# US 10,479,794 B2 · Cyclic ether derivatives of pyrazolo[1,5-a]pyrimidine-3-carboxyamide > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,479,794 B2 - Document ID: US10479794B2 - Status: Granted - Kind: B2 - Application number: 15/865,695 - Filed: 2018-01-09 - Published: 2018-05-17 - Granted: 2019-11-19 - Earliest claimed: 2015-10-13 - Assignees: Boehringer Ingelheim International GmbH - Applicants: Boehringer Ingelheim International GmbH - Inventors: Christoph Hoenke; Barbara Bertani; Marco Ferrara; Giacomo Fossati; Sara Frattini; Riccardo Giovannini; Scott Hobson - Web page: https://patentgrep.com/patent/US10479794B2 ## CPC - C07D 487/04: Ortho-condensed systems - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61P 3/04: Anorexiants; Antiobesity agents - A61P 3/06: Antihyperlipidemics - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 9/00: Drugs for disorders of the cardiovascular system - 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 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like - A61P 21/00: Drugs for disorders of the muscular or neuromuscular system - A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/02: for peripheral neuropathies - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61P 25/08: Antiepileptics; Anticonvulsants - A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia - A61P 25/16: Anti-Parkinson drugs - A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia - A61P 25/20: Hypnotics; Sedatives - A61P 25/22: Anxiolytics - A61P 25/24: Antidepressants - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61P 25/36: Opioid-abuse - A61P 27/02: Ophthalmic agents - A61P 31/18: for HIV - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - 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 - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract The invention relates to Spirocyclic ether derivatives of pyrazolo[1,5-a]pyrimidine-3-carboxyamide of general formula (I) which are inhibitors of phosphodiesterase 2, useful in treating central nervous system diseases and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention. ## Claims ### Claim 1 A method of inhibiting PDE2 in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) wherein A is selected from the group Aa consisting of wherein above mentioned groups are substituted with one R5 and one R6; R1 is selected from the group R1a consisting of halogen, C1-3-alkyl- and C3-6-cycloalkyl- wherein the above mentioned C1-3-alkyl-, and C3-6-cycloalkyl- groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, NC— and HO—; R2 is selected from the group R2a consisting of aryl and heteroaryl, wherein the above mentioned aryl and heteroaryl-groups may optionally be substituted with 1 to 5 substituents R4; R3 is selected from the group R3a consisting of H— and C1-3-alkyl-, wherein the above mentioned C1-3-alkyl-groups may optionally be substituted with 1 to 7 substituents independently from each other selected from the group consisting of halogen; R4 is independently from each other selected from the group R4a consisting of halogen, NC—, HO—, C1-4-alkyl- and C1-3-alkyl-O— wherein the above mentioned C1-4-alkyl- and C1-3-alkyl-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO— and F—; R5 is selected from the group R5a consisting of H—, halogen, NC—, HO— and C1-3-alkyl-, wherein the above mentioned C1-3-alkyl-group may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO— and F— or R5 and R6 together form an group O═; R6 is selected from the group R6a consisting of H—, halogen, NC—, HO— and C1-3-alkyl-, wherein the above mentioned C1-3-alkyl-group may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO— and F— or R5 and R6 together form a group O═; or a pharmaceutically acceptable salt thereof. ### Claim 2 (depends on 1) The method of claim 1, wherein A is selected from the group Ab consisting of wherein above mentioned groups are substituted with with one R5 and one R6, or a pharmaceutically acceptable salt thereof. ### Claim 3 (depends on 1) The method of claim 1, wherein A is selected from the group Ac consisting of or a pharmaceutically acceptable salt thereof. ### Claim 4 (depends on 1) The method of claim 1, wherein A is selected from the group Ad consisting of or a pharmaceutically acceptable salt thereof. ### Claim 5 (depends on 1) The method of claim 1, wherein R1 is selected from the group R1b consisting of F—, Cl—, C1-3-alkyl- and C3-6-cycloalkyl-, wherein the above mentioned C1-3-alkyl- and C3-6-cycloalkyl-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of F—, or a pharmaceutically acceptable salt thereof. ### Claim 6 (depends on 1) The method of claim 1, wherein R1 is selected from the group R1c consisting of F—, H3C— and cyclopropyl-, or a pharmaceutically acceptable salt thereof. ### Claim 7 (depends on 1) The method of claim 1, wherein R2 is selected from the group R2b consisting of quinolinyl, phenyl and pyridynyl, wherein the above mentioned quinoline, phenyl and pyridyl-groups may optionally be substituted with 1 to 5 substituents R4, or a pharmaceutically acceptable salt thereof. ### Claim 8 (depends on 1) The method of claim 1, wherein R2 is selected from the group R2c consisting of phenyl and pyridyl, wherein the above mentioned phenyl and pyridyl-groups may optionally be substituted with 1 to 2 substituents R4, or a pharmaceutically acceptable salt thereof. ### Claim 9 (depends on 1) The method of claim 1, wherein R3 is selected from the group R3b consisting of H—, H3C—, F3C—, F2HC—, FH2C— and F3C—, or a pharmaceutically acceptable salt thereof. ### Claim 10 (depends on 1) The method of claim 1, wherein R4 is independently from each other selected from the group R4b consisting of halogen, C1-4-alkyl- and C1-3-alkyl-O— wherein the above mentioned C1-4-alkyl- and C1-3-alkyl-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO—, and F—, or a pharmaceutically acceptable salt thereof. ### Claim 11 (depends on 1) The method of claim 1, wherein R5 is selected from the group R5b consisting of H—, HO— and C1-2-alkyl-, wherein the above mentioned C1-2-alkyl-group may optionally be substituted with 1 to 5 F—, or R5 and R6 together form an group O═, or a pharmaceutically acceptable salt thereof. ### Claim 12 (depends on 1) The method of claim 1, wherein R6 is selected from the group R6b consisting of H— and C1-2-alkyl-, wherein the above mentioned C1-2-alkyl-group may optionally be substituted with 1 to 5 F—, or R5/R6 together form a group O═, or a pharmaceutically acceptable salt thereof. ### Claim 13 (depends on 1) The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of or a pharmaceutically acceptable salt thereof. ### Claim 14 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 15 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 16 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 17 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 18 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 19 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 20 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 21 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 22 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 23 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 24 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 25 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 26 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 27 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 28 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 29 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 30 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 31 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 32 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 33 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 34 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 35 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 36 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 37 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 38 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 39 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 40 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 41 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 42 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 43 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: or a pharmaceutically acceptable salt thereof. ### Claim 44 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 45 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 46 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 47 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 48 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 49 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 50 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 51 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 52 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 53 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 54 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 55 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 56 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 57 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 58 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 59 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 60 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 61 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 62 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 63 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 64 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 65 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 66 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 67 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 68 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 69 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 70 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 71 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 72 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: ### Claim 73 (depends on 1) The method according to claim 1 wherein the compound of formula (I) is of the formula: