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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• C2-6-alkylene independently is unsubstituted, or mono-substituted with hydroxy, Ci- fluoroalkyl, or -NR N23 R N24 wherein independently R N23 is hydrogen or Ci4-alkyl, and R N24 is hydrogen, C 14-alkyl or -CO-0-Ci4-alkyl;
• X 21 represents a nitrogen atom which is unsubstituted, or mono-substituted with C 14-alkyl, C3-6-cycloalkyl, or -C0-0-Ci4-alkyl; > -CO-Ci-4-alkylene-X 22 -C2-4-alkylene-, -CO-Ci-4-alkylene-X 22 -Ci-4-alkylene-C3-6-cycloalkylene-, or -SO2- Ci-4-alkylene-X 22 -C2-4-alkylene-; wherein X 22 represents a nitrogen atom which is independently unsubstituted, or mono-substituted with Ci_4-alkyl, C3-6-cycloalkyl, or -C0-0-Ci_4-alkyl;
• enriched when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90: 10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
• halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
• -C x-y -alkenylene- refers to bivalently bound alkenyl group as defined before containing x to y carbon atoms.
• Examples of -C2-6-alkenylene- groups are notably ethen-1 ,2-diyl, prop-1 - en-2,3-diyl, and prop-1-en-1 ,3-diyl.
• Examples of -C3-8-cycloalkylene- groups are notably cyclopropane-1 , 1-diyl, cyclopropane-1 ,2-diyl, cyclobutane-1 , 1 -diyl, bicyclo[1.1.1 ]pentane-1 ,3-diyl, cyclohexane-1 ,3-diyl, and cyclohexane-1 ,4-diyl (especially cyclopropane-1 , 1 -diyl, cyclopropane-1 ,2-diyl, and cyclobutane-1 , 1-diyl).
• certain groups having tautomeric forms which may be considered predominantly aromatic are defined herein as heteroaryl groups HET 1 , even though their corresponding tautomeric forms (3-oxo-2,3-dihydro-2H-isoxazolyl, respectively, 5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl, 3-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-5-yl, 3-oxo-2,3- dihydro-1 H-pyrazol-4-yl, 2-oxo-2,3-dihydro-3H-[1 ,3,4]o
• a second embodiment relates to compounds according to embodiment 1), wherein R 1 is halogen (especially chloro).
• Another embodiment relates to compounds according to embodiments 1 ) or 2), wherein R 2 is methoxy, ethoxy, isopropoxy, cyclopropyloxy, 2-methoxy-ethoxy or 2-methoxy-1 -methyl-ethoxy (especially methoxy).
• Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar 1 represents phenyl [wherein it is understood that said phenyl is substituted with R 3 and R 4 as explicitly defined] 6) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar 1 represents a 6-membered heteroaryl containing one or two nitrogen atoms (especially pyridinyl) [wherein it is understood that said heteroaryl is substituted with R 3 and R 4 as explicitly defined]
• C2-6- alkylene independently is di-substituted wherein the substituents are independently selected from hydroxy and -NR N15 R N16 ; wherein independently R N15 is hydrogen or Ci_4-alkyl, and R N16 is hydrogen, Ci -4-alkyl or -CO-O-Ci-4-alkyl;
• R 031 is -Ci4-alkyl, -CO-Ci4-alkyl or -C0-C24-alkenyl
• R N1 is hydrogen or Ci4-alkyl
• R N2 is hydrogen; C 14-alkyl; C1-3- fluoroalkyl; C3-6-cycloalkyl; Ci-3-alkoxy-C24-alkylene; -CO-Ci4-alkyl; -S02-Ci4-alkyl; or -SCVCi-fluoroalkyl; and
• R SS1 independently represents -Ci-6-alkyl; Ci-fluoroalkyl; hydroxy; -NR N81 R N82 wherein independently R NS1 is hydrogen or Ci-4-alkyl, and R N82 is hydrogen, Ci-4-alkyl, -CO-Ci-6-alkyl; and
• Ci-4-alkyl Ci_3-alkoxy-C2-4-alkyl, C2-3-fluoroalkyl, or -CO-C 1-4-alkyl attached to a ring nitrogen atom having a free valency;
• R 031 is -Ci_4-alkyl, -CO-Ci_4-alkyl or -CO-C2-4-alkenyl; and -L 3 - independently represents
• HET 1 represents 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl),
• HET 1 represents 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl), wherein said HET 1 independently is unsubstituted or mono-, or di- substituted wherein the substituents are independently selected from Ci-4-alkyl (especially methyl); halogen; cyano; hydroxy; hydroxymethyl;
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 12), wherein the group -L-R 5 represents
• the compounds of Formula (I) according to embodiments 1) to 19) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) or parenteral administration (including topical application or inhalation).
• compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5,“Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
• the present invention also relates to a method for the prevention / prophylaxis or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of Formula (I) according to embodiments 1 ) to 19).
• compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases.
• such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (a mammal, especially a human) in need thereof, an effective amount of such compound.
• the compounds of Formula (I) according to embodiments 1) to 19) are useful for the prevention and/or treatment of fibrosis (and diseases or disorders associated with fibrosis), or of other disorders mediated by LPAi receptor signalling.
• fibrosis may in particular be defined as comprising
• pulmonary fibrosis including lung diseases associated with fibrosis, including idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to systemic inflammatory disease such as rheumatoid arthritis, scleroderma (systemic sclerosis; SSc), lupus (systemic lupus erythematosus; SLE); cryptogenic fibrosing alveolitis; pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis including radiation induced fibrosis; silicosis (silicosis-induced pulmonary fibrosis); asbestos induced pulmonary fibrosis; and pleural fibrosis;
• gut fibrosis including gut fibrosis secondary to scleroderma, and radiation induced gut fibrosis
• liver fibrosis including cirrhosis, alcohol induced liver fibrosis, nonalcoholic steatohepatitis, biliary duct injury, primary biliary cirrhosis (also known as primary biliary cholangitis), infection or viral 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 (laser-assisted in situ keratomileusis), corneal transplant, and trabeculectomy;
• fibrotic diseases e.g. endometriosis, spinal cord fibrosis, myelofibrosis, cardiac fibrosis, perivascular fibrosis; as well as formation of scar tissue, Peyronie's disease, abdominal or bowel adhesions, bladder fibrosis, fibrosis of the nasal passages, and fibrosis mediated by fibroblasts.
• prevention / prophylaxis of fibrosis includes the prevention of fibrosis in a subject that has been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of an organ or tissue, especially the risk of lung, liver or kidney fibrosis; or in a subject that has a genetic predisposition of developing fibrosis of an organ or tissue; as well as the prevention or minimization of scarring following injury including surgery.
• disorders mediated by LPAi receptor signalling notably comprise dermatological disorders, pain, malignant and benign proliferative diseases, respiratory diseases, nervous system disorders, cardiovascular diseases, and inflammatory disorders, obesity, and insulin resistance.
• the term refers to pleural mesothelioma, peritoneal mesothelioma, and bone metastases, as well as brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; neuroblastoma; pancreatic cancer including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma; gastro-intestinal cancers including colon carcinoma, 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 lympho
• the present invention further relates to the compounds of the Formula (I) for use in the treatment of the diseases and disorders mentioned herein (especially for the treatment of fibrosis) wherein the compound of Formula (I) is intended to be used in combination (whether in a single pharmaceutical composition, or in separate treatment) with one or several antifibrotic agents.
• antifibrotic agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.
• Functionality R 5 is then introduced, after deprotection, by the formation of an amine, amide, sulfonamide, carbamate, urea or sulfamide linker (L), for example, in a manner known to a person skilled in the art.
• Compounds of Structure 1 may be commercially available or may be prepared by reducing a compound of Structure 3 in a solvent such as THF, MeOH, EtOH, iPrOH etc. in the presence of Fh/Pd/C or H2 / Pt+V/C or Fe etc. (Dolle V. et at. Tetrahedron 1997 (53) 12505-12524; Mobus K. et at. Top. Catal. 2010 (53), 1126-1131 ; WO2012/055995).
• a solvent such as THF, MeOH, EtOH, iPrOH etc.
• Compounds of Structure 4 and Structure 5 may be commercially available or may be prepared (for n and/or m > 1) by reacting the appropriate 2-(2-halo-(hetero)aryl)acetonitrile (Structure 7) or methyl 2-(2-halo- (hetero)aryl)acetate (Structure 8), respectively, with A/-benzyl-A/,A/-bis(2-chloroethyl)amine or A/-boc-A/,A/-bis(2- chloroethyl)amine at 60°C or more in a solvent such as THF and in the presence of a base such as NaOH, NaH etc.
• a solvent such as THF
• a base such as NaOH, NaH etc.
• compounds of Structure 4 may be synthesized by reacting a compound of Structure 9, 10 or 1 1 with a 1 ,2-dihalo-(hetero)aryl, such as 1- bromo-2-fluorobenzene, in a solvent such as THF in the presence of a base such as KHMDS (W02012/017359).
