# US 11,439,642 B2 · Substituted 5-fluoro-1H-pyrazolopyridines and their use > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,439,642 B2 - Document ID: US11439642B2 - Status: Granted - Kind: B2 - Application number: 16/919,385 - Filed: 2020-07-02 - Published: 2020-12-24 - Granted: 2022-09-13 - Earliest claimed: 2010-05-26 - Assignees: Adverio Pharma GmbH - Applicants: Adverio Pharma GmbH - Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Jens Ackerstaff; Nils Griebenow; Walter Kroh; Andreas Knorr; Eva-Maria Becker; Frank Wunder; Volkhart Min-Jian Li; Elke Hartmann; Joachim Mittendorf; Karl-Heinz Schlemmer; Rolf Jautelat; Donald Bierer - Web page: https://patentgrep.com/patent/US11439642B2 ## CPC - A61K 31/506: not condensed and containing further heterocyclic rings - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 7/00: Drugs for disorders of the blood or the extracellular fluid - A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 9/12: Antihypertensives - A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers - A61P 11/00: Drugs for disorders of the respiratory system - A61P 13/12: of the kidneys - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - C07C 57/145: Maleic acid - C07C 309/04: containing only one sulfo group - C07C 309/05: containing at least two sulfo groups bound to the carbon skeleton - C07D 471/04: Ortho-condensed systems - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present application relates to novel substituted 5-fluoro-1H-pyrazolopyridines, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases, and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders. ## Claims ### Claim 1 A method of treating or preventing one or more of coronary heart disease, systolic or diastolic heart failure, angina pectoris, ischaemias, peripheral and cardiac vascular disorders, kidney failure, renal insufficiency, and increased microalbuminurea, comprising administering a therapeutically effective amount of a compound of formula (I-A) or a salt thereof to a human or animal in need thereof. ### Claim 2 (depends on 1) The method of claim 1, comprising administering a therapeutically effective amount of the compound of formula (I-A) ### Claim 3 (depends on 1) The method of claim 1, comprising administering a therapeutically effective amount of the salt of the compound of formula (I-A) ### Claim 4 (depends on 1) The method of claim 1, wherein the method is for treating angina pectoris. ### Claim 5 (depends on 2) The method of claim 2, wherein the method is for treating angina pectoris. ### Claim 6 (depends on 3) The method of claim 3, wherein the method is for treating angina pectoris. ### Claim 7 (depends on 1) The method of claim 1, wherein the method is for treating vascular disorders. ### Claim 8 (depends on 2) The method of claim 2, wherein the method is for treating vascular disorders. ### Claim 9 (depends on 3) The method of claim 3, wherein the method is for treating vascular disorders. ### Claim 10 (depends on 1) The method of claim 1, wherein the method is for treating kidney failure. ### Claim 11 (depends on 2) The method of claim 2, wherein the method is for treating kidney failure. ### Claim 12 (depends on 3) The method of claim 3, wherein the method is for treating kidney failure. ### Claim 13 (depends on 1) The method of claim 1, wherein the method further comprises administering a further active compound that is a cGMP-PDE inhibitor selected from the group consisting of sildenafil, vardenafil and tadalafil. ### Claim 14 (depends on 2) The method of claim 2, wherein the method further comprises administering a further active compound that is a cGMP-PDE inhibitor selected from the group consisting of sildenafil, vardenafil and tadalafil. ### Claim 15 (depends on 3) The method of claim 3, wherein the method further comprises administering a further active compound that is a cGMP-PDE inhibitor selected from the group consisting of sildenafil, vardenafil and tadalafil. ### Claim 16 (depends on 1) The method of claim 1, wherein the method further comprises administering a further active compound that is an agent having blood pressure lowering activity selected from the group consisting of losartan, candesartan, valsartan, telmisartan, embusartan, bosentan, darusentan, ambrisentan, sitaxsentan, and spironolactone and eplerenone. ### Claim 17 (depends on 2) The method of claim 2, wherein the method further comprises administering a further active compound that is an agent having blood pressure lowering activity selected from the group consisting of