination step.

[0158] Saponification: The appropriate ester (0.044 mmol) is dissolved in MeOH / THF 1:1 (1 mL) and treated with 2M LiOH (45 μL, 18.4 mmol). The solution is stirred at rt for 2 h (reaction progress monitored by LCMS). The reaction mixture is then diluted with water, acidified to pH 1 with 6N HCl at 5° C., and extracted twice with EtOAc. The organic extracts are combined, dried over MgSO4, filtered, and evaporated to give the desired product.

[0159] [Table 4]

[0160] Table 5: Examples 5-1 to 5-10: Example 5-1: N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide To a solution of Ref Ex1 (35 mg, 0.09 mmol) and TEA (39 μL, 0.28 mmol) in dioxane (1 mL) is added sulfamide (18 mg, 0.18 mmol). The reaction mixture is stirred at 100° C. for 18 h, then evaporated. The crude compound is purified by prep. HPLC (Prep-HPLC-2 conditions) to give the title compound Ex5-1 as a white solid (15 mg, 39% yield). LCMS-1:t R =0.94min, [M+1] + 423.29. 1 H NMR (400MHz, DMSO D6) δ:8.69(s, 1H), 8.15(s, 1H), 7.42-7.32(m, 3H), 7.29-7.24(m, 1H), 7.05(s, 2H), 6.89(s, 1H), 4.4 1(d, J=7.6Hz, 2H), 4.14(d, J=7.6Hz, 2H), 3.75(s, 3H), 2.75-2.64(m, 1H), 1.11(d, J=6.6Hz, 6H).

[0161] Examples 5-2 to 5-10 Examples 5-2 to 5-10 are synthesized similarly to the method described for Ex5-1 starting from the appropriate Ref Ex1 to 11.

[0162] [Table 5]

[0163] Biological testing IC against human LPAR1 50 Beta-arrestin mobilization assay to determine the value Tango® EDG2-bla U2OS cells are obtained from Invitrogen. These cells have the human LPA1 receptor cDNA bound to a TEV protease site and Gal4-VP16 transcription factor integrated into the Tango® GPCR-bla U2OS parent cell line. The parent cell line stably expresses a beta-arrestin / TEV protease fusion protein and a beta-lactamase (bla) reporter gene under the control of a UAS response element. Upon binding of LPA (agonist), the LPA1 receptor is activated, causing arrestin-protease recruitment and proteolytic release of the transcription factor; the transcription factor then controls the transcription of the beta-lactamase reporter construct, which is measured by adding a live-cell substrate.

[0164] 10'000 Tango® EDG2-bla U2 OS cells are seeded in 30 μl Freestyle 293 Expression Medium (Invitrogen) in 384-well black clear bottom plates and incubated for 20 h at 37° C., 5% CO2. For antagonist testing, 5 μl of test compound (serial dilution in DMSO / Freestyle 293 Expression medium / 0.1% fatty acid free BSA (Sigma)) or buffer control is added per well. Incubate for 30 min at 37° C., 5% CO2. 5 μl LPA 18:1 (final concentration 500 nM) per well (solution in Freestyle 293 Expression medium / 0.1% fatty acid free BSA (Sigma)) is added and the plate is incubated for 16 h at 37° C., 5% CO2. Cells are then loaded with LiveBLAzer-FRET® B / G Substrate (Invitrogen) in the dark for 2 h and fluorescence emission is measured at 460 nm and 530 nm using a SynergyMx reader (BioTek). After background subtraction from both channels, the 460 / 530 nm emission ratio is calculated for each well, then plotted and fitted to a 4-parameter logistic function to obtain the IC 50 Get the value. IC 50 is the concentration of antagonist that inhibits 50% of the maximal response.

[0165] Antagonist activity of example compounds (IC 50 Antagonist activity is shown in Table 6. When values ​​were measured multiple times, geometric mean values ​​are reported.

[0166] [Table 6]

[0167] In vivo efficacy assessment The in vivo efficacy of compounds of formula (I) can be determined using a mouse LPA-induced skin vascular leakage model. Female Balb / c mice are treated with vehicle or test compound (po) for at least 1 h before administration of the albumin marker Evans blue (50 mg / kg, iv, 0.9% NaCl) and then challenged with LPA (5 μg, id). After 30 min, the mice are sacrificed by CO2 inhalation. Skin disks are removed from the injection sites and treated in formamide (500 μl, 37° C., 24 h) and the content of Evans blue is quantified by colorimetric analysis. Results are expressed as Evans blue extravasated per skin disk (μg / disc).

[0168] For example, compared to a group of animals treated with vehicle alone, a selected compound of the present invention, Example 5-2, can effectively reduce LPA-induced vascular leakage after oral administration of 30 mg / kg to mice, and the reduction in vascular leakage compared to the vehicle group was ≧60%.

[0169] Examples of the antifibrotic effect of compounds of formula (I) in combination with pirfenidone The antifibrotic effects of Example Compound AC or Reference Compound D (BMS-986020) and pirfenidone alone or in combination can be measured in vitro in a TGFβ-induced myofibroblast differentiation assay.