• a 1 ,2-dihalo-(hetero)aryl such as 1- bromo-2-fluorobenzene
• a solvent such as THF
• a base such as KHMDS (W02012/017359).
• Structures 7 and 8 may be commercially available or may be prepared in a manner known to a person skilled in the art.
• Prep-HPLC-1 Column: Waters Zorbax SB-Aq (5 urn, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% formic acid [eluent B], Gradient:95% B— > 5% B over 5 min (flow: 75 mL/min). Detection: UVA/is + MS Preparative HPLC with basic conditions
• 1-(tert-Butoxycarbonyl)-3-(3-chloropyrazin-2-yl)azetidine-3-carboxylic acid 1-15 is prepared in analogy to procedure described for I-6 starting from 1-Boc-3-cyanoazetidine and 2,3-dichloropyrazine.
• Step 1 To a solution of 1-(tert-butoxycarbonyl)-3-(2-isopropylphenyl)azetidine-3-carboxylic acid I-6 (110 mg, 0.34 mmol) and DMF (0.3 mL) in pyridine (3 mL) is added POCI3 (47 uL, 0.52 mmol) drop wise over 35 min
• Examples 18-9 to 18-27 are synthesized from Ex 3, Ex 4, Ex 5, Ex 6 or Ex 10 by reductive amination as described for Ex 18-8.
• Functional groups such as acid or alcohol, may be protected with an appropriate protecting group.
• esters are saponified by 2N LiOH after the reductive amination step.
• Example 21-1 N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3- carboxamide
• Step 1 A solution of chlorosulfonyl isocyanate (12 uL, 0.14 mmol) in DCM (2 mL) is cooled down to 0°C and a solution of 2-bromoethanol (10 uL, 0.14 mmol) in DCM (1 mL) is added. The reaction mixture stirred for 1 h at 0°C, then Ex 3 (50 mg, 0.14 mmol) in DCM (1 mL) is added followed by TEA (78 uL, 0.55 mmol). The reaction is stirred at r.t.
• Example 22-2 N3-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-N1-methylazetidine-1 ,3- dicarboxamide
• Ex 23-2 is prepared from methoxyethyl chloroformate according to the metholology described for Ex 23-1. White solid.
• Example 24-1 N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-(3-methylpyridin-4- yl)azetidine-3-carboxamide
• Examples 24-3 to 24-26 are synthesized according to methodology described for Ex 24-2 starting from Ex 3 or Ex 10.
• DMA may be replaced by DMF
• CS2CO3 may be replaced by DIPEA.
• Functional groups, such as acid or alcohol, may be protected with an appropriate protecting group.
• esters are saponified by 2N LiOH in a second step.
• Step 1 A solution of cyanogen bromide 5N in CH3CN (164 uL, 0.04 mmol) is added to a solution of Ex 3 (48 mg, 0.13 mmol) and sodium acetate in MeOH (2.5 mL) at 0°C. The reaction mixture is stirred at r.t. overnight, is then quenched with water and diluted with EtOAc (30 mL). The organic solution is washed with aq. sat.
• Step 1 Ex 3 (40 mg, 0.1 1 mmol) is dissolved in EtOH (0.5 mL) and TEA (46.4 uL, 0.33 mmol) is added. The mixture is then added dropwise to a solution of 3,4-diethoxy-3-cyclobutene-1 ,2-dione (19.7 uL, 0.13 mmol) in EtOH (0.5 mL). The reaction mixture is stirred at r.t. overnight. Volatiles are evaporated, and the residue is purified by prep.
• the TangoTM EDG2-b/a U20S cells are obtained from Invitrogen. These cells contain the human LPAi receptor cDNA linked to a TEV protease site and a Gal4-VP16 transcription factor integrated into the TangoTM GPCR-b/a U20S parental cell line. This parental cell line stably expresses a beta-arrestin / TEV protease fusion protein and the beta-lactamase (bla) reporter gene under the control of a UAS response element.
• LPAi receptor Upon LPA (agonist) binding, LPAi receptor gets activated, leading to arrestin-protease recruitment and proteolytic release of the transcription factor: The transcription factor then regulates transcription of a beta-lactamase reporter construct, which is measured upon addition of the live-cell substrate.
• Antagonistic activities (IC5 0 values) of exemplified compounds have been measured and antagonistic activities are displayed in Table 9.
• selected compound of the present invention is able to effectively reduce LPA-induced vascular leakage after oral administration of 30 mg/kg to mice as compared to a group of animals treated with vehicle only. Reduction of vascular leakage compared to vehicle group was > 60%.

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