losartan, candesartan, valsartan, telmisartan, embusartan, bosentan, darusentan, ambrisentan, sitaxsentan, and spironolactone and eplerenone. ### Claim 18 (depends on 3) The method of claim 3, wherein the method further comprises administering a further active compound that is an agent having blood pressure lowering activity selected from the group consisting of losartan, candesartan, valsartan, telmisartan, embusartan, bosentan, darusentan, ambrisentan, sitaxsentan, and spironolactone and eplerenone. ### Claim 19 (depends on 1) The method of claim 1, wherein the method is for treating coronary heart disease. ### Claim 20 (depends on 2) The method of claim 2, wherein the method is for treating coronary heart disease. ### Claim 21 (depends on 3) The method of claim 3, wherein the method is for treating coronary heart disease. ### Claim 22 (depends on 1) The method of claim 1, wherein the method is for treating systolic or diastolic heart failure. ### Claim 23 (depends on 2) The method of claim 2, wherein the method is for treating systolic or diastolic heart failure. ### Claim 24 (depends on 3) The method of claim 3, wherein the method is for treating systolic or diastolic heart failure. ### Claim 25 (depends on 1) The method of claim 1, wherein the method is for treating renal insufficiency. ### Claim 26 (depends on 2) The method of claim 2, wherein the method is for treating renal insufficiency. ### Claim 27 (depends on 3) The method of claim 3, wherein the method is for treating renal insufficiency. ### Claim 28 (depends on 1) The method of claim 1, wherein the method is for treating increased microalbuminurea. ### Claim 29 (depends on 2) The method of claim 2, wherein the method is for treating increased microalbuminurea. ### Claim 30 (depends on 3) The method of claim 3, wherein the method is for treating increased microalbuminurea. ### Claim 31 A method of treatment of heart failure, hypertension, or pulmonary hypertension in humans and animals comprising administering an effective amount of a compound of formula (I-A) or a salt thereof to a human or animal in need thereof. ### Claim 32 (depends on 31) The method of claim 31, wherein the method is for treatment of heart failure. ### Claim 33 (depends on 31) The method of claim 31, wherein the method is for treatment of hypertension. ### Claim 34 (depends on 31) The method of claim 31, wherein the method is for treatment of pulmonary hypertension. ### Claim 35 (depends on 31) The method of claim 31, wherein an effective amount of the salt of the compound of formula (I-A) is administered. ### Claim 36 (depends on 32) The method of claim 32, wherein an effective amount of the salt of the compound of formula (I-A) is administered. ### Claim 37 (depends on 33) The method of claim 33, wherein an effective amount of the salt of the compound of formula (I-A) is administered. ### Claim 38 (depends on 34) The method of claim 34, wherein an effective amount of the salt of the compound of formula (I-A) is administered. ### Claim 39 A method of treating or preventing one or more of hypertension, pulmonary hypertension, heart failure, coronary heart disease, systolic or diastolic heart failure, angina pectoris, ischaemias, peripheral and cardiac vascular disorders, kidney failure, renal insufficiency, and increased microalbuminurea, comprising administering to a human or animal in need thereof therapeutically effective amounts of (1) a compound of formula (I-A) or a salt thereof; and (2) a further active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, agents having antithrombotic activity, agents lowering blood pressure, and agents altering lipid metabolism. ### Claim 40 (depends on 39) The method of claim 39, wherein an effective amount of the compound of formula (I-A) is administered. ### Claim 41 (depends on 39) The method of claim 39, wherein an effective amount of the salt of the compound of formula (I-A) is administered. ### Claim 42 (depends on 39) The method of claim 39, wherein the further active compound is selected from the group consisting of sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, inhaled NO, inhibitors of phosphodiesterases (PDE) 1, 2 and/or 5, platelet aggregation inhibitors, anticoagulants, profibrinolytic substances, calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, diuretics, thyroid receptor agonists, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors; PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists. ### Claim 43 (depends on 42) The method of claim 42, wherein the inhibitor of