[0170] Combination Effect Experiment: Transforming Growth Factor Beta (TGFβ)-Induced α-Smooth Muscle Actin (αSMA) Expression in Human Fibroblasts: Normal Human Lung Fibroblasts (NHLF) were obtained from Lonza. 10'000 cells were seeded in 300 μl of Fibroblast Growth Medium-2 (FGM®-2, Lonza) in 24-well plates and incubated at 37° C. and 5% CO2 for 20 hours. The medium was changed to 300 μl of Fibroblast Basal Medium (FBM®, Lonza) supplemented with 0.1% fatty acid-free BSA (Sigma) and the plates were incubated at 37° C. and 5% CO2 for 20 hours. 100 μl of "compound", pirfenidone or their combination (solution in FBM® / 0.1% fatty acid free BSA) was added per well and incubated for 30 min, then 100 μl of TGFβ (5 ng / ml final) (solution in FBM® / 0.1% fatty acid free BSA) was added and incubated at 37° C., 5% CO2 for 48 h. Cells were washed with ice-cold PBS and lysed in RIPA buffer (Sigma) supplemented with NaF, Na orthovanadate, phenylmethylsulfonyl fluoride (PMSF), dithiothreitol (DTT) and benzonase. Samples were separated by SDS-PAGE on 4-12% Novex Bis-Tris precast gels (Thermo Fischer Scientific) and analyzed by Western blot using αSMA (Sigma) and HRP-conjugated secondary antibodies. Membranes were treated with Western Lighting Enhanced Chemiluminescence Substrate (Perkin Elmer) and chemiluminescence signals were recorded with a reader, Fusion FX6 (Viber Lourmat). Signals were quantified using densitometric analysis within Fusion software. The % inhibition of TGFβ-induced αSMA expression was calculated for each "compound", pirfenidone and their combination. The additive effect was calculated by adding the % inhibition values ​​by "compound" alone and pirfenidone alone and was expressed as "expected combination inhibition". The measured % inhibition by the combination of "compound" and pirfenidone was expressed as "measured combination inhibition".Pirfenidone efficacy was determined in GraphPad Prism software using the following settings: minimum defined by vehicle control without TGFβ stimulation, maximum defined by TGFβ response in the presence or absence of Compound, no weighting and no variable slope.

[0171] The results of the combined effect experiment are shown in FIGS.

[0172] Figures 1-4: 10 nM of each Compound AD and 2 mM pirfenidone only slightly inhibited TGFβ-induced αSMA expression in NHLFs. Combination of any of the Compound AD with pirfenidone showed synergistic effects, significantly reducing αSMA expression.

[0173] FIG. 5 shows the dose-response of pirfenidone on TGFβ-induced αSMA expression in NHLFs in the absence and presence of 10 nM, 100 nM, and 1000 nM of Compound A. When combined with Compound A, the IC 50 The efficacy of pirfenidone increases as indicated by the decrease in (mM).

[0174] Examples of the antifibrotic effect of compounds of formula (I) in combination with nintedanib The antifibrotic effect of each of the Example Compounds AC and Nintedanib alone or in combination can be measured in vitro in a TGFβ-induced myofibroblast differentiation assay.

[0175] Combination Effect Experiment: TGFβ-Induced αSMA Expression in Human Fibroblasts: NHLFs were obtained from Lonza. 10'000 cells were seeded in 300 μl of FGM®-2 in 24-well plates and incubated at 37° C. under 5% CO2 for 20 h. The medium was changed to 300 μl of FBM® supplemented with 0.1% fatty acid-free BSA (Sigma) and the plates were incubated at 37° C. under 5% CO2 for 20 h. 100 μl of each "compound", nintedanib or combinations thereof (solution in FBM® / 0.1% fatty acid-free BSA) was added per well and incubated for 30 min, then 100 μl of TGFβ (5 ng / ml final) (solution in FBM® / 0.1% fatty acid-free BSA) was added and incubated at 37° C. under 5% CO2 for 48 h. Cells were washed with ice-cold PBS and lysed in RIPA buffer (Sigma) supplemented with NaF, sodium orthovanadate, phenylmethylsulfonyl fluoride (PMSF), and dithiothreitol (DTT). Samples were separated by SDS-PAGE on 4-12% Novex Bis-Tris precast gels (Thermo Fischer Scientific) and analyzed by Western blot using αSMA (Sigma) and HRP-conjugated secondary antibodies. Membranes were treated with Western Lighting Enhanced Chemiluminescence Substrate (Perkin Elmer) and chemiluminescence signals were recorded with a Fusion FX6 (Viber Lourmat) reader. Signals were quantified using densitometric analysis within Fusion software. The % inhibition of TGFβ-induced αSMA expression was calculated for each "compound", nintedanib, and their combination. Additive effects were calculated by adding the % inhibition values ​​by the "compound" alone and nintedanib alone and expressed as "expected combination inhibition". The measured % of inhibition by the combination of Compound and nintedanib was expressed as "Measured Combination Inhibition."