phosphodiesterases (PDE) 1, 2 and/or 5 is selected from the group consisting of sildenafil, vardenafil, and tadalafil. ### Claim 44 (depends on 42) The method of claim 42, wherein the angiotensin AII antagonist is selected from the group consisting of losartan, candesartan, valsartan, telmisartan, and embusartan. ### Claim 45 (depends on 42) The method of claim 42, wherein the endothelin antagonist is selected from the group consisting of bosentan, darusentan, ambrisentan, and sitaxsentan. ### Claim 46 (depends on 42) The method of claim 42, wherein the mineralocorticoid receptor antagonist is selected from the group consisting of spironolactone or eplerenone. ### Claim 47 (depends on 42) The method of claim 42, wherein an effective amount of the compound of formula (I-A) is administered. ### Claim 48 (depends on 42) The method of claim 42, wherein an effective amount of the salt of the compound of formula (I-A) is administered. ### Claim 49 A method of treating or preventing one or more of vascular disorders, thromboembolic disorders, fibrotic disorders, and arteriosclerosis comprising administering a therapeutically effective amount of a compound of formula (I) in which R1 represents hydrogen or (C1-C4)-alkyl, where (C1-C4)-alkyl may be substituted by one or two substituents independently of one another selected from the group consisting of fluorine and trifluoromethyl, or an N-oxide, salt or salt of an N-oxide thereof to a human or animal in need thereof. ### Claim 50 (depends on 49) The method of claim 49, wherein in the compound of formula (I) Rl represents hydrogen or methyl, where methyl may be substituted by a trifluoromethyl substituent. ### Claim 51 (depends on 49) The method of claim 49, wherein the compound of formula (I) is selected from the group consisting of: methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}1methylcarbamate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}(2,2,2-trifluoroethyl)carbamate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate hydrochloride methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate sulphate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate phosphate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate mesylate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate ethane-1,2-disulphonate methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate maleate and methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate nitrate. ### Claim 52 (depends on 49) The method of claim 49, wherein the compound of formula (I) is: or an N-oxide, salt, or salt of an N-oxide thereof. ### Claim 53 (depends on 49) The method of claim 49, wherein the method is for treating or preventing vascular disorders. ### Claim 54 (depends on 49) The method of claim 49, wherein the method is for treating or preventing thromboembolic disorders. ### Claim 55 (depends on 49) The method of claim 49, wherein the method is for treating or preventing fibrotic disorders. ### Claim 56 (depends on 49) The method of claim 49, wherein the method is for treating or preventing arteriosclerosis. ### Claim 57 (depends on 49) The method of claim 49, wherein the method further comprises administering a further active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, agents having antithrombotic activity, agents having blood pressure lowering activity, and agents having lipid metabolism altering activity. ### Claim 58 (depends on 57) The method of claim 57, wherein the further active compound is an organic nitrate. ### Claim 59 (depends on 57) The method of claim 57, wherein the further active compound is an NO donor. ### Claim 60 (depends on 57) The method of claim 57, wherein the further active compound is a cGMP-PDE inhibitor. ### Claim 61 (depends on 57) The method of claim 57, wherein the further active compound is an agent having antithrombotic activity. ### Claim 62 (depends on 57) The method of claim 57, wherein the further active compound is an agent having blood pressure lowering activity. ### Claim 63 (depends on 57) The method of claim 57, wherein the further active compound is an agent having lipid metabolism altering activity. ### Claim 64 (depends on 49) The method of claim 49, wherein an effective amount of a compound of formula (I-A) or a salt thereof is administered. ### Claim 65 (depends on 64) The method of claim 64, wherein an effective amount of the compound of formula (I-A) is administered. ### Claim 66 (depends on 64) The method of claim 64, wherein an effective amount of the salt of the compound of formula (I-A) is administered.