[0176] The results of the combined effect experiment are shown in Figures 6 to 8.

[0177] Figures 6-8: 10 nM of each of the Compound ACs and 1 μM of nintedanib only slightly inhibited TGFβ-induced αSMA expression in NHLFs. Combining any of the Compound ACs with nintedanib had at least an additive effect, significantly reducing αSMA expression.

Claims

1. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a fibrotic disease: 【Chemistry 1】 (In the formula, - X is CH; Y is N; and R ２ is methyl, ethyl or isopropyl; Or, - X is N; Y is CH; and R ２ is methyl, ethyl or isopropyl or difluoromethyl; R １ is fluoro, chloro, bromo or methyl; R ３ teeth, - -(CH ２ ) ２－３ -C(CH ３ ) ２ -COOH; --CO-(CH ２ ) １－２ -C(CH ３ ) ２ -COOH; or - -SO ２ -NH ２ ; ) ; And, The medicament is used in combination with one or more therapeutically active ingredients that act as antifibrotic agents, The one or more therapeutically active ingredients acting as antifibrotic agents are - pirfenidone or a pharma- ceutically acceptable salt thereof; - nintedanib or a pharma- ceutically acceptable salt thereof; Or, - both pirfenidone or a pharma- ceutically acceptable salt thereof and nintedanib or a pharma- ceutically acceptable salt thereof; 2. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

2. X is CH; Y is N; R ２ The use according to claim 1 ; wherein R is methyl, ethyl or isopropyl.

3. R １ The use according to claim 2 ; wherein is fluoro, chloro or bromo.

4. X is N; Y is CH; R ２ The use according to claim 1 ; wherein is difluoromethyl.

5. R １ The use according to claim 4 ; wherein is methyl.

6. R ３ but, - -CH ２ -CH ２ -C(CH ３ ) ２ -COOH; --CO-CH ２ -C(CH ３ ) ２ -COOH; or - -SO ２ -NH ２ ; The use according to claim 1 .

7. R ３ Ga-SO ２ -NH ２ The use according to claim 3 .

8. The compound is 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-5-oxopentanoic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; N-(2-ethoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; 4-(3-((6-chloro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-chloro-4-ethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-chloro-4-isopropoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-bromo-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 5-(3-((6-chloro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid; 5-(3-((6-chloro-4-ethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid; 4-(3-((6-chloro-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-((6-bromo-4-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-((6-chloro-4-ethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-ethoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-isopropoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-bromo-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; Or, 3-(2-isopropylphenyl)-N-(4-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; or a pharma- ceutically acceptable salt thereof; The use according to claim 1 .

9. The compound is 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; Or, N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; or a pharma- ceutically acceptable salt thereof; The use according to claim 1 .

10. The use according to any one of claims 1 to 9, wherein the medicament is used in combination with pirfenidone or a pharma- ceutically acceptable salt thereof.

11. 11. The use according to claim 10, wherein pirfenidone or a pharma- ceutically acceptable salt thereof is intended to be administered in a pharmaceutical unit dosage form suitable for oral administration in a total amount of 2403 mg or less per day.

12. The pharmaceutical composition comprises: - pulmonary fibrosis; - renal fibrosis; or - liver fibrosis; The use according to any one of claims 1 to 9, intended for the prevention or treatment of:

13. The pharmaceutical composition comprises: - idiopathic pulmonary fibrosis; - pulmonary fibrosis secondary to systemic inflammatory diseases; - pulmonary fibrosis secondary to sarcoidosis; - Radiation-induced fibrosis; -Silicosis-induced pulmonary fibrosis; - asbestos-induced pulmonary fibrosis; or - COVID-19 associated pulmonary fibrosis; The use according to claim 10, intended for the prevention or treatment of:

14. A pharmaceutical composition comprising as an active ingredient a compound of formula (I) as defined in any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof in combination with one or more therapeutically active ingredients acting as antifibrotic agents; and further comprising at least one pharma- ceutically acceptable excipient; said antifibrotic agents being pirfenidone and / or nintedanib; or a pharma- ceutically acceptable salt thereof; - idiopathic pulmonary fibrosis; - pulmonary fibrosis secondary to systemic inflammatory diseases; - pulmonary fibrosis secondary to sarcoidosis; - Radiation-induced fibrosis; -Silicosis-induced pulmonary fibrosis; - asbestos-induced pulmonary fibrosis; or - COVID-19 associated pulmonary fibrosis; A pharmaceutical composition for the prevention or treatment of.

15. 10. An antifibrotic agent comprising a compound of formula (I) as defined in any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof, in combination with pirfenidone or a pharma- ceutically acceptable salt thereof.

16. The antifibrotic agent is - idiopathic pulmonary fibrosis; - pulmonary fibrosis secondary to systemic inflammatory diseases; - pulmonary fibrosis secondary to sarcoidosis; - Radiation-induced fibrosis; -Silicosis-induced pulmonary fibrosis; - asbestos-induced pulmonary fibrosis; or - COVID-19 associated pulmonary fibrosis; The antifibrotic agent according to claim 15, which is intended for the prevention or treatment of:

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